Drug Resistant Tuberculosis
Emerging Human Concern
DrTVRao MD
DrTVRao MD 1
HISTORY ofTuberculosis
Tuberculosis Is an Ancient Disease Identified as Spinal Tuberculosis in Egyptian Mummies History dates to 1550 ndash 1080 BC Identified by PCR
DrTVRao MD 2
A Tribute to Robert Koch Discoverer of Mycobacterium
Tuberculosis
DrTVRao MD 3
Historical Background
Neolithic Time 2400 BC - Egyptian
mummies spinal columns 460 BC
Hippocrates Greece First clinical description
Phthisis Consumption (I am wasting away)
500-1500 AD Roman occupation of
Europe it spread to Britain
1650-1900 AD White plague of Europe
causing one in five deaths
DrTVRao MD 4
Diagnostic discoveries
24th March 1882 (Robert Koch) TB Day Discovery of staining
technique that identified Tuberculosis bacillus
Definite diagnosis made possible 1890 (Robert Koch)
Tuberculin discovered Diagnostic use when
injected into skin 1895 (Roentgen)
Discovery of X-rays Early diagnosis of
pulmonary disease
DrTVRao MD 5
From Tuberculosis to Tuberculin
Failure of Robert Koch Tuberculin therapy
did in fact work in Kochs laboratory even though it failed to do so almost anywhere else his reliance an animal experiments which essentially differed from what many of his contemporaries many differed with his ideas
DrTVRao MD 6
Global Status
Nine million people suffer from tuberculosis
Two million people die each year
Tuberculosis accounts for one-third of AIDS deaths world wide every year
DrTVRao MD 7
USAID Report on Tuberculosis in India
India has more new tuberculosis (TB) cases annually than any other country ranking first among the 22 high-burden TB countries worldwide according to the World Health Organizationrsquos (WHOrsquos) Global TB Report 2009 TB remains one of the leading infectious causes of mortality in India causing more than 331000 deaths in 2007 There were approximately 196 million new TB cases in India in 2007 representing more than 21 per cent of all TB cases worldwide
DrTVRao MD 8
1908-1920 (Chalmette and Guerin) Vaccine (BCG)
Attenuated strain Mycobacterium Bovis
1943 Streptomycin developed
20th November 1944 Critically ill TB patient injected
dramatically recovered
Pharmacological discoveries
DrTVRao MD 9
Selman Abraham Waksman Nobel Prize for his discovery in
1952
DrTVRao MD 10
Pharmacological discoveries
1956-1960 Combination therapy of INH and PZA
cures TB1955 Cycloserine1962 Ethambutol 1963 Rifampicin1970-1977
Combination of Rifampicin and Isoniazid adopted as International regime for treatment of TB DrTVRao MD 11
No one is Immune to TuberculosisNot only infects poor but famous
too
DrTVRao MD 12
Multi Drug Resistant
TuberculosisMDR-TB
DrTVRao MD 13
Definition
MDR-TB caused by strains of Mycobacterium Tuberculosis resistant both Rifampicin and Isoniazid with or without resistance to other drugs
Single Isoniazid or Rifampicin resistance is not MDR - TB
MDR TB is a laboratory diagnosis
DrTVRao MD 14
Classification of Drugs 3 Groups depending upon the degree
of effectiveness and potential side effects First Line (Primary agents)
are the most effective and have lowest toxicity Isoniazid Rifampin
Second LineLess effective and more toxic effectsinclude (in no particular order) p-amino
salicylic acid Streptomycin Ethambutol Third Line
are least effective and most toxic Amikacin Kanamycin Capreomycin Viomycin Kanamycin Cycloserine
DrTVRao MD 15
Basic concepts ndash Keep facts
Primary (Initial) resistanceTB patientrsquos initial Mycobacterium
tuberculosis population resistant to drugs
Secondary (Acquired) resistanceDrug-resistant M tuberculosis in initial
population selected by inappropriate drug use (inadequate treatment or non-adherence) DrTVRao MD 16
When to suspect MDR TB
Re-treatment patients whorsquos sputum smear remains positive after three monthsrsquo of intensive therapy
Treatment failure and interruption cases
Close contacts of MDR tuberculosis cases
Positive diagnoses with TB culture and susceptibility testing DrTVRao MD 17
What is extensively drug resistant tuberculosis (XDR TB)
Extensively drug resistant TB (XDR TB) is a relatively rare type of MDR TB XDR TB is defined as TB which is resistant to isoniazid and rifampin plus resistant to any fluoroquinolone and at least one of three injectable second-line drugs (ie amikacin kanamycin or capreomycin)DrTVRao MD 18
Why XDR - TB a grave concern
Because XDR TB is resistant to first-line and second line drugs patients are left with treatment options that are much less effective
XDR TB is of special concern for persons with HIV infection or other conditions that can weaken the immune system These persons are more likely to develop TB disease once they are infected and also have a higher risk of death once they develop TB
DrTVRao MD 19
Global Estimates
Classification
Estimated Number of Cases
Estimated Number of
Deaths
All forms TB
88 million 16 million
MDR TB 424000 116000
XDR TB 27000 16000
DrTVRao MD 20
Extensively Drug-Resistant Mycobacterium tuberculosis
India
The first XDR TB cases in India and the emergence of XDR TB is reported by Rajesh Mondal and Amita Jain King Georges Medical University Lucknow India Volume 13 Number 9ndashSeptember 2007 in Emerging Infectious Diseases
DrTVRao MD 21
Drug susceptible TBsect
MDR-TB
1990sect
XDR-TB
2006sect
Total DR
Resistance to HampR ndash
Treatable with 2nd line drugs
Resistance to 2nd line drugs ndashTreatment options seriously restricted
Resistance to all available drugs ndash
No treatment options
or limited resistance manageable with 4 drug regimen - DOTS
Are we Returning to a Pre-antibiotic Era
DrTVRao MD 22
Genesis of MDR TB
Resistance is a man-made amplification of a natural phenomenon
Inadequate drug delivery is main cause of secondary drug resistance
Secondary drug resistance is the main cause of primary drug resistance due to transmission of resistant strains
MDR due to spontaneous mutations is not possible as the genes encoding resistance for anti TB are unlinked
DrTVRao MD 23
Factors Contributing to Development
and Spread of MDR and XDR TB Weak TB programs (DOTS)
Low completioncure rates Lack of treatment follow up and
patient support Unreliable drug supply Diagnostic delay
Absent or inadequate infection control measures
Uncontrolled use of 2nd line drugs Fluroquinolones
DrTVRao MD 24
INHChromosomally mediatedLoss of catalaseperoxidaseMutation in mycolic acid synthesis
Regulators of peroxide response
Mechanism of resistance
DrTVRao MD 25
RifampinReduced binding to RNA polymeraseClusters of mutations at ldquoRifampin Resistance Determining Regionrdquo (RRDR)
Reduced Cell wall permeability
Mechanism of resistance
DrTVRao MD 26
Gene location associated Drug-Resistant
Mtuberculosis Drug Gene Isoniazid Kat G Inh A Kas
A Rifampicin rpo B Ethambutol emb B Streptomycin rps L Pyrazinamide pnc A Fluoroquinolones gyr A
Dubaniewicz A et al Molecular sub-type of the HLA-DR antigens in pulmonary tuberculosis Int J Infect Dis20004129-33
DrTVRao MD 27
Current Scientific Documentations on Drug Resistance in
Tuberculosis
DrTVRao MD 28
Alarming Rise of Resistant TuberculosisWHO Report on
Anti-TB Drug Resistance
490000 new cases of MDR-TB each year with gt110000 deaths1
Accounts for 5 of 9 million new cases of TB2
MDR-TB rates higher than ever (up to 223) particularly in former Soviet Union countries
XDR-TB reported by as many as 49 countries (by June 2008)3
Recent WHOIUATLD Global Surveillance report indicated 75 (3014012) of MDR TB to be XDR4
Around 40000 XDR-TB cases emerge every year1
1Tuberculosis MDR-TB amp XDR-TBmdashThe 2008 Report The Stop TB Department WHO2Hargreaves S httpinfectionthelancetcom Vol 8 April 2008 p2203Raviglione MC NEJM 2008359636-84Anti-TB Drug Resistance in the World Report No 4 The WHOIUATLD Global Project on Anti-Tuberculosis Drug Resistance Surveillance 2002-2007 World Health Organization 2008 (WHOHTMTB2008394)
DrTVRao MD 29
MDR-TB amp XDR-TBTHE 2008 REPORT
of MDR-TB among new TB cases 1994-2007
DrTVRao MD 30
MDR-TB rates higher than ever (up to 223) particularly in former Soviet Union countries
DrTVRao MD 31
Alarming Rise of Resistant TB
Resistant TB burden in countries of former Soviet Union about 50 of cases resistant to at least one drug about 20 MDR XDR-TB proportions also higher (as high as 24 in
Estonia)1
MDRXDR TB ndash essentially a man-made problem2
High numbers of resistant cases (gt400000 MDR-TB cases every year) due mainly to Underinvestment in basic TB control Poor management of anti-TB drugs Transmission of drug resistant strains1
1Anti-TB Drug Resistance in the World Report No 4 The WHOIUATLD Global Project on Anti-Tuberculosis Drug Resistance Surveillance 2002-2007 World Health Organization 2008 (WHOHTMTB2008394)
2Reichman The Lancet 20083711052-3
DrTVRao MD 32
The Much Discussed Article on XDR TB in the Lancet
Of the 221 multi-drug resistant (MDR-TB) cases 53 (24) were XDR
Almost all (52 of 53) of the XDR-TB patients died with a median survival of only 16 days from the time of diagnosis (in the 42 patients with confirmed dates of death)
All the 44 XDR TB patients who were tested for HIV were found co-infected
55 patents had never received anti-TB drugs suggesting primary transmission of XDR pathogen
67 patients had been admitted to the hospital in the preceding 2 years suggesting potential role of nosocomial transmission
Gandhi et al Lancet 20063681575-80DrTVRao MD 33
Poor mangement of infected lead to grwoing resistance
Resistance to anti-TB drugs in populations is a phenomenon that occurs primarily due to poorly managed TB care Problems include incorrect drug prescribing practices by providers poor quality drugs or erratic supply of drugs and also patient non-adherence DrTVRao MD 34
Susceptibility Testing
1048708 Direct and indirect testing1048708 Primary Drugs testing1048708 Isoniazid1048708 Rifampicin1048708 Ethambutol ()1048708 Pyrizinamide ()
DrTVRao MD 35
Drug susceptibility testing (DST)
DST is recommended for all new cases for all first line drugs with specimens taken before initiating treatment
Accuracy is more important than speed DST results should come from a small
number of well-equipped experienced laboratories who participate and perform well in an international DST quality control scheme
The WHO Supranational Laboratory Quality Control Network offers the greatest global coverage for this
DrTVRao MD 36
Drug susceptibility Testing
Assessment of growth inhibition on solid media containing various dilutions of the drug in comparison with the test strains
As the method depend observation of growth Results are not available until several weeks after isolation of the organism
DrTVRao MD 37
Other accredited Methods
Radiometric and Non radiometric methods
Nucleic acid technology ndash effective upto 95 in mutations to rifampicin resistance to gene rpoB gene
DrTVRao MD 38
Drug susceptibility testing (DST)
As a minimum laboratories supplying DST data should correctly identify resistance to isoniazid and rifampicin in over 90 of quality control samples in two out of the last three quality control roundsDrTVRao MD 39
Detection of Rifampicin Drug susceptibility testing (DST) is more important
Early identification of mycobacterial growth as M tuberculosis complex and the identification of rifampicin resistance should be the first priority as rifampicin resistance invalidates standard 6 month short-course chemotherapy and is a useful marker in most countries for MDR-TB
Laboratories should aim to identify isolates as M tuberculosis complex and perform rifampicin resistance in 90 of isolates within 1-2 working days This is technologically feasible
DrTVRao MD 40
Drug susceptibility testing
For DST laboratories modern molecular techniques permit the successful identification of isoniazid resistance in at least 75 of mycobacterial cultures within 1-2 working days and are useful preliminary screens for isoniazid resistance
DrTVRao MD 41
Secondary Drugs testing [lack of standardized
methods]
Ofloxacin quinolonesEthionamide KanamycinCapreomycin Ensure quality control and
quality assurance
DrTVRao MD 42
WHO Controls the Tuberculosis related work
The laboratory methods for anti-tuberculosis drug susceptibility testing should be selected from among those that are WHO-recommended and all laboratory processes should be quality-assured in cooperation with a partner Supranational Reference Laboratory (SRL)DrTVRao MD 43
Other WHO-Endorsed Tools
Liquid culture (eg MGIT BacTALERT)
Capilia TB Rapid strip test that detects a TB-
specific antigen from culture
Molecular line probe assays (eg GenoType MTBDRplus INNO-LiPA RifTB) Strip test for detection of TB and
drug-resistance conferring mutations
DrTVRao MD 44
BacTALERTreg
DrTVRao MD 45
CDC Updates Guidelines for Nucleic AcidAmplification Techniques to Diagnose
Tuberculosis
NAAT results should be interpreted in conjunction with the AFB smear results
NAAT and smear positive start Rx despite pending culture results PPV 95
Smear negative NAAT positive use clinical judgment to either treat or await culture
DrTVRao MD 46
Selection from automated systems for molecular and
bacteriological rapid diagnostics
PCRRocheCOBASreg Amplicorreg
amplification kitsRocheCOBASreg LightCyclerreg
(real-time-PCR)RocheCOBASreg TaqMan 48reg(increases the specificity of real-
time-PCR)
DrTVRao MD 47
Molecular Fingerprinting
26 of 30 (87) XDR TB isolates found to be genetically similar
Majority of patients had no previous history of TB treatment Suggestive of recent infection with drug-resistant strain
DrTVRao MD 48
Is PCR methods a solution
PCR cant yet replace neither microscopy culturing and competent clinical examination
DrTVRao MD 49
No testing method replaces Clinical assessment
DrTVRao MD 50
XDR-TBThe description
of XDR-TB was first used earlier in 2006 following a joint survey by WHO and the US Centres for Disease Control and Prevention (CDC) DrTVRao MD 51
How x-MDR generated
Acquired resistance is that which occurs as a result of specific previous treatment The level of primary resistance in the community is considered to reflect the efficacy of control measures in the past while the level of acquired resistance is a measure of on-going TB control measuresDrTVRao MD 52
Extreme Drug resistant Tuberculosis (XDR-TB)
Resistant to all first line drugs namely Isoniazid and Rifampin and Three or more second line drugs (SLDrsquoS) that are used to treat MDR-TB Thequinalones like Ofloaxin
Or Aminoglycosides like Capreomycin amp
Kanamycin
No third-line drugs available to treat XDR-TB since none has been developed in the last 40 years
DrTVRao MD 53
Background Extensively drug-resistant tuberculosis
Extensively drug-resistant tuberculosis has been reported in 45 countries including countries with limited resources and a high burden of tuberculosis
DrTVRao MD 54
DrTVRao MD 55
Transmissionof X -MDR
Like other forms of TB XDR-TB is spread through the air When a person with infectious TB coughs sneezes talks or spits they propel Mycobacterium into the air
DrTVRao MD 56
Best options to diagnoseX-MDR tuberculosis
To evaluate drug susceptibility the bacteria need to be cultivated and tested in a suitable laboratory Final diagnosis in this way for TB and especially for XDR-TB may take from 6 to 16 weeks To reduce the time needed for diagnosis new tools for rapid TB diagnosis are urgently needed
DrTVRao MD 57
When to suspect MDR TB
Patients not showing any reduction
in bacillary population after 3-
months of regular treatment with
Cat II regimen
Sputum positive patients who are
contacts of a known MDR TB
patient
DrTVRao MD 58
How to evaluate MDR TB
MDR TB is only a laboratory
proved HR resistance
Clinical suspicion should be
followed by lab Confirmation
Laboratories should be quality
controlledTRC
DrTVRao MD 59
Extreme Drug resistant Tuberculosis (XDR-TB) and AIDS
It can also be contracted without a patient receiving any previous treatment for TB
Mostly associated with HIV positive patients
HIV has the potential to fast tracking XDR-TB into an uncontrollable epidemic
Average survival period for patients infected with XDR-TB is 16 days
DrTVRao MD 60
Responding to MDRXDR-TB
Augment DOTS Program by
New diagnostics
New drugs New vaccines HIV incidence
reduction Advocacy1
A mathematical model projected by Basu and co-workers indicates that half of XDR-TB can be averted by 2012 by bringing synergistic effects through
Use of masks Reduced time as in-patient Improved ventilation Rapid resistance testing HIV treatment TB isolation facilities2
1Marteens and Wilkinson Lancet 20073702030-432Basu et al Quoted in Porco and Getz Lancet 20073701464-5
DrTVRao MD 61
Second Line Drug Treatment (SLDrsquos)
Less effective more costly and more toxic 50 cure rate
Four months intensive phase (5 drugs) Kanamycins Ethionamide Pyrazinamide Ofloxacin Cycloserine or Ethambutol DrTVRao MD 62
World Health Organisation (WHO) Guidelines for treatment
of MDR-TB
Strengthen basic TB care to prevent the emergence of drug-resistance
Ensure prompt diagnosis and treatment of drug resistant cases to cure existing cases and prevent further transmission
Increase collaboration between HIV and TB control programmes to provide necessary prevention and care to co-infected patients
Increase investment in laboratory infrastructures to enable better detection and management of resistant cases
DrTVRao MD 63
Treatment Guidelines
Sensitivity testing for all smear positive specimens
Patient Family and staff counselling amp education
Correct and thorough hand washing protocol and procedure
Personal protection is very important
DrTVRao MD 64
THE NEW MDR-TB Guidelines
A flexible framework approach combining both clinical and programmatic aspects of DOTS Plus based on essential programme conditions
But encouraging programs to tailor their case-finding and treatment strategies to the local epidemiological and Programme situation
Reflect GLC expert consensus and evidence and experience from GLC projects thus far
DrTVRao MD 65
Effective laboratory Diagnosis
Sputum smear examinations ndash rapid classification of species (atypical mycobacteria common in AIDS)
Culture examinations
Rapid drug sensitivity testingDrTVRao MD 66
MDR TB and HIV
MDR TB occurs with the same frequency in HIV
patients as in TB patients who are smear negative
Transmission of drug-resistant strains among HIV-
infected patients in congregate settings occurs
leading to lsquooutbreaksrsquo of MDR TB in such settings
Infection control measures absolutely essential in
settings where large number of HIV TB patients stay
togetherDrTVRao MD 67
Transmission is dependent on closeness and time of contact
In penitentiary care contacts are very close and prolonged ndash culture positive cases can also transmit TB especially to HIV positive population
DrTVRao MD 68
To Know more on MDR ndashTB Current Guidelines of WHO
Guidelines for the programmatic management of drug-resistant tuberculosis - 2011 update [pdf 904kb]
Visit helliphelliphellip WHOHTMTB20116DrTVRao MD 69
Are there any solutions for effective
Diagnosis in TB
DrTVRao MD 70
Programme Created by DrTVRao MD for Medical and Health Care
Workers in the Developing World Email
doctortvraogmailcom
DrTVRao MD 71
HISTORY ofTuberculosis
Tuberculosis Is an Ancient Disease Identified as Spinal Tuberculosis in Egyptian Mummies History dates to 1550 ndash 1080 BC Identified by PCR
DrTVRao MD 2
A Tribute to Robert Koch Discoverer of Mycobacterium
Tuberculosis
DrTVRao MD 3
Historical Background
Neolithic Time 2400 BC - Egyptian
mummies spinal columns 460 BC
Hippocrates Greece First clinical description
Phthisis Consumption (I am wasting away)
500-1500 AD Roman occupation of
Europe it spread to Britain
1650-1900 AD White plague of Europe
causing one in five deaths
DrTVRao MD 4
Diagnostic discoveries
24th March 1882 (Robert Koch) TB Day Discovery of staining
technique that identified Tuberculosis bacillus
Definite diagnosis made possible 1890 (Robert Koch)
Tuberculin discovered Diagnostic use when
injected into skin 1895 (Roentgen)
Discovery of X-rays Early diagnosis of
pulmonary disease
DrTVRao MD 5
From Tuberculosis to Tuberculin
Failure of Robert Koch Tuberculin therapy
did in fact work in Kochs laboratory even though it failed to do so almost anywhere else his reliance an animal experiments which essentially differed from what many of his contemporaries many differed with his ideas
DrTVRao MD 6
Global Status
Nine million people suffer from tuberculosis
Two million people die each year
Tuberculosis accounts for one-third of AIDS deaths world wide every year
DrTVRao MD 7
USAID Report on Tuberculosis in India
India has more new tuberculosis (TB) cases annually than any other country ranking first among the 22 high-burden TB countries worldwide according to the World Health Organizationrsquos (WHOrsquos) Global TB Report 2009 TB remains one of the leading infectious causes of mortality in India causing more than 331000 deaths in 2007 There were approximately 196 million new TB cases in India in 2007 representing more than 21 per cent of all TB cases worldwide
DrTVRao MD 8
1908-1920 (Chalmette and Guerin) Vaccine (BCG)
Attenuated strain Mycobacterium Bovis
1943 Streptomycin developed
20th November 1944 Critically ill TB patient injected
dramatically recovered
Pharmacological discoveries
DrTVRao MD 9
Selman Abraham Waksman Nobel Prize for his discovery in
1952
DrTVRao MD 10
Pharmacological discoveries
1956-1960 Combination therapy of INH and PZA
cures TB1955 Cycloserine1962 Ethambutol 1963 Rifampicin1970-1977
Combination of Rifampicin and Isoniazid adopted as International regime for treatment of TB DrTVRao MD 11
No one is Immune to TuberculosisNot only infects poor but famous
too
DrTVRao MD 12
Multi Drug Resistant
TuberculosisMDR-TB
DrTVRao MD 13
Definition
MDR-TB caused by strains of Mycobacterium Tuberculosis resistant both Rifampicin and Isoniazid with or without resistance to other drugs
Single Isoniazid or Rifampicin resistance is not MDR - TB
MDR TB is a laboratory diagnosis
DrTVRao MD 14
Classification of Drugs 3 Groups depending upon the degree
of effectiveness and potential side effects First Line (Primary agents)
are the most effective and have lowest toxicity Isoniazid Rifampin
Second LineLess effective and more toxic effectsinclude (in no particular order) p-amino
salicylic acid Streptomycin Ethambutol Third Line
are least effective and most toxic Amikacin Kanamycin Capreomycin Viomycin Kanamycin Cycloserine
DrTVRao MD 15
Basic concepts ndash Keep facts
Primary (Initial) resistanceTB patientrsquos initial Mycobacterium
tuberculosis population resistant to drugs
Secondary (Acquired) resistanceDrug-resistant M tuberculosis in initial
population selected by inappropriate drug use (inadequate treatment or non-adherence) DrTVRao MD 16
When to suspect MDR TB
Re-treatment patients whorsquos sputum smear remains positive after three monthsrsquo of intensive therapy
Treatment failure and interruption cases
Close contacts of MDR tuberculosis cases
Positive diagnoses with TB culture and susceptibility testing DrTVRao MD 17
What is extensively drug resistant tuberculosis (XDR TB)
Extensively drug resistant TB (XDR TB) is a relatively rare type of MDR TB XDR TB is defined as TB which is resistant to isoniazid and rifampin plus resistant to any fluoroquinolone and at least one of three injectable second-line drugs (ie amikacin kanamycin or capreomycin)DrTVRao MD 18
Why XDR - TB a grave concern
Because XDR TB is resistant to first-line and second line drugs patients are left with treatment options that are much less effective
XDR TB is of special concern for persons with HIV infection or other conditions that can weaken the immune system These persons are more likely to develop TB disease once they are infected and also have a higher risk of death once they develop TB
DrTVRao MD 19
Global Estimates
Classification
Estimated Number of Cases
Estimated Number of
Deaths
All forms TB
88 million 16 million
MDR TB 424000 116000
XDR TB 27000 16000
DrTVRao MD 20
Extensively Drug-Resistant Mycobacterium tuberculosis
India
The first XDR TB cases in India and the emergence of XDR TB is reported by Rajesh Mondal and Amita Jain King Georges Medical University Lucknow India Volume 13 Number 9ndashSeptember 2007 in Emerging Infectious Diseases
DrTVRao MD 21
Drug susceptible TBsect
MDR-TB
1990sect
XDR-TB
2006sect
Total DR
Resistance to HampR ndash
Treatable with 2nd line drugs
Resistance to 2nd line drugs ndashTreatment options seriously restricted
Resistance to all available drugs ndash
No treatment options
or limited resistance manageable with 4 drug regimen - DOTS
Are we Returning to a Pre-antibiotic Era
DrTVRao MD 22
Genesis of MDR TB
Resistance is a man-made amplification of a natural phenomenon
Inadequate drug delivery is main cause of secondary drug resistance
Secondary drug resistance is the main cause of primary drug resistance due to transmission of resistant strains
MDR due to spontaneous mutations is not possible as the genes encoding resistance for anti TB are unlinked
DrTVRao MD 23
Factors Contributing to Development
and Spread of MDR and XDR TB Weak TB programs (DOTS)
Low completioncure rates Lack of treatment follow up and
patient support Unreliable drug supply Diagnostic delay
Absent or inadequate infection control measures
Uncontrolled use of 2nd line drugs Fluroquinolones
DrTVRao MD 24
INHChromosomally mediatedLoss of catalaseperoxidaseMutation in mycolic acid synthesis
Regulators of peroxide response
Mechanism of resistance
DrTVRao MD 25
RifampinReduced binding to RNA polymeraseClusters of mutations at ldquoRifampin Resistance Determining Regionrdquo (RRDR)
Reduced Cell wall permeability
Mechanism of resistance
DrTVRao MD 26
Gene location associated Drug-Resistant
Mtuberculosis Drug Gene Isoniazid Kat G Inh A Kas
A Rifampicin rpo B Ethambutol emb B Streptomycin rps L Pyrazinamide pnc A Fluoroquinolones gyr A
Dubaniewicz A et al Molecular sub-type of the HLA-DR antigens in pulmonary tuberculosis Int J Infect Dis20004129-33
DrTVRao MD 27
Current Scientific Documentations on Drug Resistance in
Tuberculosis
DrTVRao MD 28
Alarming Rise of Resistant TuberculosisWHO Report on
Anti-TB Drug Resistance
490000 new cases of MDR-TB each year with gt110000 deaths1
Accounts for 5 of 9 million new cases of TB2
MDR-TB rates higher than ever (up to 223) particularly in former Soviet Union countries
XDR-TB reported by as many as 49 countries (by June 2008)3
Recent WHOIUATLD Global Surveillance report indicated 75 (3014012) of MDR TB to be XDR4
Around 40000 XDR-TB cases emerge every year1
1Tuberculosis MDR-TB amp XDR-TBmdashThe 2008 Report The Stop TB Department WHO2Hargreaves S httpinfectionthelancetcom Vol 8 April 2008 p2203Raviglione MC NEJM 2008359636-84Anti-TB Drug Resistance in the World Report No 4 The WHOIUATLD Global Project on Anti-Tuberculosis Drug Resistance Surveillance 2002-2007 World Health Organization 2008 (WHOHTMTB2008394)
DrTVRao MD 29
MDR-TB amp XDR-TBTHE 2008 REPORT
of MDR-TB among new TB cases 1994-2007
DrTVRao MD 30
MDR-TB rates higher than ever (up to 223) particularly in former Soviet Union countries
DrTVRao MD 31
Alarming Rise of Resistant TB
Resistant TB burden in countries of former Soviet Union about 50 of cases resistant to at least one drug about 20 MDR XDR-TB proportions also higher (as high as 24 in
Estonia)1
MDRXDR TB ndash essentially a man-made problem2
High numbers of resistant cases (gt400000 MDR-TB cases every year) due mainly to Underinvestment in basic TB control Poor management of anti-TB drugs Transmission of drug resistant strains1
1Anti-TB Drug Resistance in the World Report No 4 The WHOIUATLD Global Project on Anti-Tuberculosis Drug Resistance Surveillance 2002-2007 World Health Organization 2008 (WHOHTMTB2008394)
2Reichman The Lancet 20083711052-3
DrTVRao MD 32
The Much Discussed Article on XDR TB in the Lancet
Of the 221 multi-drug resistant (MDR-TB) cases 53 (24) were XDR
Almost all (52 of 53) of the XDR-TB patients died with a median survival of only 16 days from the time of diagnosis (in the 42 patients with confirmed dates of death)
All the 44 XDR TB patients who were tested for HIV were found co-infected
55 patents had never received anti-TB drugs suggesting primary transmission of XDR pathogen
67 patients had been admitted to the hospital in the preceding 2 years suggesting potential role of nosocomial transmission
Gandhi et al Lancet 20063681575-80DrTVRao MD 33
Poor mangement of infected lead to grwoing resistance
Resistance to anti-TB drugs in populations is a phenomenon that occurs primarily due to poorly managed TB care Problems include incorrect drug prescribing practices by providers poor quality drugs or erratic supply of drugs and also patient non-adherence DrTVRao MD 34
Susceptibility Testing
1048708 Direct and indirect testing1048708 Primary Drugs testing1048708 Isoniazid1048708 Rifampicin1048708 Ethambutol ()1048708 Pyrizinamide ()
DrTVRao MD 35
Drug susceptibility testing (DST)
DST is recommended for all new cases for all first line drugs with specimens taken before initiating treatment
Accuracy is more important than speed DST results should come from a small
number of well-equipped experienced laboratories who participate and perform well in an international DST quality control scheme
The WHO Supranational Laboratory Quality Control Network offers the greatest global coverage for this
DrTVRao MD 36
Drug susceptibility Testing
Assessment of growth inhibition on solid media containing various dilutions of the drug in comparison with the test strains
As the method depend observation of growth Results are not available until several weeks after isolation of the organism
DrTVRao MD 37
Other accredited Methods
Radiometric and Non radiometric methods
Nucleic acid technology ndash effective upto 95 in mutations to rifampicin resistance to gene rpoB gene
DrTVRao MD 38
Drug susceptibility testing (DST)
As a minimum laboratories supplying DST data should correctly identify resistance to isoniazid and rifampicin in over 90 of quality control samples in two out of the last three quality control roundsDrTVRao MD 39
Detection of Rifampicin Drug susceptibility testing (DST) is more important
Early identification of mycobacterial growth as M tuberculosis complex and the identification of rifampicin resistance should be the first priority as rifampicin resistance invalidates standard 6 month short-course chemotherapy and is a useful marker in most countries for MDR-TB
Laboratories should aim to identify isolates as M tuberculosis complex and perform rifampicin resistance in 90 of isolates within 1-2 working days This is technologically feasible
DrTVRao MD 40
Drug susceptibility testing
For DST laboratories modern molecular techniques permit the successful identification of isoniazid resistance in at least 75 of mycobacterial cultures within 1-2 working days and are useful preliminary screens for isoniazid resistance
DrTVRao MD 41
Secondary Drugs testing [lack of standardized
methods]
Ofloxacin quinolonesEthionamide KanamycinCapreomycin Ensure quality control and
quality assurance
DrTVRao MD 42
WHO Controls the Tuberculosis related work
The laboratory methods for anti-tuberculosis drug susceptibility testing should be selected from among those that are WHO-recommended and all laboratory processes should be quality-assured in cooperation with a partner Supranational Reference Laboratory (SRL)DrTVRao MD 43
Other WHO-Endorsed Tools
Liquid culture (eg MGIT BacTALERT)
Capilia TB Rapid strip test that detects a TB-
specific antigen from culture
Molecular line probe assays (eg GenoType MTBDRplus INNO-LiPA RifTB) Strip test for detection of TB and
drug-resistance conferring mutations
DrTVRao MD 44
BacTALERTreg
DrTVRao MD 45
CDC Updates Guidelines for Nucleic AcidAmplification Techniques to Diagnose
Tuberculosis
NAAT results should be interpreted in conjunction with the AFB smear results
NAAT and smear positive start Rx despite pending culture results PPV 95
Smear negative NAAT positive use clinical judgment to either treat or await culture
DrTVRao MD 46
Selection from automated systems for molecular and
bacteriological rapid diagnostics
PCRRocheCOBASreg Amplicorreg
amplification kitsRocheCOBASreg LightCyclerreg
(real-time-PCR)RocheCOBASreg TaqMan 48reg(increases the specificity of real-
time-PCR)
DrTVRao MD 47
Molecular Fingerprinting
26 of 30 (87) XDR TB isolates found to be genetically similar
Majority of patients had no previous history of TB treatment Suggestive of recent infection with drug-resistant strain
DrTVRao MD 48
Is PCR methods a solution
PCR cant yet replace neither microscopy culturing and competent clinical examination
DrTVRao MD 49
No testing method replaces Clinical assessment
DrTVRao MD 50
XDR-TBThe description
of XDR-TB was first used earlier in 2006 following a joint survey by WHO and the US Centres for Disease Control and Prevention (CDC) DrTVRao MD 51
How x-MDR generated
Acquired resistance is that which occurs as a result of specific previous treatment The level of primary resistance in the community is considered to reflect the efficacy of control measures in the past while the level of acquired resistance is a measure of on-going TB control measuresDrTVRao MD 52
Extreme Drug resistant Tuberculosis (XDR-TB)
Resistant to all first line drugs namely Isoniazid and Rifampin and Three or more second line drugs (SLDrsquoS) that are used to treat MDR-TB Thequinalones like Ofloaxin
Or Aminoglycosides like Capreomycin amp
Kanamycin
No third-line drugs available to treat XDR-TB since none has been developed in the last 40 years
DrTVRao MD 53
Background Extensively drug-resistant tuberculosis
Extensively drug-resistant tuberculosis has been reported in 45 countries including countries with limited resources and a high burden of tuberculosis
DrTVRao MD 54
DrTVRao MD 55
Transmissionof X -MDR
Like other forms of TB XDR-TB is spread through the air When a person with infectious TB coughs sneezes talks or spits they propel Mycobacterium into the air
DrTVRao MD 56
Best options to diagnoseX-MDR tuberculosis
To evaluate drug susceptibility the bacteria need to be cultivated and tested in a suitable laboratory Final diagnosis in this way for TB and especially for XDR-TB may take from 6 to 16 weeks To reduce the time needed for diagnosis new tools for rapid TB diagnosis are urgently needed
DrTVRao MD 57
When to suspect MDR TB
Patients not showing any reduction
in bacillary population after 3-
months of regular treatment with
Cat II regimen
Sputum positive patients who are
contacts of a known MDR TB
patient
DrTVRao MD 58
How to evaluate MDR TB
MDR TB is only a laboratory
proved HR resistance
Clinical suspicion should be
followed by lab Confirmation
Laboratories should be quality
controlledTRC
DrTVRao MD 59
Extreme Drug resistant Tuberculosis (XDR-TB) and AIDS
It can also be contracted without a patient receiving any previous treatment for TB
Mostly associated with HIV positive patients
HIV has the potential to fast tracking XDR-TB into an uncontrollable epidemic
Average survival period for patients infected with XDR-TB is 16 days
DrTVRao MD 60
Responding to MDRXDR-TB
Augment DOTS Program by
New diagnostics
New drugs New vaccines HIV incidence
reduction Advocacy1
A mathematical model projected by Basu and co-workers indicates that half of XDR-TB can be averted by 2012 by bringing synergistic effects through
Use of masks Reduced time as in-patient Improved ventilation Rapid resistance testing HIV treatment TB isolation facilities2
1Marteens and Wilkinson Lancet 20073702030-432Basu et al Quoted in Porco and Getz Lancet 20073701464-5
DrTVRao MD 61
Second Line Drug Treatment (SLDrsquos)
Less effective more costly and more toxic 50 cure rate
Four months intensive phase (5 drugs) Kanamycins Ethionamide Pyrazinamide Ofloxacin Cycloserine or Ethambutol DrTVRao MD 62
World Health Organisation (WHO) Guidelines for treatment
of MDR-TB
Strengthen basic TB care to prevent the emergence of drug-resistance
Ensure prompt diagnosis and treatment of drug resistant cases to cure existing cases and prevent further transmission
Increase collaboration between HIV and TB control programmes to provide necessary prevention and care to co-infected patients
Increase investment in laboratory infrastructures to enable better detection and management of resistant cases
DrTVRao MD 63
Treatment Guidelines
Sensitivity testing for all smear positive specimens
Patient Family and staff counselling amp education
Correct and thorough hand washing protocol and procedure
Personal protection is very important
DrTVRao MD 64
THE NEW MDR-TB Guidelines
A flexible framework approach combining both clinical and programmatic aspects of DOTS Plus based on essential programme conditions
But encouraging programs to tailor their case-finding and treatment strategies to the local epidemiological and Programme situation
Reflect GLC expert consensus and evidence and experience from GLC projects thus far
DrTVRao MD 65
Effective laboratory Diagnosis
Sputum smear examinations ndash rapid classification of species (atypical mycobacteria common in AIDS)
Culture examinations
Rapid drug sensitivity testingDrTVRao MD 66
MDR TB and HIV
MDR TB occurs with the same frequency in HIV
patients as in TB patients who are smear negative
Transmission of drug-resistant strains among HIV-
infected patients in congregate settings occurs
leading to lsquooutbreaksrsquo of MDR TB in such settings
Infection control measures absolutely essential in
settings where large number of HIV TB patients stay
togetherDrTVRao MD 67
Transmission is dependent on closeness and time of contact
In penitentiary care contacts are very close and prolonged ndash culture positive cases can also transmit TB especially to HIV positive population
DrTVRao MD 68
To Know more on MDR ndashTB Current Guidelines of WHO
Guidelines for the programmatic management of drug-resistant tuberculosis - 2011 update [pdf 904kb]
Visit helliphelliphellip WHOHTMTB20116DrTVRao MD 69
Are there any solutions for effective
Diagnosis in TB
DrTVRao MD 70
Programme Created by DrTVRao MD for Medical and Health Care
Workers in the Developing World Email
doctortvraogmailcom
DrTVRao MD 71
A Tribute to Robert Koch Discoverer of Mycobacterium
Tuberculosis
DrTVRao MD 3
Historical Background
Neolithic Time 2400 BC - Egyptian
mummies spinal columns 460 BC
Hippocrates Greece First clinical description
Phthisis Consumption (I am wasting away)
500-1500 AD Roman occupation of
Europe it spread to Britain
1650-1900 AD White plague of Europe
causing one in five deaths
DrTVRao MD 4
Diagnostic discoveries
24th March 1882 (Robert Koch) TB Day Discovery of staining
technique that identified Tuberculosis bacillus
Definite diagnosis made possible 1890 (Robert Koch)
Tuberculin discovered Diagnostic use when
injected into skin 1895 (Roentgen)
Discovery of X-rays Early diagnosis of
pulmonary disease
DrTVRao MD 5
From Tuberculosis to Tuberculin
Failure of Robert Koch Tuberculin therapy
did in fact work in Kochs laboratory even though it failed to do so almost anywhere else his reliance an animal experiments which essentially differed from what many of his contemporaries many differed with his ideas
DrTVRao MD 6
Global Status
Nine million people suffer from tuberculosis
Two million people die each year
Tuberculosis accounts for one-third of AIDS deaths world wide every year
DrTVRao MD 7
USAID Report on Tuberculosis in India
India has more new tuberculosis (TB) cases annually than any other country ranking first among the 22 high-burden TB countries worldwide according to the World Health Organizationrsquos (WHOrsquos) Global TB Report 2009 TB remains one of the leading infectious causes of mortality in India causing more than 331000 deaths in 2007 There were approximately 196 million new TB cases in India in 2007 representing more than 21 per cent of all TB cases worldwide
DrTVRao MD 8
1908-1920 (Chalmette and Guerin) Vaccine (BCG)
Attenuated strain Mycobacterium Bovis
1943 Streptomycin developed
20th November 1944 Critically ill TB patient injected
dramatically recovered
Pharmacological discoveries
DrTVRao MD 9
Selman Abraham Waksman Nobel Prize for his discovery in
1952
DrTVRao MD 10
Pharmacological discoveries
1956-1960 Combination therapy of INH and PZA
cures TB1955 Cycloserine1962 Ethambutol 1963 Rifampicin1970-1977
Combination of Rifampicin and Isoniazid adopted as International regime for treatment of TB DrTVRao MD 11
No one is Immune to TuberculosisNot only infects poor but famous
too
DrTVRao MD 12
Multi Drug Resistant
TuberculosisMDR-TB
DrTVRao MD 13
Definition
MDR-TB caused by strains of Mycobacterium Tuberculosis resistant both Rifampicin and Isoniazid with or without resistance to other drugs
Single Isoniazid or Rifampicin resistance is not MDR - TB
MDR TB is a laboratory diagnosis
DrTVRao MD 14
Classification of Drugs 3 Groups depending upon the degree
of effectiveness and potential side effects First Line (Primary agents)
are the most effective and have lowest toxicity Isoniazid Rifampin
Second LineLess effective and more toxic effectsinclude (in no particular order) p-amino
salicylic acid Streptomycin Ethambutol Third Line
are least effective and most toxic Amikacin Kanamycin Capreomycin Viomycin Kanamycin Cycloserine
DrTVRao MD 15
Basic concepts ndash Keep facts
Primary (Initial) resistanceTB patientrsquos initial Mycobacterium
tuberculosis population resistant to drugs
Secondary (Acquired) resistanceDrug-resistant M tuberculosis in initial
population selected by inappropriate drug use (inadequate treatment or non-adherence) DrTVRao MD 16
When to suspect MDR TB
Re-treatment patients whorsquos sputum smear remains positive after three monthsrsquo of intensive therapy
Treatment failure and interruption cases
Close contacts of MDR tuberculosis cases
Positive diagnoses with TB culture and susceptibility testing DrTVRao MD 17
What is extensively drug resistant tuberculosis (XDR TB)
Extensively drug resistant TB (XDR TB) is a relatively rare type of MDR TB XDR TB is defined as TB which is resistant to isoniazid and rifampin plus resistant to any fluoroquinolone and at least one of three injectable second-line drugs (ie amikacin kanamycin or capreomycin)DrTVRao MD 18
Why XDR - TB a grave concern
Because XDR TB is resistant to first-line and second line drugs patients are left with treatment options that are much less effective
XDR TB is of special concern for persons with HIV infection or other conditions that can weaken the immune system These persons are more likely to develop TB disease once they are infected and also have a higher risk of death once they develop TB
DrTVRao MD 19
Global Estimates
Classification
Estimated Number of Cases
Estimated Number of
Deaths
All forms TB
88 million 16 million
MDR TB 424000 116000
XDR TB 27000 16000
DrTVRao MD 20
Extensively Drug-Resistant Mycobacterium tuberculosis
India
The first XDR TB cases in India and the emergence of XDR TB is reported by Rajesh Mondal and Amita Jain King Georges Medical University Lucknow India Volume 13 Number 9ndashSeptember 2007 in Emerging Infectious Diseases
DrTVRao MD 21
Drug susceptible TBsect
MDR-TB
1990sect
XDR-TB
2006sect
Total DR
Resistance to HampR ndash
Treatable with 2nd line drugs
Resistance to 2nd line drugs ndashTreatment options seriously restricted
Resistance to all available drugs ndash
No treatment options
or limited resistance manageable with 4 drug regimen - DOTS
Are we Returning to a Pre-antibiotic Era
DrTVRao MD 22
Genesis of MDR TB
Resistance is a man-made amplification of a natural phenomenon
Inadequate drug delivery is main cause of secondary drug resistance
Secondary drug resistance is the main cause of primary drug resistance due to transmission of resistant strains
MDR due to spontaneous mutations is not possible as the genes encoding resistance for anti TB are unlinked
DrTVRao MD 23
Factors Contributing to Development
and Spread of MDR and XDR TB Weak TB programs (DOTS)
Low completioncure rates Lack of treatment follow up and
patient support Unreliable drug supply Diagnostic delay
Absent or inadequate infection control measures
Uncontrolled use of 2nd line drugs Fluroquinolones
DrTVRao MD 24
INHChromosomally mediatedLoss of catalaseperoxidaseMutation in mycolic acid synthesis
Regulators of peroxide response
Mechanism of resistance
DrTVRao MD 25
RifampinReduced binding to RNA polymeraseClusters of mutations at ldquoRifampin Resistance Determining Regionrdquo (RRDR)
Reduced Cell wall permeability
Mechanism of resistance
DrTVRao MD 26
Gene location associated Drug-Resistant
Mtuberculosis Drug Gene Isoniazid Kat G Inh A Kas
A Rifampicin rpo B Ethambutol emb B Streptomycin rps L Pyrazinamide pnc A Fluoroquinolones gyr A
Dubaniewicz A et al Molecular sub-type of the HLA-DR antigens in pulmonary tuberculosis Int J Infect Dis20004129-33
DrTVRao MD 27
Current Scientific Documentations on Drug Resistance in
Tuberculosis
DrTVRao MD 28
Alarming Rise of Resistant TuberculosisWHO Report on
Anti-TB Drug Resistance
490000 new cases of MDR-TB each year with gt110000 deaths1
Accounts for 5 of 9 million new cases of TB2
MDR-TB rates higher than ever (up to 223) particularly in former Soviet Union countries
XDR-TB reported by as many as 49 countries (by June 2008)3
Recent WHOIUATLD Global Surveillance report indicated 75 (3014012) of MDR TB to be XDR4
Around 40000 XDR-TB cases emerge every year1
1Tuberculosis MDR-TB amp XDR-TBmdashThe 2008 Report The Stop TB Department WHO2Hargreaves S httpinfectionthelancetcom Vol 8 April 2008 p2203Raviglione MC NEJM 2008359636-84Anti-TB Drug Resistance in the World Report No 4 The WHOIUATLD Global Project on Anti-Tuberculosis Drug Resistance Surveillance 2002-2007 World Health Organization 2008 (WHOHTMTB2008394)
DrTVRao MD 29
MDR-TB amp XDR-TBTHE 2008 REPORT
of MDR-TB among new TB cases 1994-2007
DrTVRao MD 30
MDR-TB rates higher than ever (up to 223) particularly in former Soviet Union countries
DrTVRao MD 31
Alarming Rise of Resistant TB
Resistant TB burden in countries of former Soviet Union about 50 of cases resistant to at least one drug about 20 MDR XDR-TB proportions also higher (as high as 24 in
Estonia)1
MDRXDR TB ndash essentially a man-made problem2
High numbers of resistant cases (gt400000 MDR-TB cases every year) due mainly to Underinvestment in basic TB control Poor management of anti-TB drugs Transmission of drug resistant strains1
1Anti-TB Drug Resistance in the World Report No 4 The WHOIUATLD Global Project on Anti-Tuberculosis Drug Resistance Surveillance 2002-2007 World Health Organization 2008 (WHOHTMTB2008394)
2Reichman The Lancet 20083711052-3
DrTVRao MD 32
The Much Discussed Article on XDR TB in the Lancet
Of the 221 multi-drug resistant (MDR-TB) cases 53 (24) were XDR
Almost all (52 of 53) of the XDR-TB patients died with a median survival of only 16 days from the time of diagnosis (in the 42 patients with confirmed dates of death)
All the 44 XDR TB patients who were tested for HIV were found co-infected
55 patents had never received anti-TB drugs suggesting primary transmission of XDR pathogen
67 patients had been admitted to the hospital in the preceding 2 years suggesting potential role of nosocomial transmission
Gandhi et al Lancet 20063681575-80DrTVRao MD 33
Poor mangement of infected lead to grwoing resistance
Resistance to anti-TB drugs in populations is a phenomenon that occurs primarily due to poorly managed TB care Problems include incorrect drug prescribing practices by providers poor quality drugs or erratic supply of drugs and also patient non-adherence DrTVRao MD 34
Susceptibility Testing
1048708 Direct and indirect testing1048708 Primary Drugs testing1048708 Isoniazid1048708 Rifampicin1048708 Ethambutol ()1048708 Pyrizinamide ()
DrTVRao MD 35
Drug susceptibility testing (DST)
DST is recommended for all new cases for all first line drugs with specimens taken before initiating treatment
Accuracy is more important than speed DST results should come from a small
number of well-equipped experienced laboratories who participate and perform well in an international DST quality control scheme
The WHO Supranational Laboratory Quality Control Network offers the greatest global coverage for this
DrTVRao MD 36
Drug susceptibility Testing
Assessment of growth inhibition on solid media containing various dilutions of the drug in comparison with the test strains
As the method depend observation of growth Results are not available until several weeks after isolation of the organism
DrTVRao MD 37
Other accredited Methods
Radiometric and Non radiometric methods
Nucleic acid technology ndash effective upto 95 in mutations to rifampicin resistance to gene rpoB gene
DrTVRao MD 38
Drug susceptibility testing (DST)
As a minimum laboratories supplying DST data should correctly identify resistance to isoniazid and rifampicin in over 90 of quality control samples in two out of the last three quality control roundsDrTVRao MD 39
Detection of Rifampicin Drug susceptibility testing (DST) is more important
Early identification of mycobacterial growth as M tuberculosis complex and the identification of rifampicin resistance should be the first priority as rifampicin resistance invalidates standard 6 month short-course chemotherapy and is a useful marker in most countries for MDR-TB
Laboratories should aim to identify isolates as M tuberculosis complex and perform rifampicin resistance in 90 of isolates within 1-2 working days This is technologically feasible
DrTVRao MD 40
Drug susceptibility testing
For DST laboratories modern molecular techniques permit the successful identification of isoniazid resistance in at least 75 of mycobacterial cultures within 1-2 working days and are useful preliminary screens for isoniazid resistance
DrTVRao MD 41
Secondary Drugs testing [lack of standardized
methods]
Ofloxacin quinolonesEthionamide KanamycinCapreomycin Ensure quality control and
quality assurance
DrTVRao MD 42
WHO Controls the Tuberculosis related work
The laboratory methods for anti-tuberculosis drug susceptibility testing should be selected from among those that are WHO-recommended and all laboratory processes should be quality-assured in cooperation with a partner Supranational Reference Laboratory (SRL)DrTVRao MD 43
Other WHO-Endorsed Tools
Liquid culture (eg MGIT BacTALERT)
Capilia TB Rapid strip test that detects a TB-
specific antigen from culture
Molecular line probe assays (eg GenoType MTBDRplus INNO-LiPA RifTB) Strip test for detection of TB and
drug-resistance conferring mutations
DrTVRao MD 44
BacTALERTreg
DrTVRao MD 45
CDC Updates Guidelines for Nucleic AcidAmplification Techniques to Diagnose
Tuberculosis
NAAT results should be interpreted in conjunction with the AFB smear results
NAAT and smear positive start Rx despite pending culture results PPV 95
Smear negative NAAT positive use clinical judgment to either treat or await culture
DrTVRao MD 46
Selection from automated systems for molecular and
bacteriological rapid diagnostics
PCRRocheCOBASreg Amplicorreg
amplification kitsRocheCOBASreg LightCyclerreg
(real-time-PCR)RocheCOBASreg TaqMan 48reg(increases the specificity of real-
time-PCR)
DrTVRao MD 47
Molecular Fingerprinting
26 of 30 (87) XDR TB isolates found to be genetically similar
Majority of patients had no previous history of TB treatment Suggestive of recent infection with drug-resistant strain
DrTVRao MD 48
Is PCR methods a solution
PCR cant yet replace neither microscopy culturing and competent clinical examination
DrTVRao MD 49
No testing method replaces Clinical assessment
DrTVRao MD 50
XDR-TBThe description
of XDR-TB was first used earlier in 2006 following a joint survey by WHO and the US Centres for Disease Control and Prevention (CDC) DrTVRao MD 51
How x-MDR generated
Acquired resistance is that which occurs as a result of specific previous treatment The level of primary resistance in the community is considered to reflect the efficacy of control measures in the past while the level of acquired resistance is a measure of on-going TB control measuresDrTVRao MD 52
Extreme Drug resistant Tuberculosis (XDR-TB)
Resistant to all first line drugs namely Isoniazid and Rifampin and Three or more second line drugs (SLDrsquoS) that are used to treat MDR-TB Thequinalones like Ofloaxin
Or Aminoglycosides like Capreomycin amp
Kanamycin
No third-line drugs available to treat XDR-TB since none has been developed in the last 40 years
DrTVRao MD 53
Background Extensively drug-resistant tuberculosis
Extensively drug-resistant tuberculosis has been reported in 45 countries including countries with limited resources and a high burden of tuberculosis
DrTVRao MD 54
DrTVRao MD 55
Transmissionof X -MDR
Like other forms of TB XDR-TB is spread through the air When a person with infectious TB coughs sneezes talks or spits they propel Mycobacterium into the air
DrTVRao MD 56
Best options to diagnoseX-MDR tuberculosis
To evaluate drug susceptibility the bacteria need to be cultivated and tested in a suitable laboratory Final diagnosis in this way for TB and especially for XDR-TB may take from 6 to 16 weeks To reduce the time needed for diagnosis new tools for rapid TB diagnosis are urgently needed
DrTVRao MD 57
When to suspect MDR TB
Patients not showing any reduction
in bacillary population after 3-
months of regular treatment with
Cat II regimen
Sputum positive patients who are
contacts of a known MDR TB
patient
DrTVRao MD 58
How to evaluate MDR TB
MDR TB is only a laboratory
proved HR resistance
Clinical suspicion should be
followed by lab Confirmation
Laboratories should be quality
controlledTRC
DrTVRao MD 59
Extreme Drug resistant Tuberculosis (XDR-TB) and AIDS
It can also be contracted without a patient receiving any previous treatment for TB
Mostly associated with HIV positive patients
HIV has the potential to fast tracking XDR-TB into an uncontrollable epidemic
Average survival period for patients infected with XDR-TB is 16 days
DrTVRao MD 60
Responding to MDRXDR-TB
Augment DOTS Program by
New diagnostics
New drugs New vaccines HIV incidence
reduction Advocacy1
A mathematical model projected by Basu and co-workers indicates that half of XDR-TB can be averted by 2012 by bringing synergistic effects through
Use of masks Reduced time as in-patient Improved ventilation Rapid resistance testing HIV treatment TB isolation facilities2
1Marteens and Wilkinson Lancet 20073702030-432Basu et al Quoted in Porco and Getz Lancet 20073701464-5
DrTVRao MD 61
Second Line Drug Treatment (SLDrsquos)
Less effective more costly and more toxic 50 cure rate
Four months intensive phase (5 drugs) Kanamycins Ethionamide Pyrazinamide Ofloxacin Cycloserine or Ethambutol DrTVRao MD 62
World Health Organisation (WHO) Guidelines for treatment
of MDR-TB
Strengthen basic TB care to prevent the emergence of drug-resistance
Ensure prompt diagnosis and treatment of drug resistant cases to cure existing cases and prevent further transmission
Increase collaboration between HIV and TB control programmes to provide necessary prevention and care to co-infected patients
Increase investment in laboratory infrastructures to enable better detection and management of resistant cases
DrTVRao MD 63
Treatment Guidelines
Sensitivity testing for all smear positive specimens
Patient Family and staff counselling amp education
Correct and thorough hand washing protocol and procedure
Personal protection is very important
DrTVRao MD 64
THE NEW MDR-TB Guidelines
A flexible framework approach combining both clinical and programmatic aspects of DOTS Plus based on essential programme conditions
But encouraging programs to tailor their case-finding and treatment strategies to the local epidemiological and Programme situation
Reflect GLC expert consensus and evidence and experience from GLC projects thus far
DrTVRao MD 65
Effective laboratory Diagnosis
Sputum smear examinations ndash rapid classification of species (atypical mycobacteria common in AIDS)
Culture examinations
Rapid drug sensitivity testingDrTVRao MD 66
MDR TB and HIV
MDR TB occurs with the same frequency in HIV
patients as in TB patients who are smear negative
Transmission of drug-resistant strains among HIV-
infected patients in congregate settings occurs
leading to lsquooutbreaksrsquo of MDR TB in such settings
Infection control measures absolutely essential in
settings where large number of HIV TB patients stay
togetherDrTVRao MD 67
Transmission is dependent on closeness and time of contact
In penitentiary care contacts are very close and prolonged ndash culture positive cases can also transmit TB especially to HIV positive population
DrTVRao MD 68
To Know more on MDR ndashTB Current Guidelines of WHO
Guidelines for the programmatic management of drug-resistant tuberculosis - 2011 update [pdf 904kb]
Visit helliphelliphellip WHOHTMTB20116DrTVRao MD 69
Are there any solutions for effective
Diagnosis in TB
DrTVRao MD 70
Programme Created by DrTVRao MD for Medical and Health Care
Workers in the Developing World Email
doctortvraogmailcom
DrTVRao MD 71
Historical Background
Neolithic Time 2400 BC - Egyptian
mummies spinal columns 460 BC
Hippocrates Greece First clinical description
Phthisis Consumption (I am wasting away)
500-1500 AD Roman occupation of
Europe it spread to Britain
1650-1900 AD White plague of Europe
causing one in five deaths
DrTVRao MD 4
Diagnostic discoveries
24th March 1882 (Robert Koch) TB Day Discovery of staining
technique that identified Tuberculosis bacillus
Definite diagnosis made possible 1890 (Robert Koch)
Tuberculin discovered Diagnostic use when
injected into skin 1895 (Roentgen)
Discovery of X-rays Early diagnosis of
pulmonary disease
DrTVRao MD 5
From Tuberculosis to Tuberculin
Failure of Robert Koch Tuberculin therapy
did in fact work in Kochs laboratory even though it failed to do so almost anywhere else his reliance an animal experiments which essentially differed from what many of his contemporaries many differed with his ideas
DrTVRao MD 6
Global Status
Nine million people suffer from tuberculosis
Two million people die each year
Tuberculosis accounts for one-third of AIDS deaths world wide every year
DrTVRao MD 7
USAID Report on Tuberculosis in India
India has more new tuberculosis (TB) cases annually than any other country ranking first among the 22 high-burden TB countries worldwide according to the World Health Organizationrsquos (WHOrsquos) Global TB Report 2009 TB remains one of the leading infectious causes of mortality in India causing more than 331000 deaths in 2007 There were approximately 196 million new TB cases in India in 2007 representing more than 21 per cent of all TB cases worldwide
DrTVRao MD 8
1908-1920 (Chalmette and Guerin) Vaccine (BCG)
Attenuated strain Mycobacterium Bovis
1943 Streptomycin developed
20th November 1944 Critically ill TB patient injected
dramatically recovered
Pharmacological discoveries
DrTVRao MD 9
Selman Abraham Waksman Nobel Prize for his discovery in
1952
DrTVRao MD 10
Pharmacological discoveries
1956-1960 Combination therapy of INH and PZA
cures TB1955 Cycloserine1962 Ethambutol 1963 Rifampicin1970-1977
Combination of Rifampicin and Isoniazid adopted as International regime for treatment of TB DrTVRao MD 11
No one is Immune to TuberculosisNot only infects poor but famous
too
DrTVRao MD 12
Multi Drug Resistant
TuberculosisMDR-TB
DrTVRao MD 13
Definition
MDR-TB caused by strains of Mycobacterium Tuberculosis resistant both Rifampicin and Isoniazid with or without resistance to other drugs
Single Isoniazid or Rifampicin resistance is not MDR - TB
MDR TB is a laboratory diagnosis
DrTVRao MD 14
Classification of Drugs 3 Groups depending upon the degree
of effectiveness and potential side effects First Line (Primary agents)
are the most effective and have lowest toxicity Isoniazid Rifampin
Second LineLess effective and more toxic effectsinclude (in no particular order) p-amino
salicylic acid Streptomycin Ethambutol Third Line
are least effective and most toxic Amikacin Kanamycin Capreomycin Viomycin Kanamycin Cycloserine
DrTVRao MD 15
Basic concepts ndash Keep facts
Primary (Initial) resistanceTB patientrsquos initial Mycobacterium
tuberculosis population resistant to drugs
Secondary (Acquired) resistanceDrug-resistant M tuberculosis in initial
population selected by inappropriate drug use (inadequate treatment or non-adherence) DrTVRao MD 16
When to suspect MDR TB
Re-treatment patients whorsquos sputum smear remains positive after three monthsrsquo of intensive therapy
Treatment failure and interruption cases
Close contacts of MDR tuberculosis cases
Positive diagnoses with TB culture and susceptibility testing DrTVRao MD 17
What is extensively drug resistant tuberculosis (XDR TB)
Extensively drug resistant TB (XDR TB) is a relatively rare type of MDR TB XDR TB is defined as TB which is resistant to isoniazid and rifampin plus resistant to any fluoroquinolone and at least one of three injectable second-line drugs (ie amikacin kanamycin or capreomycin)DrTVRao MD 18
Why XDR - TB a grave concern
Because XDR TB is resistant to first-line and second line drugs patients are left with treatment options that are much less effective
XDR TB is of special concern for persons with HIV infection or other conditions that can weaken the immune system These persons are more likely to develop TB disease once they are infected and also have a higher risk of death once they develop TB
DrTVRao MD 19
Global Estimates
Classification
Estimated Number of Cases
Estimated Number of
Deaths
All forms TB
88 million 16 million
MDR TB 424000 116000
XDR TB 27000 16000
DrTVRao MD 20
Extensively Drug-Resistant Mycobacterium tuberculosis
India
The first XDR TB cases in India and the emergence of XDR TB is reported by Rajesh Mondal and Amita Jain King Georges Medical University Lucknow India Volume 13 Number 9ndashSeptember 2007 in Emerging Infectious Diseases
DrTVRao MD 21
Drug susceptible TBsect
MDR-TB
1990sect
XDR-TB
2006sect
Total DR
Resistance to HampR ndash
Treatable with 2nd line drugs
Resistance to 2nd line drugs ndashTreatment options seriously restricted
Resistance to all available drugs ndash
No treatment options
or limited resistance manageable with 4 drug regimen - DOTS
Are we Returning to a Pre-antibiotic Era
DrTVRao MD 22
Genesis of MDR TB
Resistance is a man-made amplification of a natural phenomenon
Inadequate drug delivery is main cause of secondary drug resistance
Secondary drug resistance is the main cause of primary drug resistance due to transmission of resistant strains
MDR due to spontaneous mutations is not possible as the genes encoding resistance for anti TB are unlinked
DrTVRao MD 23
Factors Contributing to Development
and Spread of MDR and XDR TB Weak TB programs (DOTS)
Low completioncure rates Lack of treatment follow up and
patient support Unreliable drug supply Diagnostic delay
Absent or inadequate infection control measures
Uncontrolled use of 2nd line drugs Fluroquinolones
DrTVRao MD 24
INHChromosomally mediatedLoss of catalaseperoxidaseMutation in mycolic acid synthesis
Regulators of peroxide response
Mechanism of resistance
DrTVRao MD 25
RifampinReduced binding to RNA polymeraseClusters of mutations at ldquoRifampin Resistance Determining Regionrdquo (RRDR)
Reduced Cell wall permeability
Mechanism of resistance
DrTVRao MD 26
Gene location associated Drug-Resistant
Mtuberculosis Drug Gene Isoniazid Kat G Inh A Kas
A Rifampicin rpo B Ethambutol emb B Streptomycin rps L Pyrazinamide pnc A Fluoroquinolones gyr A
Dubaniewicz A et al Molecular sub-type of the HLA-DR antigens in pulmonary tuberculosis Int J Infect Dis20004129-33
DrTVRao MD 27
Current Scientific Documentations on Drug Resistance in
Tuberculosis
DrTVRao MD 28
Alarming Rise of Resistant TuberculosisWHO Report on
Anti-TB Drug Resistance
490000 new cases of MDR-TB each year with gt110000 deaths1
Accounts for 5 of 9 million new cases of TB2
MDR-TB rates higher than ever (up to 223) particularly in former Soviet Union countries
XDR-TB reported by as many as 49 countries (by June 2008)3
Recent WHOIUATLD Global Surveillance report indicated 75 (3014012) of MDR TB to be XDR4
Around 40000 XDR-TB cases emerge every year1
1Tuberculosis MDR-TB amp XDR-TBmdashThe 2008 Report The Stop TB Department WHO2Hargreaves S httpinfectionthelancetcom Vol 8 April 2008 p2203Raviglione MC NEJM 2008359636-84Anti-TB Drug Resistance in the World Report No 4 The WHOIUATLD Global Project on Anti-Tuberculosis Drug Resistance Surveillance 2002-2007 World Health Organization 2008 (WHOHTMTB2008394)
DrTVRao MD 29
MDR-TB amp XDR-TBTHE 2008 REPORT
of MDR-TB among new TB cases 1994-2007
DrTVRao MD 30
MDR-TB rates higher than ever (up to 223) particularly in former Soviet Union countries
DrTVRao MD 31
Alarming Rise of Resistant TB
Resistant TB burden in countries of former Soviet Union about 50 of cases resistant to at least one drug about 20 MDR XDR-TB proportions also higher (as high as 24 in
Estonia)1
MDRXDR TB ndash essentially a man-made problem2
High numbers of resistant cases (gt400000 MDR-TB cases every year) due mainly to Underinvestment in basic TB control Poor management of anti-TB drugs Transmission of drug resistant strains1
1Anti-TB Drug Resistance in the World Report No 4 The WHOIUATLD Global Project on Anti-Tuberculosis Drug Resistance Surveillance 2002-2007 World Health Organization 2008 (WHOHTMTB2008394)
2Reichman The Lancet 20083711052-3
DrTVRao MD 32
The Much Discussed Article on XDR TB in the Lancet
Of the 221 multi-drug resistant (MDR-TB) cases 53 (24) were XDR
Almost all (52 of 53) of the XDR-TB patients died with a median survival of only 16 days from the time of diagnosis (in the 42 patients with confirmed dates of death)
All the 44 XDR TB patients who were tested for HIV were found co-infected
55 patents had never received anti-TB drugs suggesting primary transmission of XDR pathogen
67 patients had been admitted to the hospital in the preceding 2 years suggesting potential role of nosocomial transmission
Gandhi et al Lancet 20063681575-80DrTVRao MD 33
Poor mangement of infected lead to grwoing resistance
Resistance to anti-TB drugs in populations is a phenomenon that occurs primarily due to poorly managed TB care Problems include incorrect drug prescribing practices by providers poor quality drugs or erratic supply of drugs and also patient non-adherence DrTVRao MD 34
Susceptibility Testing
1048708 Direct and indirect testing1048708 Primary Drugs testing1048708 Isoniazid1048708 Rifampicin1048708 Ethambutol ()1048708 Pyrizinamide ()
DrTVRao MD 35
Drug susceptibility testing (DST)
DST is recommended for all new cases for all first line drugs with specimens taken before initiating treatment
Accuracy is more important than speed DST results should come from a small
number of well-equipped experienced laboratories who participate and perform well in an international DST quality control scheme
The WHO Supranational Laboratory Quality Control Network offers the greatest global coverage for this
DrTVRao MD 36
Drug susceptibility Testing
Assessment of growth inhibition on solid media containing various dilutions of the drug in comparison with the test strains
As the method depend observation of growth Results are not available until several weeks after isolation of the organism
DrTVRao MD 37
Other accredited Methods
Radiometric and Non radiometric methods
Nucleic acid technology ndash effective upto 95 in mutations to rifampicin resistance to gene rpoB gene
DrTVRao MD 38
Drug susceptibility testing (DST)
As a minimum laboratories supplying DST data should correctly identify resistance to isoniazid and rifampicin in over 90 of quality control samples in two out of the last three quality control roundsDrTVRao MD 39
Detection of Rifampicin Drug susceptibility testing (DST) is more important
Early identification of mycobacterial growth as M tuberculosis complex and the identification of rifampicin resistance should be the first priority as rifampicin resistance invalidates standard 6 month short-course chemotherapy and is a useful marker in most countries for MDR-TB
Laboratories should aim to identify isolates as M tuberculosis complex and perform rifampicin resistance in 90 of isolates within 1-2 working days This is technologically feasible
DrTVRao MD 40
Drug susceptibility testing
For DST laboratories modern molecular techniques permit the successful identification of isoniazid resistance in at least 75 of mycobacterial cultures within 1-2 working days and are useful preliminary screens for isoniazid resistance
DrTVRao MD 41
Secondary Drugs testing [lack of standardized
methods]
Ofloxacin quinolonesEthionamide KanamycinCapreomycin Ensure quality control and
quality assurance
DrTVRao MD 42
WHO Controls the Tuberculosis related work
The laboratory methods for anti-tuberculosis drug susceptibility testing should be selected from among those that are WHO-recommended and all laboratory processes should be quality-assured in cooperation with a partner Supranational Reference Laboratory (SRL)DrTVRao MD 43
Other WHO-Endorsed Tools
Liquid culture (eg MGIT BacTALERT)
Capilia TB Rapid strip test that detects a TB-
specific antigen from culture
Molecular line probe assays (eg GenoType MTBDRplus INNO-LiPA RifTB) Strip test for detection of TB and
drug-resistance conferring mutations
DrTVRao MD 44
BacTALERTreg
DrTVRao MD 45
CDC Updates Guidelines for Nucleic AcidAmplification Techniques to Diagnose
Tuberculosis
NAAT results should be interpreted in conjunction with the AFB smear results
NAAT and smear positive start Rx despite pending culture results PPV 95
Smear negative NAAT positive use clinical judgment to either treat or await culture
DrTVRao MD 46
Selection from automated systems for molecular and
bacteriological rapid diagnostics
PCRRocheCOBASreg Amplicorreg
amplification kitsRocheCOBASreg LightCyclerreg
(real-time-PCR)RocheCOBASreg TaqMan 48reg(increases the specificity of real-
time-PCR)
DrTVRao MD 47
Molecular Fingerprinting
26 of 30 (87) XDR TB isolates found to be genetically similar
Majority of patients had no previous history of TB treatment Suggestive of recent infection with drug-resistant strain
DrTVRao MD 48
Is PCR methods a solution
PCR cant yet replace neither microscopy culturing and competent clinical examination
DrTVRao MD 49
No testing method replaces Clinical assessment
DrTVRao MD 50
XDR-TBThe description
of XDR-TB was first used earlier in 2006 following a joint survey by WHO and the US Centres for Disease Control and Prevention (CDC) DrTVRao MD 51
How x-MDR generated
Acquired resistance is that which occurs as a result of specific previous treatment The level of primary resistance in the community is considered to reflect the efficacy of control measures in the past while the level of acquired resistance is a measure of on-going TB control measuresDrTVRao MD 52
Extreme Drug resistant Tuberculosis (XDR-TB)
Resistant to all first line drugs namely Isoniazid and Rifampin and Three or more second line drugs (SLDrsquoS) that are used to treat MDR-TB Thequinalones like Ofloaxin
Or Aminoglycosides like Capreomycin amp
Kanamycin
No third-line drugs available to treat XDR-TB since none has been developed in the last 40 years
DrTVRao MD 53
Background Extensively drug-resistant tuberculosis
Extensively drug-resistant tuberculosis has been reported in 45 countries including countries with limited resources and a high burden of tuberculosis
DrTVRao MD 54
DrTVRao MD 55
Transmissionof X -MDR
Like other forms of TB XDR-TB is spread through the air When a person with infectious TB coughs sneezes talks or spits they propel Mycobacterium into the air
DrTVRao MD 56
Best options to diagnoseX-MDR tuberculosis
To evaluate drug susceptibility the bacteria need to be cultivated and tested in a suitable laboratory Final diagnosis in this way for TB and especially for XDR-TB may take from 6 to 16 weeks To reduce the time needed for diagnosis new tools for rapid TB diagnosis are urgently needed
DrTVRao MD 57
When to suspect MDR TB
Patients not showing any reduction
in bacillary population after 3-
months of regular treatment with
Cat II regimen
Sputum positive patients who are
contacts of a known MDR TB
patient
DrTVRao MD 58
How to evaluate MDR TB
MDR TB is only a laboratory
proved HR resistance
Clinical suspicion should be
followed by lab Confirmation
Laboratories should be quality
controlledTRC
DrTVRao MD 59
Extreme Drug resistant Tuberculosis (XDR-TB) and AIDS
It can also be contracted without a patient receiving any previous treatment for TB
Mostly associated with HIV positive patients
HIV has the potential to fast tracking XDR-TB into an uncontrollable epidemic
Average survival period for patients infected with XDR-TB is 16 days
DrTVRao MD 60
Responding to MDRXDR-TB
Augment DOTS Program by
New diagnostics
New drugs New vaccines HIV incidence
reduction Advocacy1
A mathematical model projected by Basu and co-workers indicates that half of XDR-TB can be averted by 2012 by bringing synergistic effects through
Use of masks Reduced time as in-patient Improved ventilation Rapid resistance testing HIV treatment TB isolation facilities2
1Marteens and Wilkinson Lancet 20073702030-432Basu et al Quoted in Porco and Getz Lancet 20073701464-5
DrTVRao MD 61
Second Line Drug Treatment (SLDrsquos)
Less effective more costly and more toxic 50 cure rate
Four months intensive phase (5 drugs) Kanamycins Ethionamide Pyrazinamide Ofloxacin Cycloserine or Ethambutol DrTVRao MD 62
World Health Organisation (WHO) Guidelines for treatment
of MDR-TB
Strengthen basic TB care to prevent the emergence of drug-resistance
Ensure prompt diagnosis and treatment of drug resistant cases to cure existing cases and prevent further transmission
Increase collaboration between HIV and TB control programmes to provide necessary prevention and care to co-infected patients
Increase investment in laboratory infrastructures to enable better detection and management of resistant cases
DrTVRao MD 63
Treatment Guidelines
Sensitivity testing for all smear positive specimens
Patient Family and staff counselling amp education
Correct and thorough hand washing protocol and procedure
Personal protection is very important
DrTVRao MD 64
THE NEW MDR-TB Guidelines
A flexible framework approach combining both clinical and programmatic aspects of DOTS Plus based on essential programme conditions
But encouraging programs to tailor their case-finding and treatment strategies to the local epidemiological and Programme situation
Reflect GLC expert consensus and evidence and experience from GLC projects thus far
DrTVRao MD 65
Effective laboratory Diagnosis
Sputum smear examinations ndash rapid classification of species (atypical mycobacteria common in AIDS)
Culture examinations
Rapid drug sensitivity testingDrTVRao MD 66
MDR TB and HIV
MDR TB occurs with the same frequency in HIV
patients as in TB patients who are smear negative
Transmission of drug-resistant strains among HIV-
infected patients in congregate settings occurs
leading to lsquooutbreaksrsquo of MDR TB in such settings
Infection control measures absolutely essential in
settings where large number of HIV TB patients stay
togetherDrTVRao MD 67
Transmission is dependent on closeness and time of contact
In penitentiary care contacts are very close and prolonged ndash culture positive cases can also transmit TB especially to HIV positive population
DrTVRao MD 68
To Know more on MDR ndashTB Current Guidelines of WHO
Guidelines for the programmatic management of drug-resistant tuberculosis - 2011 update [pdf 904kb]
Visit helliphelliphellip WHOHTMTB20116DrTVRao MD 69
Are there any solutions for effective
Diagnosis in TB
DrTVRao MD 70
Programme Created by DrTVRao MD for Medical and Health Care
Workers in the Developing World Email
doctortvraogmailcom
DrTVRao MD 71
Diagnostic discoveries
24th March 1882 (Robert Koch) TB Day Discovery of staining
technique that identified Tuberculosis bacillus
Definite diagnosis made possible 1890 (Robert Koch)
Tuberculin discovered Diagnostic use when
injected into skin 1895 (Roentgen)
Discovery of X-rays Early diagnosis of
pulmonary disease
DrTVRao MD 5
From Tuberculosis to Tuberculin
Failure of Robert Koch Tuberculin therapy
did in fact work in Kochs laboratory even though it failed to do so almost anywhere else his reliance an animal experiments which essentially differed from what many of his contemporaries many differed with his ideas
DrTVRao MD 6
Global Status
Nine million people suffer from tuberculosis
Two million people die each year
Tuberculosis accounts for one-third of AIDS deaths world wide every year
DrTVRao MD 7
USAID Report on Tuberculosis in India
India has more new tuberculosis (TB) cases annually than any other country ranking first among the 22 high-burden TB countries worldwide according to the World Health Organizationrsquos (WHOrsquos) Global TB Report 2009 TB remains one of the leading infectious causes of mortality in India causing more than 331000 deaths in 2007 There were approximately 196 million new TB cases in India in 2007 representing more than 21 per cent of all TB cases worldwide
DrTVRao MD 8
1908-1920 (Chalmette and Guerin) Vaccine (BCG)
Attenuated strain Mycobacterium Bovis
1943 Streptomycin developed
20th November 1944 Critically ill TB patient injected
dramatically recovered
Pharmacological discoveries
DrTVRao MD 9
Selman Abraham Waksman Nobel Prize for his discovery in
1952
DrTVRao MD 10
Pharmacological discoveries
1956-1960 Combination therapy of INH and PZA
cures TB1955 Cycloserine1962 Ethambutol 1963 Rifampicin1970-1977
Combination of Rifampicin and Isoniazid adopted as International regime for treatment of TB DrTVRao MD 11
No one is Immune to TuberculosisNot only infects poor but famous
too
DrTVRao MD 12
Multi Drug Resistant
TuberculosisMDR-TB
DrTVRao MD 13
Definition
MDR-TB caused by strains of Mycobacterium Tuberculosis resistant both Rifampicin and Isoniazid with or without resistance to other drugs
Single Isoniazid or Rifampicin resistance is not MDR - TB
MDR TB is a laboratory diagnosis
DrTVRao MD 14
Classification of Drugs 3 Groups depending upon the degree
of effectiveness and potential side effects First Line (Primary agents)
are the most effective and have lowest toxicity Isoniazid Rifampin
Second LineLess effective and more toxic effectsinclude (in no particular order) p-amino
salicylic acid Streptomycin Ethambutol Third Line
are least effective and most toxic Amikacin Kanamycin Capreomycin Viomycin Kanamycin Cycloserine
DrTVRao MD 15
Basic concepts ndash Keep facts
Primary (Initial) resistanceTB patientrsquos initial Mycobacterium
tuberculosis population resistant to drugs
Secondary (Acquired) resistanceDrug-resistant M tuberculosis in initial
population selected by inappropriate drug use (inadequate treatment or non-adherence) DrTVRao MD 16
When to suspect MDR TB
Re-treatment patients whorsquos sputum smear remains positive after three monthsrsquo of intensive therapy
Treatment failure and interruption cases
Close contacts of MDR tuberculosis cases
Positive diagnoses with TB culture and susceptibility testing DrTVRao MD 17
What is extensively drug resistant tuberculosis (XDR TB)
Extensively drug resistant TB (XDR TB) is a relatively rare type of MDR TB XDR TB is defined as TB which is resistant to isoniazid and rifampin plus resistant to any fluoroquinolone and at least one of three injectable second-line drugs (ie amikacin kanamycin or capreomycin)DrTVRao MD 18
Why XDR - TB a grave concern
Because XDR TB is resistant to first-line and second line drugs patients are left with treatment options that are much less effective
XDR TB is of special concern for persons with HIV infection or other conditions that can weaken the immune system These persons are more likely to develop TB disease once they are infected and also have a higher risk of death once they develop TB
DrTVRao MD 19
Global Estimates
Classification
Estimated Number of Cases
Estimated Number of
Deaths
All forms TB
88 million 16 million
MDR TB 424000 116000
XDR TB 27000 16000
DrTVRao MD 20
Extensively Drug-Resistant Mycobacterium tuberculosis
India
The first XDR TB cases in India and the emergence of XDR TB is reported by Rajesh Mondal and Amita Jain King Georges Medical University Lucknow India Volume 13 Number 9ndashSeptember 2007 in Emerging Infectious Diseases
DrTVRao MD 21
Drug susceptible TBsect
MDR-TB
1990sect
XDR-TB
2006sect
Total DR
Resistance to HampR ndash
Treatable with 2nd line drugs
Resistance to 2nd line drugs ndashTreatment options seriously restricted
Resistance to all available drugs ndash
No treatment options
or limited resistance manageable with 4 drug regimen - DOTS
Are we Returning to a Pre-antibiotic Era
DrTVRao MD 22
Genesis of MDR TB
Resistance is a man-made amplification of a natural phenomenon
Inadequate drug delivery is main cause of secondary drug resistance
Secondary drug resistance is the main cause of primary drug resistance due to transmission of resistant strains
MDR due to spontaneous mutations is not possible as the genes encoding resistance for anti TB are unlinked
DrTVRao MD 23
Factors Contributing to Development
and Spread of MDR and XDR TB Weak TB programs (DOTS)
Low completioncure rates Lack of treatment follow up and
patient support Unreliable drug supply Diagnostic delay
Absent or inadequate infection control measures
Uncontrolled use of 2nd line drugs Fluroquinolones
DrTVRao MD 24
INHChromosomally mediatedLoss of catalaseperoxidaseMutation in mycolic acid synthesis
Regulators of peroxide response
Mechanism of resistance
DrTVRao MD 25
RifampinReduced binding to RNA polymeraseClusters of mutations at ldquoRifampin Resistance Determining Regionrdquo (RRDR)
Reduced Cell wall permeability
Mechanism of resistance
DrTVRao MD 26
Gene location associated Drug-Resistant
Mtuberculosis Drug Gene Isoniazid Kat G Inh A Kas
A Rifampicin rpo B Ethambutol emb B Streptomycin rps L Pyrazinamide pnc A Fluoroquinolones gyr A
Dubaniewicz A et al Molecular sub-type of the HLA-DR antigens in pulmonary tuberculosis Int J Infect Dis20004129-33
DrTVRao MD 27
Current Scientific Documentations on Drug Resistance in
Tuberculosis
DrTVRao MD 28
Alarming Rise of Resistant TuberculosisWHO Report on
Anti-TB Drug Resistance
490000 new cases of MDR-TB each year with gt110000 deaths1
Accounts for 5 of 9 million new cases of TB2
MDR-TB rates higher than ever (up to 223) particularly in former Soviet Union countries
XDR-TB reported by as many as 49 countries (by June 2008)3
Recent WHOIUATLD Global Surveillance report indicated 75 (3014012) of MDR TB to be XDR4
Around 40000 XDR-TB cases emerge every year1
1Tuberculosis MDR-TB amp XDR-TBmdashThe 2008 Report The Stop TB Department WHO2Hargreaves S httpinfectionthelancetcom Vol 8 April 2008 p2203Raviglione MC NEJM 2008359636-84Anti-TB Drug Resistance in the World Report No 4 The WHOIUATLD Global Project on Anti-Tuberculosis Drug Resistance Surveillance 2002-2007 World Health Organization 2008 (WHOHTMTB2008394)
DrTVRao MD 29
MDR-TB amp XDR-TBTHE 2008 REPORT
of MDR-TB among new TB cases 1994-2007
DrTVRao MD 30
MDR-TB rates higher than ever (up to 223) particularly in former Soviet Union countries
DrTVRao MD 31
Alarming Rise of Resistant TB
Resistant TB burden in countries of former Soviet Union about 50 of cases resistant to at least one drug about 20 MDR XDR-TB proportions also higher (as high as 24 in
Estonia)1
MDRXDR TB ndash essentially a man-made problem2
High numbers of resistant cases (gt400000 MDR-TB cases every year) due mainly to Underinvestment in basic TB control Poor management of anti-TB drugs Transmission of drug resistant strains1
1Anti-TB Drug Resistance in the World Report No 4 The WHOIUATLD Global Project on Anti-Tuberculosis Drug Resistance Surveillance 2002-2007 World Health Organization 2008 (WHOHTMTB2008394)
2Reichman The Lancet 20083711052-3
DrTVRao MD 32
The Much Discussed Article on XDR TB in the Lancet
Of the 221 multi-drug resistant (MDR-TB) cases 53 (24) were XDR
Almost all (52 of 53) of the XDR-TB patients died with a median survival of only 16 days from the time of diagnosis (in the 42 patients with confirmed dates of death)
All the 44 XDR TB patients who were tested for HIV were found co-infected
55 patents had never received anti-TB drugs suggesting primary transmission of XDR pathogen
67 patients had been admitted to the hospital in the preceding 2 years suggesting potential role of nosocomial transmission
Gandhi et al Lancet 20063681575-80DrTVRao MD 33
Poor mangement of infected lead to grwoing resistance
Resistance to anti-TB drugs in populations is a phenomenon that occurs primarily due to poorly managed TB care Problems include incorrect drug prescribing practices by providers poor quality drugs or erratic supply of drugs and also patient non-adherence DrTVRao MD 34
Susceptibility Testing
1048708 Direct and indirect testing1048708 Primary Drugs testing1048708 Isoniazid1048708 Rifampicin1048708 Ethambutol ()1048708 Pyrizinamide ()
DrTVRao MD 35
Drug susceptibility testing (DST)
DST is recommended for all new cases for all first line drugs with specimens taken before initiating treatment
Accuracy is more important than speed DST results should come from a small
number of well-equipped experienced laboratories who participate and perform well in an international DST quality control scheme
The WHO Supranational Laboratory Quality Control Network offers the greatest global coverage for this
DrTVRao MD 36
Drug susceptibility Testing
Assessment of growth inhibition on solid media containing various dilutions of the drug in comparison with the test strains
As the method depend observation of growth Results are not available until several weeks after isolation of the organism
DrTVRao MD 37
Other accredited Methods
Radiometric and Non radiometric methods
Nucleic acid technology ndash effective upto 95 in mutations to rifampicin resistance to gene rpoB gene
DrTVRao MD 38
Drug susceptibility testing (DST)
As a minimum laboratories supplying DST data should correctly identify resistance to isoniazid and rifampicin in over 90 of quality control samples in two out of the last three quality control roundsDrTVRao MD 39
Detection of Rifampicin Drug susceptibility testing (DST) is more important
Early identification of mycobacterial growth as M tuberculosis complex and the identification of rifampicin resistance should be the first priority as rifampicin resistance invalidates standard 6 month short-course chemotherapy and is a useful marker in most countries for MDR-TB
Laboratories should aim to identify isolates as M tuberculosis complex and perform rifampicin resistance in 90 of isolates within 1-2 working days This is technologically feasible
DrTVRao MD 40
Drug susceptibility testing
For DST laboratories modern molecular techniques permit the successful identification of isoniazid resistance in at least 75 of mycobacterial cultures within 1-2 working days and are useful preliminary screens for isoniazid resistance
DrTVRao MD 41
Secondary Drugs testing [lack of standardized
methods]
Ofloxacin quinolonesEthionamide KanamycinCapreomycin Ensure quality control and
quality assurance
DrTVRao MD 42
WHO Controls the Tuberculosis related work
The laboratory methods for anti-tuberculosis drug susceptibility testing should be selected from among those that are WHO-recommended and all laboratory processes should be quality-assured in cooperation with a partner Supranational Reference Laboratory (SRL)DrTVRao MD 43
Other WHO-Endorsed Tools
Liquid culture (eg MGIT BacTALERT)
Capilia TB Rapid strip test that detects a TB-
specific antigen from culture
Molecular line probe assays (eg GenoType MTBDRplus INNO-LiPA RifTB) Strip test for detection of TB and
drug-resistance conferring mutations
DrTVRao MD 44
BacTALERTreg
DrTVRao MD 45
CDC Updates Guidelines for Nucleic AcidAmplification Techniques to Diagnose
Tuberculosis
NAAT results should be interpreted in conjunction with the AFB smear results
NAAT and smear positive start Rx despite pending culture results PPV 95
Smear negative NAAT positive use clinical judgment to either treat or await culture
DrTVRao MD 46
Selection from automated systems for molecular and
bacteriological rapid diagnostics
PCRRocheCOBASreg Amplicorreg
amplification kitsRocheCOBASreg LightCyclerreg
(real-time-PCR)RocheCOBASreg TaqMan 48reg(increases the specificity of real-
time-PCR)
DrTVRao MD 47
Molecular Fingerprinting
26 of 30 (87) XDR TB isolates found to be genetically similar
Majority of patients had no previous history of TB treatment Suggestive of recent infection with drug-resistant strain
DrTVRao MD 48
Is PCR methods a solution
PCR cant yet replace neither microscopy culturing and competent clinical examination
DrTVRao MD 49
No testing method replaces Clinical assessment
DrTVRao MD 50
XDR-TBThe description
of XDR-TB was first used earlier in 2006 following a joint survey by WHO and the US Centres for Disease Control and Prevention (CDC) DrTVRao MD 51
How x-MDR generated
Acquired resistance is that which occurs as a result of specific previous treatment The level of primary resistance in the community is considered to reflect the efficacy of control measures in the past while the level of acquired resistance is a measure of on-going TB control measuresDrTVRao MD 52
Extreme Drug resistant Tuberculosis (XDR-TB)
Resistant to all first line drugs namely Isoniazid and Rifampin and Three or more second line drugs (SLDrsquoS) that are used to treat MDR-TB Thequinalones like Ofloaxin
Or Aminoglycosides like Capreomycin amp
Kanamycin
No third-line drugs available to treat XDR-TB since none has been developed in the last 40 years
DrTVRao MD 53
Background Extensively drug-resistant tuberculosis
Extensively drug-resistant tuberculosis has been reported in 45 countries including countries with limited resources and a high burden of tuberculosis
DrTVRao MD 54
DrTVRao MD 55
Transmissionof X -MDR
Like other forms of TB XDR-TB is spread through the air When a person with infectious TB coughs sneezes talks or spits they propel Mycobacterium into the air
DrTVRao MD 56
Best options to diagnoseX-MDR tuberculosis
To evaluate drug susceptibility the bacteria need to be cultivated and tested in a suitable laboratory Final diagnosis in this way for TB and especially for XDR-TB may take from 6 to 16 weeks To reduce the time needed for diagnosis new tools for rapid TB diagnosis are urgently needed
DrTVRao MD 57
When to suspect MDR TB
Patients not showing any reduction
in bacillary population after 3-
months of regular treatment with
Cat II regimen
Sputum positive patients who are
contacts of a known MDR TB
patient
DrTVRao MD 58
How to evaluate MDR TB
MDR TB is only a laboratory
proved HR resistance
Clinical suspicion should be
followed by lab Confirmation
Laboratories should be quality
controlledTRC
DrTVRao MD 59
Extreme Drug resistant Tuberculosis (XDR-TB) and AIDS
It can also be contracted without a patient receiving any previous treatment for TB
Mostly associated with HIV positive patients
HIV has the potential to fast tracking XDR-TB into an uncontrollable epidemic
Average survival period for patients infected with XDR-TB is 16 days
DrTVRao MD 60
Responding to MDRXDR-TB
Augment DOTS Program by
New diagnostics
New drugs New vaccines HIV incidence
reduction Advocacy1
A mathematical model projected by Basu and co-workers indicates that half of XDR-TB can be averted by 2012 by bringing synergistic effects through
Use of masks Reduced time as in-patient Improved ventilation Rapid resistance testing HIV treatment TB isolation facilities2
1Marteens and Wilkinson Lancet 20073702030-432Basu et al Quoted in Porco and Getz Lancet 20073701464-5
DrTVRao MD 61
Second Line Drug Treatment (SLDrsquos)
Less effective more costly and more toxic 50 cure rate
Four months intensive phase (5 drugs) Kanamycins Ethionamide Pyrazinamide Ofloxacin Cycloserine or Ethambutol DrTVRao MD 62
World Health Organisation (WHO) Guidelines for treatment
of MDR-TB
Strengthen basic TB care to prevent the emergence of drug-resistance
Ensure prompt diagnosis and treatment of drug resistant cases to cure existing cases and prevent further transmission
Increase collaboration between HIV and TB control programmes to provide necessary prevention and care to co-infected patients
Increase investment in laboratory infrastructures to enable better detection and management of resistant cases
DrTVRao MD 63
Treatment Guidelines
Sensitivity testing for all smear positive specimens
Patient Family and staff counselling amp education
Correct and thorough hand washing protocol and procedure
Personal protection is very important
DrTVRao MD 64
THE NEW MDR-TB Guidelines
A flexible framework approach combining both clinical and programmatic aspects of DOTS Plus based on essential programme conditions
But encouraging programs to tailor their case-finding and treatment strategies to the local epidemiological and Programme situation
Reflect GLC expert consensus and evidence and experience from GLC projects thus far
DrTVRao MD 65
Effective laboratory Diagnosis
Sputum smear examinations ndash rapid classification of species (atypical mycobacteria common in AIDS)
Culture examinations
Rapid drug sensitivity testingDrTVRao MD 66
MDR TB and HIV
MDR TB occurs with the same frequency in HIV
patients as in TB patients who are smear negative
Transmission of drug-resistant strains among HIV-
infected patients in congregate settings occurs
leading to lsquooutbreaksrsquo of MDR TB in such settings
Infection control measures absolutely essential in
settings where large number of HIV TB patients stay
togetherDrTVRao MD 67
Transmission is dependent on closeness and time of contact
In penitentiary care contacts are very close and prolonged ndash culture positive cases can also transmit TB especially to HIV positive population
DrTVRao MD 68
To Know more on MDR ndashTB Current Guidelines of WHO
Guidelines for the programmatic management of drug-resistant tuberculosis - 2011 update [pdf 904kb]
Visit helliphelliphellip WHOHTMTB20116DrTVRao MD 69
Are there any solutions for effective
Diagnosis in TB
DrTVRao MD 70
Programme Created by DrTVRao MD for Medical and Health Care
Workers in the Developing World Email
doctortvraogmailcom
DrTVRao MD 71
From Tuberculosis to Tuberculin
Failure of Robert Koch Tuberculin therapy
did in fact work in Kochs laboratory even though it failed to do so almost anywhere else his reliance an animal experiments which essentially differed from what many of his contemporaries many differed with his ideas
DrTVRao MD 6
Global Status
Nine million people suffer from tuberculosis
Two million people die each year
Tuberculosis accounts for one-third of AIDS deaths world wide every year
DrTVRao MD 7
USAID Report on Tuberculosis in India
India has more new tuberculosis (TB) cases annually than any other country ranking first among the 22 high-burden TB countries worldwide according to the World Health Organizationrsquos (WHOrsquos) Global TB Report 2009 TB remains one of the leading infectious causes of mortality in India causing more than 331000 deaths in 2007 There were approximately 196 million new TB cases in India in 2007 representing more than 21 per cent of all TB cases worldwide
DrTVRao MD 8
1908-1920 (Chalmette and Guerin) Vaccine (BCG)
Attenuated strain Mycobacterium Bovis
1943 Streptomycin developed
20th November 1944 Critically ill TB patient injected
dramatically recovered
Pharmacological discoveries
DrTVRao MD 9
Selman Abraham Waksman Nobel Prize for his discovery in
1952
DrTVRao MD 10
Pharmacological discoveries
1956-1960 Combination therapy of INH and PZA
cures TB1955 Cycloserine1962 Ethambutol 1963 Rifampicin1970-1977
Combination of Rifampicin and Isoniazid adopted as International regime for treatment of TB DrTVRao MD 11
No one is Immune to TuberculosisNot only infects poor but famous
too
DrTVRao MD 12
Multi Drug Resistant
TuberculosisMDR-TB
DrTVRao MD 13
Definition
MDR-TB caused by strains of Mycobacterium Tuberculosis resistant both Rifampicin and Isoniazid with or without resistance to other drugs
Single Isoniazid or Rifampicin resistance is not MDR - TB
MDR TB is a laboratory diagnosis
DrTVRao MD 14
Classification of Drugs 3 Groups depending upon the degree
of effectiveness and potential side effects First Line (Primary agents)
are the most effective and have lowest toxicity Isoniazid Rifampin
Second LineLess effective and more toxic effectsinclude (in no particular order) p-amino
salicylic acid Streptomycin Ethambutol Third Line
are least effective and most toxic Amikacin Kanamycin Capreomycin Viomycin Kanamycin Cycloserine
DrTVRao MD 15
Basic concepts ndash Keep facts
Primary (Initial) resistanceTB patientrsquos initial Mycobacterium
tuberculosis population resistant to drugs
Secondary (Acquired) resistanceDrug-resistant M tuberculosis in initial
population selected by inappropriate drug use (inadequate treatment or non-adherence) DrTVRao MD 16
When to suspect MDR TB
Re-treatment patients whorsquos sputum smear remains positive after three monthsrsquo of intensive therapy
Treatment failure and interruption cases
Close contacts of MDR tuberculosis cases
Positive diagnoses with TB culture and susceptibility testing DrTVRao MD 17
What is extensively drug resistant tuberculosis (XDR TB)
Extensively drug resistant TB (XDR TB) is a relatively rare type of MDR TB XDR TB is defined as TB which is resistant to isoniazid and rifampin plus resistant to any fluoroquinolone and at least one of three injectable second-line drugs (ie amikacin kanamycin or capreomycin)DrTVRao MD 18
Why XDR - TB a grave concern
Because XDR TB is resistant to first-line and second line drugs patients are left with treatment options that are much less effective
XDR TB is of special concern for persons with HIV infection or other conditions that can weaken the immune system These persons are more likely to develop TB disease once they are infected and also have a higher risk of death once they develop TB
DrTVRao MD 19
Global Estimates
Classification
Estimated Number of Cases
Estimated Number of
Deaths
All forms TB
88 million 16 million
MDR TB 424000 116000
XDR TB 27000 16000
DrTVRao MD 20
Extensively Drug-Resistant Mycobacterium tuberculosis
India
The first XDR TB cases in India and the emergence of XDR TB is reported by Rajesh Mondal and Amita Jain King Georges Medical University Lucknow India Volume 13 Number 9ndashSeptember 2007 in Emerging Infectious Diseases
DrTVRao MD 21
Drug susceptible TBsect
MDR-TB
1990sect
XDR-TB
2006sect
Total DR
Resistance to HampR ndash
Treatable with 2nd line drugs
Resistance to 2nd line drugs ndashTreatment options seriously restricted
Resistance to all available drugs ndash
No treatment options
or limited resistance manageable with 4 drug regimen - DOTS
Are we Returning to a Pre-antibiotic Era
DrTVRao MD 22
Genesis of MDR TB
Resistance is a man-made amplification of a natural phenomenon
Inadequate drug delivery is main cause of secondary drug resistance
Secondary drug resistance is the main cause of primary drug resistance due to transmission of resistant strains
MDR due to spontaneous mutations is not possible as the genes encoding resistance for anti TB are unlinked
DrTVRao MD 23
Factors Contributing to Development
and Spread of MDR and XDR TB Weak TB programs (DOTS)
Low completioncure rates Lack of treatment follow up and
patient support Unreliable drug supply Diagnostic delay
Absent or inadequate infection control measures
Uncontrolled use of 2nd line drugs Fluroquinolones
DrTVRao MD 24
INHChromosomally mediatedLoss of catalaseperoxidaseMutation in mycolic acid synthesis
Regulators of peroxide response
Mechanism of resistance
DrTVRao MD 25
RifampinReduced binding to RNA polymeraseClusters of mutations at ldquoRifampin Resistance Determining Regionrdquo (RRDR)
Reduced Cell wall permeability
Mechanism of resistance
DrTVRao MD 26
Gene location associated Drug-Resistant
Mtuberculosis Drug Gene Isoniazid Kat G Inh A Kas
A Rifampicin rpo B Ethambutol emb B Streptomycin rps L Pyrazinamide pnc A Fluoroquinolones gyr A
Dubaniewicz A et al Molecular sub-type of the HLA-DR antigens in pulmonary tuberculosis Int J Infect Dis20004129-33
DrTVRao MD 27
Current Scientific Documentations on Drug Resistance in
Tuberculosis
DrTVRao MD 28
Alarming Rise of Resistant TuberculosisWHO Report on
Anti-TB Drug Resistance
490000 new cases of MDR-TB each year with gt110000 deaths1
Accounts for 5 of 9 million new cases of TB2
MDR-TB rates higher than ever (up to 223) particularly in former Soviet Union countries
XDR-TB reported by as many as 49 countries (by June 2008)3
Recent WHOIUATLD Global Surveillance report indicated 75 (3014012) of MDR TB to be XDR4
Around 40000 XDR-TB cases emerge every year1
1Tuberculosis MDR-TB amp XDR-TBmdashThe 2008 Report The Stop TB Department WHO2Hargreaves S httpinfectionthelancetcom Vol 8 April 2008 p2203Raviglione MC NEJM 2008359636-84Anti-TB Drug Resistance in the World Report No 4 The WHOIUATLD Global Project on Anti-Tuberculosis Drug Resistance Surveillance 2002-2007 World Health Organization 2008 (WHOHTMTB2008394)
DrTVRao MD 29
MDR-TB amp XDR-TBTHE 2008 REPORT
of MDR-TB among new TB cases 1994-2007
DrTVRao MD 30
MDR-TB rates higher than ever (up to 223) particularly in former Soviet Union countries
DrTVRao MD 31
Alarming Rise of Resistant TB
Resistant TB burden in countries of former Soviet Union about 50 of cases resistant to at least one drug about 20 MDR XDR-TB proportions also higher (as high as 24 in
Estonia)1
MDRXDR TB ndash essentially a man-made problem2
High numbers of resistant cases (gt400000 MDR-TB cases every year) due mainly to Underinvestment in basic TB control Poor management of anti-TB drugs Transmission of drug resistant strains1
1Anti-TB Drug Resistance in the World Report No 4 The WHOIUATLD Global Project on Anti-Tuberculosis Drug Resistance Surveillance 2002-2007 World Health Organization 2008 (WHOHTMTB2008394)
2Reichman The Lancet 20083711052-3
DrTVRao MD 32
The Much Discussed Article on XDR TB in the Lancet
Of the 221 multi-drug resistant (MDR-TB) cases 53 (24) were XDR
Almost all (52 of 53) of the XDR-TB patients died with a median survival of only 16 days from the time of diagnosis (in the 42 patients with confirmed dates of death)
All the 44 XDR TB patients who were tested for HIV were found co-infected
55 patents had never received anti-TB drugs suggesting primary transmission of XDR pathogen
67 patients had been admitted to the hospital in the preceding 2 years suggesting potential role of nosocomial transmission
Gandhi et al Lancet 20063681575-80DrTVRao MD 33
Poor mangement of infected lead to grwoing resistance
Resistance to anti-TB drugs in populations is a phenomenon that occurs primarily due to poorly managed TB care Problems include incorrect drug prescribing practices by providers poor quality drugs or erratic supply of drugs and also patient non-adherence DrTVRao MD 34
Susceptibility Testing
1048708 Direct and indirect testing1048708 Primary Drugs testing1048708 Isoniazid1048708 Rifampicin1048708 Ethambutol ()1048708 Pyrizinamide ()
DrTVRao MD 35
Drug susceptibility testing (DST)
DST is recommended for all new cases for all first line drugs with specimens taken before initiating treatment
Accuracy is more important than speed DST results should come from a small
number of well-equipped experienced laboratories who participate and perform well in an international DST quality control scheme
The WHO Supranational Laboratory Quality Control Network offers the greatest global coverage for this
DrTVRao MD 36
Drug susceptibility Testing
Assessment of growth inhibition on solid media containing various dilutions of the drug in comparison with the test strains
As the method depend observation of growth Results are not available until several weeks after isolation of the organism
DrTVRao MD 37
Other accredited Methods
Radiometric and Non radiometric methods
Nucleic acid technology ndash effective upto 95 in mutations to rifampicin resistance to gene rpoB gene
DrTVRao MD 38
Drug susceptibility testing (DST)
As a minimum laboratories supplying DST data should correctly identify resistance to isoniazid and rifampicin in over 90 of quality control samples in two out of the last three quality control roundsDrTVRao MD 39
Detection of Rifampicin Drug susceptibility testing (DST) is more important
Early identification of mycobacterial growth as M tuberculosis complex and the identification of rifampicin resistance should be the first priority as rifampicin resistance invalidates standard 6 month short-course chemotherapy and is a useful marker in most countries for MDR-TB
Laboratories should aim to identify isolates as M tuberculosis complex and perform rifampicin resistance in 90 of isolates within 1-2 working days This is technologically feasible
DrTVRao MD 40
Drug susceptibility testing
For DST laboratories modern molecular techniques permit the successful identification of isoniazid resistance in at least 75 of mycobacterial cultures within 1-2 working days and are useful preliminary screens for isoniazid resistance
DrTVRao MD 41
Secondary Drugs testing [lack of standardized
methods]
Ofloxacin quinolonesEthionamide KanamycinCapreomycin Ensure quality control and
quality assurance
DrTVRao MD 42
WHO Controls the Tuberculosis related work
The laboratory methods for anti-tuberculosis drug susceptibility testing should be selected from among those that are WHO-recommended and all laboratory processes should be quality-assured in cooperation with a partner Supranational Reference Laboratory (SRL)DrTVRao MD 43
Other WHO-Endorsed Tools
Liquid culture (eg MGIT BacTALERT)
Capilia TB Rapid strip test that detects a TB-
specific antigen from culture
Molecular line probe assays (eg GenoType MTBDRplus INNO-LiPA RifTB) Strip test for detection of TB and
drug-resistance conferring mutations
DrTVRao MD 44
BacTALERTreg
DrTVRao MD 45
CDC Updates Guidelines for Nucleic AcidAmplification Techniques to Diagnose
Tuberculosis
NAAT results should be interpreted in conjunction with the AFB smear results
NAAT and smear positive start Rx despite pending culture results PPV 95
Smear negative NAAT positive use clinical judgment to either treat or await culture
DrTVRao MD 46
Selection from automated systems for molecular and
bacteriological rapid diagnostics
PCRRocheCOBASreg Amplicorreg
amplification kitsRocheCOBASreg LightCyclerreg
(real-time-PCR)RocheCOBASreg TaqMan 48reg(increases the specificity of real-
time-PCR)
DrTVRao MD 47
Molecular Fingerprinting
26 of 30 (87) XDR TB isolates found to be genetically similar
Majority of patients had no previous history of TB treatment Suggestive of recent infection with drug-resistant strain
DrTVRao MD 48
Is PCR methods a solution
PCR cant yet replace neither microscopy culturing and competent clinical examination
DrTVRao MD 49
No testing method replaces Clinical assessment
DrTVRao MD 50
XDR-TBThe description
of XDR-TB was first used earlier in 2006 following a joint survey by WHO and the US Centres for Disease Control and Prevention (CDC) DrTVRao MD 51
How x-MDR generated
Acquired resistance is that which occurs as a result of specific previous treatment The level of primary resistance in the community is considered to reflect the efficacy of control measures in the past while the level of acquired resistance is a measure of on-going TB control measuresDrTVRao MD 52
Extreme Drug resistant Tuberculosis (XDR-TB)
Resistant to all first line drugs namely Isoniazid and Rifampin and Three or more second line drugs (SLDrsquoS) that are used to treat MDR-TB Thequinalones like Ofloaxin
Or Aminoglycosides like Capreomycin amp
Kanamycin
No third-line drugs available to treat XDR-TB since none has been developed in the last 40 years
DrTVRao MD 53
Background Extensively drug-resistant tuberculosis
Extensively drug-resistant tuberculosis has been reported in 45 countries including countries with limited resources and a high burden of tuberculosis
DrTVRao MD 54
DrTVRao MD 55
Transmissionof X -MDR
Like other forms of TB XDR-TB is spread through the air When a person with infectious TB coughs sneezes talks or spits they propel Mycobacterium into the air
DrTVRao MD 56
Best options to diagnoseX-MDR tuberculosis
To evaluate drug susceptibility the bacteria need to be cultivated and tested in a suitable laboratory Final diagnosis in this way for TB and especially for XDR-TB may take from 6 to 16 weeks To reduce the time needed for diagnosis new tools for rapid TB diagnosis are urgently needed
DrTVRao MD 57
When to suspect MDR TB
Patients not showing any reduction
in bacillary population after 3-
months of regular treatment with
Cat II regimen
Sputum positive patients who are
contacts of a known MDR TB
patient
DrTVRao MD 58
How to evaluate MDR TB
MDR TB is only a laboratory
proved HR resistance
Clinical suspicion should be
followed by lab Confirmation
Laboratories should be quality
controlledTRC
DrTVRao MD 59
Extreme Drug resistant Tuberculosis (XDR-TB) and AIDS
It can also be contracted without a patient receiving any previous treatment for TB
Mostly associated with HIV positive patients
HIV has the potential to fast tracking XDR-TB into an uncontrollable epidemic
Average survival period for patients infected with XDR-TB is 16 days
DrTVRao MD 60
Responding to MDRXDR-TB
Augment DOTS Program by
New diagnostics
New drugs New vaccines HIV incidence
reduction Advocacy1
A mathematical model projected by Basu and co-workers indicates that half of XDR-TB can be averted by 2012 by bringing synergistic effects through
Use of masks Reduced time as in-patient Improved ventilation Rapid resistance testing HIV treatment TB isolation facilities2
1Marteens and Wilkinson Lancet 20073702030-432Basu et al Quoted in Porco and Getz Lancet 20073701464-5
DrTVRao MD 61
Second Line Drug Treatment (SLDrsquos)
Less effective more costly and more toxic 50 cure rate
Four months intensive phase (5 drugs) Kanamycins Ethionamide Pyrazinamide Ofloxacin Cycloserine or Ethambutol DrTVRao MD 62
World Health Organisation (WHO) Guidelines for treatment
of MDR-TB
Strengthen basic TB care to prevent the emergence of drug-resistance
Ensure prompt diagnosis and treatment of drug resistant cases to cure existing cases and prevent further transmission
Increase collaboration between HIV and TB control programmes to provide necessary prevention and care to co-infected patients
Increase investment in laboratory infrastructures to enable better detection and management of resistant cases
DrTVRao MD 63
Treatment Guidelines
Sensitivity testing for all smear positive specimens
Patient Family and staff counselling amp education
Correct and thorough hand washing protocol and procedure
Personal protection is very important
DrTVRao MD 64
THE NEW MDR-TB Guidelines
A flexible framework approach combining both clinical and programmatic aspects of DOTS Plus based on essential programme conditions
But encouraging programs to tailor their case-finding and treatment strategies to the local epidemiological and Programme situation
Reflect GLC expert consensus and evidence and experience from GLC projects thus far
DrTVRao MD 65
Effective laboratory Diagnosis
Sputum smear examinations ndash rapid classification of species (atypical mycobacteria common in AIDS)
Culture examinations
Rapid drug sensitivity testingDrTVRao MD 66
MDR TB and HIV
MDR TB occurs with the same frequency in HIV
patients as in TB patients who are smear negative
Transmission of drug-resistant strains among HIV-
infected patients in congregate settings occurs
leading to lsquooutbreaksrsquo of MDR TB in such settings
Infection control measures absolutely essential in
settings where large number of HIV TB patients stay
togetherDrTVRao MD 67
Transmission is dependent on closeness and time of contact
In penitentiary care contacts are very close and prolonged ndash culture positive cases can also transmit TB especially to HIV positive population
DrTVRao MD 68
To Know more on MDR ndashTB Current Guidelines of WHO
Guidelines for the programmatic management of drug-resistant tuberculosis - 2011 update [pdf 904kb]
Visit helliphelliphellip WHOHTMTB20116DrTVRao MD 69
Are there any solutions for effective
Diagnosis in TB
DrTVRao MD 70
Programme Created by DrTVRao MD for Medical and Health Care
Workers in the Developing World Email
doctortvraogmailcom
DrTVRao MD 71
Global Status
Nine million people suffer from tuberculosis
Two million people die each year
Tuberculosis accounts for one-third of AIDS deaths world wide every year
DrTVRao MD 7
USAID Report on Tuberculosis in India
India has more new tuberculosis (TB) cases annually than any other country ranking first among the 22 high-burden TB countries worldwide according to the World Health Organizationrsquos (WHOrsquos) Global TB Report 2009 TB remains one of the leading infectious causes of mortality in India causing more than 331000 deaths in 2007 There were approximately 196 million new TB cases in India in 2007 representing more than 21 per cent of all TB cases worldwide
DrTVRao MD 8
1908-1920 (Chalmette and Guerin) Vaccine (BCG)
Attenuated strain Mycobacterium Bovis
1943 Streptomycin developed
20th November 1944 Critically ill TB patient injected
dramatically recovered
Pharmacological discoveries
DrTVRao MD 9
Selman Abraham Waksman Nobel Prize for his discovery in
1952
DrTVRao MD 10
Pharmacological discoveries
1956-1960 Combination therapy of INH and PZA
cures TB1955 Cycloserine1962 Ethambutol 1963 Rifampicin1970-1977
Combination of Rifampicin and Isoniazid adopted as International regime for treatment of TB DrTVRao MD 11
No one is Immune to TuberculosisNot only infects poor but famous
too
DrTVRao MD 12
Multi Drug Resistant
TuberculosisMDR-TB
DrTVRao MD 13
Definition
MDR-TB caused by strains of Mycobacterium Tuberculosis resistant both Rifampicin and Isoniazid with or without resistance to other drugs
Single Isoniazid or Rifampicin resistance is not MDR - TB
MDR TB is a laboratory diagnosis
DrTVRao MD 14
Classification of Drugs 3 Groups depending upon the degree
of effectiveness and potential side effects First Line (Primary agents)
are the most effective and have lowest toxicity Isoniazid Rifampin
Second LineLess effective and more toxic effectsinclude (in no particular order) p-amino
salicylic acid Streptomycin Ethambutol Third Line
are least effective and most toxic Amikacin Kanamycin Capreomycin Viomycin Kanamycin Cycloserine
DrTVRao MD 15
Basic concepts ndash Keep facts
Primary (Initial) resistanceTB patientrsquos initial Mycobacterium
tuberculosis population resistant to drugs
Secondary (Acquired) resistanceDrug-resistant M tuberculosis in initial
population selected by inappropriate drug use (inadequate treatment or non-adherence) DrTVRao MD 16
When to suspect MDR TB
Re-treatment patients whorsquos sputum smear remains positive after three monthsrsquo of intensive therapy
Treatment failure and interruption cases
Close contacts of MDR tuberculosis cases
Positive diagnoses with TB culture and susceptibility testing DrTVRao MD 17
What is extensively drug resistant tuberculosis (XDR TB)
Extensively drug resistant TB (XDR TB) is a relatively rare type of MDR TB XDR TB is defined as TB which is resistant to isoniazid and rifampin plus resistant to any fluoroquinolone and at least one of three injectable second-line drugs (ie amikacin kanamycin or capreomycin)DrTVRao MD 18
Why XDR - TB a grave concern
Because XDR TB is resistant to first-line and second line drugs patients are left with treatment options that are much less effective
XDR TB is of special concern for persons with HIV infection or other conditions that can weaken the immune system These persons are more likely to develop TB disease once they are infected and also have a higher risk of death once they develop TB
DrTVRao MD 19
Global Estimates
Classification
Estimated Number of Cases
Estimated Number of
Deaths
All forms TB
88 million 16 million
MDR TB 424000 116000
XDR TB 27000 16000
DrTVRao MD 20
Extensively Drug-Resistant Mycobacterium tuberculosis
India
The first XDR TB cases in India and the emergence of XDR TB is reported by Rajesh Mondal and Amita Jain King Georges Medical University Lucknow India Volume 13 Number 9ndashSeptember 2007 in Emerging Infectious Diseases
DrTVRao MD 21
Drug susceptible TBsect
MDR-TB
1990sect
XDR-TB
2006sect
Total DR
Resistance to HampR ndash
Treatable with 2nd line drugs
Resistance to 2nd line drugs ndashTreatment options seriously restricted
Resistance to all available drugs ndash
No treatment options
or limited resistance manageable with 4 drug regimen - DOTS
Are we Returning to a Pre-antibiotic Era
DrTVRao MD 22
Genesis of MDR TB
Resistance is a man-made amplification of a natural phenomenon
Inadequate drug delivery is main cause of secondary drug resistance
Secondary drug resistance is the main cause of primary drug resistance due to transmission of resistant strains
MDR due to spontaneous mutations is not possible as the genes encoding resistance for anti TB are unlinked
DrTVRao MD 23
Factors Contributing to Development
and Spread of MDR and XDR TB Weak TB programs (DOTS)
Low completioncure rates Lack of treatment follow up and
patient support Unreliable drug supply Diagnostic delay
Absent or inadequate infection control measures
Uncontrolled use of 2nd line drugs Fluroquinolones
DrTVRao MD 24
INHChromosomally mediatedLoss of catalaseperoxidaseMutation in mycolic acid synthesis
Regulators of peroxide response
Mechanism of resistance
DrTVRao MD 25
RifampinReduced binding to RNA polymeraseClusters of mutations at ldquoRifampin Resistance Determining Regionrdquo (RRDR)
Reduced Cell wall permeability
Mechanism of resistance
DrTVRao MD 26
Gene location associated Drug-Resistant
Mtuberculosis Drug Gene Isoniazid Kat G Inh A Kas
A Rifampicin rpo B Ethambutol emb B Streptomycin rps L Pyrazinamide pnc A Fluoroquinolones gyr A
Dubaniewicz A et al Molecular sub-type of the HLA-DR antigens in pulmonary tuberculosis Int J Infect Dis20004129-33
DrTVRao MD 27
Current Scientific Documentations on Drug Resistance in
Tuberculosis
DrTVRao MD 28
Alarming Rise of Resistant TuberculosisWHO Report on
Anti-TB Drug Resistance
490000 new cases of MDR-TB each year with gt110000 deaths1
Accounts for 5 of 9 million new cases of TB2
MDR-TB rates higher than ever (up to 223) particularly in former Soviet Union countries
XDR-TB reported by as many as 49 countries (by June 2008)3
Recent WHOIUATLD Global Surveillance report indicated 75 (3014012) of MDR TB to be XDR4
Around 40000 XDR-TB cases emerge every year1
1Tuberculosis MDR-TB amp XDR-TBmdashThe 2008 Report The Stop TB Department WHO2Hargreaves S httpinfectionthelancetcom Vol 8 April 2008 p2203Raviglione MC NEJM 2008359636-84Anti-TB Drug Resistance in the World Report No 4 The WHOIUATLD Global Project on Anti-Tuberculosis Drug Resistance Surveillance 2002-2007 World Health Organization 2008 (WHOHTMTB2008394)
DrTVRao MD 29
MDR-TB amp XDR-TBTHE 2008 REPORT
of MDR-TB among new TB cases 1994-2007
DrTVRao MD 30
MDR-TB rates higher than ever (up to 223) particularly in former Soviet Union countries
DrTVRao MD 31
Alarming Rise of Resistant TB
Resistant TB burden in countries of former Soviet Union about 50 of cases resistant to at least one drug about 20 MDR XDR-TB proportions also higher (as high as 24 in
Estonia)1
MDRXDR TB ndash essentially a man-made problem2
High numbers of resistant cases (gt400000 MDR-TB cases every year) due mainly to Underinvestment in basic TB control Poor management of anti-TB drugs Transmission of drug resistant strains1
1Anti-TB Drug Resistance in the World Report No 4 The WHOIUATLD Global Project on Anti-Tuberculosis Drug Resistance Surveillance 2002-2007 World Health Organization 2008 (WHOHTMTB2008394)
2Reichman The Lancet 20083711052-3
DrTVRao MD 32
The Much Discussed Article on XDR TB in the Lancet
Of the 221 multi-drug resistant (MDR-TB) cases 53 (24) were XDR
Almost all (52 of 53) of the XDR-TB patients died with a median survival of only 16 days from the time of diagnosis (in the 42 patients with confirmed dates of death)
All the 44 XDR TB patients who were tested for HIV were found co-infected
55 patents had never received anti-TB drugs suggesting primary transmission of XDR pathogen
67 patients had been admitted to the hospital in the preceding 2 years suggesting potential role of nosocomial transmission
Gandhi et al Lancet 20063681575-80DrTVRao MD 33
Poor mangement of infected lead to grwoing resistance
Resistance to anti-TB drugs in populations is a phenomenon that occurs primarily due to poorly managed TB care Problems include incorrect drug prescribing practices by providers poor quality drugs or erratic supply of drugs and also patient non-adherence DrTVRao MD 34
Susceptibility Testing
1048708 Direct and indirect testing1048708 Primary Drugs testing1048708 Isoniazid1048708 Rifampicin1048708 Ethambutol ()1048708 Pyrizinamide ()
DrTVRao MD 35
Drug susceptibility testing (DST)
DST is recommended for all new cases for all first line drugs with specimens taken before initiating treatment
Accuracy is more important than speed DST results should come from a small
number of well-equipped experienced laboratories who participate and perform well in an international DST quality control scheme
The WHO Supranational Laboratory Quality Control Network offers the greatest global coverage for this
DrTVRao MD 36
Drug susceptibility Testing
Assessment of growth inhibition on solid media containing various dilutions of the drug in comparison with the test strains
As the method depend observation of growth Results are not available until several weeks after isolation of the organism
DrTVRao MD 37
Other accredited Methods
Radiometric and Non radiometric methods
Nucleic acid technology ndash effective upto 95 in mutations to rifampicin resistance to gene rpoB gene
DrTVRao MD 38
Drug susceptibility testing (DST)
As a minimum laboratories supplying DST data should correctly identify resistance to isoniazid and rifampicin in over 90 of quality control samples in two out of the last three quality control roundsDrTVRao MD 39
Detection of Rifampicin Drug susceptibility testing (DST) is more important
Early identification of mycobacterial growth as M tuberculosis complex and the identification of rifampicin resistance should be the first priority as rifampicin resistance invalidates standard 6 month short-course chemotherapy and is a useful marker in most countries for MDR-TB
Laboratories should aim to identify isolates as M tuberculosis complex and perform rifampicin resistance in 90 of isolates within 1-2 working days This is technologically feasible
DrTVRao MD 40
Drug susceptibility testing
For DST laboratories modern molecular techniques permit the successful identification of isoniazid resistance in at least 75 of mycobacterial cultures within 1-2 working days and are useful preliminary screens for isoniazid resistance
DrTVRao MD 41
Secondary Drugs testing [lack of standardized
methods]
Ofloxacin quinolonesEthionamide KanamycinCapreomycin Ensure quality control and
quality assurance
DrTVRao MD 42
WHO Controls the Tuberculosis related work
The laboratory methods for anti-tuberculosis drug susceptibility testing should be selected from among those that are WHO-recommended and all laboratory processes should be quality-assured in cooperation with a partner Supranational Reference Laboratory (SRL)DrTVRao MD 43
Other WHO-Endorsed Tools
Liquid culture (eg MGIT BacTALERT)
Capilia TB Rapid strip test that detects a TB-
specific antigen from culture
Molecular line probe assays (eg GenoType MTBDRplus INNO-LiPA RifTB) Strip test for detection of TB and
drug-resistance conferring mutations
DrTVRao MD 44
BacTALERTreg
DrTVRao MD 45
CDC Updates Guidelines for Nucleic AcidAmplification Techniques to Diagnose
Tuberculosis
NAAT results should be interpreted in conjunction with the AFB smear results
NAAT and smear positive start Rx despite pending culture results PPV 95
Smear negative NAAT positive use clinical judgment to either treat or await culture
DrTVRao MD 46
Selection from automated systems for molecular and
bacteriological rapid diagnostics
PCRRocheCOBASreg Amplicorreg
amplification kitsRocheCOBASreg LightCyclerreg
(real-time-PCR)RocheCOBASreg TaqMan 48reg(increases the specificity of real-
time-PCR)
DrTVRao MD 47
Molecular Fingerprinting
26 of 30 (87) XDR TB isolates found to be genetically similar
Majority of patients had no previous history of TB treatment Suggestive of recent infection with drug-resistant strain
DrTVRao MD 48
Is PCR methods a solution
PCR cant yet replace neither microscopy culturing and competent clinical examination
DrTVRao MD 49
No testing method replaces Clinical assessment
DrTVRao MD 50
XDR-TBThe description
of XDR-TB was first used earlier in 2006 following a joint survey by WHO and the US Centres for Disease Control and Prevention (CDC) DrTVRao MD 51
How x-MDR generated
Acquired resistance is that which occurs as a result of specific previous treatment The level of primary resistance in the community is considered to reflect the efficacy of control measures in the past while the level of acquired resistance is a measure of on-going TB control measuresDrTVRao MD 52
Extreme Drug resistant Tuberculosis (XDR-TB)
Resistant to all first line drugs namely Isoniazid and Rifampin and Three or more second line drugs (SLDrsquoS) that are used to treat MDR-TB Thequinalones like Ofloaxin
Or Aminoglycosides like Capreomycin amp
Kanamycin
No third-line drugs available to treat XDR-TB since none has been developed in the last 40 years
DrTVRao MD 53
Background Extensively drug-resistant tuberculosis
Extensively drug-resistant tuberculosis has been reported in 45 countries including countries with limited resources and a high burden of tuberculosis
DrTVRao MD 54
DrTVRao MD 55
Transmissionof X -MDR
Like other forms of TB XDR-TB is spread through the air When a person with infectious TB coughs sneezes talks or spits they propel Mycobacterium into the air
DrTVRao MD 56
Best options to diagnoseX-MDR tuberculosis
To evaluate drug susceptibility the bacteria need to be cultivated and tested in a suitable laboratory Final diagnosis in this way for TB and especially for XDR-TB may take from 6 to 16 weeks To reduce the time needed for diagnosis new tools for rapid TB diagnosis are urgently needed
DrTVRao MD 57
When to suspect MDR TB
Patients not showing any reduction
in bacillary population after 3-
months of regular treatment with
Cat II regimen
Sputum positive patients who are
contacts of a known MDR TB
patient
DrTVRao MD 58
How to evaluate MDR TB
MDR TB is only a laboratory
proved HR resistance
Clinical suspicion should be
followed by lab Confirmation
Laboratories should be quality
controlledTRC
DrTVRao MD 59
Extreme Drug resistant Tuberculosis (XDR-TB) and AIDS
It can also be contracted without a patient receiving any previous treatment for TB
Mostly associated with HIV positive patients
HIV has the potential to fast tracking XDR-TB into an uncontrollable epidemic
Average survival period for patients infected with XDR-TB is 16 days
DrTVRao MD 60
Responding to MDRXDR-TB
Augment DOTS Program by
New diagnostics
New drugs New vaccines HIV incidence
reduction Advocacy1
A mathematical model projected by Basu and co-workers indicates that half of XDR-TB can be averted by 2012 by bringing synergistic effects through
Use of masks Reduced time as in-patient Improved ventilation Rapid resistance testing HIV treatment TB isolation facilities2
1Marteens and Wilkinson Lancet 20073702030-432Basu et al Quoted in Porco and Getz Lancet 20073701464-5
DrTVRao MD 61
Second Line Drug Treatment (SLDrsquos)
Less effective more costly and more toxic 50 cure rate
Four months intensive phase (5 drugs) Kanamycins Ethionamide Pyrazinamide Ofloxacin Cycloserine or Ethambutol DrTVRao MD 62
World Health Organisation (WHO) Guidelines for treatment
of MDR-TB
Strengthen basic TB care to prevent the emergence of drug-resistance
Ensure prompt diagnosis and treatment of drug resistant cases to cure existing cases and prevent further transmission
Increase collaboration between HIV and TB control programmes to provide necessary prevention and care to co-infected patients
Increase investment in laboratory infrastructures to enable better detection and management of resistant cases
DrTVRao MD 63
Treatment Guidelines
Sensitivity testing for all smear positive specimens
Patient Family and staff counselling amp education
Correct and thorough hand washing protocol and procedure
Personal protection is very important
DrTVRao MD 64
THE NEW MDR-TB Guidelines
A flexible framework approach combining both clinical and programmatic aspects of DOTS Plus based on essential programme conditions
But encouraging programs to tailor their case-finding and treatment strategies to the local epidemiological and Programme situation
Reflect GLC expert consensus and evidence and experience from GLC projects thus far
DrTVRao MD 65
Effective laboratory Diagnosis
Sputum smear examinations ndash rapid classification of species (atypical mycobacteria common in AIDS)
Culture examinations
Rapid drug sensitivity testingDrTVRao MD 66
MDR TB and HIV
MDR TB occurs with the same frequency in HIV
patients as in TB patients who are smear negative
Transmission of drug-resistant strains among HIV-
infected patients in congregate settings occurs
leading to lsquooutbreaksrsquo of MDR TB in such settings
Infection control measures absolutely essential in
settings where large number of HIV TB patients stay
togetherDrTVRao MD 67
Transmission is dependent on closeness and time of contact
In penitentiary care contacts are very close and prolonged ndash culture positive cases can also transmit TB especially to HIV positive population
DrTVRao MD 68
To Know more on MDR ndashTB Current Guidelines of WHO
Guidelines for the programmatic management of drug-resistant tuberculosis - 2011 update [pdf 904kb]
Visit helliphelliphellip WHOHTMTB20116DrTVRao MD 69
Are there any solutions for effective
Diagnosis in TB
DrTVRao MD 70
Programme Created by DrTVRao MD for Medical and Health Care
Workers in the Developing World Email
doctortvraogmailcom
DrTVRao MD 71
USAID Report on Tuberculosis in India
India has more new tuberculosis (TB) cases annually than any other country ranking first among the 22 high-burden TB countries worldwide according to the World Health Organizationrsquos (WHOrsquos) Global TB Report 2009 TB remains one of the leading infectious causes of mortality in India causing more than 331000 deaths in 2007 There were approximately 196 million new TB cases in India in 2007 representing more than 21 per cent of all TB cases worldwide
DrTVRao MD 8
1908-1920 (Chalmette and Guerin) Vaccine (BCG)
Attenuated strain Mycobacterium Bovis
1943 Streptomycin developed
20th November 1944 Critically ill TB patient injected
dramatically recovered
Pharmacological discoveries
DrTVRao MD 9
Selman Abraham Waksman Nobel Prize for his discovery in
1952
DrTVRao MD 10
Pharmacological discoveries
1956-1960 Combination therapy of INH and PZA
cures TB1955 Cycloserine1962 Ethambutol 1963 Rifampicin1970-1977
Combination of Rifampicin and Isoniazid adopted as International regime for treatment of TB DrTVRao MD 11
No one is Immune to TuberculosisNot only infects poor but famous
too
DrTVRao MD 12
Multi Drug Resistant
TuberculosisMDR-TB
DrTVRao MD 13
Definition
MDR-TB caused by strains of Mycobacterium Tuberculosis resistant both Rifampicin and Isoniazid with or without resistance to other drugs
Single Isoniazid or Rifampicin resistance is not MDR - TB
MDR TB is a laboratory diagnosis
DrTVRao MD 14
Classification of Drugs 3 Groups depending upon the degree
of effectiveness and potential side effects First Line (Primary agents)
are the most effective and have lowest toxicity Isoniazid Rifampin
Second LineLess effective and more toxic effectsinclude (in no particular order) p-amino
salicylic acid Streptomycin Ethambutol Third Line
are least effective and most toxic Amikacin Kanamycin Capreomycin Viomycin Kanamycin Cycloserine
DrTVRao MD 15
Basic concepts ndash Keep facts
Primary (Initial) resistanceTB patientrsquos initial Mycobacterium
tuberculosis population resistant to drugs
Secondary (Acquired) resistanceDrug-resistant M tuberculosis in initial
population selected by inappropriate drug use (inadequate treatment or non-adherence) DrTVRao MD 16
When to suspect MDR TB
Re-treatment patients whorsquos sputum smear remains positive after three monthsrsquo of intensive therapy
Treatment failure and interruption cases
Close contacts of MDR tuberculosis cases
Positive diagnoses with TB culture and susceptibility testing DrTVRao MD 17
What is extensively drug resistant tuberculosis (XDR TB)
Extensively drug resistant TB (XDR TB) is a relatively rare type of MDR TB XDR TB is defined as TB which is resistant to isoniazid and rifampin plus resistant to any fluoroquinolone and at least one of three injectable second-line drugs (ie amikacin kanamycin or capreomycin)DrTVRao MD 18
Why XDR - TB a grave concern
Because XDR TB is resistant to first-line and second line drugs patients are left with treatment options that are much less effective
XDR TB is of special concern for persons with HIV infection or other conditions that can weaken the immune system These persons are more likely to develop TB disease once they are infected and also have a higher risk of death once they develop TB
DrTVRao MD 19
Global Estimates
Classification
Estimated Number of Cases
Estimated Number of
Deaths
All forms TB
88 million 16 million
MDR TB 424000 116000
XDR TB 27000 16000
DrTVRao MD 20
Extensively Drug-Resistant Mycobacterium tuberculosis
India
The first XDR TB cases in India and the emergence of XDR TB is reported by Rajesh Mondal and Amita Jain King Georges Medical University Lucknow India Volume 13 Number 9ndashSeptember 2007 in Emerging Infectious Diseases
DrTVRao MD 21
Drug susceptible TBsect
MDR-TB
1990sect
XDR-TB
2006sect
Total DR
Resistance to HampR ndash
Treatable with 2nd line drugs
Resistance to 2nd line drugs ndashTreatment options seriously restricted
Resistance to all available drugs ndash
No treatment options
or limited resistance manageable with 4 drug regimen - DOTS
Are we Returning to a Pre-antibiotic Era
DrTVRao MD 22
Genesis of MDR TB
Resistance is a man-made amplification of a natural phenomenon
Inadequate drug delivery is main cause of secondary drug resistance
Secondary drug resistance is the main cause of primary drug resistance due to transmission of resistant strains
MDR due to spontaneous mutations is not possible as the genes encoding resistance for anti TB are unlinked
DrTVRao MD 23
Factors Contributing to Development
and Spread of MDR and XDR TB Weak TB programs (DOTS)
Low completioncure rates Lack of treatment follow up and
patient support Unreliable drug supply Diagnostic delay
Absent or inadequate infection control measures
Uncontrolled use of 2nd line drugs Fluroquinolones
DrTVRao MD 24
INHChromosomally mediatedLoss of catalaseperoxidaseMutation in mycolic acid synthesis
Regulators of peroxide response
Mechanism of resistance
DrTVRao MD 25
RifampinReduced binding to RNA polymeraseClusters of mutations at ldquoRifampin Resistance Determining Regionrdquo (RRDR)
Reduced Cell wall permeability
Mechanism of resistance
DrTVRao MD 26
Gene location associated Drug-Resistant
Mtuberculosis Drug Gene Isoniazid Kat G Inh A Kas
A Rifampicin rpo B Ethambutol emb B Streptomycin rps L Pyrazinamide pnc A Fluoroquinolones gyr A
Dubaniewicz A et al Molecular sub-type of the HLA-DR antigens in pulmonary tuberculosis Int J Infect Dis20004129-33
DrTVRao MD 27
Current Scientific Documentations on Drug Resistance in
Tuberculosis
DrTVRao MD 28
Alarming Rise of Resistant TuberculosisWHO Report on
Anti-TB Drug Resistance
490000 new cases of MDR-TB each year with gt110000 deaths1
Accounts for 5 of 9 million new cases of TB2
MDR-TB rates higher than ever (up to 223) particularly in former Soviet Union countries
XDR-TB reported by as many as 49 countries (by June 2008)3
Recent WHOIUATLD Global Surveillance report indicated 75 (3014012) of MDR TB to be XDR4
Around 40000 XDR-TB cases emerge every year1
1Tuberculosis MDR-TB amp XDR-TBmdashThe 2008 Report The Stop TB Department WHO2Hargreaves S httpinfectionthelancetcom Vol 8 April 2008 p2203Raviglione MC NEJM 2008359636-84Anti-TB Drug Resistance in the World Report No 4 The WHOIUATLD Global Project on Anti-Tuberculosis Drug Resistance Surveillance 2002-2007 World Health Organization 2008 (WHOHTMTB2008394)
DrTVRao MD 29
MDR-TB amp XDR-TBTHE 2008 REPORT
of MDR-TB among new TB cases 1994-2007
DrTVRao MD 30
MDR-TB rates higher than ever (up to 223) particularly in former Soviet Union countries
DrTVRao MD 31
Alarming Rise of Resistant TB
Resistant TB burden in countries of former Soviet Union about 50 of cases resistant to at least one drug about 20 MDR XDR-TB proportions also higher (as high as 24 in
Estonia)1
MDRXDR TB ndash essentially a man-made problem2
High numbers of resistant cases (gt400000 MDR-TB cases every year) due mainly to Underinvestment in basic TB control Poor management of anti-TB drugs Transmission of drug resistant strains1
1Anti-TB Drug Resistance in the World Report No 4 The WHOIUATLD Global Project on Anti-Tuberculosis Drug Resistance Surveillance 2002-2007 World Health Organization 2008 (WHOHTMTB2008394)
2Reichman The Lancet 20083711052-3
DrTVRao MD 32
The Much Discussed Article on XDR TB in the Lancet
Of the 221 multi-drug resistant (MDR-TB) cases 53 (24) were XDR
Almost all (52 of 53) of the XDR-TB patients died with a median survival of only 16 days from the time of diagnosis (in the 42 patients with confirmed dates of death)
All the 44 XDR TB patients who were tested for HIV were found co-infected
55 patents had never received anti-TB drugs suggesting primary transmission of XDR pathogen
67 patients had been admitted to the hospital in the preceding 2 years suggesting potential role of nosocomial transmission
Gandhi et al Lancet 20063681575-80DrTVRao MD 33
Poor mangement of infected lead to grwoing resistance
Resistance to anti-TB drugs in populations is a phenomenon that occurs primarily due to poorly managed TB care Problems include incorrect drug prescribing practices by providers poor quality drugs or erratic supply of drugs and also patient non-adherence DrTVRao MD 34
Susceptibility Testing
1048708 Direct and indirect testing1048708 Primary Drugs testing1048708 Isoniazid1048708 Rifampicin1048708 Ethambutol ()1048708 Pyrizinamide ()
DrTVRao MD 35
Drug susceptibility testing (DST)
DST is recommended for all new cases for all first line drugs with specimens taken before initiating treatment
Accuracy is more important than speed DST results should come from a small
number of well-equipped experienced laboratories who participate and perform well in an international DST quality control scheme
The WHO Supranational Laboratory Quality Control Network offers the greatest global coverage for this
DrTVRao MD 36
Drug susceptibility Testing
Assessment of growth inhibition on solid media containing various dilutions of the drug in comparison with the test strains
As the method depend observation of growth Results are not available until several weeks after isolation of the organism
DrTVRao MD 37
Other accredited Methods
Radiometric and Non radiometric methods
Nucleic acid technology ndash effective upto 95 in mutations to rifampicin resistance to gene rpoB gene
DrTVRao MD 38
Drug susceptibility testing (DST)
As a minimum laboratories supplying DST data should correctly identify resistance to isoniazid and rifampicin in over 90 of quality control samples in two out of the last three quality control roundsDrTVRao MD 39
Detection of Rifampicin Drug susceptibility testing (DST) is more important
Early identification of mycobacterial growth as M tuberculosis complex and the identification of rifampicin resistance should be the first priority as rifampicin resistance invalidates standard 6 month short-course chemotherapy and is a useful marker in most countries for MDR-TB
Laboratories should aim to identify isolates as M tuberculosis complex and perform rifampicin resistance in 90 of isolates within 1-2 working days This is technologically feasible
DrTVRao MD 40
Drug susceptibility testing
For DST laboratories modern molecular techniques permit the successful identification of isoniazid resistance in at least 75 of mycobacterial cultures within 1-2 working days and are useful preliminary screens for isoniazid resistance
DrTVRao MD 41
Secondary Drugs testing [lack of standardized
methods]
Ofloxacin quinolonesEthionamide KanamycinCapreomycin Ensure quality control and
quality assurance
DrTVRao MD 42
WHO Controls the Tuberculosis related work
The laboratory methods for anti-tuberculosis drug susceptibility testing should be selected from among those that are WHO-recommended and all laboratory processes should be quality-assured in cooperation with a partner Supranational Reference Laboratory (SRL)DrTVRao MD 43
Other WHO-Endorsed Tools
Liquid culture (eg MGIT BacTALERT)
Capilia TB Rapid strip test that detects a TB-
specific antigen from culture
Molecular line probe assays (eg GenoType MTBDRplus INNO-LiPA RifTB) Strip test for detection of TB and
drug-resistance conferring mutations
DrTVRao MD 44
BacTALERTreg
DrTVRao MD 45
CDC Updates Guidelines for Nucleic AcidAmplification Techniques to Diagnose
Tuberculosis
NAAT results should be interpreted in conjunction with the AFB smear results
NAAT and smear positive start Rx despite pending culture results PPV 95
Smear negative NAAT positive use clinical judgment to either treat or await culture
DrTVRao MD 46
Selection from automated systems for molecular and
bacteriological rapid diagnostics
PCRRocheCOBASreg Amplicorreg
amplification kitsRocheCOBASreg LightCyclerreg
(real-time-PCR)RocheCOBASreg TaqMan 48reg(increases the specificity of real-
time-PCR)
DrTVRao MD 47
Molecular Fingerprinting
26 of 30 (87) XDR TB isolates found to be genetically similar
Majority of patients had no previous history of TB treatment Suggestive of recent infection with drug-resistant strain
DrTVRao MD 48
Is PCR methods a solution
PCR cant yet replace neither microscopy culturing and competent clinical examination
DrTVRao MD 49
No testing method replaces Clinical assessment
DrTVRao MD 50
XDR-TBThe description
of XDR-TB was first used earlier in 2006 following a joint survey by WHO and the US Centres for Disease Control and Prevention (CDC) DrTVRao MD 51
How x-MDR generated
Acquired resistance is that which occurs as a result of specific previous treatment The level of primary resistance in the community is considered to reflect the efficacy of control measures in the past while the level of acquired resistance is a measure of on-going TB control measuresDrTVRao MD 52
Extreme Drug resistant Tuberculosis (XDR-TB)
Resistant to all first line drugs namely Isoniazid and Rifampin and Three or more second line drugs (SLDrsquoS) that are used to treat MDR-TB Thequinalones like Ofloaxin
Or Aminoglycosides like Capreomycin amp
Kanamycin
No third-line drugs available to treat XDR-TB since none has been developed in the last 40 years
DrTVRao MD 53
Background Extensively drug-resistant tuberculosis
Extensively drug-resistant tuberculosis has been reported in 45 countries including countries with limited resources and a high burden of tuberculosis
DrTVRao MD 54
DrTVRao MD 55
Transmissionof X -MDR
Like other forms of TB XDR-TB is spread through the air When a person with infectious TB coughs sneezes talks or spits they propel Mycobacterium into the air
DrTVRao MD 56
Best options to diagnoseX-MDR tuberculosis
To evaluate drug susceptibility the bacteria need to be cultivated and tested in a suitable laboratory Final diagnosis in this way for TB and especially for XDR-TB may take from 6 to 16 weeks To reduce the time needed for diagnosis new tools for rapid TB diagnosis are urgently needed
DrTVRao MD 57
When to suspect MDR TB
Patients not showing any reduction
in bacillary population after 3-
months of regular treatment with
Cat II regimen
Sputum positive patients who are
contacts of a known MDR TB
patient
DrTVRao MD 58
How to evaluate MDR TB
MDR TB is only a laboratory
proved HR resistance
Clinical suspicion should be
followed by lab Confirmation
Laboratories should be quality
controlledTRC
DrTVRao MD 59
Extreme Drug resistant Tuberculosis (XDR-TB) and AIDS
It can also be contracted without a patient receiving any previous treatment for TB
Mostly associated with HIV positive patients
HIV has the potential to fast tracking XDR-TB into an uncontrollable epidemic
Average survival period for patients infected with XDR-TB is 16 days
DrTVRao MD 60
Responding to MDRXDR-TB
Augment DOTS Program by
New diagnostics
New drugs New vaccines HIV incidence
reduction Advocacy1
A mathematical model projected by Basu and co-workers indicates that half of XDR-TB can be averted by 2012 by bringing synergistic effects through
Use of masks Reduced time as in-patient Improved ventilation Rapid resistance testing HIV treatment TB isolation facilities2
1Marteens and Wilkinson Lancet 20073702030-432Basu et al Quoted in Porco and Getz Lancet 20073701464-5
DrTVRao MD 61
Second Line Drug Treatment (SLDrsquos)
Less effective more costly and more toxic 50 cure rate
Four months intensive phase (5 drugs) Kanamycins Ethionamide Pyrazinamide Ofloxacin Cycloserine or Ethambutol DrTVRao MD 62
World Health Organisation (WHO) Guidelines for treatment
of MDR-TB
Strengthen basic TB care to prevent the emergence of drug-resistance
Ensure prompt diagnosis and treatment of drug resistant cases to cure existing cases and prevent further transmission
Increase collaboration between HIV and TB control programmes to provide necessary prevention and care to co-infected patients
Increase investment in laboratory infrastructures to enable better detection and management of resistant cases
DrTVRao MD 63
Treatment Guidelines
Sensitivity testing for all smear positive specimens
Patient Family and staff counselling amp education
Correct and thorough hand washing protocol and procedure
Personal protection is very important
DrTVRao MD 64
THE NEW MDR-TB Guidelines
A flexible framework approach combining both clinical and programmatic aspects of DOTS Plus based on essential programme conditions
But encouraging programs to tailor their case-finding and treatment strategies to the local epidemiological and Programme situation
Reflect GLC expert consensus and evidence and experience from GLC projects thus far
DrTVRao MD 65
Effective laboratory Diagnosis
Sputum smear examinations ndash rapid classification of species (atypical mycobacteria common in AIDS)
Culture examinations
Rapid drug sensitivity testingDrTVRao MD 66
MDR TB and HIV
MDR TB occurs with the same frequency in HIV
patients as in TB patients who are smear negative
Transmission of drug-resistant strains among HIV-
infected patients in congregate settings occurs
leading to lsquooutbreaksrsquo of MDR TB in such settings
Infection control measures absolutely essential in
settings where large number of HIV TB patients stay
togetherDrTVRao MD 67
Transmission is dependent on closeness and time of contact
In penitentiary care contacts are very close and prolonged ndash culture positive cases can also transmit TB especially to HIV positive population
DrTVRao MD 68
To Know more on MDR ndashTB Current Guidelines of WHO
Guidelines for the programmatic management of drug-resistant tuberculosis - 2011 update [pdf 904kb]
Visit helliphelliphellip WHOHTMTB20116DrTVRao MD 69
Are there any solutions for effective
Diagnosis in TB
DrTVRao MD 70
Programme Created by DrTVRao MD for Medical and Health Care
Workers in the Developing World Email
doctortvraogmailcom
DrTVRao MD 71
1908-1920 (Chalmette and Guerin) Vaccine (BCG)
Attenuated strain Mycobacterium Bovis
1943 Streptomycin developed
20th November 1944 Critically ill TB patient injected
dramatically recovered
Pharmacological discoveries
DrTVRao MD 9
Selman Abraham Waksman Nobel Prize for his discovery in
1952
DrTVRao MD 10
Pharmacological discoveries
1956-1960 Combination therapy of INH and PZA
cures TB1955 Cycloserine1962 Ethambutol 1963 Rifampicin1970-1977
Combination of Rifampicin and Isoniazid adopted as International regime for treatment of TB DrTVRao MD 11
No one is Immune to TuberculosisNot only infects poor but famous
too
DrTVRao MD 12
Multi Drug Resistant
TuberculosisMDR-TB
DrTVRao MD 13
Definition
MDR-TB caused by strains of Mycobacterium Tuberculosis resistant both Rifampicin and Isoniazid with or without resistance to other drugs
Single Isoniazid or Rifampicin resistance is not MDR - TB
MDR TB is a laboratory diagnosis
DrTVRao MD 14
Classification of Drugs 3 Groups depending upon the degree
of effectiveness and potential side effects First Line (Primary agents)
are the most effective and have lowest toxicity Isoniazid Rifampin
Second LineLess effective and more toxic effectsinclude (in no particular order) p-amino
salicylic acid Streptomycin Ethambutol Third Line
are least effective and most toxic Amikacin Kanamycin Capreomycin Viomycin Kanamycin Cycloserine
DrTVRao MD 15
Basic concepts ndash Keep facts
Primary (Initial) resistanceTB patientrsquos initial Mycobacterium
tuberculosis population resistant to drugs
Secondary (Acquired) resistanceDrug-resistant M tuberculosis in initial
population selected by inappropriate drug use (inadequate treatment or non-adherence) DrTVRao MD 16
When to suspect MDR TB
Re-treatment patients whorsquos sputum smear remains positive after three monthsrsquo of intensive therapy
Treatment failure and interruption cases
Close contacts of MDR tuberculosis cases
Positive diagnoses with TB culture and susceptibility testing DrTVRao MD 17
What is extensively drug resistant tuberculosis (XDR TB)
Extensively drug resistant TB (XDR TB) is a relatively rare type of MDR TB XDR TB is defined as TB which is resistant to isoniazid and rifampin plus resistant to any fluoroquinolone and at least one of three injectable second-line drugs (ie amikacin kanamycin or capreomycin)DrTVRao MD 18
Why XDR - TB a grave concern
Because XDR TB is resistant to first-line and second line drugs patients are left with treatment options that are much less effective
XDR TB is of special concern for persons with HIV infection or other conditions that can weaken the immune system These persons are more likely to develop TB disease once they are infected and also have a higher risk of death once they develop TB
DrTVRao MD 19
Global Estimates
Classification
Estimated Number of Cases
Estimated Number of
Deaths
All forms TB
88 million 16 million
MDR TB 424000 116000
XDR TB 27000 16000
DrTVRao MD 20
Extensively Drug-Resistant Mycobacterium tuberculosis
India
The first XDR TB cases in India and the emergence of XDR TB is reported by Rajesh Mondal and Amita Jain King Georges Medical University Lucknow India Volume 13 Number 9ndashSeptember 2007 in Emerging Infectious Diseases
DrTVRao MD 21
Drug susceptible TBsect
MDR-TB
1990sect
XDR-TB
2006sect
Total DR
Resistance to HampR ndash
Treatable with 2nd line drugs
Resistance to 2nd line drugs ndashTreatment options seriously restricted
Resistance to all available drugs ndash
No treatment options
or limited resistance manageable with 4 drug regimen - DOTS
Are we Returning to a Pre-antibiotic Era
DrTVRao MD 22
Genesis of MDR TB
Resistance is a man-made amplification of a natural phenomenon
Inadequate drug delivery is main cause of secondary drug resistance
Secondary drug resistance is the main cause of primary drug resistance due to transmission of resistant strains
MDR due to spontaneous mutations is not possible as the genes encoding resistance for anti TB are unlinked
DrTVRao MD 23
Factors Contributing to Development
and Spread of MDR and XDR TB Weak TB programs (DOTS)
Low completioncure rates Lack of treatment follow up and
patient support Unreliable drug supply Diagnostic delay
Absent or inadequate infection control measures
Uncontrolled use of 2nd line drugs Fluroquinolones
DrTVRao MD 24
INHChromosomally mediatedLoss of catalaseperoxidaseMutation in mycolic acid synthesis
Regulators of peroxide response
Mechanism of resistance
DrTVRao MD 25
RifampinReduced binding to RNA polymeraseClusters of mutations at ldquoRifampin Resistance Determining Regionrdquo (RRDR)
Reduced Cell wall permeability
Mechanism of resistance
DrTVRao MD 26
Gene location associated Drug-Resistant
Mtuberculosis Drug Gene Isoniazid Kat G Inh A Kas
A Rifampicin rpo B Ethambutol emb B Streptomycin rps L Pyrazinamide pnc A Fluoroquinolones gyr A
Dubaniewicz A et al Molecular sub-type of the HLA-DR antigens in pulmonary tuberculosis Int J Infect Dis20004129-33
DrTVRao MD 27
Current Scientific Documentations on Drug Resistance in
Tuberculosis
DrTVRao MD 28
Alarming Rise of Resistant TuberculosisWHO Report on
Anti-TB Drug Resistance
490000 new cases of MDR-TB each year with gt110000 deaths1
Accounts for 5 of 9 million new cases of TB2
MDR-TB rates higher than ever (up to 223) particularly in former Soviet Union countries
XDR-TB reported by as many as 49 countries (by June 2008)3
Recent WHOIUATLD Global Surveillance report indicated 75 (3014012) of MDR TB to be XDR4
Around 40000 XDR-TB cases emerge every year1
1Tuberculosis MDR-TB amp XDR-TBmdashThe 2008 Report The Stop TB Department WHO2Hargreaves S httpinfectionthelancetcom Vol 8 April 2008 p2203Raviglione MC NEJM 2008359636-84Anti-TB Drug Resistance in the World Report No 4 The WHOIUATLD Global Project on Anti-Tuberculosis Drug Resistance Surveillance 2002-2007 World Health Organization 2008 (WHOHTMTB2008394)
DrTVRao MD 29
MDR-TB amp XDR-TBTHE 2008 REPORT
of MDR-TB among new TB cases 1994-2007
DrTVRao MD 30
MDR-TB rates higher than ever (up to 223) particularly in former Soviet Union countries
DrTVRao MD 31
Alarming Rise of Resistant TB
Resistant TB burden in countries of former Soviet Union about 50 of cases resistant to at least one drug about 20 MDR XDR-TB proportions also higher (as high as 24 in
Estonia)1
MDRXDR TB ndash essentially a man-made problem2
High numbers of resistant cases (gt400000 MDR-TB cases every year) due mainly to Underinvestment in basic TB control Poor management of anti-TB drugs Transmission of drug resistant strains1
1Anti-TB Drug Resistance in the World Report No 4 The WHOIUATLD Global Project on Anti-Tuberculosis Drug Resistance Surveillance 2002-2007 World Health Organization 2008 (WHOHTMTB2008394)
2Reichman The Lancet 20083711052-3
DrTVRao MD 32
The Much Discussed Article on XDR TB in the Lancet
Of the 221 multi-drug resistant (MDR-TB) cases 53 (24) were XDR
Almost all (52 of 53) of the XDR-TB patients died with a median survival of only 16 days from the time of diagnosis (in the 42 patients with confirmed dates of death)
All the 44 XDR TB patients who were tested for HIV were found co-infected
55 patents had never received anti-TB drugs suggesting primary transmission of XDR pathogen
67 patients had been admitted to the hospital in the preceding 2 years suggesting potential role of nosocomial transmission
Gandhi et al Lancet 20063681575-80DrTVRao MD 33
Poor mangement of infected lead to grwoing resistance
Resistance to anti-TB drugs in populations is a phenomenon that occurs primarily due to poorly managed TB care Problems include incorrect drug prescribing practices by providers poor quality drugs or erratic supply of drugs and also patient non-adherence DrTVRao MD 34
Susceptibility Testing
1048708 Direct and indirect testing1048708 Primary Drugs testing1048708 Isoniazid1048708 Rifampicin1048708 Ethambutol ()1048708 Pyrizinamide ()
DrTVRao MD 35
Drug susceptibility testing (DST)
DST is recommended for all new cases for all first line drugs with specimens taken before initiating treatment
Accuracy is more important than speed DST results should come from a small
number of well-equipped experienced laboratories who participate and perform well in an international DST quality control scheme
The WHO Supranational Laboratory Quality Control Network offers the greatest global coverage for this
DrTVRao MD 36
Drug susceptibility Testing
Assessment of growth inhibition on solid media containing various dilutions of the drug in comparison with the test strains
As the method depend observation of growth Results are not available until several weeks after isolation of the organism
DrTVRao MD 37
Other accredited Methods
Radiometric and Non radiometric methods
Nucleic acid technology ndash effective upto 95 in mutations to rifampicin resistance to gene rpoB gene
DrTVRao MD 38
Drug susceptibility testing (DST)
As a minimum laboratories supplying DST data should correctly identify resistance to isoniazid and rifampicin in over 90 of quality control samples in two out of the last three quality control roundsDrTVRao MD 39
Detection of Rifampicin Drug susceptibility testing (DST) is more important
Early identification of mycobacterial growth as M tuberculosis complex and the identification of rifampicin resistance should be the first priority as rifampicin resistance invalidates standard 6 month short-course chemotherapy and is a useful marker in most countries for MDR-TB
Laboratories should aim to identify isolates as M tuberculosis complex and perform rifampicin resistance in 90 of isolates within 1-2 working days This is technologically feasible
DrTVRao MD 40
Drug susceptibility testing
For DST laboratories modern molecular techniques permit the successful identification of isoniazid resistance in at least 75 of mycobacterial cultures within 1-2 working days and are useful preliminary screens for isoniazid resistance
DrTVRao MD 41
Secondary Drugs testing [lack of standardized
methods]
Ofloxacin quinolonesEthionamide KanamycinCapreomycin Ensure quality control and
quality assurance
DrTVRao MD 42
WHO Controls the Tuberculosis related work
The laboratory methods for anti-tuberculosis drug susceptibility testing should be selected from among those that are WHO-recommended and all laboratory processes should be quality-assured in cooperation with a partner Supranational Reference Laboratory (SRL)DrTVRao MD 43
Other WHO-Endorsed Tools
Liquid culture (eg MGIT BacTALERT)
Capilia TB Rapid strip test that detects a TB-
specific antigen from culture
Molecular line probe assays (eg GenoType MTBDRplus INNO-LiPA RifTB) Strip test for detection of TB and
drug-resistance conferring mutations
DrTVRao MD 44
BacTALERTreg
DrTVRao MD 45
CDC Updates Guidelines for Nucleic AcidAmplification Techniques to Diagnose
Tuberculosis
NAAT results should be interpreted in conjunction with the AFB smear results
NAAT and smear positive start Rx despite pending culture results PPV 95
Smear negative NAAT positive use clinical judgment to either treat or await culture
DrTVRao MD 46
Selection from automated systems for molecular and
bacteriological rapid diagnostics
PCRRocheCOBASreg Amplicorreg
amplification kitsRocheCOBASreg LightCyclerreg
(real-time-PCR)RocheCOBASreg TaqMan 48reg(increases the specificity of real-
time-PCR)
DrTVRao MD 47
Molecular Fingerprinting
26 of 30 (87) XDR TB isolates found to be genetically similar
Majority of patients had no previous history of TB treatment Suggestive of recent infection with drug-resistant strain
DrTVRao MD 48
Is PCR methods a solution
PCR cant yet replace neither microscopy culturing and competent clinical examination
DrTVRao MD 49
No testing method replaces Clinical assessment
DrTVRao MD 50
XDR-TBThe description
of XDR-TB was first used earlier in 2006 following a joint survey by WHO and the US Centres for Disease Control and Prevention (CDC) DrTVRao MD 51
How x-MDR generated
Acquired resistance is that which occurs as a result of specific previous treatment The level of primary resistance in the community is considered to reflect the efficacy of control measures in the past while the level of acquired resistance is a measure of on-going TB control measuresDrTVRao MD 52
Extreme Drug resistant Tuberculosis (XDR-TB)
Resistant to all first line drugs namely Isoniazid and Rifampin and Three or more second line drugs (SLDrsquoS) that are used to treat MDR-TB Thequinalones like Ofloaxin
Or Aminoglycosides like Capreomycin amp
Kanamycin
No third-line drugs available to treat XDR-TB since none has been developed in the last 40 years
DrTVRao MD 53
Background Extensively drug-resistant tuberculosis
Extensively drug-resistant tuberculosis has been reported in 45 countries including countries with limited resources and a high burden of tuberculosis
DrTVRao MD 54
DrTVRao MD 55
Transmissionof X -MDR
Like other forms of TB XDR-TB is spread through the air When a person with infectious TB coughs sneezes talks or spits they propel Mycobacterium into the air
DrTVRao MD 56
Best options to diagnoseX-MDR tuberculosis
To evaluate drug susceptibility the bacteria need to be cultivated and tested in a suitable laboratory Final diagnosis in this way for TB and especially for XDR-TB may take from 6 to 16 weeks To reduce the time needed for diagnosis new tools for rapid TB diagnosis are urgently needed
DrTVRao MD 57
When to suspect MDR TB
Patients not showing any reduction
in bacillary population after 3-
months of regular treatment with
Cat II regimen
Sputum positive patients who are
contacts of a known MDR TB
patient
DrTVRao MD 58
How to evaluate MDR TB
MDR TB is only a laboratory
proved HR resistance
Clinical suspicion should be
followed by lab Confirmation
Laboratories should be quality
controlledTRC
DrTVRao MD 59
Extreme Drug resistant Tuberculosis (XDR-TB) and AIDS
It can also be contracted without a patient receiving any previous treatment for TB
Mostly associated with HIV positive patients
HIV has the potential to fast tracking XDR-TB into an uncontrollable epidemic
Average survival period for patients infected with XDR-TB is 16 days
DrTVRao MD 60
Responding to MDRXDR-TB
Augment DOTS Program by
New diagnostics
New drugs New vaccines HIV incidence
reduction Advocacy1
A mathematical model projected by Basu and co-workers indicates that half of XDR-TB can be averted by 2012 by bringing synergistic effects through
Use of masks Reduced time as in-patient Improved ventilation Rapid resistance testing HIV treatment TB isolation facilities2
1Marteens and Wilkinson Lancet 20073702030-432Basu et al Quoted in Porco and Getz Lancet 20073701464-5
DrTVRao MD 61
Second Line Drug Treatment (SLDrsquos)
Less effective more costly and more toxic 50 cure rate
Four months intensive phase (5 drugs) Kanamycins Ethionamide Pyrazinamide Ofloxacin Cycloserine or Ethambutol DrTVRao MD 62
World Health Organisation (WHO) Guidelines for treatment
of MDR-TB
Strengthen basic TB care to prevent the emergence of drug-resistance
Ensure prompt diagnosis and treatment of drug resistant cases to cure existing cases and prevent further transmission
Increase collaboration between HIV and TB control programmes to provide necessary prevention and care to co-infected patients
Increase investment in laboratory infrastructures to enable better detection and management of resistant cases
DrTVRao MD 63
Treatment Guidelines
Sensitivity testing for all smear positive specimens
Patient Family and staff counselling amp education
Correct and thorough hand washing protocol and procedure
Personal protection is very important
DrTVRao MD 64
THE NEW MDR-TB Guidelines
A flexible framework approach combining both clinical and programmatic aspects of DOTS Plus based on essential programme conditions
But encouraging programs to tailor their case-finding and treatment strategies to the local epidemiological and Programme situation
Reflect GLC expert consensus and evidence and experience from GLC projects thus far
DrTVRao MD 65
Effective laboratory Diagnosis
Sputum smear examinations ndash rapid classification of species (atypical mycobacteria common in AIDS)
Culture examinations
Rapid drug sensitivity testingDrTVRao MD 66
MDR TB and HIV
MDR TB occurs with the same frequency in HIV
patients as in TB patients who are smear negative
Transmission of drug-resistant strains among HIV-
infected patients in congregate settings occurs
leading to lsquooutbreaksrsquo of MDR TB in such settings
Infection control measures absolutely essential in
settings where large number of HIV TB patients stay
togetherDrTVRao MD 67
Transmission is dependent on closeness and time of contact
In penitentiary care contacts are very close and prolonged ndash culture positive cases can also transmit TB especially to HIV positive population
DrTVRao MD 68
To Know more on MDR ndashTB Current Guidelines of WHO
Guidelines for the programmatic management of drug-resistant tuberculosis - 2011 update [pdf 904kb]
Visit helliphelliphellip WHOHTMTB20116DrTVRao MD 69
Are there any solutions for effective
Diagnosis in TB
DrTVRao MD 70
Programme Created by DrTVRao MD for Medical and Health Care
Workers in the Developing World Email
doctortvraogmailcom
DrTVRao MD 71
Selman Abraham Waksman Nobel Prize for his discovery in
1952
DrTVRao MD 10
Pharmacological discoveries
1956-1960 Combination therapy of INH and PZA
cures TB1955 Cycloserine1962 Ethambutol 1963 Rifampicin1970-1977
Combination of Rifampicin and Isoniazid adopted as International regime for treatment of TB DrTVRao MD 11
No one is Immune to TuberculosisNot only infects poor but famous
too
DrTVRao MD 12
Multi Drug Resistant
TuberculosisMDR-TB
DrTVRao MD 13
Definition
MDR-TB caused by strains of Mycobacterium Tuberculosis resistant both Rifampicin and Isoniazid with or without resistance to other drugs
Single Isoniazid or Rifampicin resistance is not MDR - TB
MDR TB is a laboratory diagnosis
DrTVRao MD 14
Classification of Drugs 3 Groups depending upon the degree
of effectiveness and potential side effects First Line (Primary agents)
are the most effective and have lowest toxicity Isoniazid Rifampin
Second LineLess effective and more toxic effectsinclude (in no particular order) p-amino
salicylic acid Streptomycin Ethambutol Third Line
are least effective and most toxic Amikacin Kanamycin Capreomycin Viomycin Kanamycin Cycloserine
DrTVRao MD 15
Basic concepts ndash Keep facts
Primary (Initial) resistanceTB patientrsquos initial Mycobacterium
tuberculosis population resistant to drugs
Secondary (Acquired) resistanceDrug-resistant M tuberculosis in initial
population selected by inappropriate drug use (inadequate treatment or non-adherence) DrTVRao MD 16
When to suspect MDR TB
Re-treatment patients whorsquos sputum smear remains positive after three monthsrsquo of intensive therapy
Treatment failure and interruption cases
Close contacts of MDR tuberculosis cases
Positive diagnoses with TB culture and susceptibility testing DrTVRao MD 17
What is extensively drug resistant tuberculosis (XDR TB)
Extensively drug resistant TB (XDR TB) is a relatively rare type of MDR TB XDR TB is defined as TB which is resistant to isoniazid and rifampin plus resistant to any fluoroquinolone and at least one of three injectable second-line drugs (ie amikacin kanamycin or capreomycin)DrTVRao MD 18
Why XDR - TB a grave concern
Because XDR TB is resistant to first-line and second line drugs patients are left with treatment options that are much less effective
XDR TB is of special concern for persons with HIV infection or other conditions that can weaken the immune system These persons are more likely to develop TB disease once they are infected and also have a higher risk of death once they develop TB
DrTVRao MD 19
Global Estimates
Classification
Estimated Number of Cases
Estimated Number of
Deaths
All forms TB
88 million 16 million
MDR TB 424000 116000
XDR TB 27000 16000
DrTVRao MD 20
Extensively Drug-Resistant Mycobacterium tuberculosis
India
The first XDR TB cases in India and the emergence of XDR TB is reported by Rajesh Mondal and Amita Jain King Georges Medical University Lucknow India Volume 13 Number 9ndashSeptember 2007 in Emerging Infectious Diseases
DrTVRao MD 21
Drug susceptible TBsect
MDR-TB
1990sect
XDR-TB
2006sect
Total DR
Resistance to HampR ndash
Treatable with 2nd line drugs
Resistance to 2nd line drugs ndashTreatment options seriously restricted
Resistance to all available drugs ndash
No treatment options
or limited resistance manageable with 4 drug regimen - DOTS
Are we Returning to a Pre-antibiotic Era
DrTVRao MD 22
Genesis of MDR TB
Resistance is a man-made amplification of a natural phenomenon
Inadequate drug delivery is main cause of secondary drug resistance
Secondary drug resistance is the main cause of primary drug resistance due to transmission of resistant strains
MDR due to spontaneous mutations is not possible as the genes encoding resistance for anti TB are unlinked
DrTVRao MD 23
Factors Contributing to Development
and Spread of MDR and XDR TB Weak TB programs (DOTS)
Low completioncure rates Lack of treatment follow up and
patient support Unreliable drug supply Diagnostic delay
Absent or inadequate infection control measures
Uncontrolled use of 2nd line drugs Fluroquinolones
DrTVRao MD 24
INHChromosomally mediatedLoss of catalaseperoxidaseMutation in mycolic acid synthesis
Regulators of peroxide response
Mechanism of resistance
DrTVRao MD 25
RifampinReduced binding to RNA polymeraseClusters of mutations at ldquoRifampin Resistance Determining Regionrdquo (RRDR)
Reduced Cell wall permeability
Mechanism of resistance
DrTVRao MD 26
Gene location associated Drug-Resistant
Mtuberculosis Drug Gene Isoniazid Kat G Inh A Kas
A Rifampicin rpo B Ethambutol emb B Streptomycin rps L Pyrazinamide pnc A Fluoroquinolones gyr A
Dubaniewicz A et al Molecular sub-type of the HLA-DR antigens in pulmonary tuberculosis Int J Infect Dis20004129-33
DrTVRao MD 27
Current Scientific Documentations on Drug Resistance in
Tuberculosis
DrTVRao MD 28
Alarming Rise of Resistant TuberculosisWHO Report on
Anti-TB Drug Resistance
490000 new cases of MDR-TB each year with gt110000 deaths1
Accounts for 5 of 9 million new cases of TB2
MDR-TB rates higher than ever (up to 223) particularly in former Soviet Union countries
XDR-TB reported by as many as 49 countries (by June 2008)3
Recent WHOIUATLD Global Surveillance report indicated 75 (3014012) of MDR TB to be XDR4
Around 40000 XDR-TB cases emerge every year1
1Tuberculosis MDR-TB amp XDR-TBmdashThe 2008 Report The Stop TB Department WHO2Hargreaves S httpinfectionthelancetcom Vol 8 April 2008 p2203Raviglione MC NEJM 2008359636-84Anti-TB Drug Resistance in the World Report No 4 The WHOIUATLD Global Project on Anti-Tuberculosis Drug Resistance Surveillance 2002-2007 World Health Organization 2008 (WHOHTMTB2008394)
DrTVRao MD 29
MDR-TB amp XDR-TBTHE 2008 REPORT
of MDR-TB among new TB cases 1994-2007
DrTVRao MD 30
MDR-TB rates higher than ever (up to 223) particularly in former Soviet Union countries
DrTVRao MD 31
Alarming Rise of Resistant TB
Resistant TB burden in countries of former Soviet Union about 50 of cases resistant to at least one drug about 20 MDR XDR-TB proportions also higher (as high as 24 in
Estonia)1
MDRXDR TB ndash essentially a man-made problem2
High numbers of resistant cases (gt400000 MDR-TB cases every year) due mainly to Underinvestment in basic TB control Poor management of anti-TB drugs Transmission of drug resistant strains1
1Anti-TB Drug Resistance in the World Report No 4 The WHOIUATLD Global Project on Anti-Tuberculosis Drug Resistance Surveillance 2002-2007 World Health Organization 2008 (WHOHTMTB2008394)
2Reichman The Lancet 20083711052-3
DrTVRao MD 32
The Much Discussed Article on XDR TB in the Lancet
Of the 221 multi-drug resistant (MDR-TB) cases 53 (24) were XDR
Almost all (52 of 53) of the XDR-TB patients died with a median survival of only 16 days from the time of diagnosis (in the 42 patients with confirmed dates of death)
All the 44 XDR TB patients who were tested for HIV were found co-infected
55 patents had never received anti-TB drugs suggesting primary transmission of XDR pathogen
67 patients had been admitted to the hospital in the preceding 2 years suggesting potential role of nosocomial transmission
Gandhi et al Lancet 20063681575-80DrTVRao MD 33
Poor mangement of infected lead to grwoing resistance
Resistance to anti-TB drugs in populations is a phenomenon that occurs primarily due to poorly managed TB care Problems include incorrect drug prescribing practices by providers poor quality drugs or erratic supply of drugs and also patient non-adherence DrTVRao MD 34
Susceptibility Testing
1048708 Direct and indirect testing1048708 Primary Drugs testing1048708 Isoniazid1048708 Rifampicin1048708 Ethambutol ()1048708 Pyrizinamide ()
DrTVRao MD 35
Drug susceptibility testing (DST)
DST is recommended for all new cases for all first line drugs with specimens taken before initiating treatment
Accuracy is more important than speed DST results should come from a small
number of well-equipped experienced laboratories who participate and perform well in an international DST quality control scheme
The WHO Supranational Laboratory Quality Control Network offers the greatest global coverage for this
DrTVRao MD 36
Drug susceptibility Testing
Assessment of growth inhibition on solid media containing various dilutions of the drug in comparison with the test strains
As the method depend observation of growth Results are not available until several weeks after isolation of the organism
DrTVRao MD 37
Other accredited Methods
Radiometric and Non radiometric methods
Nucleic acid technology ndash effective upto 95 in mutations to rifampicin resistance to gene rpoB gene
DrTVRao MD 38
Drug susceptibility testing (DST)
As a minimum laboratories supplying DST data should correctly identify resistance to isoniazid and rifampicin in over 90 of quality control samples in two out of the last three quality control roundsDrTVRao MD 39
Detection of Rifampicin Drug susceptibility testing (DST) is more important
Early identification of mycobacterial growth as M tuberculosis complex and the identification of rifampicin resistance should be the first priority as rifampicin resistance invalidates standard 6 month short-course chemotherapy and is a useful marker in most countries for MDR-TB
Laboratories should aim to identify isolates as M tuberculosis complex and perform rifampicin resistance in 90 of isolates within 1-2 working days This is technologically feasible
DrTVRao MD 40
Drug susceptibility testing
For DST laboratories modern molecular techniques permit the successful identification of isoniazid resistance in at least 75 of mycobacterial cultures within 1-2 working days and are useful preliminary screens for isoniazid resistance
DrTVRao MD 41
Secondary Drugs testing [lack of standardized
methods]
Ofloxacin quinolonesEthionamide KanamycinCapreomycin Ensure quality control and
quality assurance
DrTVRao MD 42
WHO Controls the Tuberculosis related work
The laboratory methods for anti-tuberculosis drug susceptibility testing should be selected from among those that are WHO-recommended and all laboratory processes should be quality-assured in cooperation with a partner Supranational Reference Laboratory (SRL)DrTVRao MD 43
Other WHO-Endorsed Tools
Liquid culture (eg MGIT BacTALERT)
Capilia TB Rapid strip test that detects a TB-
specific antigen from culture
Molecular line probe assays (eg GenoType MTBDRplus INNO-LiPA RifTB) Strip test for detection of TB and
drug-resistance conferring mutations
DrTVRao MD 44
BacTALERTreg
DrTVRao MD 45
CDC Updates Guidelines for Nucleic AcidAmplification Techniques to Diagnose
Tuberculosis
NAAT results should be interpreted in conjunction with the AFB smear results
NAAT and smear positive start Rx despite pending culture results PPV 95
Smear negative NAAT positive use clinical judgment to either treat or await culture
DrTVRao MD 46
Selection from automated systems for molecular and
bacteriological rapid diagnostics
PCRRocheCOBASreg Amplicorreg
amplification kitsRocheCOBASreg LightCyclerreg
(real-time-PCR)RocheCOBASreg TaqMan 48reg(increases the specificity of real-
time-PCR)
DrTVRao MD 47
Molecular Fingerprinting
26 of 30 (87) XDR TB isolates found to be genetically similar
Majority of patients had no previous history of TB treatment Suggestive of recent infection with drug-resistant strain
DrTVRao MD 48
Is PCR methods a solution
PCR cant yet replace neither microscopy culturing and competent clinical examination
DrTVRao MD 49
No testing method replaces Clinical assessment
DrTVRao MD 50
XDR-TBThe description
of XDR-TB was first used earlier in 2006 following a joint survey by WHO and the US Centres for Disease Control and Prevention (CDC) DrTVRao MD 51
How x-MDR generated
Acquired resistance is that which occurs as a result of specific previous treatment The level of primary resistance in the community is considered to reflect the efficacy of control measures in the past while the level of acquired resistance is a measure of on-going TB control measuresDrTVRao MD 52
Extreme Drug resistant Tuberculosis (XDR-TB)
Resistant to all first line drugs namely Isoniazid and Rifampin and Three or more second line drugs (SLDrsquoS) that are used to treat MDR-TB Thequinalones like Ofloaxin
Or Aminoglycosides like Capreomycin amp
Kanamycin
No third-line drugs available to treat XDR-TB since none has been developed in the last 40 years
DrTVRao MD 53
Background Extensively drug-resistant tuberculosis
Extensively drug-resistant tuberculosis has been reported in 45 countries including countries with limited resources and a high burden of tuberculosis
DrTVRao MD 54
DrTVRao MD 55
Transmissionof X -MDR
Like other forms of TB XDR-TB is spread through the air When a person with infectious TB coughs sneezes talks or spits they propel Mycobacterium into the air
DrTVRao MD 56
Best options to diagnoseX-MDR tuberculosis
To evaluate drug susceptibility the bacteria need to be cultivated and tested in a suitable laboratory Final diagnosis in this way for TB and especially for XDR-TB may take from 6 to 16 weeks To reduce the time needed for diagnosis new tools for rapid TB diagnosis are urgently needed
DrTVRao MD 57
When to suspect MDR TB
Patients not showing any reduction
in bacillary population after 3-
months of regular treatment with
Cat II regimen
Sputum positive patients who are
contacts of a known MDR TB
patient
DrTVRao MD 58
How to evaluate MDR TB
MDR TB is only a laboratory
proved HR resistance
Clinical suspicion should be
followed by lab Confirmation
Laboratories should be quality
controlledTRC
DrTVRao MD 59
Extreme Drug resistant Tuberculosis (XDR-TB) and AIDS
It can also be contracted without a patient receiving any previous treatment for TB
Mostly associated with HIV positive patients
HIV has the potential to fast tracking XDR-TB into an uncontrollable epidemic
Average survival period for patients infected with XDR-TB is 16 days
DrTVRao MD 60
Responding to MDRXDR-TB
Augment DOTS Program by
New diagnostics
New drugs New vaccines HIV incidence
reduction Advocacy1
A mathematical model projected by Basu and co-workers indicates that half of XDR-TB can be averted by 2012 by bringing synergistic effects through
Use of masks Reduced time as in-patient Improved ventilation Rapid resistance testing HIV treatment TB isolation facilities2
1Marteens and Wilkinson Lancet 20073702030-432Basu et al Quoted in Porco and Getz Lancet 20073701464-5
DrTVRao MD 61
Second Line Drug Treatment (SLDrsquos)
Less effective more costly and more toxic 50 cure rate
Four months intensive phase (5 drugs) Kanamycins Ethionamide Pyrazinamide Ofloxacin Cycloserine or Ethambutol DrTVRao MD 62
World Health Organisation (WHO) Guidelines for treatment
of MDR-TB
Strengthen basic TB care to prevent the emergence of drug-resistance
Ensure prompt diagnosis and treatment of drug resistant cases to cure existing cases and prevent further transmission
Increase collaboration between HIV and TB control programmes to provide necessary prevention and care to co-infected patients
Increase investment in laboratory infrastructures to enable better detection and management of resistant cases
DrTVRao MD 63
Treatment Guidelines
Sensitivity testing for all smear positive specimens
Patient Family and staff counselling amp education
Correct and thorough hand washing protocol and procedure
Personal protection is very important
DrTVRao MD 64
THE NEW MDR-TB Guidelines
A flexible framework approach combining both clinical and programmatic aspects of DOTS Plus based on essential programme conditions
But encouraging programs to tailor their case-finding and treatment strategies to the local epidemiological and Programme situation
Reflect GLC expert consensus and evidence and experience from GLC projects thus far
DrTVRao MD 65
Effective laboratory Diagnosis
Sputum smear examinations ndash rapid classification of species (atypical mycobacteria common in AIDS)
Culture examinations
Rapid drug sensitivity testingDrTVRao MD 66
MDR TB and HIV
MDR TB occurs with the same frequency in HIV
patients as in TB patients who are smear negative
Transmission of drug-resistant strains among HIV-
infected patients in congregate settings occurs
leading to lsquooutbreaksrsquo of MDR TB in such settings
Infection control measures absolutely essential in
settings where large number of HIV TB patients stay
togetherDrTVRao MD 67
Transmission is dependent on closeness and time of contact
In penitentiary care contacts are very close and prolonged ndash culture positive cases can also transmit TB especially to HIV positive population
DrTVRao MD 68
To Know more on MDR ndashTB Current Guidelines of WHO
Guidelines for the programmatic management of drug-resistant tuberculosis - 2011 update [pdf 904kb]
Visit helliphelliphellip WHOHTMTB20116DrTVRao MD 69
Are there any solutions for effective
Diagnosis in TB
DrTVRao MD 70
Programme Created by DrTVRao MD for Medical and Health Care
Workers in the Developing World Email
doctortvraogmailcom
DrTVRao MD 71
Pharmacological discoveries
1956-1960 Combination therapy of INH and PZA
cures TB1955 Cycloserine1962 Ethambutol 1963 Rifampicin1970-1977
Combination of Rifampicin and Isoniazid adopted as International regime for treatment of TB DrTVRao MD 11
No one is Immune to TuberculosisNot only infects poor but famous
too
DrTVRao MD 12
Multi Drug Resistant
TuberculosisMDR-TB
DrTVRao MD 13
Definition
MDR-TB caused by strains of Mycobacterium Tuberculosis resistant both Rifampicin and Isoniazid with or without resistance to other drugs
Single Isoniazid or Rifampicin resistance is not MDR - TB
MDR TB is a laboratory diagnosis
DrTVRao MD 14
Classification of Drugs 3 Groups depending upon the degree
of effectiveness and potential side effects First Line (Primary agents)
are the most effective and have lowest toxicity Isoniazid Rifampin
Second LineLess effective and more toxic effectsinclude (in no particular order) p-amino
salicylic acid Streptomycin Ethambutol Third Line
are least effective and most toxic Amikacin Kanamycin Capreomycin Viomycin Kanamycin Cycloserine
DrTVRao MD 15
Basic concepts ndash Keep facts
Primary (Initial) resistanceTB patientrsquos initial Mycobacterium
tuberculosis population resistant to drugs
Secondary (Acquired) resistanceDrug-resistant M tuberculosis in initial
population selected by inappropriate drug use (inadequate treatment or non-adherence) DrTVRao MD 16
When to suspect MDR TB
Re-treatment patients whorsquos sputum smear remains positive after three monthsrsquo of intensive therapy
Treatment failure and interruption cases
Close contacts of MDR tuberculosis cases
Positive diagnoses with TB culture and susceptibility testing DrTVRao MD 17
What is extensively drug resistant tuberculosis (XDR TB)
Extensively drug resistant TB (XDR TB) is a relatively rare type of MDR TB XDR TB is defined as TB which is resistant to isoniazid and rifampin plus resistant to any fluoroquinolone and at least one of three injectable second-line drugs (ie amikacin kanamycin or capreomycin)DrTVRao MD 18
Why XDR - TB a grave concern
Because XDR TB is resistant to first-line and second line drugs patients are left with treatment options that are much less effective
XDR TB is of special concern for persons with HIV infection or other conditions that can weaken the immune system These persons are more likely to develop TB disease once they are infected and also have a higher risk of death once they develop TB
DrTVRao MD 19
Global Estimates
Classification
Estimated Number of Cases
Estimated Number of
Deaths
All forms TB
88 million 16 million
MDR TB 424000 116000
XDR TB 27000 16000
DrTVRao MD 20
Extensively Drug-Resistant Mycobacterium tuberculosis
India
The first XDR TB cases in India and the emergence of XDR TB is reported by Rajesh Mondal and Amita Jain King Georges Medical University Lucknow India Volume 13 Number 9ndashSeptember 2007 in Emerging Infectious Diseases
DrTVRao MD 21
Drug susceptible TBsect
MDR-TB
1990sect
XDR-TB
2006sect
Total DR
Resistance to HampR ndash
Treatable with 2nd line drugs
Resistance to 2nd line drugs ndashTreatment options seriously restricted
Resistance to all available drugs ndash
No treatment options
or limited resistance manageable with 4 drug regimen - DOTS
Are we Returning to a Pre-antibiotic Era
DrTVRao MD 22
Genesis of MDR TB
Resistance is a man-made amplification of a natural phenomenon
Inadequate drug delivery is main cause of secondary drug resistance
Secondary drug resistance is the main cause of primary drug resistance due to transmission of resistant strains
MDR due to spontaneous mutations is not possible as the genes encoding resistance for anti TB are unlinked
DrTVRao MD 23
Factors Contributing to Development
and Spread of MDR and XDR TB Weak TB programs (DOTS)
Low completioncure rates Lack of treatment follow up and
patient support Unreliable drug supply Diagnostic delay
Absent or inadequate infection control measures
Uncontrolled use of 2nd line drugs Fluroquinolones
DrTVRao MD 24
INHChromosomally mediatedLoss of catalaseperoxidaseMutation in mycolic acid synthesis
Regulators of peroxide response
Mechanism of resistance
DrTVRao MD 25
RifampinReduced binding to RNA polymeraseClusters of mutations at ldquoRifampin Resistance Determining Regionrdquo (RRDR)
Reduced Cell wall permeability
Mechanism of resistance
DrTVRao MD 26
Gene location associated Drug-Resistant
Mtuberculosis Drug Gene Isoniazid Kat G Inh A Kas
A Rifampicin rpo B Ethambutol emb B Streptomycin rps L Pyrazinamide pnc A Fluoroquinolones gyr A
Dubaniewicz A et al Molecular sub-type of the HLA-DR antigens in pulmonary tuberculosis Int J Infect Dis20004129-33
DrTVRao MD 27
Current Scientific Documentations on Drug Resistance in
Tuberculosis
DrTVRao MD 28
Alarming Rise of Resistant TuberculosisWHO Report on
Anti-TB Drug Resistance
490000 new cases of MDR-TB each year with gt110000 deaths1
Accounts for 5 of 9 million new cases of TB2
MDR-TB rates higher than ever (up to 223) particularly in former Soviet Union countries
XDR-TB reported by as many as 49 countries (by June 2008)3
Recent WHOIUATLD Global Surveillance report indicated 75 (3014012) of MDR TB to be XDR4
Around 40000 XDR-TB cases emerge every year1
1Tuberculosis MDR-TB amp XDR-TBmdashThe 2008 Report The Stop TB Department WHO2Hargreaves S httpinfectionthelancetcom Vol 8 April 2008 p2203Raviglione MC NEJM 2008359636-84Anti-TB Drug Resistance in the World Report No 4 The WHOIUATLD Global Project on Anti-Tuberculosis Drug Resistance Surveillance 2002-2007 World Health Organization 2008 (WHOHTMTB2008394)
DrTVRao MD 29
MDR-TB amp XDR-TBTHE 2008 REPORT
of MDR-TB among new TB cases 1994-2007
DrTVRao MD 30
MDR-TB rates higher than ever (up to 223) particularly in former Soviet Union countries
DrTVRao MD 31
Alarming Rise of Resistant TB
Resistant TB burden in countries of former Soviet Union about 50 of cases resistant to at least one drug about 20 MDR XDR-TB proportions also higher (as high as 24 in
Estonia)1
MDRXDR TB ndash essentially a man-made problem2
High numbers of resistant cases (gt400000 MDR-TB cases every year) due mainly to Underinvestment in basic TB control Poor management of anti-TB drugs Transmission of drug resistant strains1
1Anti-TB Drug Resistance in the World Report No 4 The WHOIUATLD Global Project on Anti-Tuberculosis Drug Resistance Surveillance 2002-2007 World Health Organization 2008 (WHOHTMTB2008394)
2Reichman The Lancet 20083711052-3
DrTVRao MD 32
The Much Discussed Article on XDR TB in the Lancet
Of the 221 multi-drug resistant (MDR-TB) cases 53 (24) were XDR
Almost all (52 of 53) of the XDR-TB patients died with a median survival of only 16 days from the time of diagnosis (in the 42 patients with confirmed dates of death)
All the 44 XDR TB patients who were tested for HIV were found co-infected
55 patents had never received anti-TB drugs suggesting primary transmission of XDR pathogen
67 patients had been admitted to the hospital in the preceding 2 years suggesting potential role of nosocomial transmission
Gandhi et al Lancet 20063681575-80DrTVRao MD 33
Poor mangement of infected lead to grwoing resistance
Resistance to anti-TB drugs in populations is a phenomenon that occurs primarily due to poorly managed TB care Problems include incorrect drug prescribing practices by providers poor quality drugs or erratic supply of drugs and also patient non-adherence DrTVRao MD 34
Susceptibility Testing
1048708 Direct and indirect testing1048708 Primary Drugs testing1048708 Isoniazid1048708 Rifampicin1048708 Ethambutol ()1048708 Pyrizinamide ()
DrTVRao MD 35
Drug susceptibility testing (DST)
DST is recommended for all new cases for all first line drugs with specimens taken before initiating treatment
Accuracy is more important than speed DST results should come from a small
number of well-equipped experienced laboratories who participate and perform well in an international DST quality control scheme
The WHO Supranational Laboratory Quality Control Network offers the greatest global coverage for this
DrTVRao MD 36
Drug susceptibility Testing
Assessment of growth inhibition on solid media containing various dilutions of the drug in comparison with the test strains
As the method depend observation of growth Results are not available until several weeks after isolation of the organism
DrTVRao MD 37
Other accredited Methods
Radiometric and Non radiometric methods
Nucleic acid technology ndash effective upto 95 in mutations to rifampicin resistance to gene rpoB gene
DrTVRao MD 38
Drug susceptibility testing (DST)
As a minimum laboratories supplying DST data should correctly identify resistance to isoniazid and rifampicin in over 90 of quality control samples in two out of the last three quality control roundsDrTVRao MD 39
Detection of Rifampicin Drug susceptibility testing (DST) is more important
Early identification of mycobacterial growth as M tuberculosis complex and the identification of rifampicin resistance should be the first priority as rifampicin resistance invalidates standard 6 month short-course chemotherapy and is a useful marker in most countries for MDR-TB
Laboratories should aim to identify isolates as M tuberculosis complex and perform rifampicin resistance in 90 of isolates within 1-2 working days This is technologically feasible
DrTVRao MD 40
Drug susceptibility testing
For DST laboratories modern molecular techniques permit the successful identification of isoniazid resistance in at least 75 of mycobacterial cultures within 1-2 working days and are useful preliminary screens for isoniazid resistance
DrTVRao MD 41
Secondary Drugs testing [lack of standardized
methods]
Ofloxacin quinolonesEthionamide KanamycinCapreomycin Ensure quality control and
quality assurance
DrTVRao MD 42
WHO Controls the Tuberculosis related work
The laboratory methods for anti-tuberculosis drug susceptibility testing should be selected from among those that are WHO-recommended and all laboratory processes should be quality-assured in cooperation with a partner Supranational Reference Laboratory (SRL)DrTVRao MD 43
Other WHO-Endorsed Tools
Liquid culture (eg MGIT BacTALERT)
Capilia TB Rapid strip test that detects a TB-
specific antigen from culture
Molecular line probe assays (eg GenoType MTBDRplus INNO-LiPA RifTB) Strip test for detection of TB and
drug-resistance conferring mutations
DrTVRao MD 44
BacTALERTreg
DrTVRao MD 45
CDC Updates Guidelines for Nucleic AcidAmplification Techniques to Diagnose
Tuberculosis
NAAT results should be interpreted in conjunction with the AFB smear results
NAAT and smear positive start Rx despite pending culture results PPV 95
Smear negative NAAT positive use clinical judgment to either treat or await culture
DrTVRao MD 46
Selection from automated systems for molecular and
bacteriological rapid diagnostics
PCRRocheCOBASreg Amplicorreg
amplification kitsRocheCOBASreg LightCyclerreg
(real-time-PCR)RocheCOBASreg TaqMan 48reg(increases the specificity of real-
time-PCR)
DrTVRao MD 47
Molecular Fingerprinting
26 of 30 (87) XDR TB isolates found to be genetically similar
Majority of patients had no previous history of TB treatment Suggestive of recent infection with drug-resistant strain
DrTVRao MD 48
Is PCR methods a solution
PCR cant yet replace neither microscopy culturing and competent clinical examination
DrTVRao MD 49
No testing method replaces Clinical assessment
DrTVRao MD 50
XDR-TBThe description
of XDR-TB was first used earlier in 2006 following a joint survey by WHO and the US Centres for Disease Control and Prevention (CDC) DrTVRao MD 51
How x-MDR generated
Acquired resistance is that which occurs as a result of specific previous treatment The level of primary resistance in the community is considered to reflect the efficacy of control measures in the past while the level of acquired resistance is a measure of on-going TB control measuresDrTVRao MD 52
Extreme Drug resistant Tuberculosis (XDR-TB)
Resistant to all first line drugs namely Isoniazid and Rifampin and Three or more second line drugs (SLDrsquoS) that are used to treat MDR-TB Thequinalones like Ofloaxin
Or Aminoglycosides like Capreomycin amp
Kanamycin
No third-line drugs available to treat XDR-TB since none has been developed in the last 40 years
DrTVRao MD 53
Background Extensively drug-resistant tuberculosis
Extensively drug-resistant tuberculosis has been reported in 45 countries including countries with limited resources and a high burden of tuberculosis
DrTVRao MD 54
DrTVRao MD 55
Transmissionof X -MDR
Like other forms of TB XDR-TB is spread through the air When a person with infectious TB coughs sneezes talks or spits they propel Mycobacterium into the air
DrTVRao MD 56
Best options to diagnoseX-MDR tuberculosis
To evaluate drug susceptibility the bacteria need to be cultivated and tested in a suitable laboratory Final diagnosis in this way for TB and especially for XDR-TB may take from 6 to 16 weeks To reduce the time needed for diagnosis new tools for rapid TB diagnosis are urgently needed
DrTVRao MD 57
When to suspect MDR TB
Patients not showing any reduction
in bacillary population after 3-
months of regular treatment with
Cat II regimen
Sputum positive patients who are
contacts of a known MDR TB
patient
DrTVRao MD 58
How to evaluate MDR TB
MDR TB is only a laboratory
proved HR resistance
Clinical suspicion should be
followed by lab Confirmation
Laboratories should be quality
controlledTRC
DrTVRao MD 59
Extreme Drug resistant Tuberculosis (XDR-TB) and AIDS
It can also be contracted without a patient receiving any previous treatment for TB
Mostly associated with HIV positive patients
HIV has the potential to fast tracking XDR-TB into an uncontrollable epidemic
Average survival period for patients infected with XDR-TB is 16 days
DrTVRao MD 60
Responding to MDRXDR-TB
Augment DOTS Program by
New diagnostics
New drugs New vaccines HIV incidence
reduction Advocacy1
A mathematical model projected by Basu and co-workers indicates that half of XDR-TB can be averted by 2012 by bringing synergistic effects through
Use of masks Reduced time as in-patient Improved ventilation Rapid resistance testing HIV treatment TB isolation facilities2
1Marteens and Wilkinson Lancet 20073702030-432Basu et al Quoted in Porco and Getz Lancet 20073701464-5
DrTVRao MD 61
Second Line Drug Treatment (SLDrsquos)
Less effective more costly and more toxic 50 cure rate
Four months intensive phase (5 drugs) Kanamycins Ethionamide Pyrazinamide Ofloxacin Cycloserine or Ethambutol DrTVRao MD 62
World Health Organisation (WHO) Guidelines for treatment
of MDR-TB
Strengthen basic TB care to prevent the emergence of drug-resistance
Ensure prompt diagnosis and treatment of drug resistant cases to cure existing cases and prevent further transmission
Increase collaboration between HIV and TB control programmes to provide necessary prevention and care to co-infected patients
Increase investment in laboratory infrastructures to enable better detection and management of resistant cases
DrTVRao MD 63
Treatment Guidelines
Sensitivity testing for all smear positive specimens
Patient Family and staff counselling amp education
Correct and thorough hand washing protocol and procedure
Personal protection is very important
DrTVRao MD 64
THE NEW MDR-TB Guidelines
A flexible framework approach combining both clinical and programmatic aspects of DOTS Plus based on essential programme conditions
But encouraging programs to tailor their case-finding and treatment strategies to the local epidemiological and Programme situation
Reflect GLC expert consensus and evidence and experience from GLC projects thus far
DrTVRao MD 65
Effective laboratory Diagnosis
Sputum smear examinations ndash rapid classification of species (atypical mycobacteria common in AIDS)
Culture examinations
Rapid drug sensitivity testingDrTVRao MD 66
MDR TB and HIV
MDR TB occurs with the same frequency in HIV
patients as in TB patients who are smear negative
Transmission of drug-resistant strains among HIV-
infected patients in congregate settings occurs
leading to lsquooutbreaksrsquo of MDR TB in such settings
Infection control measures absolutely essential in
settings where large number of HIV TB patients stay
togetherDrTVRao MD 67
Transmission is dependent on closeness and time of contact
In penitentiary care contacts are very close and prolonged ndash culture positive cases can also transmit TB especially to HIV positive population
DrTVRao MD 68
To Know more on MDR ndashTB Current Guidelines of WHO
Guidelines for the programmatic management of drug-resistant tuberculosis - 2011 update [pdf 904kb]
Visit helliphelliphellip WHOHTMTB20116DrTVRao MD 69
Are there any solutions for effective
Diagnosis in TB
DrTVRao MD 70
Programme Created by DrTVRao MD for Medical and Health Care
Workers in the Developing World Email
doctortvraogmailcom
DrTVRao MD 71
No one is Immune to TuberculosisNot only infects poor but famous
too
DrTVRao MD 12
Multi Drug Resistant
TuberculosisMDR-TB
DrTVRao MD 13
Definition
MDR-TB caused by strains of Mycobacterium Tuberculosis resistant both Rifampicin and Isoniazid with or without resistance to other drugs
Single Isoniazid or Rifampicin resistance is not MDR - TB
MDR TB is a laboratory diagnosis
DrTVRao MD 14
Classification of Drugs 3 Groups depending upon the degree
of effectiveness and potential side effects First Line (Primary agents)
are the most effective and have lowest toxicity Isoniazid Rifampin
Second LineLess effective and more toxic effectsinclude (in no particular order) p-amino
salicylic acid Streptomycin Ethambutol Third Line
are least effective and most toxic Amikacin Kanamycin Capreomycin Viomycin Kanamycin Cycloserine
DrTVRao MD 15
Basic concepts ndash Keep facts
Primary (Initial) resistanceTB patientrsquos initial Mycobacterium
tuberculosis population resistant to drugs
Secondary (Acquired) resistanceDrug-resistant M tuberculosis in initial
population selected by inappropriate drug use (inadequate treatment or non-adherence) DrTVRao MD 16
When to suspect MDR TB
Re-treatment patients whorsquos sputum smear remains positive after three monthsrsquo of intensive therapy
Treatment failure and interruption cases
Close contacts of MDR tuberculosis cases
Positive diagnoses with TB culture and susceptibility testing DrTVRao MD 17
What is extensively drug resistant tuberculosis (XDR TB)
Extensively drug resistant TB (XDR TB) is a relatively rare type of MDR TB XDR TB is defined as TB which is resistant to isoniazid and rifampin plus resistant to any fluoroquinolone and at least one of three injectable second-line drugs (ie amikacin kanamycin or capreomycin)DrTVRao MD 18
Why XDR - TB a grave concern
Because XDR TB is resistant to first-line and second line drugs patients are left with treatment options that are much less effective
XDR TB is of special concern for persons with HIV infection or other conditions that can weaken the immune system These persons are more likely to develop TB disease once they are infected and also have a higher risk of death once they develop TB
DrTVRao MD 19
Global Estimates
Classification
Estimated Number of Cases
Estimated Number of
Deaths
All forms TB
88 million 16 million
MDR TB 424000 116000
XDR TB 27000 16000
DrTVRao MD 20
Extensively Drug-Resistant Mycobacterium tuberculosis
India
The first XDR TB cases in India and the emergence of XDR TB is reported by Rajesh Mondal and Amita Jain King Georges Medical University Lucknow India Volume 13 Number 9ndashSeptember 2007 in Emerging Infectious Diseases
DrTVRao MD 21
Drug susceptible TBsect
MDR-TB
1990sect
XDR-TB
2006sect
Total DR
Resistance to HampR ndash
Treatable with 2nd line drugs
Resistance to 2nd line drugs ndashTreatment options seriously restricted
Resistance to all available drugs ndash
No treatment options
or limited resistance manageable with 4 drug regimen - DOTS
Are we Returning to a Pre-antibiotic Era
DrTVRao MD 22
Genesis of MDR TB
Resistance is a man-made amplification of a natural phenomenon
Inadequate drug delivery is main cause of secondary drug resistance
Secondary drug resistance is the main cause of primary drug resistance due to transmission of resistant strains
MDR due to spontaneous mutations is not possible as the genes encoding resistance for anti TB are unlinked
DrTVRao MD 23
Factors Contributing to Development
and Spread of MDR and XDR TB Weak TB programs (DOTS)
Low completioncure rates Lack of treatment follow up and
patient support Unreliable drug supply Diagnostic delay
Absent or inadequate infection control measures
Uncontrolled use of 2nd line drugs Fluroquinolones
DrTVRao MD 24
INHChromosomally mediatedLoss of catalaseperoxidaseMutation in mycolic acid synthesis
Regulators of peroxide response
Mechanism of resistance
DrTVRao MD 25
RifampinReduced binding to RNA polymeraseClusters of mutations at ldquoRifampin Resistance Determining Regionrdquo (RRDR)
Reduced Cell wall permeability
Mechanism of resistance
DrTVRao MD 26
Gene location associated Drug-Resistant
Mtuberculosis Drug Gene Isoniazid Kat G Inh A Kas
A Rifampicin rpo B Ethambutol emb B Streptomycin rps L Pyrazinamide pnc A Fluoroquinolones gyr A
Dubaniewicz A et al Molecular sub-type of the HLA-DR antigens in pulmonary tuberculosis Int J Infect Dis20004129-33
DrTVRao MD 27
Current Scientific Documentations on Drug Resistance in
Tuberculosis
DrTVRao MD 28
Alarming Rise of Resistant TuberculosisWHO Report on
Anti-TB Drug Resistance
490000 new cases of MDR-TB each year with gt110000 deaths1
Accounts for 5 of 9 million new cases of TB2
MDR-TB rates higher than ever (up to 223) particularly in former Soviet Union countries
XDR-TB reported by as many as 49 countries (by June 2008)3
Recent WHOIUATLD Global Surveillance report indicated 75 (3014012) of MDR TB to be XDR4
Around 40000 XDR-TB cases emerge every year1
1Tuberculosis MDR-TB amp XDR-TBmdashThe 2008 Report The Stop TB Department WHO2Hargreaves S httpinfectionthelancetcom Vol 8 April 2008 p2203Raviglione MC NEJM 2008359636-84Anti-TB Drug Resistance in the World Report No 4 The WHOIUATLD Global Project on Anti-Tuberculosis Drug Resistance Surveillance 2002-2007 World Health Organization 2008 (WHOHTMTB2008394)
DrTVRao MD 29
MDR-TB amp XDR-TBTHE 2008 REPORT
of MDR-TB among new TB cases 1994-2007
DrTVRao MD 30
MDR-TB rates higher than ever (up to 223) particularly in former Soviet Union countries
DrTVRao MD 31
Alarming Rise of Resistant TB
Resistant TB burden in countries of former Soviet Union about 50 of cases resistant to at least one drug about 20 MDR XDR-TB proportions also higher (as high as 24 in
Estonia)1
MDRXDR TB ndash essentially a man-made problem2
High numbers of resistant cases (gt400000 MDR-TB cases every year) due mainly to Underinvestment in basic TB control Poor management of anti-TB drugs Transmission of drug resistant strains1
1Anti-TB Drug Resistance in the World Report No 4 The WHOIUATLD Global Project on Anti-Tuberculosis Drug Resistance Surveillance 2002-2007 World Health Organization 2008 (WHOHTMTB2008394)
2Reichman The Lancet 20083711052-3
DrTVRao MD 32
The Much Discussed Article on XDR TB in the Lancet
Of the 221 multi-drug resistant (MDR-TB) cases 53 (24) were XDR
Almost all (52 of 53) of the XDR-TB patients died with a median survival of only 16 days from the time of diagnosis (in the 42 patients with confirmed dates of death)
All the 44 XDR TB patients who were tested for HIV were found co-infected
55 patents had never received anti-TB drugs suggesting primary transmission of XDR pathogen
67 patients had been admitted to the hospital in the preceding 2 years suggesting potential role of nosocomial transmission
Gandhi et al Lancet 20063681575-80DrTVRao MD 33
Poor mangement of infected lead to grwoing resistance
Resistance to anti-TB drugs in populations is a phenomenon that occurs primarily due to poorly managed TB care Problems include incorrect drug prescribing practices by providers poor quality drugs or erratic supply of drugs and also patient non-adherence DrTVRao MD 34
Susceptibility Testing
1048708 Direct and indirect testing1048708 Primary Drugs testing1048708 Isoniazid1048708 Rifampicin1048708 Ethambutol ()1048708 Pyrizinamide ()
DrTVRao MD 35
Drug susceptibility testing (DST)
DST is recommended for all new cases for all first line drugs with specimens taken before initiating treatment
Accuracy is more important than speed DST results should come from a small
number of well-equipped experienced laboratories who participate and perform well in an international DST quality control scheme
The WHO Supranational Laboratory Quality Control Network offers the greatest global coverage for this
DrTVRao MD 36
Drug susceptibility Testing
Assessment of growth inhibition on solid media containing various dilutions of the drug in comparison with the test strains
As the method depend observation of growth Results are not available until several weeks after isolation of the organism
DrTVRao MD 37
Other accredited Methods
Radiometric and Non radiometric methods
Nucleic acid technology ndash effective upto 95 in mutations to rifampicin resistance to gene rpoB gene
DrTVRao MD 38
Drug susceptibility testing (DST)
As a minimum laboratories supplying DST data should correctly identify resistance to isoniazid and rifampicin in over 90 of quality control samples in two out of the last three quality control roundsDrTVRao MD 39
Detection of Rifampicin Drug susceptibility testing (DST) is more important
Early identification of mycobacterial growth as M tuberculosis complex and the identification of rifampicin resistance should be the first priority as rifampicin resistance invalidates standard 6 month short-course chemotherapy and is a useful marker in most countries for MDR-TB
Laboratories should aim to identify isolates as M tuberculosis complex and perform rifampicin resistance in 90 of isolates within 1-2 working days This is technologically feasible
DrTVRao MD 40
Drug susceptibility testing
For DST laboratories modern molecular techniques permit the successful identification of isoniazid resistance in at least 75 of mycobacterial cultures within 1-2 working days and are useful preliminary screens for isoniazid resistance
DrTVRao MD 41
Secondary Drugs testing [lack of standardized
methods]
Ofloxacin quinolonesEthionamide KanamycinCapreomycin Ensure quality control and
quality assurance
DrTVRao MD 42
WHO Controls the Tuberculosis related work
The laboratory methods for anti-tuberculosis drug susceptibility testing should be selected from among those that are WHO-recommended and all laboratory processes should be quality-assured in cooperation with a partner Supranational Reference Laboratory (SRL)DrTVRao MD 43
Other WHO-Endorsed Tools
Liquid culture (eg MGIT BacTALERT)
Capilia TB Rapid strip test that detects a TB-
specific antigen from culture
Molecular line probe assays (eg GenoType MTBDRplus INNO-LiPA RifTB) Strip test for detection of TB and
drug-resistance conferring mutations
DrTVRao MD 44
BacTALERTreg
DrTVRao MD 45
CDC Updates Guidelines for Nucleic AcidAmplification Techniques to Diagnose
Tuberculosis
NAAT results should be interpreted in conjunction with the AFB smear results
NAAT and smear positive start Rx despite pending culture results PPV 95
Smear negative NAAT positive use clinical judgment to either treat or await culture
DrTVRao MD 46
Selection from automated systems for molecular and
bacteriological rapid diagnostics
PCRRocheCOBASreg Amplicorreg
amplification kitsRocheCOBASreg LightCyclerreg
(real-time-PCR)RocheCOBASreg TaqMan 48reg(increases the specificity of real-
time-PCR)
DrTVRao MD 47
Molecular Fingerprinting
26 of 30 (87) XDR TB isolates found to be genetically similar
Majority of patients had no previous history of TB treatment Suggestive of recent infection with drug-resistant strain
DrTVRao MD 48
Is PCR methods a solution
PCR cant yet replace neither microscopy culturing and competent clinical examination
DrTVRao MD 49
No testing method replaces Clinical assessment
DrTVRao MD 50
XDR-TBThe description
of XDR-TB was first used earlier in 2006 following a joint survey by WHO and the US Centres for Disease Control and Prevention (CDC) DrTVRao MD 51
How x-MDR generated
Acquired resistance is that which occurs as a result of specific previous treatment The level of primary resistance in the community is considered to reflect the efficacy of control measures in the past while the level of acquired resistance is a measure of on-going TB control measuresDrTVRao MD 52
Extreme Drug resistant Tuberculosis (XDR-TB)
Resistant to all first line drugs namely Isoniazid and Rifampin and Three or more second line drugs (SLDrsquoS) that are used to treat MDR-TB Thequinalones like Ofloaxin
Or Aminoglycosides like Capreomycin amp
Kanamycin
No third-line drugs available to treat XDR-TB since none has been developed in the last 40 years
DrTVRao MD 53
Background Extensively drug-resistant tuberculosis
Extensively drug-resistant tuberculosis has been reported in 45 countries including countries with limited resources and a high burden of tuberculosis
DrTVRao MD 54
DrTVRao MD 55
Transmissionof X -MDR
Like other forms of TB XDR-TB is spread through the air When a person with infectious TB coughs sneezes talks or spits they propel Mycobacterium into the air
DrTVRao MD 56
Best options to diagnoseX-MDR tuberculosis
To evaluate drug susceptibility the bacteria need to be cultivated and tested in a suitable laboratory Final diagnosis in this way for TB and especially for XDR-TB may take from 6 to 16 weeks To reduce the time needed for diagnosis new tools for rapid TB diagnosis are urgently needed
DrTVRao MD 57
When to suspect MDR TB
Patients not showing any reduction
in bacillary population after 3-
months of regular treatment with
Cat II regimen
Sputum positive patients who are
contacts of a known MDR TB
patient
DrTVRao MD 58
How to evaluate MDR TB
MDR TB is only a laboratory
proved HR resistance
Clinical suspicion should be
followed by lab Confirmation
Laboratories should be quality
controlledTRC
DrTVRao MD 59
Extreme Drug resistant Tuberculosis (XDR-TB) and AIDS
It can also be contracted without a patient receiving any previous treatment for TB
Mostly associated with HIV positive patients
HIV has the potential to fast tracking XDR-TB into an uncontrollable epidemic
Average survival period for patients infected with XDR-TB is 16 days
DrTVRao MD 60
Responding to MDRXDR-TB
Augment DOTS Program by
New diagnostics
New drugs New vaccines HIV incidence
reduction Advocacy1
A mathematical model projected by Basu and co-workers indicates that half of XDR-TB can be averted by 2012 by bringing synergistic effects through
Use of masks Reduced time as in-patient Improved ventilation Rapid resistance testing HIV treatment TB isolation facilities2
1Marteens and Wilkinson Lancet 20073702030-432Basu et al Quoted in Porco and Getz Lancet 20073701464-5
DrTVRao MD 61
Second Line Drug Treatment (SLDrsquos)
Less effective more costly and more toxic 50 cure rate
Four months intensive phase (5 drugs) Kanamycins Ethionamide Pyrazinamide Ofloxacin Cycloserine or Ethambutol DrTVRao MD 62
World Health Organisation (WHO) Guidelines for treatment
of MDR-TB
Strengthen basic TB care to prevent the emergence of drug-resistance
Ensure prompt diagnosis and treatment of drug resistant cases to cure existing cases and prevent further transmission
Increase collaboration between HIV and TB control programmes to provide necessary prevention and care to co-infected patients
Increase investment in laboratory infrastructures to enable better detection and management of resistant cases
DrTVRao MD 63
Treatment Guidelines
Sensitivity testing for all smear positive specimens
Patient Family and staff counselling amp education
Correct and thorough hand washing protocol and procedure
Personal protection is very important
DrTVRao MD 64
THE NEW MDR-TB Guidelines
A flexible framework approach combining both clinical and programmatic aspects of DOTS Plus based on essential programme conditions
But encouraging programs to tailor their case-finding and treatment strategies to the local epidemiological and Programme situation
Reflect GLC expert consensus and evidence and experience from GLC projects thus far
DrTVRao MD 65
Effective laboratory Diagnosis
Sputum smear examinations ndash rapid classification of species (atypical mycobacteria common in AIDS)
Culture examinations
Rapid drug sensitivity testingDrTVRao MD 66
MDR TB and HIV
MDR TB occurs with the same frequency in HIV
patients as in TB patients who are smear negative
Transmission of drug-resistant strains among HIV-
infected patients in congregate settings occurs
leading to lsquooutbreaksrsquo of MDR TB in such settings
Infection control measures absolutely essential in
settings where large number of HIV TB patients stay
togetherDrTVRao MD 67
Transmission is dependent on closeness and time of contact
In penitentiary care contacts are very close and prolonged ndash culture positive cases can also transmit TB especially to HIV positive population
DrTVRao MD 68
To Know more on MDR ndashTB Current Guidelines of WHO
Guidelines for the programmatic management of drug-resistant tuberculosis - 2011 update [pdf 904kb]
Visit helliphelliphellip WHOHTMTB20116DrTVRao MD 69
Are there any solutions for effective
Diagnosis in TB
DrTVRao MD 70
Programme Created by DrTVRao MD for Medical and Health Care
Workers in the Developing World Email
doctortvraogmailcom
DrTVRao MD 71
Multi Drug Resistant
TuberculosisMDR-TB
DrTVRao MD 13
Definition
MDR-TB caused by strains of Mycobacterium Tuberculosis resistant both Rifampicin and Isoniazid with or without resistance to other drugs
Single Isoniazid or Rifampicin resistance is not MDR - TB
MDR TB is a laboratory diagnosis
DrTVRao MD 14
Classification of Drugs 3 Groups depending upon the degree
of effectiveness and potential side effects First Line (Primary agents)
are the most effective and have lowest toxicity Isoniazid Rifampin
Second LineLess effective and more toxic effectsinclude (in no particular order) p-amino
salicylic acid Streptomycin Ethambutol Third Line
are least effective and most toxic Amikacin Kanamycin Capreomycin Viomycin Kanamycin Cycloserine
DrTVRao MD 15
Basic concepts ndash Keep facts
Primary (Initial) resistanceTB patientrsquos initial Mycobacterium
tuberculosis population resistant to drugs
Secondary (Acquired) resistanceDrug-resistant M tuberculosis in initial
population selected by inappropriate drug use (inadequate treatment or non-adherence) DrTVRao MD 16
When to suspect MDR TB
Re-treatment patients whorsquos sputum smear remains positive after three monthsrsquo of intensive therapy
Treatment failure and interruption cases
Close contacts of MDR tuberculosis cases
Positive diagnoses with TB culture and susceptibility testing DrTVRao MD 17
What is extensively drug resistant tuberculosis (XDR TB)
Extensively drug resistant TB (XDR TB) is a relatively rare type of MDR TB XDR TB is defined as TB which is resistant to isoniazid and rifampin plus resistant to any fluoroquinolone and at least one of three injectable second-line drugs (ie amikacin kanamycin or capreomycin)DrTVRao MD 18
Why XDR - TB a grave concern
Because XDR TB is resistant to first-line and second line drugs patients are left with treatment options that are much less effective
XDR TB is of special concern for persons with HIV infection or other conditions that can weaken the immune system These persons are more likely to develop TB disease once they are infected and also have a higher risk of death once they develop TB
DrTVRao MD 19
Global Estimates
Classification
Estimated Number of Cases
Estimated Number of
Deaths
All forms TB
88 million 16 million
MDR TB 424000 116000
XDR TB 27000 16000
DrTVRao MD 20
Extensively Drug-Resistant Mycobacterium tuberculosis
India
The first XDR TB cases in India and the emergence of XDR TB is reported by Rajesh Mondal and Amita Jain King Georges Medical University Lucknow India Volume 13 Number 9ndashSeptember 2007 in Emerging Infectious Diseases
DrTVRao MD 21
Drug susceptible TBsect
MDR-TB
1990sect
XDR-TB
2006sect
Total DR
Resistance to HampR ndash
Treatable with 2nd line drugs
Resistance to 2nd line drugs ndashTreatment options seriously restricted
Resistance to all available drugs ndash
No treatment options
or limited resistance manageable with 4 drug regimen - DOTS
Are we Returning to a Pre-antibiotic Era
DrTVRao MD 22
Genesis of MDR TB
Resistance is a man-made amplification of a natural phenomenon
Inadequate drug delivery is main cause of secondary drug resistance
Secondary drug resistance is the main cause of primary drug resistance due to transmission of resistant strains
MDR due to spontaneous mutations is not possible as the genes encoding resistance for anti TB are unlinked
DrTVRao MD 23
Factors Contributing to Development
and Spread of MDR and XDR TB Weak TB programs (DOTS)
Low completioncure rates Lack of treatment follow up and
patient support Unreliable drug supply Diagnostic delay
Absent or inadequate infection control measures
Uncontrolled use of 2nd line drugs Fluroquinolones
DrTVRao MD 24
INHChromosomally mediatedLoss of catalaseperoxidaseMutation in mycolic acid synthesis
Regulators of peroxide response
Mechanism of resistance
DrTVRao MD 25
RifampinReduced binding to RNA polymeraseClusters of mutations at ldquoRifampin Resistance Determining Regionrdquo (RRDR)
Reduced Cell wall permeability
Mechanism of resistance
DrTVRao MD 26
Gene location associated Drug-Resistant
Mtuberculosis Drug Gene Isoniazid Kat G Inh A Kas
A Rifampicin rpo B Ethambutol emb B Streptomycin rps L Pyrazinamide pnc A Fluoroquinolones gyr A
Dubaniewicz A et al Molecular sub-type of the HLA-DR antigens in pulmonary tuberculosis Int J Infect Dis20004129-33
DrTVRao MD 27
Current Scientific Documentations on Drug Resistance in
Tuberculosis
DrTVRao MD 28
Alarming Rise of Resistant TuberculosisWHO Report on
Anti-TB Drug Resistance
490000 new cases of MDR-TB each year with gt110000 deaths1
Accounts for 5 of 9 million new cases of TB2
MDR-TB rates higher than ever (up to 223) particularly in former Soviet Union countries
XDR-TB reported by as many as 49 countries (by June 2008)3
Recent WHOIUATLD Global Surveillance report indicated 75 (3014012) of MDR TB to be XDR4
Around 40000 XDR-TB cases emerge every year1
1Tuberculosis MDR-TB amp XDR-TBmdashThe 2008 Report The Stop TB Department WHO2Hargreaves S httpinfectionthelancetcom Vol 8 April 2008 p2203Raviglione MC NEJM 2008359636-84Anti-TB Drug Resistance in the World Report No 4 The WHOIUATLD Global Project on Anti-Tuberculosis Drug Resistance Surveillance 2002-2007 World Health Organization 2008 (WHOHTMTB2008394)
DrTVRao MD 29
MDR-TB amp XDR-TBTHE 2008 REPORT
of MDR-TB among new TB cases 1994-2007
DrTVRao MD 30
MDR-TB rates higher than ever (up to 223) particularly in former Soviet Union countries
DrTVRao MD 31
Alarming Rise of Resistant TB
Resistant TB burden in countries of former Soviet Union about 50 of cases resistant to at least one drug about 20 MDR XDR-TB proportions also higher (as high as 24 in
Estonia)1
MDRXDR TB ndash essentially a man-made problem2
High numbers of resistant cases (gt400000 MDR-TB cases every year) due mainly to Underinvestment in basic TB control Poor management of anti-TB drugs Transmission of drug resistant strains1
1Anti-TB Drug Resistance in the World Report No 4 The WHOIUATLD Global Project on Anti-Tuberculosis Drug Resistance Surveillance 2002-2007 World Health Organization 2008 (WHOHTMTB2008394)
2Reichman The Lancet 20083711052-3
DrTVRao MD 32
The Much Discussed Article on XDR TB in the Lancet
Of the 221 multi-drug resistant (MDR-TB) cases 53 (24) were XDR
Almost all (52 of 53) of the XDR-TB patients died with a median survival of only 16 days from the time of diagnosis (in the 42 patients with confirmed dates of death)
All the 44 XDR TB patients who were tested for HIV were found co-infected
55 patents had never received anti-TB drugs suggesting primary transmission of XDR pathogen
67 patients had been admitted to the hospital in the preceding 2 years suggesting potential role of nosocomial transmission
Gandhi et al Lancet 20063681575-80DrTVRao MD 33
Poor mangement of infected lead to grwoing resistance
Resistance to anti-TB drugs in populations is a phenomenon that occurs primarily due to poorly managed TB care Problems include incorrect drug prescribing practices by providers poor quality drugs or erratic supply of drugs and also patient non-adherence DrTVRao MD 34
Susceptibility Testing
1048708 Direct and indirect testing1048708 Primary Drugs testing1048708 Isoniazid1048708 Rifampicin1048708 Ethambutol ()1048708 Pyrizinamide ()
DrTVRao MD 35
Drug susceptibility testing (DST)
DST is recommended for all new cases for all first line drugs with specimens taken before initiating treatment
Accuracy is more important than speed DST results should come from a small
number of well-equipped experienced laboratories who participate and perform well in an international DST quality control scheme
The WHO Supranational Laboratory Quality Control Network offers the greatest global coverage for this
DrTVRao MD 36
Drug susceptibility Testing
Assessment of growth inhibition on solid media containing various dilutions of the drug in comparison with the test strains
As the method depend observation of growth Results are not available until several weeks after isolation of the organism
DrTVRao MD 37
Other accredited Methods
Radiometric and Non radiometric methods
Nucleic acid technology ndash effective upto 95 in mutations to rifampicin resistance to gene rpoB gene
DrTVRao MD 38
Drug susceptibility testing (DST)
As a minimum laboratories supplying DST data should correctly identify resistance to isoniazid and rifampicin in over 90 of quality control samples in two out of the last three quality control roundsDrTVRao MD 39
Detection of Rifampicin Drug susceptibility testing (DST) is more important
Early identification of mycobacterial growth as M tuberculosis complex and the identification of rifampicin resistance should be the first priority as rifampicin resistance invalidates standard 6 month short-course chemotherapy and is a useful marker in most countries for MDR-TB
Laboratories should aim to identify isolates as M tuberculosis complex and perform rifampicin resistance in 90 of isolates within 1-2 working days This is technologically feasible
DrTVRao MD 40
Drug susceptibility testing
For DST laboratories modern molecular techniques permit the successful identification of isoniazid resistance in at least 75 of mycobacterial cultures within 1-2 working days and are useful preliminary screens for isoniazid resistance
DrTVRao MD 41
Secondary Drugs testing [lack of standardized
methods]
Ofloxacin quinolonesEthionamide KanamycinCapreomycin Ensure quality control and
quality assurance
DrTVRao MD 42
WHO Controls the Tuberculosis related work
The laboratory methods for anti-tuberculosis drug susceptibility testing should be selected from among those that are WHO-recommended and all laboratory processes should be quality-assured in cooperation with a partner Supranational Reference Laboratory (SRL)DrTVRao MD 43
Other WHO-Endorsed Tools
Liquid culture (eg MGIT BacTALERT)
Capilia TB Rapid strip test that detects a TB-
specific antigen from culture
Molecular line probe assays (eg GenoType MTBDRplus INNO-LiPA RifTB) Strip test for detection of TB and
drug-resistance conferring mutations
DrTVRao MD 44
BacTALERTreg
DrTVRao MD 45
CDC Updates Guidelines for Nucleic AcidAmplification Techniques to Diagnose
Tuberculosis
NAAT results should be interpreted in conjunction with the AFB smear results
NAAT and smear positive start Rx despite pending culture results PPV 95
Smear negative NAAT positive use clinical judgment to either treat or await culture
DrTVRao MD 46
Selection from automated systems for molecular and
bacteriological rapid diagnostics
PCRRocheCOBASreg Amplicorreg
amplification kitsRocheCOBASreg LightCyclerreg
(real-time-PCR)RocheCOBASreg TaqMan 48reg(increases the specificity of real-
time-PCR)
DrTVRao MD 47
Molecular Fingerprinting
26 of 30 (87) XDR TB isolates found to be genetically similar
Majority of patients had no previous history of TB treatment Suggestive of recent infection with drug-resistant strain
DrTVRao MD 48
Is PCR methods a solution
PCR cant yet replace neither microscopy culturing and competent clinical examination
DrTVRao MD 49
No testing method replaces Clinical assessment
DrTVRao MD 50
XDR-TBThe description
of XDR-TB was first used earlier in 2006 following a joint survey by WHO and the US Centres for Disease Control and Prevention (CDC) DrTVRao MD 51
How x-MDR generated
Acquired resistance is that which occurs as a result of specific previous treatment The level of primary resistance in the community is considered to reflect the efficacy of control measures in the past while the level of acquired resistance is a measure of on-going TB control measuresDrTVRao MD 52
Extreme Drug resistant Tuberculosis (XDR-TB)
Resistant to all first line drugs namely Isoniazid and Rifampin and Three or more second line drugs (SLDrsquoS) that are used to treat MDR-TB Thequinalones like Ofloaxin
Or Aminoglycosides like Capreomycin amp
Kanamycin
No third-line drugs available to treat XDR-TB since none has been developed in the last 40 years
DrTVRao MD 53
Background Extensively drug-resistant tuberculosis
Extensively drug-resistant tuberculosis has been reported in 45 countries including countries with limited resources and a high burden of tuberculosis
DrTVRao MD 54
DrTVRao MD 55
Transmissionof X -MDR
Like other forms of TB XDR-TB is spread through the air When a person with infectious TB coughs sneezes talks or spits they propel Mycobacterium into the air
DrTVRao MD 56
Best options to diagnoseX-MDR tuberculosis
To evaluate drug susceptibility the bacteria need to be cultivated and tested in a suitable laboratory Final diagnosis in this way for TB and especially for XDR-TB may take from 6 to 16 weeks To reduce the time needed for diagnosis new tools for rapid TB diagnosis are urgently needed
DrTVRao MD 57
When to suspect MDR TB
Patients not showing any reduction
in bacillary population after 3-
months of regular treatment with
Cat II regimen
Sputum positive patients who are
contacts of a known MDR TB
patient
DrTVRao MD 58
How to evaluate MDR TB
MDR TB is only a laboratory
proved HR resistance
Clinical suspicion should be
followed by lab Confirmation
Laboratories should be quality
controlledTRC
DrTVRao MD 59
Extreme Drug resistant Tuberculosis (XDR-TB) and AIDS
It can also be contracted without a patient receiving any previous treatment for TB
Mostly associated with HIV positive patients
HIV has the potential to fast tracking XDR-TB into an uncontrollable epidemic
Average survival period for patients infected with XDR-TB is 16 days
DrTVRao MD 60
Responding to MDRXDR-TB
Augment DOTS Program by
New diagnostics
New drugs New vaccines HIV incidence
reduction Advocacy1
A mathematical model projected by Basu and co-workers indicates that half of XDR-TB can be averted by 2012 by bringing synergistic effects through
Use of masks Reduced time as in-patient Improved ventilation Rapid resistance testing HIV treatment TB isolation facilities2
1Marteens and Wilkinson Lancet 20073702030-432Basu et al Quoted in Porco and Getz Lancet 20073701464-5
DrTVRao MD 61
Second Line Drug Treatment (SLDrsquos)
Less effective more costly and more toxic 50 cure rate
Four months intensive phase (5 drugs) Kanamycins Ethionamide Pyrazinamide Ofloxacin Cycloserine or Ethambutol DrTVRao MD 62
World Health Organisation (WHO) Guidelines for treatment
of MDR-TB
Strengthen basic TB care to prevent the emergence of drug-resistance
Ensure prompt diagnosis and treatment of drug resistant cases to cure existing cases and prevent further transmission
Increase collaboration between HIV and TB control programmes to provide necessary prevention and care to co-infected patients
Increase investment in laboratory infrastructures to enable better detection and management of resistant cases
DrTVRao MD 63
Treatment Guidelines
Sensitivity testing for all smear positive specimens
Patient Family and staff counselling amp education
Correct and thorough hand washing protocol and procedure
Personal protection is very important
DrTVRao MD 64
THE NEW MDR-TB Guidelines
A flexible framework approach combining both clinical and programmatic aspects of DOTS Plus based on essential programme conditions
But encouraging programs to tailor their case-finding and treatment strategies to the local epidemiological and Programme situation
Reflect GLC expert consensus and evidence and experience from GLC projects thus far
DrTVRao MD 65
Effective laboratory Diagnosis
Sputum smear examinations ndash rapid classification of species (atypical mycobacteria common in AIDS)
Culture examinations
Rapid drug sensitivity testingDrTVRao MD 66
MDR TB and HIV
MDR TB occurs with the same frequency in HIV
patients as in TB patients who are smear negative
Transmission of drug-resistant strains among HIV-
infected patients in congregate settings occurs
leading to lsquooutbreaksrsquo of MDR TB in such settings
Infection control measures absolutely essential in
settings where large number of HIV TB patients stay
togetherDrTVRao MD 67
Transmission is dependent on closeness and time of contact
In penitentiary care contacts are very close and prolonged ndash culture positive cases can also transmit TB especially to HIV positive population
DrTVRao MD 68
To Know more on MDR ndashTB Current Guidelines of WHO
Guidelines for the programmatic management of drug-resistant tuberculosis - 2011 update [pdf 904kb]
Visit helliphelliphellip WHOHTMTB20116DrTVRao MD 69
Are there any solutions for effective
Diagnosis in TB
DrTVRao MD 70
Programme Created by DrTVRao MD for Medical and Health Care
Workers in the Developing World Email
doctortvraogmailcom
DrTVRao MD 71
Definition
MDR-TB caused by strains of Mycobacterium Tuberculosis resistant both Rifampicin and Isoniazid with or without resistance to other drugs
Single Isoniazid or Rifampicin resistance is not MDR - TB
MDR TB is a laboratory diagnosis
DrTVRao MD 14
Classification of Drugs 3 Groups depending upon the degree
of effectiveness and potential side effects First Line (Primary agents)
are the most effective and have lowest toxicity Isoniazid Rifampin
Second LineLess effective and more toxic effectsinclude (in no particular order) p-amino
salicylic acid Streptomycin Ethambutol Third Line
are least effective and most toxic Amikacin Kanamycin Capreomycin Viomycin Kanamycin Cycloserine
DrTVRao MD 15
Basic concepts ndash Keep facts
Primary (Initial) resistanceTB patientrsquos initial Mycobacterium
tuberculosis population resistant to drugs
Secondary (Acquired) resistanceDrug-resistant M tuberculosis in initial
population selected by inappropriate drug use (inadequate treatment or non-adherence) DrTVRao MD 16
When to suspect MDR TB
Re-treatment patients whorsquos sputum smear remains positive after three monthsrsquo of intensive therapy
Treatment failure and interruption cases
Close contacts of MDR tuberculosis cases
Positive diagnoses with TB culture and susceptibility testing DrTVRao MD 17
What is extensively drug resistant tuberculosis (XDR TB)
Extensively drug resistant TB (XDR TB) is a relatively rare type of MDR TB XDR TB is defined as TB which is resistant to isoniazid and rifampin plus resistant to any fluoroquinolone and at least one of three injectable second-line drugs (ie amikacin kanamycin or capreomycin)DrTVRao MD 18
Why XDR - TB a grave concern
Because XDR TB is resistant to first-line and second line drugs patients are left with treatment options that are much less effective
XDR TB is of special concern for persons with HIV infection or other conditions that can weaken the immune system These persons are more likely to develop TB disease once they are infected and also have a higher risk of death once they develop TB
DrTVRao MD 19
Global Estimates
Classification
Estimated Number of Cases
Estimated Number of
Deaths
All forms TB
88 million 16 million
MDR TB 424000 116000
XDR TB 27000 16000
DrTVRao MD 20
Extensively Drug-Resistant Mycobacterium tuberculosis
India
The first XDR TB cases in India and the emergence of XDR TB is reported by Rajesh Mondal and Amita Jain King Georges Medical University Lucknow India Volume 13 Number 9ndashSeptember 2007 in Emerging Infectious Diseases
DrTVRao MD 21
Drug susceptible TBsect
MDR-TB
1990sect
XDR-TB
2006sect
Total DR
Resistance to HampR ndash
Treatable with 2nd line drugs
Resistance to 2nd line drugs ndashTreatment options seriously restricted
Resistance to all available drugs ndash
No treatment options
or limited resistance manageable with 4 drug regimen - DOTS
Are we Returning to a Pre-antibiotic Era
DrTVRao MD 22
Genesis of MDR TB
Resistance is a man-made amplification of a natural phenomenon
Inadequate drug delivery is main cause of secondary drug resistance
Secondary drug resistance is the main cause of primary drug resistance due to transmission of resistant strains
MDR due to spontaneous mutations is not possible as the genes encoding resistance for anti TB are unlinked
DrTVRao MD 23
Factors Contributing to Development
and Spread of MDR and XDR TB Weak TB programs (DOTS)
Low completioncure rates Lack of treatment follow up and
patient support Unreliable drug supply Diagnostic delay
Absent or inadequate infection control measures
Uncontrolled use of 2nd line drugs Fluroquinolones
DrTVRao MD 24
INHChromosomally mediatedLoss of catalaseperoxidaseMutation in mycolic acid synthesis
Regulators of peroxide response
Mechanism of resistance
DrTVRao MD 25
RifampinReduced binding to RNA polymeraseClusters of mutations at ldquoRifampin Resistance Determining Regionrdquo (RRDR)
Reduced Cell wall permeability
Mechanism of resistance
DrTVRao MD 26
Gene location associated Drug-Resistant
Mtuberculosis Drug Gene Isoniazid Kat G Inh A Kas
A Rifampicin rpo B Ethambutol emb B Streptomycin rps L Pyrazinamide pnc A Fluoroquinolones gyr A
Dubaniewicz A et al Molecular sub-type of the HLA-DR antigens in pulmonary tuberculosis Int J Infect Dis20004129-33
DrTVRao MD 27
Current Scientific Documentations on Drug Resistance in
Tuberculosis
DrTVRao MD 28
Alarming Rise of Resistant TuberculosisWHO Report on
Anti-TB Drug Resistance
490000 new cases of MDR-TB each year with gt110000 deaths1
Accounts for 5 of 9 million new cases of TB2
MDR-TB rates higher than ever (up to 223) particularly in former Soviet Union countries
XDR-TB reported by as many as 49 countries (by June 2008)3
Recent WHOIUATLD Global Surveillance report indicated 75 (3014012) of MDR TB to be XDR4
Around 40000 XDR-TB cases emerge every year1
1Tuberculosis MDR-TB amp XDR-TBmdashThe 2008 Report The Stop TB Department WHO2Hargreaves S httpinfectionthelancetcom Vol 8 April 2008 p2203Raviglione MC NEJM 2008359636-84Anti-TB Drug Resistance in the World Report No 4 The WHOIUATLD Global Project on Anti-Tuberculosis Drug Resistance Surveillance 2002-2007 World Health Organization 2008 (WHOHTMTB2008394)
DrTVRao MD 29
MDR-TB amp XDR-TBTHE 2008 REPORT
of MDR-TB among new TB cases 1994-2007
DrTVRao MD 30
MDR-TB rates higher than ever (up to 223) particularly in former Soviet Union countries
DrTVRao MD 31
Alarming Rise of Resistant TB
Resistant TB burden in countries of former Soviet Union about 50 of cases resistant to at least one drug about 20 MDR XDR-TB proportions also higher (as high as 24 in
Estonia)1
MDRXDR TB ndash essentially a man-made problem2
High numbers of resistant cases (gt400000 MDR-TB cases every year) due mainly to Underinvestment in basic TB control Poor management of anti-TB drugs Transmission of drug resistant strains1
1Anti-TB Drug Resistance in the World Report No 4 The WHOIUATLD Global Project on Anti-Tuberculosis Drug Resistance Surveillance 2002-2007 World Health Organization 2008 (WHOHTMTB2008394)
2Reichman The Lancet 20083711052-3
DrTVRao MD 32
The Much Discussed Article on XDR TB in the Lancet
Of the 221 multi-drug resistant (MDR-TB) cases 53 (24) were XDR
Almost all (52 of 53) of the XDR-TB patients died with a median survival of only 16 days from the time of diagnosis (in the 42 patients with confirmed dates of death)
All the 44 XDR TB patients who were tested for HIV were found co-infected
55 patents had never received anti-TB drugs suggesting primary transmission of XDR pathogen
67 patients had been admitted to the hospital in the preceding 2 years suggesting potential role of nosocomial transmission
Gandhi et al Lancet 20063681575-80DrTVRao MD 33
Poor mangement of infected lead to grwoing resistance
Resistance to anti-TB drugs in populations is a phenomenon that occurs primarily due to poorly managed TB care Problems include incorrect drug prescribing practices by providers poor quality drugs or erratic supply of drugs and also patient non-adherence DrTVRao MD 34
Susceptibility Testing
1048708 Direct and indirect testing1048708 Primary Drugs testing1048708 Isoniazid1048708 Rifampicin1048708 Ethambutol ()1048708 Pyrizinamide ()
DrTVRao MD 35
Drug susceptibility testing (DST)
DST is recommended for all new cases for all first line drugs with specimens taken before initiating treatment
Accuracy is more important than speed DST results should come from a small
number of well-equipped experienced laboratories who participate and perform well in an international DST quality control scheme
The WHO Supranational Laboratory Quality Control Network offers the greatest global coverage for this
DrTVRao MD 36
Drug susceptibility Testing
Assessment of growth inhibition on solid media containing various dilutions of the drug in comparison with the test strains
As the method depend observation of growth Results are not available until several weeks after isolation of the organism
DrTVRao MD 37
Other accredited Methods
Radiometric and Non radiometric methods
Nucleic acid technology ndash effective upto 95 in mutations to rifampicin resistance to gene rpoB gene
DrTVRao MD 38
Drug susceptibility testing (DST)
As a minimum laboratories supplying DST data should correctly identify resistance to isoniazid and rifampicin in over 90 of quality control samples in two out of the last three quality control roundsDrTVRao MD 39
Detection of Rifampicin Drug susceptibility testing (DST) is more important
Early identification of mycobacterial growth as M tuberculosis complex and the identification of rifampicin resistance should be the first priority as rifampicin resistance invalidates standard 6 month short-course chemotherapy and is a useful marker in most countries for MDR-TB
Laboratories should aim to identify isolates as M tuberculosis complex and perform rifampicin resistance in 90 of isolates within 1-2 working days This is technologically feasible
DrTVRao MD 40
Drug susceptibility testing
For DST laboratories modern molecular techniques permit the successful identification of isoniazid resistance in at least 75 of mycobacterial cultures within 1-2 working days and are useful preliminary screens for isoniazid resistance
DrTVRao MD 41
Secondary Drugs testing [lack of standardized
methods]
Ofloxacin quinolonesEthionamide KanamycinCapreomycin Ensure quality control and
quality assurance
DrTVRao MD 42
WHO Controls the Tuberculosis related work
The laboratory methods for anti-tuberculosis drug susceptibility testing should be selected from among those that are WHO-recommended and all laboratory processes should be quality-assured in cooperation with a partner Supranational Reference Laboratory (SRL)DrTVRao MD 43
Other WHO-Endorsed Tools
Liquid culture (eg MGIT BacTALERT)
Capilia TB Rapid strip test that detects a TB-
specific antigen from culture
Molecular line probe assays (eg GenoType MTBDRplus INNO-LiPA RifTB) Strip test for detection of TB and
drug-resistance conferring mutations
DrTVRao MD 44
BacTALERTreg
DrTVRao MD 45
CDC Updates Guidelines for Nucleic AcidAmplification Techniques to Diagnose
Tuberculosis
NAAT results should be interpreted in conjunction with the AFB smear results
NAAT and smear positive start Rx despite pending culture results PPV 95
Smear negative NAAT positive use clinical judgment to either treat or await culture
DrTVRao MD 46
Selection from automated systems for molecular and
bacteriological rapid diagnostics
PCRRocheCOBASreg Amplicorreg
amplification kitsRocheCOBASreg LightCyclerreg
(real-time-PCR)RocheCOBASreg TaqMan 48reg(increases the specificity of real-
time-PCR)
DrTVRao MD 47
Molecular Fingerprinting
26 of 30 (87) XDR TB isolates found to be genetically similar
Majority of patients had no previous history of TB treatment Suggestive of recent infection with drug-resistant strain
DrTVRao MD 48
Is PCR methods a solution
PCR cant yet replace neither microscopy culturing and competent clinical examination
DrTVRao MD 49
No testing method replaces Clinical assessment
DrTVRao MD 50
XDR-TBThe description
of XDR-TB was first used earlier in 2006 following a joint survey by WHO and the US Centres for Disease Control and Prevention (CDC) DrTVRao MD 51
How x-MDR generated
Acquired resistance is that which occurs as a result of specific previous treatment The level of primary resistance in the community is considered to reflect the efficacy of control measures in the past while the level of acquired resistance is a measure of on-going TB control measuresDrTVRao MD 52
Extreme Drug resistant Tuberculosis (XDR-TB)
Resistant to all first line drugs namely Isoniazid and Rifampin and Three or more second line drugs (SLDrsquoS) that are used to treat MDR-TB Thequinalones like Ofloaxin
Or Aminoglycosides like Capreomycin amp
Kanamycin
No third-line drugs available to treat XDR-TB since none has been developed in the last 40 years
DrTVRao MD 53
Background Extensively drug-resistant tuberculosis
Extensively drug-resistant tuberculosis has been reported in 45 countries including countries with limited resources and a high burden of tuberculosis
DrTVRao MD 54
DrTVRao MD 55
Transmissionof X -MDR
Like other forms of TB XDR-TB is spread through the air When a person with infectious TB coughs sneezes talks or spits they propel Mycobacterium into the air
DrTVRao MD 56
Best options to diagnoseX-MDR tuberculosis
To evaluate drug susceptibility the bacteria need to be cultivated and tested in a suitable laboratory Final diagnosis in this way for TB and especially for XDR-TB may take from 6 to 16 weeks To reduce the time needed for diagnosis new tools for rapid TB diagnosis are urgently needed
DrTVRao MD 57
When to suspect MDR TB
Patients not showing any reduction
in bacillary population after 3-
months of regular treatment with
Cat II regimen
Sputum positive patients who are
contacts of a known MDR TB
patient
DrTVRao MD 58
How to evaluate MDR TB
MDR TB is only a laboratory
proved HR resistance
Clinical suspicion should be
followed by lab Confirmation
Laboratories should be quality
controlledTRC
DrTVRao MD 59
Extreme Drug resistant Tuberculosis (XDR-TB) and AIDS
It can also be contracted without a patient receiving any previous treatment for TB
Mostly associated with HIV positive patients
HIV has the potential to fast tracking XDR-TB into an uncontrollable epidemic
Average survival period for patients infected with XDR-TB is 16 days
DrTVRao MD 60
Responding to MDRXDR-TB
Augment DOTS Program by
New diagnostics
New drugs New vaccines HIV incidence
reduction Advocacy1
A mathematical model projected by Basu and co-workers indicates that half of XDR-TB can be averted by 2012 by bringing synergistic effects through
Use of masks Reduced time as in-patient Improved ventilation Rapid resistance testing HIV treatment TB isolation facilities2
1Marteens and Wilkinson Lancet 20073702030-432Basu et al Quoted in Porco and Getz Lancet 20073701464-5
DrTVRao MD 61
Second Line Drug Treatment (SLDrsquos)
Less effective more costly and more toxic 50 cure rate
Four months intensive phase (5 drugs) Kanamycins Ethionamide Pyrazinamide Ofloxacin Cycloserine or Ethambutol DrTVRao MD 62
World Health Organisation (WHO) Guidelines for treatment
of MDR-TB
Strengthen basic TB care to prevent the emergence of drug-resistance
Ensure prompt diagnosis and treatment of drug resistant cases to cure existing cases and prevent further transmission
Increase collaboration between HIV and TB control programmes to provide necessary prevention and care to co-infected patients
Increase investment in laboratory infrastructures to enable better detection and management of resistant cases
DrTVRao MD 63
Treatment Guidelines
Sensitivity testing for all smear positive specimens
Patient Family and staff counselling amp education
Correct and thorough hand washing protocol and procedure
Personal protection is very important
DrTVRao MD 64
THE NEW MDR-TB Guidelines
A flexible framework approach combining both clinical and programmatic aspects of DOTS Plus based on essential programme conditions
But encouraging programs to tailor their case-finding and treatment strategies to the local epidemiological and Programme situation
Reflect GLC expert consensus and evidence and experience from GLC projects thus far
DrTVRao MD 65
Effective laboratory Diagnosis
Sputum smear examinations ndash rapid classification of species (atypical mycobacteria common in AIDS)
Culture examinations
Rapid drug sensitivity testingDrTVRao MD 66
MDR TB and HIV
MDR TB occurs with the same frequency in HIV
patients as in TB patients who are smear negative
Transmission of drug-resistant strains among HIV-
infected patients in congregate settings occurs
leading to lsquooutbreaksrsquo of MDR TB in such settings
Infection control measures absolutely essential in
settings where large number of HIV TB patients stay
togetherDrTVRao MD 67
Transmission is dependent on closeness and time of contact
In penitentiary care contacts are very close and prolonged ndash culture positive cases can also transmit TB especially to HIV positive population
DrTVRao MD 68
To Know more on MDR ndashTB Current Guidelines of WHO
Guidelines for the programmatic management of drug-resistant tuberculosis - 2011 update [pdf 904kb]
Visit helliphelliphellip WHOHTMTB20116DrTVRao MD 69
Are there any solutions for effective
Diagnosis in TB
DrTVRao MD 70
Programme Created by DrTVRao MD for Medical and Health Care
Workers in the Developing World Email
doctortvraogmailcom
DrTVRao MD 71
Classification of Drugs 3 Groups depending upon the degree
of effectiveness and potential side effects First Line (Primary agents)
are the most effective and have lowest toxicity Isoniazid Rifampin
Second LineLess effective and more toxic effectsinclude (in no particular order) p-amino
salicylic acid Streptomycin Ethambutol Third Line
are least effective and most toxic Amikacin Kanamycin Capreomycin Viomycin Kanamycin Cycloserine
DrTVRao MD 15
Basic concepts ndash Keep facts
Primary (Initial) resistanceTB patientrsquos initial Mycobacterium
tuberculosis population resistant to drugs
Secondary (Acquired) resistanceDrug-resistant M tuberculosis in initial
population selected by inappropriate drug use (inadequate treatment or non-adherence) DrTVRao MD 16
When to suspect MDR TB
Re-treatment patients whorsquos sputum smear remains positive after three monthsrsquo of intensive therapy
Treatment failure and interruption cases
Close contacts of MDR tuberculosis cases
Positive diagnoses with TB culture and susceptibility testing DrTVRao MD 17
What is extensively drug resistant tuberculosis (XDR TB)
Extensively drug resistant TB (XDR TB) is a relatively rare type of MDR TB XDR TB is defined as TB which is resistant to isoniazid and rifampin plus resistant to any fluoroquinolone and at least one of three injectable second-line drugs (ie amikacin kanamycin or capreomycin)DrTVRao MD 18
Why XDR - TB a grave concern
Because XDR TB is resistant to first-line and second line drugs patients are left with treatment options that are much less effective
XDR TB is of special concern for persons with HIV infection or other conditions that can weaken the immune system These persons are more likely to develop TB disease once they are infected and also have a higher risk of death once they develop TB
DrTVRao MD 19
Global Estimates
Classification
Estimated Number of Cases
Estimated Number of
Deaths
All forms TB
88 million 16 million
MDR TB 424000 116000
XDR TB 27000 16000
DrTVRao MD 20
Extensively Drug-Resistant Mycobacterium tuberculosis
India
The first XDR TB cases in India and the emergence of XDR TB is reported by Rajesh Mondal and Amita Jain King Georges Medical University Lucknow India Volume 13 Number 9ndashSeptember 2007 in Emerging Infectious Diseases
DrTVRao MD 21
Drug susceptible TBsect
MDR-TB
1990sect
XDR-TB
2006sect
Total DR
Resistance to HampR ndash
Treatable with 2nd line drugs
Resistance to 2nd line drugs ndashTreatment options seriously restricted
Resistance to all available drugs ndash
No treatment options
or limited resistance manageable with 4 drug regimen - DOTS
Are we Returning to a Pre-antibiotic Era
DrTVRao MD 22
Genesis of MDR TB
Resistance is a man-made amplification of a natural phenomenon
Inadequate drug delivery is main cause of secondary drug resistance
Secondary drug resistance is the main cause of primary drug resistance due to transmission of resistant strains
MDR due to spontaneous mutations is not possible as the genes encoding resistance for anti TB are unlinked
DrTVRao MD 23
Factors Contributing to Development
and Spread of MDR and XDR TB Weak TB programs (DOTS)
Low completioncure rates Lack of treatment follow up and
patient support Unreliable drug supply Diagnostic delay
Absent or inadequate infection control measures
Uncontrolled use of 2nd line drugs Fluroquinolones
DrTVRao MD 24
INHChromosomally mediatedLoss of catalaseperoxidaseMutation in mycolic acid synthesis
Regulators of peroxide response
Mechanism of resistance
DrTVRao MD 25
RifampinReduced binding to RNA polymeraseClusters of mutations at ldquoRifampin Resistance Determining Regionrdquo (RRDR)
Reduced Cell wall permeability
Mechanism of resistance
DrTVRao MD 26
Gene location associated Drug-Resistant
Mtuberculosis Drug Gene Isoniazid Kat G Inh A Kas
A Rifampicin rpo B Ethambutol emb B Streptomycin rps L Pyrazinamide pnc A Fluoroquinolones gyr A
Dubaniewicz A et al Molecular sub-type of the HLA-DR antigens in pulmonary tuberculosis Int J Infect Dis20004129-33
DrTVRao MD 27
Current Scientific Documentations on Drug Resistance in
Tuberculosis
DrTVRao MD 28
Alarming Rise of Resistant TuberculosisWHO Report on
Anti-TB Drug Resistance
490000 new cases of MDR-TB each year with gt110000 deaths1
Accounts for 5 of 9 million new cases of TB2
MDR-TB rates higher than ever (up to 223) particularly in former Soviet Union countries
XDR-TB reported by as many as 49 countries (by June 2008)3
Recent WHOIUATLD Global Surveillance report indicated 75 (3014012) of MDR TB to be XDR4
Around 40000 XDR-TB cases emerge every year1
1Tuberculosis MDR-TB amp XDR-TBmdashThe 2008 Report The Stop TB Department WHO2Hargreaves S httpinfectionthelancetcom Vol 8 April 2008 p2203Raviglione MC NEJM 2008359636-84Anti-TB Drug Resistance in the World Report No 4 The WHOIUATLD Global Project on Anti-Tuberculosis Drug Resistance Surveillance 2002-2007 World Health Organization 2008 (WHOHTMTB2008394)
DrTVRao MD 29
MDR-TB amp XDR-TBTHE 2008 REPORT
of MDR-TB among new TB cases 1994-2007
DrTVRao MD 30
MDR-TB rates higher than ever (up to 223) particularly in former Soviet Union countries
DrTVRao MD 31
Alarming Rise of Resistant TB
Resistant TB burden in countries of former Soviet Union about 50 of cases resistant to at least one drug about 20 MDR XDR-TB proportions also higher (as high as 24 in
Estonia)1
MDRXDR TB ndash essentially a man-made problem2
High numbers of resistant cases (gt400000 MDR-TB cases every year) due mainly to Underinvestment in basic TB control Poor management of anti-TB drugs Transmission of drug resistant strains1
1Anti-TB Drug Resistance in the World Report No 4 The WHOIUATLD Global Project on Anti-Tuberculosis Drug Resistance Surveillance 2002-2007 World Health Organization 2008 (WHOHTMTB2008394)
2Reichman The Lancet 20083711052-3
DrTVRao MD 32
The Much Discussed Article on XDR TB in the Lancet
Of the 221 multi-drug resistant (MDR-TB) cases 53 (24) were XDR
Almost all (52 of 53) of the XDR-TB patients died with a median survival of only 16 days from the time of diagnosis (in the 42 patients with confirmed dates of death)
All the 44 XDR TB patients who were tested for HIV were found co-infected
55 patents had never received anti-TB drugs suggesting primary transmission of XDR pathogen
67 patients had been admitted to the hospital in the preceding 2 years suggesting potential role of nosocomial transmission
Gandhi et al Lancet 20063681575-80DrTVRao MD 33
Poor mangement of infected lead to grwoing resistance
Resistance to anti-TB drugs in populations is a phenomenon that occurs primarily due to poorly managed TB care Problems include incorrect drug prescribing practices by providers poor quality drugs or erratic supply of drugs and also patient non-adherence DrTVRao MD 34
Susceptibility Testing
1048708 Direct and indirect testing1048708 Primary Drugs testing1048708 Isoniazid1048708 Rifampicin1048708 Ethambutol ()1048708 Pyrizinamide ()
DrTVRao MD 35
Drug susceptibility testing (DST)
DST is recommended for all new cases for all first line drugs with specimens taken before initiating treatment
Accuracy is more important than speed DST results should come from a small
number of well-equipped experienced laboratories who participate and perform well in an international DST quality control scheme
The WHO Supranational Laboratory Quality Control Network offers the greatest global coverage for this
DrTVRao MD 36
Drug susceptibility Testing
Assessment of growth inhibition on solid media containing various dilutions of the drug in comparison with the test strains
As the method depend observation of growth Results are not available until several weeks after isolation of the organism
DrTVRao MD 37
Other accredited Methods
Radiometric and Non radiometric methods
Nucleic acid technology ndash effective upto 95 in mutations to rifampicin resistance to gene rpoB gene
DrTVRao MD 38
Drug susceptibility testing (DST)
As a minimum laboratories supplying DST data should correctly identify resistance to isoniazid and rifampicin in over 90 of quality control samples in two out of the last three quality control roundsDrTVRao MD 39
Detection of Rifampicin Drug susceptibility testing (DST) is more important
Early identification of mycobacterial growth as M tuberculosis complex and the identification of rifampicin resistance should be the first priority as rifampicin resistance invalidates standard 6 month short-course chemotherapy and is a useful marker in most countries for MDR-TB
Laboratories should aim to identify isolates as M tuberculosis complex and perform rifampicin resistance in 90 of isolates within 1-2 working days This is technologically feasible
DrTVRao MD 40
Drug susceptibility testing
For DST laboratories modern molecular techniques permit the successful identification of isoniazid resistance in at least 75 of mycobacterial cultures within 1-2 working days and are useful preliminary screens for isoniazid resistance
DrTVRao MD 41
Secondary Drugs testing [lack of standardized
methods]
Ofloxacin quinolonesEthionamide KanamycinCapreomycin Ensure quality control and
quality assurance
DrTVRao MD 42
WHO Controls the Tuberculosis related work
The laboratory methods for anti-tuberculosis drug susceptibility testing should be selected from among those that are WHO-recommended and all laboratory processes should be quality-assured in cooperation with a partner Supranational Reference Laboratory (SRL)DrTVRao MD 43
Other WHO-Endorsed Tools
Liquid culture (eg MGIT BacTALERT)
Capilia TB Rapid strip test that detects a TB-
specific antigen from culture
Molecular line probe assays (eg GenoType MTBDRplus INNO-LiPA RifTB) Strip test for detection of TB and
drug-resistance conferring mutations
DrTVRao MD 44
BacTALERTreg
DrTVRao MD 45
CDC Updates Guidelines for Nucleic AcidAmplification Techniques to Diagnose
Tuberculosis
NAAT results should be interpreted in conjunction with the AFB smear results
NAAT and smear positive start Rx despite pending culture results PPV 95
Smear negative NAAT positive use clinical judgment to either treat or await culture
DrTVRao MD 46
Selection from automated systems for molecular and
bacteriological rapid diagnostics
PCRRocheCOBASreg Amplicorreg
amplification kitsRocheCOBASreg LightCyclerreg
(real-time-PCR)RocheCOBASreg TaqMan 48reg(increases the specificity of real-
time-PCR)
DrTVRao MD 47
Molecular Fingerprinting
26 of 30 (87) XDR TB isolates found to be genetically similar
Majority of patients had no previous history of TB treatment Suggestive of recent infection with drug-resistant strain
DrTVRao MD 48
Is PCR methods a solution
PCR cant yet replace neither microscopy culturing and competent clinical examination
DrTVRao MD 49
No testing method replaces Clinical assessment
DrTVRao MD 50
XDR-TBThe description
of XDR-TB was first used earlier in 2006 following a joint survey by WHO and the US Centres for Disease Control and Prevention (CDC) DrTVRao MD 51
How x-MDR generated
Acquired resistance is that which occurs as a result of specific previous treatment The level of primary resistance in the community is considered to reflect the efficacy of control measures in the past while the level of acquired resistance is a measure of on-going TB control measuresDrTVRao MD 52
Extreme Drug resistant Tuberculosis (XDR-TB)
Resistant to all first line drugs namely Isoniazid and Rifampin and Three or more second line drugs (SLDrsquoS) that are used to treat MDR-TB Thequinalones like Ofloaxin
Or Aminoglycosides like Capreomycin amp
Kanamycin
No third-line drugs available to treat XDR-TB since none has been developed in the last 40 years
DrTVRao MD 53
Background Extensively drug-resistant tuberculosis
Extensively drug-resistant tuberculosis has been reported in 45 countries including countries with limited resources and a high burden of tuberculosis
DrTVRao MD 54
DrTVRao MD 55
Transmissionof X -MDR
Like other forms of TB XDR-TB is spread through the air When a person with infectious TB coughs sneezes talks or spits they propel Mycobacterium into the air
DrTVRao MD 56
Best options to diagnoseX-MDR tuberculosis
To evaluate drug susceptibility the bacteria need to be cultivated and tested in a suitable laboratory Final diagnosis in this way for TB and especially for XDR-TB may take from 6 to 16 weeks To reduce the time needed for diagnosis new tools for rapid TB diagnosis are urgently needed
DrTVRao MD 57
When to suspect MDR TB
Patients not showing any reduction
in bacillary population after 3-
months of regular treatment with
Cat II regimen
Sputum positive patients who are
contacts of a known MDR TB
patient
DrTVRao MD 58
How to evaluate MDR TB
MDR TB is only a laboratory
proved HR resistance
Clinical suspicion should be
followed by lab Confirmation
Laboratories should be quality
controlledTRC
DrTVRao MD 59
Extreme Drug resistant Tuberculosis (XDR-TB) and AIDS
It can also be contracted without a patient receiving any previous treatment for TB
Mostly associated with HIV positive patients
HIV has the potential to fast tracking XDR-TB into an uncontrollable epidemic
Average survival period for patients infected with XDR-TB is 16 days
DrTVRao MD 60
Responding to MDRXDR-TB
Augment DOTS Program by
New diagnostics
New drugs New vaccines HIV incidence
reduction Advocacy1
A mathematical model projected by Basu and co-workers indicates that half of XDR-TB can be averted by 2012 by bringing synergistic effects through
Use of masks Reduced time as in-patient Improved ventilation Rapid resistance testing HIV treatment TB isolation facilities2
1Marteens and Wilkinson Lancet 20073702030-432Basu et al Quoted in Porco and Getz Lancet 20073701464-5
DrTVRao MD 61
Second Line Drug Treatment (SLDrsquos)
Less effective more costly and more toxic 50 cure rate
Four months intensive phase (5 drugs) Kanamycins Ethionamide Pyrazinamide Ofloxacin Cycloserine or Ethambutol DrTVRao MD 62
World Health Organisation (WHO) Guidelines for treatment
of MDR-TB
Strengthen basic TB care to prevent the emergence of drug-resistance
Ensure prompt diagnosis and treatment of drug resistant cases to cure existing cases and prevent further transmission
Increase collaboration between HIV and TB control programmes to provide necessary prevention and care to co-infected patients
Increase investment in laboratory infrastructures to enable better detection and management of resistant cases
DrTVRao MD 63
Treatment Guidelines
Sensitivity testing for all smear positive specimens
Patient Family and staff counselling amp education
Correct and thorough hand washing protocol and procedure
Personal protection is very important
DrTVRao MD 64
THE NEW MDR-TB Guidelines
A flexible framework approach combining both clinical and programmatic aspects of DOTS Plus based on essential programme conditions
But encouraging programs to tailor their case-finding and treatment strategies to the local epidemiological and Programme situation
Reflect GLC expert consensus and evidence and experience from GLC projects thus far
DrTVRao MD 65
Effective laboratory Diagnosis
Sputum smear examinations ndash rapid classification of species (atypical mycobacteria common in AIDS)
Culture examinations
Rapid drug sensitivity testingDrTVRao MD 66
MDR TB and HIV
MDR TB occurs with the same frequency in HIV
patients as in TB patients who are smear negative
Transmission of drug-resistant strains among HIV-
infected patients in congregate settings occurs
leading to lsquooutbreaksrsquo of MDR TB in such settings
Infection control measures absolutely essential in
settings where large number of HIV TB patients stay
togetherDrTVRao MD 67
Transmission is dependent on closeness and time of contact
In penitentiary care contacts are very close and prolonged ndash culture positive cases can also transmit TB especially to HIV positive population
DrTVRao MD 68
To Know more on MDR ndashTB Current Guidelines of WHO
Guidelines for the programmatic management of drug-resistant tuberculosis - 2011 update [pdf 904kb]
Visit helliphelliphellip WHOHTMTB20116DrTVRao MD 69
Are there any solutions for effective
Diagnosis in TB
DrTVRao MD 70
Programme Created by DrTVRao MD for Medical and Health Care
Workers in the Developing World Email
doctortvraogmailcom
DrTVRao MD 71
Basic concepts ndash Keep facts
Primary (Initial) resistanceTB patientrsquos initial Mycobacterium
tuberculosis population resistant to drugs
Secondary (Acquired) resistanceDrug-resistant M tuberculosis in initial
population selected by inappropriate drug use (inadequate treatment or non-adherence) DrTVRao MD 16
When to suspect MDR TB
Re-treatment patients whorsquos sputum smear remains positive after three monthsrsquo of intensive therapy
Treatment failure and interruption cases
Close contacts of MDR tuberculosis cases
Positive diagnoses with TB culture and susceptibility testing DrTVRao MD 17
What is extensively drug resistant tuberculosis (XDR TB)
Extensively drug resistant TB (XDR TB) is a relatively rare type of MDR TB XDR TB is defined as TB which is resistant to isoniazid and rifampin plus resistant to any fluoroquinolone and at least one of three injectable second-line drugs (ie amikacin kanamycin or capreomycin)DrTVRao MD 18
Why XDR - TB a grave concern
Because XDR TB is resistant to first-line and second line drugs patients are left with treatment options that are much less effective
XDR TB is of special concern for persons with HIV infection or other conditions that can weaken the immune system These persons are more likely to develop TB disease once they are infected and also have a higher risk of death once they develop TB
DrTVRao MD 19
Global Estimates
Classification
Estimated Number of Cases
Estimated Number of
Deaths
All forms TB
88 million 16 million
MDR TB 424000 116000
XDR TB 27000 16000
DrTVRao MD 20
Extensively Drug-Resistant Mycobacterium tuberculosis
India
The first XDR TB cases in India and the emergence of XDR TB is reported by Rajesh Mondal and Amita Jain King Georges Medical University Lucknow India Volume 13 Number 9ndashSeptember 2007 in Emerging Infectious Diseases
DrTVRao MD 21
Drug susceptible TBsect
MDR-TB
1990sect
XDR-TB
2006sect
Total DR
Resistance to HampR ndash
Treatable with 2nd line drugs
Resistance to 2nd line drugs ndashTreatment options seriously restricted
Resistance to all available drugs ndash
No treatment options
or limited resistance manageable with 4 drug regimen - DOTS
Are we Returning to a Pre-antibiotic Era
DrTVRao MD 22
Genesis of MDR TB
Resistance is a man-made amplification of a natural phenomenon
Inadequate drug delivery is main cause of secondary drug resistance
Secondary drug resistance is the main cause of primary drug resistance due to transmission of resistant strains
MDR due to spontaneous mutations is not possible as the genes encoding resistance for anti TB are unlinked
DrTVRao MD 23
Factors Contributing to Development
and Spread of MDR and XDR TB Weak TB programs (DOTS)
Low completioncure rates Lack of treatment follow up and
patient support Unreliable drug supply Diagnostic delay
Absent or inadequate infection control measures
Uncontrolled use of 2nd line drugs Fluroquinolones
DrTVRao MD 24
INHChromosomally mediatedLoss of catalaseperoxidaseMutation in mycolic acid synthesis
Regulators of peroxide response
Mechanism of resistance
DrTVRao MD 25
RifampinReduced binding to RNA polymeraseClusters of mutations at ldquoRifampin Resistance Determining Regionrdquo (RRDR)
Reduced Cell wall permeability
Mechanism of resistance
DrTVRao MD 26
Gene location associated Drug-Resistant
Mtuberculosis Drug Gene Isoniazid Kat G Inh A Kas
A Rifampicin rpo B Ethambutol emb B Streptomycin rps L Pyrazinamide pnc A Fluoroquinolones gyr A
Dubaniewicz A et al Molecular sub-type of the HLA-DR antigens in pulmonary tuberculosis Int J Infect Dis20004129-33
DrTVRao MD 27
Current Scientific Documentations on Drug Resistance in
Tuberculosis
DrTVRao MD 28
Alarming Rise of Resistant TuberculosisWHO Report on
Anti-TB Drug Resistance
490000 new cases of MDR-TB each year with gt110000 deaths1
Accounts for 5 of 9 million new cases of TB2
MDR-TB rates higher than ever (up to 223) particularly in former Soviet Union countries
XDR-TB reported by as many as 49 countries (by June 2008)3
Recent WHOIUATLD Global Surveillance report indicated 75 (3014012) of MDR TB to be XDR4
Around 40000 XDR-TB cases emerge every year1
1Tuberculosis MDR-TB amp XDR-TBmdashThe 2008 Report The Stop TB Department WHO2Hargreaves S httpinfectionthelancetcom Vol 8 April 2008 p2203Raviglione MC NEJM 2008359636-84Anti-TB Drug Resistance in the World Report No 4 The WHOIUATLD Global Project on Anti-Tuberculosis Drug Resistance Surveillance 2002-2007 World Health Organization 2008 (WHOHTMTB2008394)
DrTVRao MD 29
MDR-TB amp XDR-TBTHE 2008 REPORT
of MDR-TB among new TB cases 1994-2007
DrTVRao MD 30
MDR-TB rates higher than ever (up to 223) particularly in former Soviet Union countries
DrTVRao MD 31
Alarming Rise of Resistant TB
Resistant TB burden in countries of former Soviet Union about 50 of cases resistant to at least one drug about 20 MDR XDR-TB proportions also higher (as high as 24 in
Estonia)1
MDRXDR TB ndash essentially a man-made problem2
High numbers of resistant cases (gt400000 MDR-TB cases every year) due mainly to Underinvestment in basic TB control Poor management of anti-TB drugs Transmission of drug resistant strains1
1Anti-TB Drug Resistance in the World Report No 4 The WHOIUATLD Global Project on Anti-Tuberculosis Drug Resistance Surveillance 2002-2007 World Health Organization 2008 (WHOHTMTB2008394)
2Reichman The Lancet 20083711052-3
DrTVRao MD 32
The Much Discussed Article on XDR TB in the Lancet
Of the 221 multi-drug resistant (MDR-TB) cases 53 (24) were XDR
Almost all (52 of 53) of the XDR-TB patients died with a median survival of only 16 days from the time of diagnosis (in the 42 patients with confirmed dates of death)
All the 44 XDR TB patients who were tested for HIV were found co-infected
55 patents had never received anti-TB drugs suggesting primary transmission of XDR pathogen
67 patients had been admitted to the hospital in the preceding 2 years suggesting potential role of nosocomial transmission
Gandhi et al Lancet 20063681575-80DrTVRao MD 33
Poor mangement of infected lead to grwoing resistance
Resistance to anti-TB drugs in populations is a phenomenon that occurs primarily due to poorly managed TB care Problems include incorrect drug prescribing practices by providers poor quality drugs or erratic supply of drugs and also patient non-adherence DrTVRao MD 34
Susceptibility Testing
1048708 Direct and indirect testing1048708 Primary Drugs testing1048708 Isoniazid1048708 Rifampicin1048708 Ethambutol ()1048708 Pyrizinamide ()
DrTVRao MD 35
Drug susceptibility testing (DST)
DST is recommended for all new cases for all first line drugs with specimens taken before initiating treatment
Accuracy is more important than speed DST results should come from a small
number of well-equipped experienced laboratories who participate and perform well in an international DST quality control scheme
The WHO Supranational Laboratory Quality Control Network offers the greatest global coverage for this
DrTVRao MD 36
Drug susceptibility Testing
Assessment of growth inhibition on solid media containing various dilutions of the drug in comparison with the test strains
As the method depend observation of growth Results are not available until several weeks after isolation of the organism
DrTVRao MD 37
Other accredited Methods
Radiometric and Non radiometric methods
Nucleic acid technology ndash effective upto 95 in mutations to rifampicin resistance to gene rpoB gene
DrTVRao MD 38
Drug susceptibility testing (DST)
As a minimum laboratories supplying DST data should correctly identify resistance to isoniazid and rifampicin in over 90 of quality control samples in two out of the last three quality control roundsDrTVRao MD 39
Detection of Rifampicin Drug susceptibility testing (DST) is more important
Early identification of mycobacterial growth as M tuberculosis complex and the identification of rifampicin resistance should be the first priority as rifampicin resistance invalidates standard 6 month short-course chemotherapy and is a useful marker in most countries for MDR-TB
Laboratories should aim to identify isolates as M tuberculosis complex and perform rifampicin resistance in 90 of isolates within 1-2 working days This is technologically feasible
DrTVRao MD 40
Drug susceptibility testing
For DST laboratories modern molecular techniques permit the successful identification of isoniazid resistance in at least 75 of mycobacterial cultures within 1-2 working days and are useful preliminary screens for isoniazid resistance
DrTVRao MD 41
Secondary Drugs testing [lack of standardized
methods]
Ofloxacin quinolonesEthionamide KanamycinCapreomycin Ensure quality control and
quality assurance
DrTVRao MD 42
WHO Controls the Tuberculosis related work
The laboratory methods for anti-tuberculosis drug susceptibility testing should be selected from among those that are WHO-recommended and all laboratory processes should be quality-assured in cooperation with a partner Supranational Reference Laboratory (SRL)DrTVRao MD 43
Other WHO-Endorsed Tools
Liquid culture (eg MGIT BacTALERT)
Capilia TB Rapid strip test that detects a TB-
specific antigen from culture
Molecular line probe assays (eg GenoType MTBDRplus INNO-LiPA RifTB) Strip test for detection of TB and
drug-resistance conferring mutations
DrTVRao MD 44
BacTALERTreg
DrTVRao MD 45
CDC Updates Guidelines for Nucleic AcidAmplification Techniques to Diagnose
Tuberculosis
NAAT results should be interpreted in conjunction with the AFB smear results
NAAT and smear positive start Rx despite pending culture results PPV 95
Smear negative NAAT positive use clinical judgment to either treat or await culture
DrTVRao MD 46
Selection from automated systems for molecular and
bacteriological rapid diagnostics
PCRRocheCOBASreg Amplicorreg
amplification kitsRocheCOBASreg LightCyclerreg
(real-time-PCR)RocheCOBASreg TaqMan 48reg(increases the specificity of real-
time-PCR)
DrTVRao MD 47
Molecular Fingerprinting
26 of 30 (87) XDR TB isolates found to be genetically similar
Majority of patients had no previous history of TB treatment Suggestive of recent infection with drug-resistant strain
DrTVRao MD 48
Is PCR methods a solution
PCR cant yet replace neither microscopy culturing and competent clinical examination
DrTVRao MD 49
No testing method replaces Clinical assessment
DrTVRao MD 50
XDR-TBThe description
of XDR-TB was first used earlier in 2006 following a joint survey by WHO and the US Centres for Disease Control and Prevention (CDC) DrTVRao MD 51
How x-MDR generated
Acquired resistance is that which occurs as a result of specific previous treatment The level of primary resistance in the community is considered to reflect the efficacy of control measures in the past while the level of acquired resistance is a measure of on-going TB control measuresDrTVRao MD 52
Extreme Drug resistant Tuberculosis (XDR-TB)
Resistant to all first line drugs namely Isoniazid and Rifampin and Three or more second line drugs (SLDrsquoS) that are used to treat MDR-TB Thequinalones like Ofloaxin
Or Aminoglycosides like Capreomycin amp
Kanamycin
No third-line drugs available to treat XDR-TB since none has been developed in the last 40 years
DrTVRao MD 53
Background Extensively drug-resistant tuberculosis
Extensively drug-resistant tuberculosis has been reported in 45 countries including countries with limited resources and a high burden of tuberculosis
DrTVRao MD 54
DrTVRao MD 55
Transmissionof X -MDR
Like other forms of TB XDR-TB is spread through the air When a person with infectious TB coughs sneezes talks or spits they propel Mycobacterium into the air
DrTVRao MD 56
Best options to diagnoseX-MDR tuberculosis
To evaluate drug susceptibility the bacteria need to be cultivated and tested in a suitable laboratory Final diagnosis in this way for TB and especially for XDR-TB may take from 6 to 16 weeks To reduce the time needed for diagnosis new tools for rapid TB diagnosis are urgently needed
DrTVRao MD 57
When to suspect MDR TB
Patients not showing any reduction
in bacillary population after 3-
months of regular treatment with
Cat II regimen
Sputum positive patients who are
contacts of a known MDR TB
patient
DrTVRao MD 58
How to evaluate MDR TB
MDR TB is only a laboratory
proved HR resistance
Clinical suspicion should be
followed by lab Confirmation
Laboratories should be quality
controlledTRC
DrTVRao MD 59
Extreme Drug resistant Tuberculosis (XDR-TB) and AIDS
It can also be contracted without a patient receiving any previous treatment for TB
Mostly associated with HIV positive patients
HIV has the potential to fast tracking XDR-TB into an uncontrollable epidemic
Average survival period for patients infected with XDR-TB is 16 days
DrTVRao MD 60
Responding to MDRXDR-TB
Augment DOTS Program by
New diagnostics
New drugs New vaccines HIV incidence
reduction Advocacy1
A mathematical model projected by Basu and co-workers indicates that half of XDR-TB can be averted by 2012 by bringing synergistic effects through
Use of masks Reduced time as in-patient Improved ventilation Rapid resistance testing HIV treatment TB isolation facilities2
1Marteens and Wilkinson Lancet 20073702030-432Basu et al Quoted in Porco and Getz Lancet 20073701464-5
DrTVRao MD 61
Second Line Drug Treatment (SLDrsquos)
Less effective more costly and more toxic 50 cure rate
Four months intensive phase (5 drugs) Kanamycins Ethionamide Pyrazinamide Ofloxacin Cycloserine or Ethambutol DrTVRao MD 62
World Health Organisation (WHO) Guidelines for treatment
of MDR-TB
Strengthen basic TB care to prevent the emergence of drug-resistance
Ensure prompt diagnosis and treatment of drug resistant cases to cure existing cases and prevent further transmission
Increase collaboration between HIV and TB control programmes to provide necessary prevention and care to co-infected patients
Increase investment in laboratory infrastructures to enable better detection and management of resistant cases
DrTVRao MD 63
Treatment Guidelines
Sensitivity testing for all smear positive specimens
Patient Family and staff counselling amp education
Correct and thorough hand washing protocol and procedure
Personal protection is very important
DrTVRao MD 64
THE NEW MDR-TB Guidelines
A flexible framework approach combining both clinical and programmatic aspects of DOTS Plus based on essential programme conditions
But encouraging programs to tailor their case-finding and treatment strategies to the local epidemiological and Programme situation
Reflect GLC expert consensus and evidence and experience from GLC projects thus far
DrTVRao MD 65
Effective laboratory Diagnosis
Sputum smear examinations ndash rapid classification of species (atypical mycobacteria common in AIDS)
Culture examinations
Rapid drug sensitivity testingDrTVRao MD 66
MDR TB and HIV
MDR TB occurs with the same frequency in HIV
patients as in TB patients who are smear negative
Transmission of drug-resistant strains among HIV-
infected patients in congregate settings occurs
leading to lsquooutbreaksrsquo of MDR TB in such settings
Infection control measures absolutely essential in
settings where large number of HIV TB patients stay
togetherDrTVRao MD 67
Transmission is dependent on closeness and time of contact
In penitentiary care contacts are very close and prolonged ndash culture positive cases can also transmit TB especially to HIV positive population
DrTVRao MD 68
To Know more on MDR ndashTB Current Guidelines of WHO
Guidelines for the programmatic management of drug-resistant tuberculosis - 2011 update [pdf 904kb]
Visit helliphelliphellip WHOHTMTB20116DrTVRao MD 69
Are there any solutions for effective
Diagnosis in TB
DrTVRao MD 70
Programme Created by DrTVRao MD for Medical and Health Care
Workers in the Developing World Email
doctortvraogmailcom
DrTVRao MD 71
When to suspect MDR TB
Re-treatment patients whorsquos sputum smear remains positive after three monthsrsquo of intensive therapy
Treatment failure and interruption cases
Close contacts of MDR tuberculosis cases
Positive diagnoses with TB culture and susceptibility testing DrTVRao MD 17
What is extensively drug resistant tuberculosis (XDR TB)
Extensively drug resistant TB (XDR TB) is a relatively rare type of MDR TB XDR TB is defined as TB which is resistant to isoniazid and rifampin plus resistant to any fluoroquinolone and at least one of three injectable second-line drugs (ie amikacin kanamycin or capreomycin)DrTVRao MD 18
Why XDR - TB a grave concern
Because XDR TB is resistant to first-line and second line drugs patients are left with treatment options that are much less effective
XDR TB is of special concern for persons with HIV infection or other conditions that can weaken the immune system These persons are more likely to develop TB disease once they are infected and also have a higher risk of death once they develop TB
DrTVRao MD 19
Global Estimates
Classification
Estimated Number of Cases
Estimated Number of
Deaths
All forms TB
88 million 16 million
MDR TB 424000 116000
XDR TB 27000 16000
DrTVRao MD 20
Extensively Drug-Resistant Mycobacterium tuberculosis
India
The first XDR TB cases in India and the emergence of XDR TB is reported by Rajesh Mondal and Amita Jain King Georges Medical University Lucknow India Volume 13 Number 9ndashSeptember 2007 in Emerging Infectious Diseases
DrTVRao MD 21
Drug susceptible TBsect
MDR-TB
1990sect
XDR-TB
2006sect
Total DR
Resistance to HampR ndash
Treatable with 2nd line drugs
Resistance to 2nd line drugs ndashTreatment options seriously restricted
Resistance to all available drugs ndash
No treatment options
or limited resistance manageable with 4 drug regimen - DOTS
Are we Returning to a Pre-antibiotic Era
DrTVRao MD 22
Genesis of MDR TB
Resistance is a man-made amplification of a natural phenomenon
Inadequate drug delivery is main cause of secondary drug resistance
Secondary drug resistance is the main cause of primary drug resistance due to transmission of resistant strains
MDR due to spontaneous mutations is not possible as the genes encoding resistance for anti TB are unlinked
DrTVRao MD 23
Factors Contributing to Development
and Spread of MDR and XDR TB Weak TB programs (DOTS)
Low completioncure rates Lack of treatment follow up and
patient support Unreliable drug supply Diagnostic delay
Absent or inadequate infection control measures
Uncontrolled use of 2nd line drugs Fluroquinolones
DrTVRao MD 24
INHChromosomally mediatedLoss of catalaseperoxidaseMutation in mycolic acid synthesis
Regulators of peroxide response
Mechanism of resistance
DrTVRao MD 25
RifampinReduced binding to RNA polymeraseClusters of mutations at ldquoRifampin Resistance Determining Regionrdquo (RRDR)
Reduced Cell wall permeability
Mechanism of resistance
DrTVRao MD 26
Gene location associated Drug-Resistant
Mtuberculosis Drug Gene Isoniazid Kat G Inh A Kas
A Rifampicin rpo B Ethambutol emb B Streptomycin rps L Pyrazinamide pnc A Fluoroquinolones gyr A
Dubaniewicz A et al Molecular sub-type of the HLA-DR antigens in pulmonary tuberculosis Int J Infect Dis20004129-33
DrTVRao MD 27
Current Scientific Documentations on Drug Resistance in
Tuberculosis
DrTVRao MD 28
Alarming Rise of Resistant TuberculosisWHO Report on
Anti-TB Drug Resistance
490000 new cases of MDR-TB each year with gt110000 deaths1
Accounts for 5 of 9 million new cases of TB2
MDR-TB rates higher than ever (up to 223) particularly in former Soviet Union countries
XDR-TB reported by as many as 49 countries (by June 2008)3
Recent WHOIUATLD Global Surveillance report indicated 75 (3014012) of MDR TB to be XDR4
Around 40000 XDR-TB cases emerge every year1
1Tuberculosis MDR-TB amp XDR-TBmdashThe 2008 Report The Stop TB Department WHO2Hargreaves S httpinfectionthelancetcom Vol 8 April 2008 p2203Raviglione MC NEJM 2008359636-84Anti-TB Drug Resistance in the World Report No 4 The WHOIUATLD Global Project on Anti-Tuberculosis Drug Resistance Surveillance 2002-2007 World Health Organization 2008 (WHOHTMTB2008394)
DrTVRao MD 29
MDR-TB amp XDR-TBTHE 2008 REPORT
of MDR-TB among new TB cases 1994-2007
DrTVRao MD 30
MDR-TB rates higher than ever (up to 223) particularly in former Soviet Union countries
DrTVRao MD 31
Alarming Rise of Resistant TB
Resistant TB burden in countries of former Soviet Union about 50 of cases resistant to at least one drug about 20 MDR XDR-TB proportions also higher (as high as 24 in
Estonia)1
MDRXDR TB ndash essentially a man-made problem2
High numbers of resistant cases (gt400000 MDR-TB cases every year) due mainly to Underinvestment in basic TB control Poor management of anti-TB drugs Transmission of drug resistant strains1
1Anti-TB Drug Resistance in the World Report No 4 The WHOIUATLD Global Project on Anti-Tuberculosis Drug Resistance Surveillance 2002-2007 World Health Organization 2008 (WHOHTMTB2008394)
2Reichman The Lancet 20083711052-3
DrTVRao MD 32
The Much Discussed Article on XDR TB in the Lancet
Of the 221 multi-drug resistant (MDR-TB) cases 53 (24) were XDR
Almost all (52 of 53) of the XDR-TB patients died with a median survival of only 16 days from the time of diagnosis (in the 42 patients with confirmed dates of death)
All the 44 XDR TB patients who were tested for HIV were found co-infected
55 patents had never received anti-TB drugs suggesting primary transmission of XDR pathogen
67 patients had been admitted to the hospital in the preceding 2 years suggesting potential role of nosocomial transmission
Gandhi et al Lancet 20063681575-80DrTVRao MD 33
Poor mangement of infected lead to grwoing resistance
Resistance to anti-TB drugs in populations is a phenomenon that occurs primarily due to poorly managed TB care Problems include incorrect drug prescribing practices by providers poor quality drugs or erratic supply of drugs and also patient non-adherence DrTVRao MD 34
Susceptibility Testing
1048708 Direct and indirect testing1048708 Primary Drugs testing1048708 Isoniazid1048708 Rifampicin1048708 Ethambutol ()1048708 Pyrizinamide ()
DrTVRao MD 35
Drug susceptibility testing (DST)
DST is recommended for all new cases for all first line drugs with specimens taken before initiating treatment
Accuracy is more important than speed DST results should come from a small
number of well-equipped experienced laboratories who participate and perform well in an international DST quality control scheme
The WHO Supranational Laboratory Quality Control Network offers the greatest global coverage for this
DrTVRao MD 36
Drug susceptibility Testing
Assessment of growth inhibition on solid media containing various dilutions of the drug in comparison with the test strains
As the method depend observation of growth Results are not available until several weeks after isolation of the organism
DrTVRao MD 37
Other accredited Methods
Radiometric and Non radiometric methods
Nucleic acid technology ndash effective upto 95 in mutations to rifampicin resistance to gene rpoB gene
DrTVRao MD 38
Drug susceptibility testing (DST)
As a minimum laboratories supplying DST data should correctly identify resistance to isoniazid and rifampicin in over 90 of quality control samples in two out of the last three quality control roundsDrTVRao MD 39
Detection of Rifampicin Drug susceptibility testing (DST) is more important
Early identification of mycobacterial growth as M tuberculosis complex and the identification of rifampicin resistance should be the first priority as rifampicin resistance invalidates standard 6 month short-course chemotherapy and is a useful marker in most countries for MDR-TB
Laboratories should aim to identify isolates as M tuberculosis complex and perform rifampicin resistance in 90 of isolates within 1-2 working days This is technologically feasible
DrTVRao MD 40
Drug susceptibility testing
For DST laboratories modern molecular techniques permit the successful identification of isoniazid resistance in at least 75 of mycobacterial cultures within 1-2 working days and are useful preliminary screens for isoniazid resistance
DrTVRao MD 41
Secondary Drugs testing [lack of standardized
methods]
Ofloxacin quinolonesEthionamide KanamycinCapreomycin Ensure quality control and
quality assurance
DrTVRao MD 42
WHO Controls the Tuberculosis related work
The laboratory methods for anti-tuberculosis drug susceptibility testing should be selected from among those that are WHO-recommended and all laboratory processes should be quality-assured in cooperation with a partner Supranational Reference Laboratory (SRL)DrTVRao MD 43
Other WHO-Endorsed Tools
Liquid culture (eg MGIT BacTALERT)
Capilia TB Rapid strip test that detects a TB-
specific antigen from culture
Molecular line probe assays (eg GenoType MTBDRplus INNO-LiPA RifTB) Strip test for detection of TB and
drug-resistance conferring mutations
DrTVRao MD 44
BacTALERTreg
DrTVRao MD 45
CDC Updates Guidelines for Nucleic AcidAmplification Techniques to Diagnose
Tuberculosis
NAAT results should be interpreted in conjunction with the AFB smear results
NAAT and smear positive start Rx despite pending culture results PPV 95
Smear negative NAAT positive use clinical judgment to either treat or await culture
DrTVRao MD 46
Selection from automated systems for molecular and
bacteriological rapid diagnostics
PCRRocheCOBASreg Amplicorreg
amplification kitsRocheCOBASreg LightCyclerreg
(real-time-PCR)RocheCOBASreg TaqMan 48reg(increases the specificity of real-
time-PCR)
DrTVRao MD 47
Molecular Fingerprinting
26 of 30 (87) XDR TB isolates found to be genetically similar
Majority of patients had no previous history of TB treatment Suggestive of recent infection with drug-resistant strain
DrTVRao MD 48
Is PCR methods a solution
PCR cant yet replace neither microscopy culturing and competent clinical examination
DrTVRao MD 49
No testing method replaces Clinical assessment
DrTVRao MD 50
XDR-TBThe description
of XDR-TB was first used earlier in 2006 following a joint survey by WHO and the US Centres for Disease Control and Prevention (CDC) DrTVRao MD 51
How x-MDR generated
Acquired resistance is that which occurs as a result of specific previous treatment The level of primary resistance in the community is considered to reflect the efficacy of control measures in the past while the level of acquired resistance is a measure of on-going TB control measuresDrTVRao MD 52
Extreme Drug resistant Tuberculosis (XDR-TB)
Resistant to all first line drugs namely Isoniazid and Rifampin and Three or more second line drugs (SLDrsquoS) that are used to treat MDR-TB Thequinalones like Ofloaxin
Or Aminoglycosides like Capreomycin amp
Kanamycin
No third-line drugs available to treat XDR-TB since none has been developed in the last 40 years
DrTVRao MD 53
Background Extensively drug-resistant tuberculosis
Extensively drug-resistant tuberculosis has been reported in 45 countries including countries with limited resources and a high burden of tuberculosis
DrTVRao MD 54
DrTVRao MD 55
Transmissionof X -MDR
Like other forms of TB XDR-TB is spread through the air When a person with infectious TB coughs sneezes talks or spits they propel Mycobacterium into the air
DrTVRao MD 56
Best options to diagnoseX-MDR tuberculosis
To evaluate drug susceptibility the bacteria need to be cultivated and tested in a suitable laboratory Final diagnosis in this way for TB and especially for XDR-TB may take from 6 to 16 weeks To reduce the time needed for diagnosis new tools for rapid TB diagnosis are urgently needed
DrTVRao MD 57
When to suspect MDR TB
Patients not showing any reduction
in bacillary population after 3-
months of regular treatment with
Cat II regimen
Sputum positive patients who are
contacts of a known MDR TB
patient
DrTVRao MD 58
How to evaluate MDR TB
MDR TB is only a laboratory
proved HR resistance
Clinical suspicion should be
followed by lab Confirmation
Laboratories should be quality
controlledTRC
DrTVRao MD 59
Extreme Drug resistant Tuberculosis (XDR-TB) and AIDS
It can also be contracted without a patient receiving any previous treatment for TB
Mostly associated with HIV positive patients
HIV has the potential to fast tracking XDR-TB into an uncontrollable epidemic
Average survival period for patients infected with XDR-TB is 16 days
DrTVRao MD 60
Responding to MDRXDR-TB
Augment DOTS Program by
New diagnostics
New drugs New vaccines HIV incidence
reduction Advocacy1
A mathematical model projected by Basu and co-workers indicates that half of XDR-TB can be averted by 2012 by bringing synergistic effects through
Use of masks Reduced time as in-patient Improved ventilation Rapid resistance testing HIV treatment TB isolation facilities2
1Marteens and Wilkinson Lancet 20073702030-432Basu et al Quoted in Porco and Getz Lancet 20073701464-5
DrTVRao MD 61
Second Line Drug Treatment (SLDrsquos)
Less effective more costly and more toxic 50 cure rate
Four months intensive phase (5 drugs) Kanamycins Ethionamide Pyrazinamide Ofloxacin Cycloserine or Ethambutol DrTVRao MD 62
World Health Organisation (WHO) Guidelines for treatment
of MDR-TB
Strengthen basic TB care to prevent the emergence of drug-resistance
Ensure prompt diagnosis and treatment of drug resistant cases to cure existing cases and prevent further transmission
Increase collaboration between HIV and TB control programmes to provide necessary prevention and care to co-infected patients
Increase investment in laboratory infrastructures to enable better detection and management of resistant cases
DrTVRao MD 63
Treatment Guidelines
Sensitivity testing for all smear positive specimens
Patient Family and staff counselling amp education
Correct and thorough hand washing protocol and procedure
Personal protection is very important
DrTVRao MD 64
THE NEW MDR-TB Guidelines
A flexible framework approach combining both clinical and programmatic aspects of DOTS Plus based on essential programme conditions
But encouraging programs to tailor their case-finding and treatment strategies to the local epidemiological and Programme situation
Reflect GLC expert consensus and evidence and experience from GLC projects thus far
DrTVRao MD 65
Effective laboratory Diagnosis
Sputum smear examinations ndash rapid classification of species (atypical mycobacteria common in AIDS)
Culture examinations
Rapid drug sensitivity testingDrTVRao MD 66
MDR TB and HIV
MDR TB occurs with the same frequency in HIV
patients as in TB patients who are smear negative
Transmission of drug-resistant strains among HIV-
infected patients in congregate settings occurs
leading to lsquooutbreaksrsquo of MDR TB in such settings
Infection control measures absolutely essential in
settings where large number of HIV TB patients stay
togetherDrTVRao MD 67
Transmission is dependent on closeness and time of contact
In penitentiary care contacts are very close and prolonged ndash culture positive cases can also transmit TB especially to HIV positive population
DrTVRao MD 68
To Know more on MDR ndashTB Current Guidelines of WHO
Guidelines for the programmatic management of drug-resistant tuberculosis - 2011 update [pdf 904kb]
Visit helliphelliphellip WHOHTMTB20116DrTVRao MD 69
Are there any solutions for effective
Diagnosis in TB
DrTVRao MD 70
Programme Created by DrTVRao MD for Medical and Health Care
Workers in the Developing World Email
doctortvraogmailcom
DrTVRao MD 71
What is extensively drug resistant tuberculosis (XDR TB)
Extensively drug resistant TB (XDR TB) is a relatively rare type of MDR TB XDR TB is defined as TB which is resistant to isoniazid and rifampin plus resistant to any fluoroquinolone and at least one of three injectable second-line drugs (ie amikacin kanamycin or capreomycin)DrTVRao MD 18
Why XDR - TB a grave concern
Because XDR TB is resistant to first-line and second line drugs patients are left with treatment options that are much less effective
XDR TB is of special concern for persons with HIV infection or other conditions that can weaken the immune system These persons are more likely to develop TB disease once they are infected and also have a higher risk of death once they develop TB
DrTVRao MD 19
Global Estimates
Classification
Estimated Number of Cases
Estimated Number of
Deaths
All forms TB
88 million 16 million
MDR TB 424000 116000
XDR TB 27000 16000
DrTVRao MD 20
Extensively Drug-Resistant Mycobacterium tuberculosis
India
The first XDR TB cases in India and the emergence of XDR TB is reported by Rajesh Mondal and Amita Jain King Georges Medical University Lucknow India Volume 13 Number 9ndashSeptember 2007 in Emerging Infectious Diseases
DrTVRao MD 21
Drug susceptible TBsect
MDR-TB
1990sect
XDR-TB
2006sect
Total DR
Resistance to HampR ndash
Treatable with 2nd line drugs
Resistance to 2nd line drugs ndashTreatment options seriously restricted
Resistance to all available drugs ndash
No treatment options
or limited resistance manageable with 4 drug regimen - DOTS
Are we Returning to a Pre-antibiotic Era
DrTVRao MD 22
Genesis of MDR TB
Resistance is a man-made amplification of a natural phenomenon
Inadequate drug delivery is main cause of secondary drug resistance
Secondary drug resistance is the main cause of primary drug resistance due to transmission of resistant strains
MDR due to spontaneous mutations is not possible as the genes encoding resistance for anti TB are unlinked
DrTVRao MD 23
Factors Contributing to Development
and Spread of MDR and XDR TB Weak TB programs (DOTS)
Low completioncure rates Lack of treatment follow up and
patient support Unreliable drug supply Diagnostic delay
Absent or inadequate infection control measures
Uncontrolled use of 2nd line drugs Fluroquinolones
DrTVRao MD 24
INHChromosomally mediatedLoss of catalaseperoxidaseMutation in mycolic acid synthesis
Regulators of peroxide response
Mechanism of resistance
DrTVRao MD 25
RifampinReduced binding to RNA polymeraseClusters of mutations at ldquoRifampin Resistance Determining Regionrdquo (RRDR)
Reduced Cell wall permeability
Mechanism of resistance
DrTVRao MD 26
Gene location associated Drug-Resistant
Mtuberculosis Drug Gene Isoniazid Kat G Inh A Kas
A Rifampicin rpo B Ethambutol emb B Streptomycin rps L Pyrazinamide pnc A Fluoroquinolones gyr A
Dubaniewicz A et al Molecular sub-type of the HLA-DR antigens in pulmonary tuberculosis Int J Infect Dis20004129-33
DrTVRao MD 27
Current Scientific Documentations on Drug Resistance in
Tuberculosis
DrTVRao MD 28
Alarming Rise of Resistant TuberculosisWHO Report on
Anti-TB Drug Resistance
490000 new cases of MDR-TB each year with gt110000 deaths1
Accounts for 5 of 9 million new cases of TB2
MDR-TB rates higher than ever (up to 223) particularly in former Soviet Union countries
XDR-TB reported by as many as 49 countries (by June 2008)3
Recent WHOIUATLD Global Surveillance report indicated 75 (3014012) of MDR TB to be XDR4
Around 40000 XDR-TB cases emerge every year1
1Tuberculosis MDR-TB amp XDR-TBmdashThe 2008 Report The Stop TB Department WHO2Hargreaves S httpinfectionthelancetcom Vol 8 April 2008 p2203Raviglione MC NEJM 2008359636-84Anti-TB Drug Resistance in the World Report No 4 The WHOIUATLD Global Project on Anti-Tuberculosis Drug Resistance Surveillance 2002-2007 World Health Organization 2008 (WHOHTMTB2008394)
DrTVRao MD 29
MDR-TB amp XDR-TBTHE 2008 REPORT
of MDR-TB among new TB cases 1994-2007
DrTVRao MD 30
MDR-TB rates higher than ever (up to 223) particularly in former Soviet Union countries
DrTVRao MD 31
Alarming Rise of Resistant TB
Resistant TB burden in countries of former Soviet Union about 50 of cases resistant to at least one drug about 20 MDR XDR-TB proportions also higher (as high as 24 in
Estonia)1
MDRXDR TB ndash essentially a man-made problem2
High numbers of resistant cases (gt400000 MDR-TB cases every year) due mainly to Underinvestment in basic TB control Poor management of anti-TB drugs Transmission of drug resistant strains1
1Anti-TB Drug Resistance in the World Report No 4 The WHOIUATLD Global Project on Anti-Tuberculosis Drug Resistance Surveillance 2002-2007 World Health Organization 2008 (WHOHTMTB2008394)
2Reichman The Lancet 20083711052-3
DrTVRao MD 32
The Much Discussed Article on XDR TB in the Lancet
Of the 221 multi-drug resistant (MDR-TB) cases 53 (24) were XDR
Almost all (52 of 53) of the XDR-TB patients died with a median survival of only 16 days from the time of diagnosis (in the 42 patients with confirmed dates of death)
All the 44 XDR TB patients who were tested for HIV were found co-infected
55 patents had never received anti-TB drugs suggesting primary transmission of XDR pathogen
67 patients had been admitted to the hospital in the preceding 2 years suggesting potential role of nosocomial transmission
Gandhi et al Lancet 20063681575-80DrTVRao MD 33
Poor mangement of infected lead to grwoing resistance
Resistance to anti-TB drugs in populations is a phenomenon that occurs primarily due to poorly managed TB care Problems include incorrect drug prescribing practices by providers poor quality drugs or erratic supply of drugs and also patient non-adherence DrTVRao MD 34
Susceptibility Testing
1048708 Direct and indirect testing1048708 Primary Drugs testing1048708 Isoniazid1048708 Rifampicin1048708 Ethambutol ()1048708 Pyrizinamide ()
DrTVRao MD 35
Drug susceptibility testing (DST)
DST is recommended for all new cases for all first line drugs with specimens taken before initiating treatment
Accuracy is more important than speed DST results should come from a small
number of well-equipped experienced laboratories who participate and perform well in an international DST quality control scheme
The WHO Supranational Laboratory Quality Control Network offers the greatest global coverage for this
DrTVRao MD 36
Drug susceptibility Testing
Assessment of growth inhibition on solid media containing various dilutions of the drug in comparison with the test strains
As the method depend observation of growth Results are not available until several weeks after isolation of the organism
DrTVRao MD 37
Other accredited Methods
Radiometric and Non radiometric methods
Nucleic acid technology ndash effective upto 95 in mutations to rifampicin resistance to gene rpoB gene
DrTVRao MD 38
Drug susceptibility testing (DST)
As a minimum laboratories supplying DST data should correctly identify resistance to isoniazid and rifampicin in over 90 of quality control samples in two out of the last three quality control roundsDrTVRao MD 39
Detection of Rifampicin Drug susceptibility testing (DST) is more important
Early identification of mycobacterial growth as M tuberculosis complex and the identification of rifampicin resistance should be the first priority as rifampicin resistance invalidates standard 6 month short-course chemotherapy and is a useful marker in most countries for MDR-TB
Laboratories should aim to identify isolates as M tuberculosis complex and perform rifampicin resistance in 90 of isolates within 1-2 working days This is technologically feasible
DrTVRao MD 40
Drug susceptibility testing
For DST laboratories modern molecular techniques permit the successful identification of isoniazid resistance in at least 75 of mycobacterial cultures within 1-2 working days and are useful preliminary screens for isoniazid resistance
DrTVRao MD 41
Secondary Drugs testing [lack of standardized
methods]
Ofloxacin quinolonesEthionamide KanamycinCapreomycin Ensure quality control and
quality assurance
DrTVRao MD 42
WHO Controls the Tuberculosis related work
The laboratory methods for anti-tuberculosis drug susceptibility testing should be selected from among those that are WHO-recommended and all laboratory processes should be quality-assured in cooperation with a partner Supranational Reference Laboratory (SRL)DrTVRao MD 43
Other WHO-Endorsed Tools
Liquid culture (eg MGIT BacTALERT)
Capilia TB Rapid strip test that detects a TB-
specific antigen from culture
Molecular line probe assays (eg GenoType MTBDRplus INNO-LiPA RifTB) Strip test for detection of TB and
drug-resistance conferring mutations
DrTVRao MD 44
BacTALERTreg
DrTVRao MD 45
CDC Updates Guidelines for Nucleic AcidAmplification Techniques to Diagnose
Tuberculosis
NAAT results should be interpreted in conjunction with the AFB smear results
NAAT and smear positive start Rx despite pending culture results PPV 95
Smear negative NAAT positive use clinical judgment to either treat or await culture
DrTVRao MD 46
Selection from automated systems for molecular and
bacteriological rapid diagnostics
PCRRocheCOBASreg Amplicorreg
amplification kitsRocheCOBASreg LightCyclerreg
(real-time-PCR)RocheCOBASreg TaqMan 48reg(increases the specificity of real-
time-PCR)
DrTVRao MD 47
Molecular Fingerprinting
26 of 30 (87) XDR TB isolates found to be genetically similar
Majority of patients had no previous history of TB treatment Suggestive of recent infection with drug-resistant strain
DrTVRao MD 48
Is PCR methods a solution
PCR cant yet replace neither microscopy culturing and competent clinical examination
DrTVRao MD 49
No testing method replaces Clinical assessment
DrTVRao MD 50
XDR-TBThe description
of XDR-TB was first used earlier in 2006 following a joint survey by WHO and the US Centres for Disease Control and Prevention (CDC) DrTVRao MD 51
How x-MDR generated
Acquired resistance is that which occurs as a result of specific previous treatment The level of primary resistance in the community is considered to reflect the efficacy of control measures in the past while the level of acquired resistance is a measure of on-going TB control measuresDrTVRao MD 52
Extreme Drug resistant Tuberculosis (XDR-TB)
Resistant to all first line drugs namely Isoniazid and Rifampin and Three or more second line drugs (SLDrsquoS) that are used to treat MDR-TB Thequinalones like Ofloaxin
Or Aminoglycosides like Capreomycin amp
Kanamycin
No third-line drugs available to treat XDR-TB since none has been developed in the last 40 years
DrTVRao MD 53
Background Extensively drug-resistant tuberculosis
Extensively drug-resistant tuberculosis has been reported in 45 countries including countries with limited resources and a high burden of tuberculosis
DrTVRao MD 54
DrTVRao MD 55
Transmissionof X -MDR
Like other forms of TB XDR-TB is spread through the air When a person with infectious TB coughs sneezes talks or spits they propel Mycobacterium into the air
DrTVRao MD 56
Best options to diagnoseX-MDR tuberculosis
To evaluate drug susceptibility the bacteria need to be cultivated and tested in a suitable laboratory Final diagnosis in this way for TB and especially for XDR-TB may take from 6 to 16 weeks To reduce the time needed for diagnosis new tools for rapid TB diagnosis are urgently needed
DrTVRao MD 57
When to suspect MDR TB
Patients not showing any reduction
in bacillary population after 3-
months of regular treatment with
Cat II regimen
Sputum positive patients who are
contacts of a known MDR TB
patient
DrTVRao MD 58
How to evaluate MDR TB
MDR TB is only a laboratory
proved HR resistance
Clinical suspicion should be
followed by lab Confirmation
Laboratories should be quality
controlledTRC
DrTVRao MD 59
Extreme Drug resistant Tuberculosis (XDR-TB) and AIDS
It can also be contracted without a patient receiving any previous treatment for TB
Mostly associated with HIV positive patients
HIV has the potential to fast tracking XDR-TB into an uncontrollable epidemic
Average survival period for patients infected with XDR-TB is 16 days
DrTVRao MD 60
Responding to MDRXDR-TB
Augment DOTS Program by
New diagnostics
New drugs New vaccines HIV incidence
reduction Advocacy1
A mathematical model projected by Basu and co-workers indicates that half of XDR-TB can be averted by 2012 by bringing synergistic effects through
Use of masks Reduced time as in-patient Improved ventilation Rapid resistance testing HIV treatment TB isolation facilities2
1Marteens and Wilkinson Lancet 20073702030-432Basu et al Quoted in Porco and Getz Lancet 20073701464-5
DrTVRao MD 61
Second Line Drug Treatment (SLDrsquos)
Less effective more costly and more toxic 50 cure rate
Four months intensive phase (5 drugs) Kanamycins Ethionamide Pyrazinamide Ofloxacin Cycloserine or Ethambutol DrTVRao MD 62
World Health Organisation (WHO) Guidelines for treatment
of MDR-TB
Strengthen basic TB care to prevent the emergence of drug-resistance
Ensure prompt diagnosis and treatment of drug resistant cases to cure existing cases and prevent further transmission
Increase collaboration between HIV and TB control programmes to provide necessary prevention and care to co-infected patients
Increase investment in laboratory infrastructures to enable better detection and management of resistant cases
DrTVRao MD 63
Treatment Guidelines
Sensitivity testing for all smear positive specimens
Patient Family and staff counselling amp education
Correct and thorough hand washing protocol and procedure
Personal protection is very important
DrTVRao MD 64
THE NEW MDR-TB Guidelines
A flexible framework approach combining both clinical and programmatic aspects of DOTS Plus based on essential programme conditions
But encouraging programs to tailor their case-finding and treatment strategies to the local epidemiological and Programme situation
Reflect GLC expert consensus and evidence and experience from GLC projects thus far
DrTVRao MD 65
Effective laboratory Diagnosis
Sputum smear examinations ndash rapid classification of species (atypical mycobacteria common in AIDS)
Culture examinations
Rapid drug sensitivity testingDrTVRao MD 66
MDR TB and HIV
MDR TB occurs with the same frequency in HIV
patients as in TB patients who are smear negative
Transmission of drug-resistant strains among HIV-
infected patients in congregate settings occurs
leading to lsquooutbreaksrsquo of MDR TB in such settings
Infection control measures absolutely essential in
settings where large number of HIV TB patients stay
togetherDrTVRao MD 67
Transmission is dependent on closeness and time of contact
In penitentiary care contacts are very close and prolonged ndash culture positive cases can also transmit TB especially to HIV positive population
DrTVRao MD 68
To Know more on MDR ndashTB Current Guidelines of WHO
Guidelines for the programmatic management of drug-resistant tuberculosis - 2011 update [pdf 904kb]
Visit helliphelliphellip WHOHTMTB20116DrTVRao MD 69
Are there any solutions for effective
Diagnosis in TB
DrTVRao MD 70
Programme Created by DrTVRao MD for Medical and Health Care
Workers in the Developing World Email
doctortvraogmailcom
DrTVRao MD 71
Why XDR - TB a grave concern
Because XDR TB is resistant to first-line and second line drugs patients are left with treatment options that are much less effective
XDR TB is of special concern for persons with HIV infection or other conditions that can weaken the immune system These persons are more likely to develop TB disease once they are infected and also have a higher risk of death once they develop TB
DrTVRao MD 19
Global Estimates
Classification
Estimated Number of Cases
Estimated Number of
Deaths
All forms TB
88 million 16 million
MDR TB 424000 116000
XDR TB 27000 16000
DrTVRao MD 20
Extensively Drug-Resistant Mycobacterium tuberculosis
India
The first XDR TB cases in India and the emergence of XDR TB is reported by Rajesh Mondal and Amita Jain King Georges Medical University Lucknow India Volume 13 Number 9ndashSeptember 2007 in Emerging Infectious Diseases
DrTVRao MD 21
Drug susceptible TBsect
MDR-TB
1990sect
XDR-TB
2006sect
Total DR
Resistance to HampR ndash
Treatable with 2nd line drugs
Resistance to 2nd line drugs ndashTreatment options seriously restricted
Resistance to all available drugs ndash
No treatment options
or limited resistance manageable with 4 drug regimen - DOTS
Are we Returning to a Pre-antibiotic Era
DrTVRao MD 22
Genesis of MDR TB
Resistance is a man-made amplification of a natural phenomenon
Inadequate drug delivery is main cause of secondary drug resistance
Secondary drug resistance is the main cause of primary drug resistance due to transmission of resistant strains
MDR due to spontaneous mutations is not possible as the genes encoding resistance for anti TB are unlinked
DrTVRao MD 23
Factors Contributing to Development
and Spread of MDR and XDR TB Weak TB programs (DOTS)
Low completioncure rates Lack of treatment follow up and
patient support Unreliable drug supply Diagnostic delay
Absent or inadequate infection control measures
Uncontrolled use of 2nd line drugs Fluroquinolones
DrTVRao MD 24
INHChromosomally mediatedLoss of catalaseperoxidaseMutation in mycolic acid synthesis
Regulators of peroxide response
Mechanism of resistance
DrTVRao MD 25
RifampinReduced binding to RNA polymeraseClusters of mutations at ldquoRifampin Resistance Determining Regionrdquo (RRDR)
Reduced Cell wall permeability
Mechanism of resistance
DrTVRao MD 26
Gene location associated Drug-Resistant
Mtuberculosis Drug Gene Isoniazid Kat G Inh A Kas
A Rifampicin rpo B Ethambutol emb B Streptomycin rps L Pyrazinamide pnc A Fluoroquinolones gyr A
Dubaniewicz A et al Molecular sub-type of the HLA-DR antigens in pulmonary tuberculosis Int J Infect Dis20004129-33
DrTVRao MD 27
Current Scientific Documentations on Drug Resistance in
Tuberculosis
DrTVRao MD 28
Alarming Rise of Resistant TuberculosisWHO Report on
Anti-TB Drug Resistance
490000 new cases of MDR-TB each year with gt110000 deaths1
Accounts for 5 of 9 million new cases of TB2
MDR-TB rates higher than ever (up to 223) particularly in former Soviet Union countries
XDR-TB reported by as many as 49 countries (by June 2008)3
Recent WHOIUATLD Global Surveillance report indicated 75 (3014012) of MDR TB to be XDR4
Around 40000 XDR-TB cases emerge every year1
1Tuberculosis MDR-TB amp XDR-TBmdashThe 2008 Report The Stop TB Department WHO2Hargreaves S httpinfectionthelancetcom Vol 8 April 2008 p2203Raviglione MC NEJM 2008359636-84Anti-TB Drug Resistance in the World Report No 4 The WHOIUATLD Global Project on Anti-Tuberculosis Drug Resistance Surveillance 2002-2007 World Health Organization 2008 (WHOHTMTB2008394)
DrTVRao MD 29
MDR-TB amp XDR-TBTHE 2008 REPORT
of MDR-TB among new TB cases 1994-2007
DrTVRao MD 30
MDR-TB rates higher than ever (up to 223) particularly in former Soviet Union countries
DrTVRao MD 31
Alarming Rise of Resistant TB
Resistant TB burden in countries of former Soviet Union about 50 of cases resistant to at least one drug about 20 MDR XDR-TB proportions also higher (as high as 24 in
Estonia)1
MDRXDR TB ndash essentially a man-made problem2
High numbers of resistant cases (gt400000 MDR-TB cases every year) due mainly to Underinvestment in basic TB control Poor management of anti-TB drugs Transmission of drug resistant strains1
1Anti-TB Drug Resistance in the World Report No 4 The WHOIUATLD Global Project on Anti-Tuberculosis Drug Resistance Surveillance 2002-2007 World Health Organization 2008 (WHOHTMTB2008394)
2Reichman The Lancet 20083711052-3
DrTVRao MD 32
The Much Discussed Article on XDR TB in the Lancet
Of the 221 multi-drug resistant (MDR-TB) cases 53 (24) were XDR
Almost all (52 of 53) of the XDR-TB patients died with a median survival of only 16 days from the time of diagnosis (in the 42 patients with confirmed dates of death)
All the 44 XDR TB patients who were tested for HIV were found co-infected
55 patents had never received anti-TB drugs suggesting primary transmission of XDR pathogen
67 patients had been admitted to the hospital in the preceding 2 years suggesting potential role of nosocomial transmission
Gandhi et al Lancet 20063681575-80DrTVRao MD 33
Poor mangement of infected lead to grwoing resistance
Resistance to anti-TB drugs in populations is a phenomenon that occurs primarily due to poorly managed TB care Problems include incorrect drug prescribing practices by providers poor quality drugs or erratic supply of drugs and also patient non-adherence DrTVRao MD 34
Susceptibility Testing
1048708 Direct and indirect testing1048708 Primary Drugs testing1048708 Isoniazid1048708 Rifampicin1048708 Ethambutol ()1048708 Pyrizinamide ()
DrTVRao MD 35
Drug susceptibility testing (DST)
DST is recommended for all new cases for all first line drugs with specimens taken before initiating treatment
Accuracy is more important than speed DST results should come from a small
number of well-equipped experienced laboratories who participate and perform well in an international DST quality control scheme
The WHO Supranational Laboratory Quality Control Network offers the greatest global coverage for this
DrTVRao MD 36
Drug susceptibility Testing
Assessment of growth inhibition on solid media containing various dilutions of the drug in comparison with the test strains
As the method depend observation of growth Results are not available until several weeks after isolation of the organism
DrTVRao MD 37
Other accredited Methods
Radiometric and Non radiometric methods
Nucleic acid technology ndash effective upto 95 in mutations to rifampicin resistance to gene rpoB gene
DrTVRao MD 38
Drug susceptibility testing (DST)
As a minimum laboratories supplying DST data should correctly identify resistance to isoniazid and rifampicin in over 90 of quality control samples in two out of the last three quality control roundsDrTVRao MD 39
Detection of Rifampicin Drug susceptibility testing (DST) is more important
Early identification of mycobacterial growth as M tuberculosis complex and the identification of rifampicin resistance should be the first priority as rifampicin resistance invalidates standard 6 month short-course chemotherapy and is a useful marker in most countries for MDR-TB
Laboratories should aim to identify isolates as M tuberculosis complex and perform rifampicin resistance in 90 of isolates within 1-2 working days This is technologically feasible
DrTVRao MD 40
Drug susceptibility testing
For DST laboratories modern molecular techniques permit the successful identification of isoniazid resistance in at least 75 of mycobacterial cultures within 1-2 working days and are useful preliminary screens for isoniazid resistance
DrTVRao MD 41
Secondary Drugs testing [lack of standardized
methods]
Ofloxacin quinolonesEthionamide KanamycinCapreomycin Ensure quality control and
quality assurance
DrTVRao MD 42
WHO Controls the Tuberculosis related work
The laboratory methods for anti-tuberculosis drug susceptibility testing should be selected from among those that are WHO-recommended and all laboratory processes should be quality-assured in cooperation with a partner Supranational Reference Laboratory (SRL)DrTVRao MD 43
Other WHO-Endorsed Tools
Liquid culture (eg MGIT BacTALERT)
Capilia TB Rapid strip test that detects a TB-
specific antigen from culture
Molecular line probe assays (eg GenoType MTBDRplus INNO-LiPA RifTB) Strip test for detection of TB and
drug-resistance conferring mutations
DrTVRao MD 44
BacTALERTreg
DrTVRao MD 45
CDC Updates Guidelines for Nucleic AcidAmplification Techniques to Diagnose
Tuberculosis
NAAT results should be interpreted in conjunction with the AFB smear results
NAAT and smear positive start Rx despite pending culture results PPV 95
Smear negative NAAT positive use clinical judgment to either treat or await culture
DrTVRao MD 46
Selection from automated systems for molecular and
bacteriological rapid diagnostics
PCRRocheCOBASreg Amplicorreg
amplification kitsRocheCOBASreg LightCyclerreg
(real-time-PCR)RocheCOBASreg TaqMan 48reg(increases the specificity of real-
time-PCR)
DrTVRao MD 47
Molecular Fingerprinting
26 of 30 (87) XDR TB isolates found to be genetically similar
Majority of patients had no previous history of TB treatment Suggestive of recent infection with drug-resistant strain
DrTVRao MD 48
Is PCR methods a solution
PCR cant yet replace neither microscopy culturing and competent clinical examination
DrTVRao MD 49
No testing method replaces Clinical assessment
DrTVRao MD 50
XDR-TBThe description
of XDR-TB was first used earlier in 2006 following a joint survey by WHO and the US Centres for Disease Control and Prevention (CDC) DrTVRao MD 51
How x-MDR generated
Acquired resistance is that which occurs as a result of specific previous treatment The level of primary resistance in the community is considered to reflect the efficacy of control measures in the past while the level of acquired resistance is a measure of on-going TB control measuresDrTVRao MD 52
Extreme Drug resistant Tuberculosis (XDR-TB)
Resistant to all first line drugs namely Isoniazid and Rifampin and Three or more second line drugs (SLDrsquoS) that are used to treat MDR-TB Thequinalones like Ofloaxin
Or Aminoglycosides like Capreomycin amp
Kanamycin
No third-line drugs available to treat XDR-TB since none has been developed in the last 40 years
DrTVRao MD 53
Background Extensively drug-resistant tuberculosis
Extensively drug-resistant tuberculosis has been reported in 45 countries including countries with limited resources and a high burden of tuberculosis
DrTVRao MD 54
DrTVRao MD 55
Transmissionof X -MDR
Like other forms of TB XDR-TB is spread through the air When a person with infectious TB coughs sneezes talks or spits they propel Mycobacterium into the air
DrTVRao MD 56
Best options to diagnoseX-MDR tuberculosis
To evaluate drug susceptibility the bacteria need to be cultivated and tested in a suitable laboratory Final diagnosis in this way for TB and especially for XDR-TB may take from 6 to 16 weeks To reduce the time needed for diagnosis new tools for rapid TB diagnosis are urgently needed
DrTVRao MD 57
When to suspect MDR TB
Patients not showing any reduction
in bacillary population after 3-
months of regular treatment with
Cat II regimen
Sputum positive patients who are
contacts of a known MDR TB
patient
DrTVRao MD 58
How to evaluate MDR TB
MDR TB is only a laboratory
proved HR resistance
Clinical suspicion should be
followed by lab Confirmation
Laboratories should be quality
controlledTRC
DrTVRao MD 59
Extreme Drug resistant Tuberculosis (XDR-TB) and AIDS
It can also be contracted without a patient receiving any previous treatment for TB
Mostly associated with HIV positive patients
HIV has the potential to fast tracking XDR-TB into an uncontrollable epidemic
Average survival period for patients infected with XDR-TB is 16 days
DrTVRao MD 60
Responding to MDRXDR-TB
Augment DOTS Program by
New diagnostics
New drugs New vaccines HIV incidence
reduction Advocacy1
A mathematical model projected by Basu and co-workers indicates that half of XDR-TB can be averted by 2012 by bringing synergistic effects through
Use of masks Reduced time as in-patient Improved ventilation Rapid resistance testing HIV treatment TB isolation facilities2
1Marteens and Wilkinson Lancet 20073702030-432Basu et al Quoted in Porco and Getz Lancet 20073701464-5
DrTVRao MD 61
Second Line Drug Treatment (SLDrsquos)
Less effective more costly and more toxic 50 cure rate
Four months intensive phase (5 drugs) Kanamycins Ethionamide Pyrazinamide Ofloxacin Cycloserine or Ethambutol DrTVRao MD 62
World Health Organisation (WHO) Guidelines for treatment
of MDR-TB
Strengthen basic TB care to prevent the emergence of drug-resistance
Ensure prompt diagnosis and treatment of drug resistant cases to cure existing cases and prevent further transmission
Increase collaboration between HIV and TB control programmes to provide necessary prevention and care to co-infected patients
Increase investment in laboratory infrastructures to enable better detection and management of resistant cases
DrTVRao MD 63
Treatment Guidelines
Sensitivity testing for all smear positive specimens
Patient Family and staff counselling amp education
Correct and thorough hand washing protocol and procedure
Personal protection is very important
DrTVRao MD 64
THE NEW MDR-TB Guidelines
A flexible framework approach combining both clinical and programmatic aspects of DOTS Plus based on essential programme conditions
But encouraging programs to tailor their case-finding and treatment strategies to the local epidemiological and Programme situation
Reflect GLC expert consensus and evidence and experience from GLC projects thus far
DrTVRao MD 65
Effective laboratory Diagnosis
Sputum smear examinations ndash rapid classification of species (atypical mycobacteria common in AIDS)
Culture examinations
Rapid drug sensitivity testingDrTVRao MD 66
MDR TB and HIV
MDR TB occurs with the same frequency in HIV
patients as in TB patients who are smear negative
Transmission of drug-resistant strains among HIV-
infected patients in congregate settings occurs
leading to lsquooutbreaksrsquo of MDR TB in such settings
Infection control measures absolutely essential in
settings where large number of HIV TB patients stay
togetherDrTVRao MD 67
Transmission is dependent on closeness and time of contact
In penitentiary care contacts are very close and prolonged ndash culture positive cases can also transmit TB especially to HIV positive population
DrTVRao MD 68
To Know more on MDR ndashTB Current Guidelines of WHO
Guidelines for the programmatic management of drug-resistant tuberculosis - 2011 update [pdf 904kb]
Visit helliphelliphellip WHOHTMTB20116DrTVRao MD 69
Are there any solutions for effective
Diagnosis in TB
DrTVRao MD 70
Programme Created by DrTVRao MD for Medical and Health Care
Workers in the Developing World Email
doctortvraogmailcom
DrTVRao MD 71
Global Estimates
Classification
Estimated Number of Cases
Estimated Number of
Deaths
All forms TB
88 million 16 million
MDR TB 424000 116000
XDR TB 27000 16000
DrTVRao MD 20
Extensively Drug-Resistant Mycobacterium tuberculosis
India
The first XDR TB cases in India and the emergence of XDR TB is reported by Rajesh Mondal and Amita Jain King Georges Medical University Lucknow India Volume 13 Number 9ndashSeptember 2007 in Emerging Infectious Diseases
DrTVRao MD 21
Drug susceptible TBsect
MDR-TB
1990sect
XDR-TB
2006sect
Total DR
Resistance to HampR ndash
Treatable with 2nd line drugs
Resistance to 2nd line drugs ndashTreatment options seriously restricted
Resistance to all available drugs ndash
No treatment options
or limited resistance manageable with 4 drug regimen - DOTS
Are we Returning to a Pre-antibiotic Era
DrTVRao MD 22
Genesis of MDR TB
Resistance is a man-made amplification of a natural phenomenon
Inadequate drug delivery is main cause of secondary drug resistance
Secondary drug resistance is the main cause of primary drug resistance due to transmission of resistant strains
MDR due to spontaneous mutations is not possible as the genes encoding resistance for anti TB are unlinked
DrTVRao MD 23
Factors Contributing to Development
and Spread of MDR and XDR TB Weak TB programs (DOTS)
Low completioncure rates Lack of treatment follow up and
patient support Unreliable drug supply Diagnostic delay
Absent or inadequate infection control measures
Uncontrolled use of 2nd line drugs Fluroquinolones
DrTVRao MD 24
INHChromosomally mediatedLoss of catalaseperoxidaseMutation in mycolic acid synthesis
Regulators of peroxide response
Mechanism of resistance
DrTVRao MD 25
RifampinReduced binding to RNA polymeraseClusters of mutations at ldquoRifampin Resistance Determining Regionrdquo (RRDR)
Reduced Cell wall permeability
Mechanism of resistance
DrTVRao MD 26
Gene location associated Drug-Resistant
Mtuberculosis Drug Gene Isoniazid Kat G Inh A Kas
A Rifampicin rpo B Ethambutol emb B Streptomycin rps L Pyrazinamide pnc A Fluoroquinolones gyr A
Dubaniewicz A et al Molecular sub-type of the HLA-DR antigens in pulmonary tuberculosis Int J Infect Dis20004129-33
DrTVRao MD 27
Current Scientific Documentations on Drug Resistance in
Tuberculosis
DrTVRao MD 28
Alarming Rise of Resistant TuberculosisWHO Report on
Anti-TB Drug Resistance
490000 new cases of MDR-TB each year with gt110000 deaths1
Accounts for 5 of 9 million new cases of TB2
MDR-TB rates higher than ever (up to 223) particularly in former Soviet Union countries
XDR-TB reported by as many as 49 countries (by June 2008)3
Recent WHOIUATLD Global Surveillance report indicated 75 (3014012) of MDR TB to be XDR4
Around 40000 XDR-TB cases emerge every year1
1Tuberculosis MDR-TB amp XDR-TBmdashThe 2008 Report The Stop TB Department WHO2Hargreaves S httpinfectionthelancetcom Vol 8 April 2008 p2203Raviglione MC NEJM 2008359636-84Anti-TB Drug Resistance in the World Report No 4 The WHOIUATLD Global Project on Anti-Tuberculosis Drug Resistance Surveillance 2002-2007 World Health Organization 2008 (WHOHTMTB2008394)
DrTVRao MD 29
MDR-TB amp XDR-TBTHE 2008 REPORT
of MDR-TB among new TB cases 1994-2007
DrTVRao MD 30
MDR-TB rates higher than ever (up to 223) particularly in former Soviet Union countries
DrTVRao MD 31
Alarming Rise of Resistant TB
Resistant TB burden in countries of former Soviet Union about 50 of cases resistant to at least one drug about 20 MDR XDR-TB proportions also higher (as high as 24 in
Estonia)1
MDRXDR TB ndash essentially a man-made problem2
High numbers of resistant cases (gt400000 MDR-TB cases every year) due mainly to Underinvestment in basic TB control Poor management of anti-TB drugs Transmission of drug resistant strains1
1Anti-TB Drug Resistance in the World Report No 4 The WHOIUATLD Global Project on Anti-Tuberculosis Drug Resistance Surveillance 2002-2007 World Health Organization 2008 (WHOHTMTB2008394)
2Reichman The Lancet 20083711052-3
DrTVRao MD 32
The Much Discussed Article on XDR TB in the Lancet
Of the 221 multi-drug resistant (MDR-TB) cases 53 (24) were XDR
Almost all (52 of 53) of the XDR-TB patients died with a median survival of only 16 days from the time of diagnosis (in the 42 patients with confirmed dates of death)
All the 44 XDR TB patients who were tested for HIV were found co-infected
55 patents had never received anti-TB drugs suggesting primary transmission of XDR pathogen
67 patients had been admitted to the hospital in the preceding 2 years suggesting potential role of nosocomial transmission
Gandhi et al Lancet 20063681575-80DrTVRao MD 33
Poor mangement of infected lead to grwoing resistance
Resistance to anti-TB drugs in populations is a phenomenon that occurs primarily due to poorly managed TB care Problems include incorrect drug prescribing practices by providers poor quality drugs or erratic supply of drugs and also patient non-adherence DrTVRao MD 34
Susceptibility Testing
1048708 Direct and indirect testing1048708 Primary Drugs testing1048708 Isoniazid1048708 Rifampicin1048708 Ethambutol ()1048708 Pyrizinamide ()
DrTVRao MD 35
Drug susceptibility testing (DST)
DST is recommended for all new cases for all first line drugs with specimens taken before initiating treatment
Accuracy is more important than speed DST results should come from a small
number of well-equipped experienced laboratories who participate and perform well in an international DST quality control scheme
The WHO Supranational Laboratory Quality Control Network offers the greatest global coverage for this
DrTVRao MD 36
Drug susceptibility Testing
Assessment of growth inhibition on solid media containing various dilutions of the drug in comparison with the test strains
As the method depend observation of growth Results are not available until several weeks after isolation of the organism
DrTVRao MD 37
Other accredited Methods
Radiometric and Non radiometric methods
Nucleic acid technology ndash effective upto 95 in mutations to rifampicin resistance to gene rpoB gene
DrTVRao MD 38
Drug susceptibility testing (DST)
As a minimum laboratories supplying DST data should correctly identify resistance to isoniazid and rifampicin in over 90 of quality control samples in two out of the last three quality control roundsDrTVRao MD 39
Detection of Rifampicin Drug susceptibility testing (DST) is more important
Early identification of mycobacterial growth as M tuberculosis complex and the identification of rifampicin resistance should be the first priority as rifampicin resistance invalidates standard 6 month short-course chemotherapy and is a useful marker in most countries for MDR-TB
Laboratories should aim to identify isolates as M tuberculosis complex and perform rifampicin resistance in 90 of isolates within 1-2 working days This is technologically feasible
DrTVRao MD 40
Drug susceptibility testing
For DST laboratories modern molecular techniques permit the successful identification of isoniazid resistance in at least 75 of mycobacterial cultures within 1-2 working days and are useful preliminary screens for isoniazid resistance
DrTVRao MD 41
Secondary Drugs testing [lack of standardized
methods]
Ofloxacin quinolonesEthionamide KanamycinCapreomycin Ensure quality control and
quality assurance
DrTVRao MD 42
WHO Controls the Tuberculosis related work
The laboratory methods for anti-tuberculosis drug susceptibility testing should be selected from among those that are WHO-recommended and all laboratory processes should be quality-assured in cooperation with a partner Supranational Reference Laboratory (SRL)DrTVRao MD 43
Other WHO-Endorsed Tools
Liquid culture (eg MGIT BacTALERT)
Capilia TB Rapid strip test that detects a TB-
specific antigen from culture
Molecular line probe assays (eg GenoType MTBDRplus INNO-LiPA RifTB) Strip test for detection of TB and
drug-resistance conferring mutations
DrTVRao MD 44
BacTALERTreg
DrTVRao MD 45
CDC Updates Guidelines for Nucleic AcidAmplification Techniques to Diagnose
Tuberculosis
NAAT results should be interpreted in conjunction with the AFB smear results
NAAT and smear positive start Rx despite pending culture results PPV 95
Smear negative NAAT positive use clinical judgment to either treat or await culture
DrTVRao MD 46
Selection from automated systems for molecular and
bacteriological rapid diagnostics
PCRRocheCOBASreg Amplicorreg
amplification kitsRocheCOBASreg LightCyclerreg
(real-time-PCR)RocheCOBASreg TaqMan 48reg(increases the specificity of real-
time-PCR)
DrTVRao MD 47
Molecular Fingerprinting
26 of 30 (87) XDR TB isolates found to be genetically similar
Majority of patients had no previous history of TB treatment Suggestive of recent infection with drug-resistant strain
DrTVRao MD 48
Is PCR methods a solution
PCR cant yet replace neither microscopy culturing and competent clinical examination
DrTVRao MD 49
No testing method replaces Clinical assessment
DrTVRao MD 50
XDR-TBThe description
of XDR-TB was first used earlier in 2006 following a joint survey by WHO and the US Centres for Disease Control and Prevention (CDC) DrTVRao MD 51
How x-MDR generated
Acquired resistance is that which occurs as a result of specific previous treatment The level of primary resistance in the community is considered to reflect the efficacy of control measures in the past while the level of acquired resistance is a measure of on-going TB control measuresDrTVRao MD 52
Extreme Drug resistant Tuberculosis (XDR-TB)
Resistant to all first line drugs namely Isoniazid and Rifampin and Three or more second line drugs (SLDrsquoS) that are used to treat MDR-TB Thequinalones like Ofloaxin
Or Aminoglycosides like Capreomycin amp
Kanamycin
No third-line drugs available to treat XDR-TB since none has been developed in the last 40 years
DrTVRao MD 53
Background Extensively drug-resistant tuberculosis
Extensively drug-resistant tuberculosis has been reported in 45 countries including countries with limited resources and a high burden of tuberculosis
DrTVRao MD 54
DrTVRao MD 55
Transmissionof X -MDR
Like other forms of TB XDR-TB is spread through the air When a person with infectious TB coughs sneezes talks or spits they propel Mycobacterium into the air
DrTVRao MD 56
Best options to diagnoseX-MDR tuberculosis
To evaluate drug susceptibility the bacteria need to be cultivated and tested in a suitable laboratory Final diagnosis in this way for TB and especially for XDR-TB may take from 6 to 16 weeks To reduce the time needed for diagnosis new tools for rapid TB diagnosis are urgently needed
DrTVRao MD 57
When to suspect MDR TB
Patients not showing any reduction
in bacillary population after 3-
months of regular treatment with
Cat II regimen
Sputum positive patients who are
contacts of a known MDR TB
patient
DrTVRao MD 58
How to evaluate MDR TB
MDR TB is only a laboratory
proved HR resistance
Clinical suspicion should be
followed by lab Confirmation
Laboratories should be quality
controlledTRC
DrTVRao MD 59
Extreme Drug resistant Tuberculosis (XDR-TB) and AIDS
It can also be contracted without a patient receiving any previous treatment for TB
Mostly associated with HIV positive patients
HIV has the potential to fast tracking XDR-TB into an uncontrollable epidemic
Average survival period for patients infected with XDR-TB is 16 days
DrTVRao MD 60
Responding to MDRXDR-TB
Augment DOTS Program by
New diagnostics
New drugs New vaccines HIV incidence
reduction Advocacy1
A mathematical model projected by Basu and co-workers indicates that half of XDR-TB can be averted by 2012 by bringing synergistic effects through
Use of masks Reduced time as in-patient Improved ventilation Rapid resistance testing HIV treatment TB isolation facilities2
1Marteens and Wilkinson Lancet 20073702030-432Basu et al Quoted in Porco and Getz Lancet 20073701464-5
DrTVRao MD 61
Second Line Drug Treatment (SLDrsquos)
Less effective more costly and more toxic 50 cure rate
Four months intensive phase (5 drugs) Kanamycins Ethionamide Pyrazinamide Ofloxacin Cycloserine or Ethambutol DrTVRao MD 62
World Health Organisation (WHO) Guidelines for treatment
of MDR-TB
Strengthen basic TB care to prevent the emergence of drug-resistance
Ensure prompt diagnosis and treatment of drug resistant cases to cure existing cases and prevent further transmission
Increase collaboration between HIV and TB control programmes to provide necessary prevention and care to co-infected patients
Increase investment in laboratory infrastructures to enable better detection and management of resistant cases
DrTVRao MD 63
Treatment Guidelines
Sensitivity testing for all smear positive specimens
Patient Family and staff counselling amp education
Correct and thorough hand washing protocol and procedure
Personal protection is very important
DrTVRao MD 64
THE NEW MDR-TB Guidelines
A flexible framework approach combining both clinical and programmatic aspects of DOTS Plus based on essential programme conditions
But encouraging programs to tailor their case-finding and treatment strategies to the local epidemiological and Programme situation
Reflect GLC expert consensus and evidence and experience from GLC projects thus far
DrTVRao MD 65
Effective laboratory Diagnosis
Sputum smear examinations ndash rapid classification of species (atypical mycobacteria common in AIDS)
Culture examinations
Rapid drug sensitivity testingDrTVRao MD 66
MDR TB and HIV
MDR TB occurs with the same frequency in HIV
patients as in TB patients who are smear negative
Transmission of drug-resistant strains among HIV-
infected patients in congregate settings occurs
leading to lsquooutbreaksrsquo of MDR TB in such settings
Infection control measures absolutely essential in
settings where large number of HIV TB patients stay
togetherDrTVRao MD 67
Transmission is dependent on closeness and time of contact
In penitentiary care contacts are very close and prolonged ndash culture positive cases can also transmit TB especially to HIV positive population
DrTVRao MD 68
To Know more on MDR ndashTB Current Guidelines of WHO
Guidelines for the programmatic management of drug-resistant tuberculosis - 2011 update [pdf 904kb]
Visit helliphelliphellip WHOHTMTB20116DrTVRao MD 69
Are there any solutions for effective
Diagnosis in TB
DrTVRao MD 70
Programme Created by DrTVRao MD for Medical and Health Care
Workers in the Developing World Email
doctortvraogmailcom
DrTVRao MD 71
Extensively Drug-Resistant Mycobacterium tuberculosis
India
The first XDR TB cases in India and the emergence of XDR TB is reported by Rajesh Mondal and Amita Jain King Georges Medical University Lucknow India Volume 13 Number 9ndashSeptember 2007 in Emerging Infectious Diseases
DrTVRao MD 21
Drug susceptible TBsect
MDR-TB
1990sect
XDR-TB
2006sect
Total DR
Resistance to HampR ndash
Treatable with 2nd line drugs
Resistance to 2nd line drugs ndashTreatment options seriously restricted
Resistance to all available drugs ndash
No treatment options
or limited resistance manageable with 4 drug regimen - DOTS
Are we Returning to a Pre-antibiotic Era
DrTVRao MD 22
Genesis of MDR TB
Resistance is a man-made amplification of a natural phenomenon
Inadequate drug delivery is main cause of secondary drug resistance
Secondary drug resistance is the main cause of primary drug resistance due to transmission of resistant strains
MDR due to spontaneous mutations is not possible as the genes encoding resistance for anti TB are unlinked
DrTVRao MD 23
Factors Contributing to Development
and Spread of MDR and XDR TB Weak TB programs (DOTS)
Low completioncure rates Lack of treatment follow up and
patient support Unreliable drug supply Diagnostic delay
Absent or inadequate infection control measures
Uncontrolled use of 2nd line drugs Fluroquinolones
DrTVRao MD 24
INHChromosomally mediatedLoss of catalaseperoxidaseMutation in mycolic acid synthesis
Regulators of peroxide response
Mechanism of resistance
DrTVRao MD 25
RifampinReduced binding to RNA polymeraseClusters of mutations at ldquoRifampin Resistance Determining Regionrdquo (RRDR)
Reduced Cell wall permeability
Mechanism of resistance
DrTVRao MD 26
Gene location associated Drug-Resistant
Mtuberculosis Drug Gene Isoniazid Kat G Inh A Kas
A Rifampicin rpo B Ethambutol emb B Streptomycin rps L Pyrazinamide pnc A Fluoroquinolones gyr A
Dubaniewicz A et al Molecular sub-type of the HLA-DR antigens in pulmonary tuberculosis Int J Infect Dis20004129-33
DrTVRao MD 27
Current Scientific Documentations on Drug Resistance in
Tuberculosis
DrTVRao MD 28
Alarming Rise of Resistant TuberculosisWHO Report on
Anti-TB Drug Resistance
490000 new cases of MDR-TB each year with gt110000 deaths1
Accounts for 5 of 9 million new cases of TB2
MDR-TB rates higher than ever (up to 223) particularly in former Soviet Union countries
XDR-TB reported by as many as 49 countries (by June 2008)3
Recent WHOIUATLD Global Surveillance report indicated 75 (3014012) of MDR TB to be XDR4
Around 40000 XDR-TB cases emerge every year1
1Tuberculosis MDR-TB amp XDR-TBmdashThe 2008 Report The Stop TB Department WHO2Hargreaves S httpinfectionthelancetcom Vol 8 April 2008 p2203Raviglione MC NEJM 2008359636-84Anti-TB Drug Resistance in the World Report No 4 The WHOIUATLD Global Project on Anti-Tuberculosis Drug Resistance Surveillance 2002-2007 World Health Organization 2008 (WHOHTMTB2008394)
DrTVRao MD 29
MDR-TB amp XDR-TBTHE 2008 REPORT
of MDR-TB among new TB cases 1994-2007
DrTVRao MD 30
MDR-TB rates higher than ever (up to 223) particularly in former Soviet Union countries
DrTVRao MD 31
Alarming Rise of Resistant TB
Resistant TB burden in countries of former Soviet Union about 50 of cases resistant to at least one drug about 20 MDR XDR-TB proportions also higher (as high as 24 in
Estonia)1
MDRXDR TB ndash essentially a man-made problem2
High numbers of resistant cases (gt400000 MDR-TB cases every year) due mainly to Underinvestment in basic TB control Poor management of anti-TB drugs Transmission of drug resistant strains1
1Anti-TB Drug Resistance in the World Report No 4 The WHOIUATLD Global Project on Anti-Tuberculosis Drug Resistance Surveillance 2002-2007 World Health Organization 2008 (WHOHTMTB2008394)
2Reichman The Lancet 20083711052-3
DrTVRao MD 32
The Much Discussed Article on XDR TB in the Lancet
Of the 221 multi-drug resistant (MDR-TB) cases 53 (24) were XDR
Almost all (52 of 53) of the XDR-TB patients died with a median survival of only 16 days from the time of diagnosis (in the 42 patients with confirmed dates of death)
All the 44 XDR TB patients who were tested for HIV were found co-infected
55 patents had never received anti-TB drugs suggesting primary transmission of XDR pathogen
67 patients had been admitted to the hospital in the preceding 2 years suggesting potential role of nosocomial transmission
Gandhi et al Lancet 20063681575-80DrTVRao MD 33
Poor mangement of infected lead to grwoing resistance
Resistance to anti-TB drugs in populations is a phenomenon that occurs primarily due to poorly managed TB care Problems include incorrect drug prescribing practices by providers poor quality drugs or erratic supply of drugs and also patient non-adherence DrTVRao MD 34
Susceptibility Testing
1048708 Direct and indirect testing1048708 Primary Drugs testing1048708 Isoniazid1048708 Rifampicin1048708 Ethambutol ()1048708 Pyrizinamide ()
DrTVRao MD 35
Drug susceptibility testing (DST)
DST is recommended for all new cases for all first line drugs with specimens taken before initiating treatment
Accuracy is more important than speed DST results should come from a small
number of well-equipped experienced laboratories who participate and perform well in an international DST quality control scheme
The WHO Supranational Laboratory Quality Control Network offers the greatest global coverage for this
DrTVRao MD 36
Drug susceptibility Testing
Assessment of growth inhibition on solid media containing various dilutions of the drug in comparison with the test strains
As the method depend observation of growth Results are not available until several weeks after isolation of the organism
DrTVRao MD 37
Other accredited Methods
Radiometric and Non radiometric methods
Nucleic acid technology ndash effective upto 95 in mutations to rifampicin resistance to gene rpoB gene
DrTVRao MD 38
Drug susceptibility testing (DST)
As a minimum laboratories supplying DST data should correctly identify resistance to isoniazid and rifampicin in over 90 of quality control samples in two out of the last three quality control roundsDrTVRao MD 39
Detection of Rifampicin Drug susceptibility testing (DST) is more important
Early identification of mycobacterial growth as M tuberculosis complex and the identification of rifampicin resistance should be the first priority as rifampicin resistance invalidates standard 6 month short-course chemotherapy and is a useful marker in most countries for MDR-TB
Laboratories should aim to identify isolates as M tuberculosis complex and perform rifampicin resistance in 90 of isolates within 1-2 working days This is technologically feasible
DrTVRao MD 40
Drug susceptibility testing
For DST laboratories modern molecular techniques permit the successful identification of isoniazid resistance in at least 75 of mycobacterial cultures within 1-2 working days and are useful preliminary screens for isoniazid resistance
DrTVRao MD 41
Secondary Drugs testing [lack of standardized
methods]
Ofloxacin quinolonesEthionamide KanamycinCapreomycin Ensure quality control and
quality assurance
DrTVRao MD 42
WHO Controls the Tuberculosis related work
The laboratory methods for anti-tuberculosis drug susceptibility testing should be selected from among those that are WHO-recommended and all laboratory processes should be quality-assured in cooperation with a partner Supranational Reference Laboratory (SRL)DrTVRao MD 43
Other WHO-Endorsed Tools
Liquid culture (eg MGIT BacTALERT)
Capilia TB Rapid strip test that detects a TB-
specific antigen from culture
Molecular line probe assays (eg GenoType MTBDRplus INNO-LiPA RifTB) Strip test for detection of TB and
drug-resistance conferring mutations
DrTVRao MD 44
BacTALERTreg
DrTVRao MD 45
CDC Updates Guidelines for Nucleic AcidAmplification Techniques to Diagnose
Tuberculosis
NAAT results should be interpreted in conjunction with the AFB smear results
NAAT and smear positive start Rx despite pending culture results PPV 95
Smear negative NAAT positive use clinical judgment to either treat or await culture
DrTVRao MD 46
Selection from automated systems for molecular and
bacteriological rapid diagnostics
PCRRocheCOBASreg Amplicorreg
amplification kitsRocheCOBASreg LightCyclerreg
(real-time-PCR)RocheCOBASreg TaqMan 48reg(increases the specificity of real-
time-PCR)
DrTVRao MD 47
Molecular Fingerprinting
26 of 30 (87) XDR TB isolates found to be genetically similar
Majority of patients had no previous history of TB treatment Suggestive of recent infection with drug-resistant strain
DrTVRao MD 48
Is PCR methods a solution
PCR cant yet replace neither microscopy culturing and competent clinical examination
DrTVRao MD 49
No testing method replaces Clinical assessment
DrTVRao MD 50
XDR-TBThe description
of XDR-TB was first used earlier in 2006 following a joint survey by WHO and the US Centres for Disease Control and Prevention (CDC) DrTVRao MD 51
How x-MDR generated
Acquired resistance is that which occurs as a result of specific previous treatment The level of primary resistance in the community is considered to reflect the efficacy of control measures in the past while the level of acquired resistance is a measure of on-going TB control measuresDrTVRao MD 52
Extreme Drug resistant Tuberculosis (XDR-TB)
Resistant to all first line drugs namely Isoniazid and Rifampin and Three or more second line drugs (SLDrsquoS) that are used to treat MDR-TB Thequinalones like Ofloaxin
Or Aminoglycosides like Capreomycin amp
Kanamycin
No third-line drugs available to treat XDR-TB since none has been developed in the last 40 years
DrTVRao MD 53
Background Extensively drug-resistant tuberculosis
Extensively drug-resistant tuberculosis has been reported in 45 countries including countries with limited resources and a high burden of tuberculosis
DrTVRao MD 54
DrTVRao MD 55
Transmissionof X -MDR
Like other forms of TB XDR-TB is spread through the air When a person with infectious TB coughs sneezes talks or spits they propel Mycobacterium into the air
DrTVRao MD 56
Best options to diagnoseX-MDR tuberculosis
To evaluate drug susceptibility the bacteria need to be cultivated and tested in a suitable laboratory Final diagnosis in this way for TB and especially for XDR-TB may take from 6 to 16 weeks To reduce the time needed for diagnosis new tools for rapid TB diagnosis are urgently needed
DrTVRao MD 57
When to suspect MDR TB
Patients not showing any reduction
in bacillary population after 3-
months of regular treatment with
Cat II regimen
Sputum positive patients who are
contacts of a known MDR TB
patient
DrTVRao MD 58
How to evaluate MDR TB
MDR TB is only a laboratory
proved HR resistance
Clinical suspicion should be
followed by lab Confirmation
Laboratories should be quality
controlledTRC
DrTVRao MD 59
Extreme Drug resistant Tuberculosis (XDR-TB) and AIDS
It can also be contracted without a patient receiving any previous treatment for TB
Mostly associated with HIV positive patients
HIV has the potential to fast tracking XDR-TB into an uncontrollable epidemic
Average survival period for patients infected with XDR-TB is 16 days
DrTVRao MD 60
Responding to MDRXDR-TB
Augment DOTS Program by
New diagnostics
New drugs New vaccines HIV incidence
reduction Advocacy1
A mathematical model projected by Basu and co-workers indicates that half of XDR-TB can be averted by 2012 by bringing synergistic effects through
Use of masks Reduced time as in-patient Improved ventilation Rapid resistance testing HIV treatment TB isolation facilities2
1Marteens and Wilkinson Lancet 20073702030-432Basu et al Quoted in Porco and Getz Lancet 20073701464-5
DrTVRao MD 61
Second Line Drug Treatment (SLDrsquos)
Less effective more costly and more toxic 50 cure rate
Four months intensive phase (5 drugs) Kanamycins Ethionamide Pyrazinamide Ofloxacin Cycloserine or Ethambutol DrTVRao MD 62
World Health Organisation (WHO) Guidelines for treatment
of MDR-TB
Strengthen basic TB care to prevent the emergence of drug-resistance
Ensure prompt diagnosis and treatment of drug resistant cases to cure existing cases and prevent further transmission
Increase collaboration between HIV and TB control programmes to provide necessary prevention and care to co-infected patients
Increase investment in laboratory infrastructures to enable better detection and management of resistant cases
DrTVRao MD 63
Treatment Guidelines
Sensitivity testing for all smear positive specimens
Patient Family and staff counselling amp education
Correct and thorough hand washing protocol and procedure
Personal protection is very important
DrTVRao MD 64
THE NEW MDR-TB Guidelines
A flexible framework approach combining both clinical and programmatic aspects of DOTS Plus based on essential programme conditions
But encouraging programs to tailor their case-finding and treatment strategies to the local epidemiological and Programme situation
Reflect GLC expert consensus and evidence and experience from GLC projects thus far
DrTVRao MD 65
Effective laboratory Diagnosis
Sputum smear examinations ndash rapid classification of species (atypical mycobacteria common in AIDS)
Culture examinations
Rapid drug sensitivity testingDrTVRao MD 66
MDR TB and HIV
MDR TB occurs with the same frequency in HIV
patients as in TB patients who are smear negative
Transmission of drug-resistant strains among HIV-
infected patients in congregate settings occurs
leading to lsquooutbreaksrsquo of MDR TB in such settings
Infection control measures absolutely essential in
settings where large number of HIV TB patients stay
togetherDrTVRao MD 67
Transmission is dependent on closeness and time of contact
In penitentiary care contacts are very close and prolonged ndash culture positive cases can also transmit TB especially to HIV positive population
DrTVRao MD 68
To Know more on MDR ndashTB Current Guidelines of WHO
Guidelines for the programmatic management of drug-resistant tuberculosis - 2011 update [pdf 904kb]
Visit helliphelliphellip WHOHTMTB20116DrTVRao MD 69
Are there any solutions for effective
Diagnosis in TB
DrTVRao MD 70
Programme Created by DrTVRao MD for Medical and Health Care
Workers in the Developing World Email
doctortvraogmailcom
DrTVRao MD 71
Drug susceptible TBsect
MDR-TB
1990sect
XDR-TB
2006sect
Total DR
Resistance to HampR ndash
Treatable with 2nd line drugs
Resistance to 2nd line drugs ndashTreatment options seriously restricted
Resistance to all available drugs ndash
No treatment options
or limited resistance manageable with 4 drug regimen - DOTS
Are we Returning to a Pre-antibiotic Era
DrTVRao MD 22
Genesis of MDR TB
Resistance is a man-made amplification of a natural phenomenon
Inadequate drug delivery is main cause of secondary drug resistance
Secondary drug resistance is the main cause of primary drug resistance due to transmission of resistant strains
MDR due to spontaneous mutations is not possible as the genes encoding resistance for anti TB are unlinked
DrTVRao MD 23
Factors Contributing to Development
and Spread of MDR and XDR TB Weak TB programs (DOTS)
Low completioncure rates Lack of treatment follow up and
patient support Unreliable drug supply Diagnostic delay
Absent or inadequate infection control measures
Uncontrolled use of 2nd line drugs Fluroquinolones
DrTVRao MD 24
INHChromosomally mediatedLoss of catalaseperoxidaseMutation in mycolic acid synthesis
Regulators of peroxide response
Mechanism of resistance
DrTVRao MD 25
RifampinReduced binding to RNA polymeraseClusters of mutations at ldquoRifampin Resistance Determining Regionrdquo (RRDR)
Reduced Cell wall permeability
Mechanism of resistance
DrTVRao MD 26
Gene location associated Drug-Resistant
Mtuberculosis Drug Gene Isoniazid Kat G Inh A Kas
A Rifampicin rpo B Ethambutol emb B Streptomycin rps L Pyrazinamide pnc A Fluoroquinolones gyr A
Dubaniewicz A et al Molecular sub-type of the HLA-DR antigens in pulmonary tuberculosis Int J Infect Dis20004129-33
DrTVRao MD 27
Current Scientific Documentations on Drug Resistance in
Tuberculosis
DrTVRao MD 28
Alarming Rise of Resistant TuberculosisWHO Report on
Anti-TB Drug Resistance
490000 new cases of MDR-TB each year with gt110000 deaths1
Accounts for 5 of 9 million new cases of TB2
MDR-TB rates higher than ever (up to 223) particularly in former Soviet Union countries
XDR-TB reported by as many as 49 countries (by June 2008)3
Recent WHOIUATLD Global Surveillance report indicated 75 (3014012) of MDR TB to be XDR4
Around 40000 XDR-TB cases emerge every year1
1Tuberculosis MDR-TB amp XDR-TBmdashThe 2008 Report The Stop TB Department WHO2Hargreaves S httpinfectionthelancetcom Vol 8 April 2008 p2203Raviglione MC NEJM 2008359636-84Anti-TB Drug Resistance in the World Report No 4 The WHOIUATLD Global Project on Anti-Tuberculosis Drug Resistance Surveillance 2002-2007 World Health Organization 2008 (WHOHTMTB2008394)
DrTVRao MD 29
MDR-TB amp XDR-TBTHE 2008 REPORT
of MDR-TB among new TB cases 1994-2007
DrTVRao MD 30
MDR-TB rates higher than ever (up to 223) particularly in former Soviet Union countries
DrTVRao MD 31
Alarming Rise of Resistant TB
Resistant TB burden in countries of former Soviet Union about 50 of cases resistant to at least one drug about 20 MDR XDR-TB proportions also higher (as high as 24 in
Estonia)1
MDRXDR TB ndash essentially a man-made problem2
High numbers of resistant cases (gt400000 MDR-TB cases every year) due mainly to Underinvestment in basic TB control Poor management of anti-TB drugs Transmission of drug resistant strains1
1Anti-TB Drug Resistance in the World Report No 4 The WHOIUATLD Global Project on Anti-Tuberculosis Drug Resistance Surveillance 2002-2007 World Health Organization 2008 (WHOHTMTB2008394)
2Reichman The Lancet 20083711052-3
DrTVRao MD 32
The Much Discussed Article on XDR TB in the Lancet
Of the 221 multi-drug resistant (MDR-TB) cases 53 (24) were XDR
Almost all (52 of 53) of the XDR-TB patients died with a median survival of only 16 days from the time of diagnosis (in the 42 patients with confirmed dates of death)
All the 44 XDR TB patients who were tested for HIV were found co-infected
55 patents had never received anti-TB drugs suggesting primary transmission of XDR pathogen
67 patients had been admitted to the hospital in the preceding 2 years suggesting potential role of nosocomial transmission
Gandhi et al Lancet 20063681575-80DrTVRao MD 33
Poor mangement of infected lead to grwoing resistance
Resistance to anti-TB drugs in populations is a phenomenon that occurs primarily due to poorly managed TB care Problems include incorrect drug prescribing practices by providers poor quality drugs or erratic supply of drugs and also patient non-adherence DrTVRao MD 34
Susceptibility Testing
1048708 Direct and indirect testing1048708 Primary Drugs testing1048708 Isoniazid1048708 Rifampicin1048708 Ethambutol ()1048708 Pyrizinamide ()
DrTVRao MD 35
Drug susceptibility testing (DST)
DST is recommended for all new cases for all first line drugs with specimens taken before initiating treatment
Accuracy is more important than speed DST results should come from a small
number of well-equipped experienced laboratories who participate and perform well in an international DST quality control scheme
The WHO Supranational Laboratory Quality Control Network offers the greatest global coverage for this
DrTVRao MD 36
Drug susceptibility Testing
Assessment of growth inhibition on solid media containing various dilutions of the drug in comparison with the test strains
As the method depend observation of growth Results are not available until several weeks after isolation of the organism
DrTVRao MD 37
Other accredited Methods
Radiometric and Non radiometric methods
Nucleic acid technology ndash effective upto 95 in mutations to rifampicin resistance to gene rpoB gene
DrTVRao MD 38
Drug susceptibility testing (DST)
As a minimum laboratories supplying DST data should correctly identify resistance to isoniazid and rifampicin in over 90 of quality control samples in two out of the last three quality control roundsDrTVRao MD 39
Detection of Rifampicin Drug susceptibility testing (DST) is more important
Early identification of mycobacterial growth as M tuberculosis complex and the identification of rifampicin resistance should be the first priority as rifampicin resistance invalidates standard 6 month short-course chemotherapy and is a useful marker in most countries for MDR-TB
Laboratories should aim to identify isolates as M tuberculosis complex and perform rifampicin resistance in 90 of isolates within 1-2 working days This is technologically feasible
DrTVRao MD 40
Drug susceptibility testing
For DST laboratories modern molecular techniques permit the successful identification of isoniazid resistance in at least 75 of mycobacterial cultures within 1-2 working days and are useful preliminary screens for isoniazid resistance
DrTVRao MD 41
Secondary Drugs testing [lack of standardized
methods]
Ofloxacin quinolonesEthionamide KanamycinCapreomycin Ensure quality control and
quality assurance
DrTVRao MD 42
WHO Controls the Tuberculosis related work
The laboratory methods for anti-tuberculosis drug susceptibility testing should be selected from among those that are WHO-recommended and all laboratory processes should be quality-assured in cooperation with a partner Supranational Reference Laboratory (SRL)DrTVRao MD 43
Other WHO-Endorsed Tools
Liquid culture (eg MGIT BacTALERT)
Capilia TB Rapid strip test that detects a TB-
specific antigen from culture
Molecular line probe assays (eg GenoType MTBDRplus INNO-LiPA RifTB) Strip test for detection of TB and
drug-resistance conferring mutations
DrTVRao MD 44
BacTALERTreg
DrTVRao MD 45
CDC Updates Guidelines for Nucleic AcidAmplification Techniques to Diagnose
Tuberculosis
NAAT results should be interpreted in conjunction with the AFB smear results
NAAT and smear positive start Rx despite pending culture results PPV 95
Smear negative NAAT positive use clinical judgment to either treat or await culture
DrTVRao MD 46
Selection from automated systems for molecular and
bacteriological rapid diagnostics
PCRRocheCOBASreg Amplicorreg
amplification kitsRocheCOBASreg LightCyclerreg
(real-time-PCR)RocheCOBASreg TaqMan 48reg(increases the specificity of real-
time-PCR)
DrTVRao MD 47
Molecular Fingerprinting
26 of 30 (87) XDR TB isolates found to be genetically similar
Majority of patients had no previous history of TB treatment Suggestive of recent infection with drug-resistant strain
DrTVRao MD 48
Is PCR methods a solution
PCR cant yet replace neither microscopy culturing and competent clinical examination
DrTVRao MD 49
No testing method replaces Clinical assessment
DrTVRao MD 50
XDR-TBThe description
of XDR-TB was first used earlier in 2006 following a joint survey by WHO and the US Centres for Disease Control and Prevention (CDC) DrTVRao MD 51
How x-MDR generated
Acquired resistance is that which occurs as a result of specific previous treatment The level of primary resistance in the community is considered to reflect the efficacy of control measures in the past while the level of acquired resistance is a measure of on-going TB control measuresDrTVRao MD 52
Extreme Drug resistant Tuberculosis (XDR-TB)
Resistant to all first line drugs namely Isoniazid and Rifampin and Three or more second line drugs (SLDrsquoS) that are used to treat MDR-TB Thequinalones like Ofloaxin
Or Aminoglycosides like Capreomycin amp
Kanamycin
No third-line drugs available to treat XDR-TB since none has been developed in the last 40 years
DrTVRao MD 53
Background Extensively drug-resistant tuberculosis
Extensively drug-resistant tuberculosis has been reported in 45 countries including countries with limited resources and a high burden of tuberculosis
DrTVRao MD 54
DrTVRao MD 55
Transmissionof X -MDR
Like other forms of TB XDR-TB is spread through the air When a person with infectious TB coughs sneezes talks or spits they propel Mycobacterium into the air
DrTVRao MD 56
Best options to diagnoseX-MDR tuberculosis
To evaluate drug susceptibility the bacteria need to be cultivated and tested in a suitable laboratory Final diagnosis in this way for TB and especially for XDR-TB may take from 6 to 16 weeks To reduce the time needed for diagnosis new tools for rapid TB diagnosis are urgently needed
DrTVRao MD 57
When to suspect MDR TB
Patients not showing any reduction
in bacillary population after 3-
months of regular treatment with
Cat II regimen
Sputum positive patients who are
contacts of a known MDR TB
patient
DrTVRao MD 58
How to evaluate MDR TB
MDR TB is only a laboratory
proved HR resistance
Clinical suspicion should be
followed by lab Confirmation
Laboratories should be quality
controlledTRC
DrTVRao MD 59
Extreme Drug resistant Tuberculosis (XDR-TB) and AIDS
It can also be contracted without a patient receiving any previous treatment for TB
Mostly associated with HIV positive patients
HIV has the potential to fast tracking XDR-TB into an uncontrollable epidemic
Average survival period for patients infected with XDR-TB is 16 days
DrTVRao MD 60
Responding to MDRXDR-TB
Augment DOTS Program by
New diagnostics
New drugs New vaccines HIV incidence
reduction Advocacy1
A mathematical model projected by Basu and co-workers indicates that half of XDR-TB can be averted by 2012 by bringing synergistic effects through
Use of masks Reduced time as in-patient Improved ventilation Rapid resistance testing HIV treatment TB isolation facilities2
1Marteens and Wilkinson Lancet 20073702030-432Basu et al Quoted in Porco and Getz Lancet 20073701464-5
DrTVRao MD 61
Second Line Drug Treatment (SLDrsquos)
Less effective more costly and more toxic 50 cure rate
Four months intensive phase (5 drugs) Kanamycins Ethionamide Pyrazinamide Ofloxacin Cycloserine or Ethambutol DrTVRao MD 62
World Health Organisation (WHO) Guidelines for treatment
of MDR-TB
Strengthen basic TB care to prevent the emergence of drug-resistance
Ensure prompt diagnosis and treatment of drug resistant cases to cure existing cases and prevent further transmission
Increase collaboration between HIV and TB control programmes to provide necessary prevention and care to co-infected patients
Increase investment in laboratory infrastructures to enable better detection and management of resistant cases
DrTVRao MD 63
Treatment Guidelines
Sensitivity testing for all smear positive specimens
Patient Family and staff counselling amp education
Correct and thorough hand washing protocol and procedure
Personal protection is very important
DrTVRao MD 64
THE NEW MDR-TB Guidelines
A flexible framework approach combining both clinical and programmatic aspects of DOTS Plus based on essential programme conditions
But encouraging programs to tailor their case-finding and treatment strategies to the local epidemiological and Programme situation
Reflect GLC expert consensus and evidence and experience from GLC projects thus far
DrTVRao MD 65
Effective laboratory Diagnosis
Sputum smear examinations ndash rapid classification of species (atypical mycobacteria common in AIDS)
Culture examinations
Rapid drug sensitivity testingDrTVRao MD 66
MDR TB and HIV
MDR TB occurs with the same frequency in HIV
patients as in TB patients who are smear negative
Transmission of drug-resistant strains among HIV-
infected patients in congregate settings occurs
leading to lsquooutbreaksrsquo of MDR TB in such settings
Infection control measures absolutely essential in
settings where large number of HIV TB patients stay
togetherDrTVRao MD 67
Transmission is dependent on closeness and time of contact
In penitentiary care contacts are very close and prolonged ndash culture positive cases can also transmit TB especially to HIV positive population
DrTVRao MD 68
To Know more on MDR ndashTB Current Guidelines of WHO
Guidelines for the programmatic management of drug-resistant tuberculosis - 2011 update [pdf 904kb]
Visit helliphelliphellip WHOHTMTB20116DrTVRao MD 69
Are there any solutions for effective
Diagnosis in TB
DrTVRao MD 70
Programme Created by DrTVRao MD for Medical and Health Care
Workers in the Developing World Email
doctortvraogmailcom
DrTVRao MD 71
Genesis of MDR TB
Resistance is a man-made amplification of a natural phenomenon
Inadequate drug delivery is main cause of secondary drug resistance
Secondary drug resistance is the main cause of primary drug resistance due to transmission of resistant strains
MDR due to spontaneous mutations is not possible as the genes encoding resistance for anti TB are unlinked
DrTVRao MD 23
Factors Contributing to Development
and Spread of MDR and XDR TB Weak TB programs (DOTS)
Low completioncure rates Lack of treatment follow up and
patient support Unreliable drug supply Diagnostic delay
Absent or inadequate infection control measures
Uncontrolled use of 2nd line drugs Fluroquinolones
DrTVRao MD 24
INHChromosomally mediatedLoss of catalaseperoxidaseMutation in mycolic acid synthesis
Regulators of peroxide response
Mechanism of resistance
DrTVRao MD 25
RifampinReduced binding to RNA polymeraseClusters of mutations at ldquoRifampin Resistance Determining Regionrdquo (RRDR)
Reduced Cell wall permeability
Mechanism of resistance
DrTVRao MD 26
Gene location associated Drug-Resistant
Mtuberculosis Drug Gene Isoniazid Kat G Inh A Kas
A Rifampicin rpo B Ethambutol emb B Streptomycin rps L Pyrazinamide pnc A Fluoroquinolones gyr A
Dubaniewicz A et al Molecular sub-type of the HLA-DR antigens in pulmonary tuberculosis Int J Infect Dis20004129-33
DrTVRao MD 27
Current Scientific Documentations on Drug Resistance in
Tuberculosis
DrTVRao MD 28
Alarming Rise of Resistant TuberculosisWHO Report on
Anti-TB Drug Resistance
490000 new cases of MDR-TB each year with gt110000 deaths1
Accounts for 5 of 9 million new cases of TB2
MDR-TB rates higher than ever (up to 223) particularly in former Soviet Union countries
XDR-TB reported by as many as 49 countries (by June 2008)3
Recent WHOIUATLD Global Surveillance report indicated 75 (3014012) of MDR TB to be XDR4
Around 40000 XDR-TB cases emerge every year1
1Tuberculosis MDR-TB amp XDR-TBmdashThe 2008 Report The Stop TB Department WHO2Hargreaves S httpinfectionthelancetcom Vol 8 April 2008 p2203Raviglione MC NEJM 2008359636-84Anti-TB Drug Resistance in the World Report No 4 The WHOIUATLD Global Project on Anti-Tuberculosis Drug Resistance Surveillance 2002-2007 World Health Organization 2008 (WHOHTMTB2008394)
DrTVRao MD 29
MDR-TB amp XDR-TBTHE 2008 REPORT
of MDR-TB among new TB cases 1994-2007
DrTVRao MD 30
MDR-TB rates higher than ever (up to 223) particularly in former Soviet Union countries
DrTVRao MD 31
Alarming Rise of Resistant TB
Resistant TB burden in countries of former Soviet Union about 50 of cases resistant to at least one drug about 20 MDR XDR-TB proportions also higher (as high as 24 in
Estonia)1
MDRXDR TB ndash essentially a man-made problem2
High numbers of resistant cases (gt400000 MDR-TB cases every year) due mainly to Underinvestment in basic TB control Poor management of anti-TB drugs Transmission of drug resistant strains1
1Anti-TB Drug Resistance in the World Report No 4 The WHOIUATLD Global Project on Anti-Tuberculosis Drug Resistance Surveillance 2002-2007 World Health Organization 2008 (WHOHTMTB2008394)
2Reichman The Lancet 20083711052-3
DrTVRao MD 32
The Much Discussed Article on XDR TB in the Lancet
Of the 221 multi-drug resistant (MDR-TB) cases 53 (24) were XDR
Almost all (52 of 53) of the XDR-TB patients died with a median survival of only 16 days from the time of diagnosis (in the 42 patients with confirmed dates of death)
All the 44 XDR TB patients who were tested for HIV were found co-infected
55 patents had never received anti-TB drugs suggesting primary transmission of XDR pathogen
67 patients had been admitted to the hospital in the preceding 2 years suggesting potential role of nosocomial transmission
Gandhi et al Lancet 20063681575-80DrTVRao MD 33
Poor mangement of infected lead to grwoing resistance
Resistance to anti-TB drugs in populations is a phenomenon that occurs primarily due to poorly managed TB care Problems include incorrect drug prescribing practices by providers poor quality drugs or erratic supply of drugs and also patient non-adherence DrTVRao MD 34
Susceptibility Testing
1048708 Direct and indirect testing1048708 Primary Drugs testing1048708 Isoniazid1048708 Rifampicin1048708 Ethambutol ()1048708 Pyrizinamide ()
DrTVRao MD 35
Drug susceptibility testing (DST)
DST is recommended for all new cases for all first line drugs with specimens taken before initiating treatment
Accuracy is more important than speed DST results should come from a small
number of well-equipped experienced laboratories who participate and perform well in an international DST quality control scheme
The WHO Supranational Laboratory Quality Control Network offers the greatest global coverage for this
DrTVRao MD 36
Drug susceptibility Testing
Assessment of growth inhibition on solid media containing various dilutions of the drug in comparison with the test strains
As the method depend observation of growth Results are not available until several weeks after isolation of the organism
DrTVRao MD 37
Other accredited Methods
Radiometric and Non radiometric methods
Nucleic acid technology ndash effective upto 95 in mutations to rifampicin resistance to gene rpoB gene
DrTVRao MD 38
Drug susceptibility testing (DST)
As a minimum laboratories supplying DST data should correctly identify resistance to isoniazid and rifampicin in over 90 of quality control samples in two out of the last three quality control roundsDrTVRao MD 39
Detection of Rifampicin Drug susceptibility testing (DST) is more important
Early identification of mycobacterial growth as M tuberculosis complex and the identification of rifampicin resistance should be the first priority as rifampicin resistance invalidates standard 6 month short-course chemotherapy and is a useful marker in most countries for MDR-TB
Laboratories should aim to identify isolates as M tuberculosis complex and perform rifampicin resistance in 90 of isolates within 1-2 working days This is technologically feasible
DrTVRao MD 40
Drug susceptibility testing
For DST laboratories modern molecular techniques permit the successful identification of isoniazid resistance in at least 75 of mycobacterial cultures within 1-2 working days and are useful preliminary screens for isoniazid resistance
DrTVRao MD 41
Secondary Drugs testing [lack of standardized
methods]
Ofloxacin quinolonesEthionamide KanamycinCapreomycin Ensure quality control and
quality assurance
DrTVRao MD 42
WHO Controls the Tuberculosis related work
The laboratory methods for anti-tuberculosis drug susceptibility testing should be selected from among those that are WHO-recommended and all laboratory processes should be quality-assured in cooperation with a partner Supranational Reference Laboratory (SRL)DrTVRao MD 43
Other WHO-Endorsed Tools
Liquid culture (eg MGIT BacTALERT)
Capilia TB Rapid strip test that detects a TB-
specific antigen from culture
Molecular line probe assays (eg GenoType MTBDRplus INNO-LiPA RifTB) Strip test for detection of TB and
drug-resistance conferring mutations
DrTVRao MD 44
BacTALERTreg
DrTVRao MD 45
CDC Updates Guidelines for Nucleic AcidAmplification Techniques to Diagnose
Tuberculosis
NAAT results should be interpreted in conjunction with the AFB smear results
NAAT and smear positive start Rx despite pending culture results PPV 95
Smear negative NAAT positive use clinical judgment to either treat or await culture
DrTVRao MD 46
Selection from automated systems for molecular and
bacteriological rapid diagnostics
PCRRocheCOBASreg Amplicorreg
amplification kitsRocheCOBASreg LightCyclerreg
(real-time-PCR)RocheCOBASreg TaqMan 48reg(increases the specificity of real-
time-PCR)
DrTVRao MD 47
Molecular Fingerprinting
26 of 30 (87) XDR TB isolates found to be genetically similar
Majority of patients had no previous history of TB treatment Suggestive of recent infection with drug-resistant strain
DrTVRao MD 48
Is PCR methods a solution
PCR cant yet replace neither microscopy culturing and competent clinical examination
DrTVRao MD 49
No testing method replaces Clinical assessment
DrTVRao MD 50
XDR-TBThe description
of XDR-TB was first used earlier in 2006 following a joint survey by WHO and the US Centres for Disease Control and Prevention (CDC) DrTVRao MD 51
How x-MDR generated
Acquired resistance is that which occurs as a result of specific previous treatment The level of primary resistance in the community is considered to reflect the efficacy of control measures in the past while the level of acquired resistance is a measure of on-going TB control measuresDrTVRao MD 52
Extreme Drug resistant Tuberculosis (XDR-TB)
Resistant to all first line drugs namely Isoniazid and Rifampin and Three or more second line drugs (SLDrsquoS) that are used to treat MDR-TB Thequinalones like Ofloaxin
Or Aminoglycosides like Capreomycin amp
Kanamycin
No third-line drugs available to treat XDR-TB since none has been developed in the last 40 years
DrTVRao MD 53
Background Extensively drug-resistant tuberculosis
Extensively drug-resistant tuberculosis has been reported in 45 countries including countries with limited resources and a high burden of tuberculosis
DrTVRao MD 54
DrTVRao MD 55
Transmissionof X -MDR
Like other forms of TB XDR-TB is spread through the air When a person with infectious TB coughs sneezes talks or spits they propel Mycobacterium into the air
DrTVRao MD 56
Best options to diagnoseX-MDR tuberculosis
To evaluate drug susceptibility the bacteria need to be cultivated and tested in a suitable laboratory Final diagnosis in this way for TB and especially for XDR-TB may take from 6 to 16 weeks To reduce the time needed for diagnosis new tools for rapid TB diagnosis are urgently needed
DrTVRao MD 57
When to suspect MDR TB
Patients not showing any reduction
in bacillary population after 3-
months of regular treatment with
Cat II regimen
Sputum positive patients who are
contacts of a known MDR TB
patient
DrTVRao MD 58
How to evaluate MDR TB
MDR TB is only a laboratory
proved HR resistance
Clinical suspicion should be
followed by lab Confirmation
Laboratories should be quality
controlledTRC
DrTVRao MD 59
Extreme Drug resistant Tuberculosis (XDR-TB) and AIDS
It can also be contracted without a patient receiving any previous treatment for TB
Mostly associated with HIV positive patients
HIV has the potential to fast tracking XDR-TB into an uncontrollable epidemic
Average survival period for patients infected with XDR-TB is 16 days
DrTVRao MD 60
Responding to MDRXDR-TB
Augment DOTS Program by
New diagnostics
New drugs New vaccines HIV incidence
reduction Advocacy1
A mathematical model projected by Basu and co-workers indicates that half of XDR-TB can be averted by 2012 by bringing synergistic effects through
Use of masks Reduced time as in-patient Improved ventilation Rapid resistance testing HIV treatment TB isolation facilities2
1Marteens and Wilkinson Lancet 20073702030-432Basu et al Quoted in Porco and Getz Lancet 20073701464-5
DrTVRao MD 61
Second Line Drug Treatment (SLDrsquos)
Less effective more costly and more toxic 50 cure rate
Four months intensive phase (5 drugs) Kanamycins Ethionamide Pyrazinamide Ofloxacin Cycloserine or Ethambutol DrTVRao MD 62
World Health Organisation (WHO) Guidelines for treatment
of MDR-TB
Strengthen basic TB care to prevent the emergence of drug-resistance
Ensure prompt diagnosis and treatment of drug resistant cases to cure existing cases and prevent further transmission
Increase collaboration between HIV and TB control programmes to provide necessary prevention and care to co-infected patients
Increase investment in laboratory infrastructures to enable better detection and management of resistant cases
DrTVRao MD 63
Treatment Guidelines
Sensitivity testing for all smear positive specimens
Patient Family and staff counselling amp education
Correct and thorough hand washing protocol and procedure
Personal protection is very important
DrTVRao MD 64
THE NEW MDR-TB Guidelines
A flexible framework approach combining both clinical and programmatic aspects of DOTS Plus based on essential programme conditions
But encouraging programs to tailor their case-finding and treatment strategies to the local epidemiological and Programme situation
Reflect GLC expert consensus and evidence and experience from GLC projects thus far
DrTVRao MD 65
Effective laboratory Diagnosis
Sputum smear examinations ndash rapid classification of species (atypical mycobacteria common in AIDS)
Culture examinations
Rapid drug sensitivity testingDrTVRao MD 66
MDR TB and HIV
MDR TB occurs with the same frequency in HIV
patients as in TB patients who are smear negative
Transmission of drug-resistant strains among HIV-
infected patients in congregate settings occurs
leading to lsquooutbreaksrsquo of MDR TB in such settings
Infection control measures absolutely essential in
settings where large number of HIV TB patients stay
togetherDrTVRao MD 67
Transmission is dependent on closeness and time of contact
In penitentiary care contacts are very close and prolonged ndash culture positive cases can also transmit TB especially to HIV positive population
DrTVRao MD 68
To Know more on MDR ndashTB Current Guidelines of WHO
Guidelines for the programmatic management of drug-resistant tuberculosis - 2011 update [pdf 904kb]
Visit helliphelliphellip WHOHTMTB20116DrTVRao MD 69
Are there any solutions for effective
Diagnosis in TB
DrTVRao MD 70
Programme Created by DrTVRao MD for Medical and Health Care
Workers in the Developing World Email
doctortvraogmailcom
DrTVRao MD 71
Factors Contributing to Development
and Spread of MDR and XDR TB Weak TB programs (DOTS)
Low completioncure rates Lack of treatment follow up and
patient support Unreliable drug supply Diagnostic delay
Absent or inadequate infection control measures
Uncontrolled use of 2nd line drugs Fluroquinolones
DrTVRao MD 24
INHChromosomally mediatedLoss of catalaseperoxidaseMutation in mycolic acid synthesis
Regulators of peroxide response
Mechanism of resistance
DrTVRao MD 25
RifampinReduced binding to RNA polymeraseClusters of mutations at ldquoRifampin Resistance Determining Regionrdquo (RRDR)
Reduced Cell wall permeability
Mechanism of resistance
DrTVRao MD 26
Gene location associated Drug-Resistant
Mtuberculosis Drug Gene Isoniazid Kat G Inh A Kas
A Rifampicin rpo B Ethambutol emb B Streptomycin rps L Pyrazinamide pnc A Fluoroquinolones gyr A
Dubaniewicz A et al Molecular sub-type of the HLA-DR antigens in pulmonary tuberculosis Int J Infect Dis20004129-33
DrTVRao MD 27
Current Scientific Documentations on Drug Resistance in
Tuberculosis
DrTVRao MD 28
Alarming Rise of Resistant TuberculosisWHO Report on
Anti-TB Drug Resistance
490000 new cases of MDR-TB each year with gt110000 deaths1
Accounts for 5 of 9 million new cases of TB2
MDR-TB rates higher than ever (up to 223) particularly in former Soviet Union countries
XDR-TB reported by as many as 49 countries (by June 2008)3
Recent WHOIUATLD Global Surveillance report indicated 75 (3014012) of MDR TB to be XDR4
Around 40000 XDR-TB cases emerge every year1
1Tuberculosis MDR-TB amp XDR-TBmdashThe 2008 Report The Stop TB Department WHO2Hargreaves S httpinfectionthelancetcom Vol 8 April 2008 p2203Raviglione MC NEJM 2008359636-84Anti-TB Drug Resistance in the World Report No 4 The WHOIUATLD Global Project on Anti-Tuberculosis Drug Resistance Surveillance 2002-2007 World Health Organization 2008 (WHOHTMTB2008394)
DrTVRao MD 29
MDR-TB amp XDR-TBTHE 2008 REPORT
of MDR-TB among new TB cases 1994-2007
DrTVRao MD 30
MDR-TB rates higher than ever (up to 223) particularly in former Soviet Union countries
DrTVRao MD 31
Alarming Rise of Resistant TB
Resistant TB burden in countries of former Soviet Union about 50 of cases resistant to at least one drug about 20 MDR XDR-TB proportions also higher (as high as 24 in
Estonia)1
MDRXDR TB ndash essentially a man-made problem2
High numbers of resistant cases (gt400000 MDR-TB cases every year) due mainly to Underinvestment in basic TB control Poor management of anti-TB drugs Transmission of drug resistant strains1
1Anti-TB Drug Resistance in the World Report No 4 The WHOIUATLD Global Project on Anti-Tuberculosis Drug Resistance Surveillance 2002-2007 World Health Organization 2008 (WHOHTMTB2008394)
2Reichman The Lancet 20083711052-3
DrTVRao MD 32
The Much Discussed Article on XDR TB in the Lancet
Of the 221 multi-drug resistant (MDR-TB) cases 53 (24) were XDR
Almost all (52 of 53) of the XDR-TB patients died with a median survival of only 16 days from the time of diagnosis (in the 42 patients with confirmed dates of death)
All the 44 XDR TB patients who were tested for HIV were found co-infected
55 patents had never received anti-TB drugs suggesting primary transmission of XDR pathogen
67 patients had been admitted to the hospital in the preceding 2 years suggesting potential role of nosocomial transmission
Gandhi et al Lancet 20063681575-80DrTVRao MD 33
Poor mangement of infected lead to grwoing resistance
Resistance to anti-TB drugs in populations is a phenomenon that occurs primarily due to poorly managed TB care Problems include incorrect drug prescribing practices by providers poor quality drugs or erratic supply of drugs and also patient non-adherence DrTVRao MD 34
Susceptibility Testing
1048708 Direct and indirect testing1048708 Primary Drugs testing1048708 Isoniazid1048708 Rifampicin1048708 Ethambutol ()1048708 Pyrizinamide ()
DrTVRao MD 35
Drug susceptibility testing (DST)
DST is recommended for all new cases for all first line drugs with specimens taken before initiating treatment
Accuracy is more important than speed DST results should come from a small
number of well-equipped experienced laboratories who participate and perform well in an international DST quality control scheme
The WHO Supranational Laboratory Quality Control Network offers the greatest global coverage for this
DrTVRao MD 36
Drug susceptibility Testing
Assessment of growth inhibition on solid media containing various dilutions of the drug in comparison with the test strains
As the method depend observation of growth Results are not available until several weeks after isolation of the organism
DrTVRao MD 37
Other accredited Methods
Radiometric and Non radiometric methods
Nucleic acid technology ndash effective upto 95 in mutations to rifampicin resistance to gene rpoB gene
DrTVRao MD 38
Drug susceptibility testing (DST)
As a minimum laboratories supplying DST data should correctly identify resistance to isoniazid and rifampicin in over 90 of quality control samples in two out of the last three quality control roundsDrTVRao MD 39
Detection of Rifampicin Drug susceptibility testing (DST) is more important
Early identification of mycobacterial growth as M tuberculosis complex and the identification of rifampicin resistance should be the first priority as rifampicin resistance invalidates standard 6 month short-course chemotherapy and is a useful marker in most countries for MDR-TB
Laboratories should aim to identify isolates as M tuberculosis complex and perform rifampicin resistance in 90 of isolates within 1-2 working days This is technologically feasible
DrTVRao MD 40
Drug susceptibility testing
For DST laboratories modern molecular techniques permit the successful identification of isoniazid resistance in at least 75 of mycobacterial cultures within 1-2 working days and are useful preliminary screens for isoniazid resistance
DrTVRao MD 41
Secondary Drugs testing [lack of standardized
methods]
Ofloxacin quinolonesEthionamide KanamycinCapreomycin Ensure quality control and
quality assurance
DrTVRao MD 42
WHO Controls the Tuberculosis related work
The laboratory methods for anti-tuberculosis drug susceptibility testing should be selected from among those that are WHO-recommended and all laboratory processes should be quality-assured in cooperation with a partner Supranational Reference Laboratory (SRL)DrTVRao MD 43
Other WHO-Endorsed Tools
Liquid culture (eg MGIT BacTALERT)
Capilia TB Rapid strip test that detects a TB-
specific antigen from culture
Molecular line probe assays (eg GenoType MTBDRplus INNO-LiPA RifTB) Strip test for detection of TB and
drug-resistance conferring mutations
DrTVRao MD 44
BacTALERTreg
DrTVRao MD 45
CDC Updates Guidelines for Nucleic AcidAmplification Techniques to Diagnose
Tuberculosis
NAAT results should be interpreted in conjunction with the AFB smear results
NAAT and smear positive start Rx despite pending culture results PPV 95
Smear negative NAAT positive use clinical judgment to either treat or await culture
DrTVRao MD 46
Selection from automated systems for molecular and
bacteriological rapid diagnostics
PCRRocheCOBASreg Amplicorreg
amplification kitsRocheCOBASreg LightCyclerreg
(real-time-PCR)RocheCOBASreg TaqMan 48reg(increases the specificity of real-
time-PCR)
DrTVRao MD 47
Molecular Fingerprinting
26 of 30 (87) XDR TB isolates found to be genetically similar
Majority of patients had no previous history of TB treatment Suggestive of recent infection with drug-resistant strain
DrTVRao MD 48
Is PCR methods a solution
PCR cant yet replace neither microscopy culturing and competent clinical examination
DrTVRao MD 49
No testing method replaces Clinical assessment
DrTVRao MD 50
XDR-TBThe description
of XDR-TB was first used earlier in 2006 following a joint survey by WHO and the US Centres for Disease Control and Prevention (CDC) DrTVRao MD 51
How x-MDR generated
Acquired resistance is that which occurs as a result of specific previous treatment The level of primary resistance in the community is considered to reflect the efficacy of control measures in the past while the level of acquired resistance is a measure of on-going TB control measuresDrTVRao MD 52
Extreme Drug resistant Tuberculosis (XDR-TB)
Resistant to all first line drugs namely Isoniazid and Rifampin and Three or more second line drugs (SLDrsquoS) that are used to treat MDR-TB Thequinalones like Ofloaxin
Or Aminoglycosides like Capreomycin amp
Kanamycin
No third-line drugs available to treat XDR-TB since none has been developed in the last 40 years
DrTVRao MD 53
Background Extensively drug-resistant tuberculosis
Extensively drug-resistant tuberculosis has been reported in 45 countries including countries with limited resources and a high burden of tuberculosis
DrTVRao MD 54
DrTVRao MD 55
Transmissionof X -MDR
Like other forms of TB XDR-TB is spread through the air When a person with infectious TB coughs sneezes talks or spits they propel Mycobacterium into the air
DrTVRao MD 56
Best options to diagnoseX-MDR tuberculosis
To evaluate drug susceptibility the bacteria need to be cultivated and tested in a suitable laboratory Final diagnosis in this way for TB and especially for XDR-TB may take from 6 to 16 weeks To reduce the time needed for diagnosis new tools for rapid TB diagnosis are urgently needed
DrTVRao MD 57
When to suspect MDR TB
Patients not showing any reduction
in bacillary population after 3-
months of regular treatment with
Cat II regimen
Sputum positive patients who are
contacts of a known MDR TB
patient
DrTVRao MD 58
How to evaluate MDR TB
MDR TB is only a laboratory
proved HR resistance
Clinical suspicion should be
followed by lab Confirmation
Laboratories should be quality
controlledTRC
DrTVRao MD 59
Extreme Drug resistant Tuberculosis (XDR-TB) and AIDS
It can also be contracted without a patient receiving any previous treatment for TB
Mostly associated with HIV positive patients
HIV has the potential to fast tracking XDR-TB into an uncontrollable epidemic
Average survival period for patients infected with XDR-TB is 16 days
DrTVRao MD 60
Responding to MDRXDR-TB
Augment DOTS Program by
New diagnostics
New drugs New vaccines HIV incidence
reduction Advocacy1
A mathematical model projected by Basu and co-workers indicates that half of XDR-TB can be averted by 2012 by bringing synergistic effects through
Use of masks Reduced time as in-patient Improved ventilation Rapid resistance testing HIV treatment TB isolation facilities2
1Marteens and Wilkinson Lancet 20073702030-432Basu et al Quoted in Porco and Getz Lancet 20073701464-5
DrTVRao MD 61
Second Line Drug Treatment (SLDrsquos)
Less effective more costly and more toxic 50 cure rate
Four months intensive phase (5 drugs) Kanamycins Ethionamide Pyrazinamide Ofloxacin Cycloserine or Ethambutol DrTVRao MD 62
World Health Organisation (WHO) Guidelines for treatment
of MDR-TB
Strengthen basic TB care to prevent the emergence of drug-resistance
Ensure prompt diagnosis and treatment of drug resistant cases to cure existing cases and prevent further transmission
Increase collaboration between HIV and TB control programmes to provide necessary prevention and care to co-infected patients
Increase investment in laboratory infrastructures to enable better detection and management of resistant cases
DrTVRao MD 63
Treatment Guidelines
Sensitivity testing for all smear positive specimens
Patient Family and staff counselling amp education
Correct and thorough hand washing protocol and procedure
Personal protection is very important
DrTVRao MD 64
THE NEW MDR-TB Guidelines
A flexible framework approach combining both clinical and programmatic aspects of DOTS Plus based on essential programme conditions
But encouraging programs to tailor their case-finding and treatment strategies to the local epidemiological and Programme situation
Reflect GLC expert consensus and evidence and experience from GLC projects thus far
DrTVRao MD 65
Effective laboratory Diagnosis
Sputum smear examinations ndash rapid classification of species (atypical mycobacteria common in AIDS)
Culture examinations
Rapid drug sensitivity testingDrTVRao MD 66
MDR TB and HIV
MDR TB occurs with the same frequency in HIV
patients as in TB patients who are smear negative
Transmission of drug-resistant strains among HIV-
infected patients in congregate settings occurs
leading to lsquooutbreaksrsquo of MDR TB in such settings
Infection control measures absolutely essential in
settings where large number of HIV TB patients stay
togetherDrTVRao MD 67
Transmission is dependent on closeness and time of contact
In penitentiary care contacts are very close and prolonged ndash culture positive cases can also transmit TB especially to HIV positive population
DrTVRao MD 68
To Know more on MDR ndashTB Current Guidelines of WHO
Guidelines for the programmatic management of drug-resistant tuberculosis - 2011 update [pdf 904kb]
Visit helliphelliphellip WHOHTMTB20116DrTVRao MD 69
Are there any solutions for effective
Diagnosis in TB
DrTVRao MD 70
Programme Created by DrTVRao MD for Medical and Health Care
Workers in the Developing World Email
doctortvraogmailcom
DrTVRao MD 71
INHChromosomally mediatedLoss of catalaseperoxidaseMutation in mycolic acid synthesis
Regulators of peroxide response
Mechanism of resistance
DrTVRao MD 25
RifampinReduced binding to RNA polymeraseClusters of mutations at ldquoRifampin Resistance Determining Regionrdquo (RRDR)
Reduced Cell wall permeability
Mechanism of resistance
DrTVRao MD 26
Gene location associated Drug-Resistant
Mtuberculosis Drug Gene Isoniazid Kat G Inh A Kas
A Rifampicin rpo B Ethambutol emb B Streptomycin rps L Pyrazinamide pnc A Fluoroquinolones gyr A
Dubaniewicz A et al Molecular sub-type of the HLA-DR antigens in pulmonary tuberculosis Int J Infect Dis20004129-33
DrTVRao MD 27
Current Scientific Documentations on Drug Resistance in
Tuberculosis
DrTVRao MD 28
Alarming Rise of Resistant TuberculosisWHO Report on
Anti-TB Drug Resistance
490000 new cases of MDR-TB each year with gt110000 deaths1
Accounts for 5 of 9 million new cases of TB2
MDR-TB rates higher than ever (up to 223) particularly in former Soviet Union countries
XDR-TB reported by as many as 49 countries (by June 2008)3
Recent WHOIUATLD Global Surveillance report indicated 75 (3014012) of MDR TB to be XDR4
Around 40000 XDR-TB cases emerge every year1
1Tuberculosis MDR-TB amp XDR-TBmdashThe 2008 Report The Stop TB Department WHO2Hargreaves S httpinfectionthelancetcom Vol 8 April 2008 p2203Raviglione MC NEJM 2008359636-84Anti-TB Drug Resistance in the World Report No 4 The WHOIUATLD Global Project on Anti-Tuberculosis Drug Resistance Surveillance 2002-2007 World Health Organization 2008 (WHOHTMTB2008394)
DrTVRao MD 29
MDR-TB amp XDR-TBTHE 2008 REPORT
of MDR-TB among new TB cases 1994-2007
DrTVRao MD 30
MDR-TB rates higher than ever (up to 223) particularly in former Soviet Union countries
DrTVRao MD 31
Alarming Rise of Resistant TB
Resistant TB burden in countries of former Soviet Union about 50 of cases resistant to at least one drug about 20 MDR XDR-TB proportions also higher (as high as 24 in
Estonia)1
MDRXDR TB ndash essentially a man-made problem2
High numbers of resistant cases (gt400000 MDR-TB cases every year) due mainly to Underinvestment in basic TB control Poor management of anti-TB drugs Transmission of drug resistant strains1
1Anti-TB Drug Resistance in the World Report No 4 The WHOIUATLD Global Project on Anti-Tuberculosis Drug Resistance Surveillance 2002-2007 World Health Organization 2008 (WHOHTMTB2008394)
2Reichman The Lancet 20083711052-3
DrTVRao MD 32
The Much Discussed Article on XDR TB in the Lancet
Of the 221 multi-drug resistant (MDR-TB) cases 53 (24) were XDR
Almost all (52 of 53) of the XDR-TB patients died with a median survival of only 16 days from the time of diagnosis (in the 42 patients with confirmed dates of death)
All the 44 XDR TB patients who were tested for HIV were found co-infected
55 patents had never received anti-TB drugs suggesting primary transmission of XDR pathogen
67 patients had been admitted to the hospital in the preceding 2 years suggesting potential role of nosocomial transmission
Gandhi et al Lancet 20063681575-80DrTVRao MD 33
Poor mangement of infected lead to grwoing resistance
Resistance to anti-TB drugs in populations is a phenomenon that occurs primarily due to poorly managed TB care Problems include incorrect drug prescribing practices by providers poor quality drugs or erratic supply of drugs and also patient non-adherence DrTVRao MD 34
Susceptibility Testing
1048708 Direct and indirect testing1048708 Primary Drugs testing1048708 Isoniazid1048708 Rifampicin1048708 Ethambutol ()1048708 Pyrizinamide ()
DrTVRao MD 35
Drug susceptibility testing (DST)
DST is recommended for all new cases for all first line drugs with specimens taken before initiating treatment
Accuracy is more important than speed DST results should come from a small
number of well-equipped experienced laboratories who participate and perform well in an international DST quality control scheme
The WHO Supranational Laboratory Quality Control Network offers the greatest global coverage for this
DrTVRao MD 36
Drug susceptibility Testing
Assessment of growth inhibition on solid media containing various dilutions of the drug in comparison with the test strains
As the method depend observation of growth Results are not available until several weeks after isolation of the organism
DrTVRao MD 37
Other accredited Methods
Radiometric and Non radiometric methods
Nucleic acid technology ndash effective upto 95 in mutations to rifampicin resistance to gene rpoB gene
DrTVRao MD 38
Drug susceptibility testing (DST)
As a minimum laboratories supplying DST data should correctly identify resistance to isoniazid and rifampicin in over 90 of quality control samples in two out of the last three quality control roundsDrTVRao MD 39
Detection of Rifampicin Drug susceptibility testing (DST) is more important
Early identification of mycobacterial growth as M tuberculosis complex and the identification of rifampicin resistance should be the first priority as rifampicin resistance invalidates standard 6 month short-course chemotherapy and is a useful marker in most countries for MDR-TB
Laboratories should aim to identify isolates as M tuberculosis complex and perform rifampicin resistance in 90 of isolates within 1-2 working days This is technologically feasible
DrTVRao MD 40
Drug susceptibility testing
For DST laboratories modern molecular techniques permit the successful identification of isoniazid resistance in at least 75 of mycobacterial cultures within 1-2 working days and are useful preliminary screens for isoniazid resistance
DrTVRao MD 41
Secondary Drugs testing [lack of standardized
methods]
Ofloxacin quinolonesEthionamide KanamycinCapreomycin Ensure quality control and
quality assurance
DrTVRao MD 42
WHO Controls the Tuberculosis related work
The laboratory methods for anti-tuberculosis drug susceptibility testing should be selected from among those that are WHO-recommended and all laboratory processes should be quality-assured in cooperation with a partner Supranational Reference Laboratory (SRL)DrTVRao MD 43
Other WHO-Endorsed Tools
Liquid culture (eg MGIT BacTALERT)
Capilia TB Rapid strip test that detects a TB-
specific antigen from culture
Molecular line probe assays (eg GenoType MTBDRplus INNO-LiPA RifTB) Strip test for detection of TB and
drug-resistance conferring mutations
DrTVRao MD 44
BacTALERTreg
DrTVRao MD 45
CDC Updates Guidelines for Nucleic AcidAmplification Techniques to Diagnose
Tuberculosis
NAAT results should be interpreted in conjunction with the AFB smear results
NAAT and smear positive start Rx despite pending culture results PPV 95
Smear negative NAAT positive use clinical judgment to either treat or await culture
DrTVRao MD 46
Selection from automated systems for molecular and
bacteriological rapid diagnostics
PCRRocheCOBASreg Amplicorreg
amplification kitsRocheCOBASreg LightCyclerreg
(real-time-PCR)RocheCOBASreg TaqMan 48reg(increases the specificity of real-
time-PCR)
DrTVRao MD 47
Molecular Fingerprinting
26 of 30 (87) XDR TB isolates found to be genetically similar
Majority of patients had no previous history of TB treatment Suggestive of recent infection with drug-resistant strain
DrTVRao MD 48
Is PCR methods a solution
PCR cant yet replace neither microscopy culturing and competent clinical examination
DrTVRao MD 49
No testing method replaces Clinical assessment
DrTVRao MD 50
XDR-TBThe description
of XDR-TB was first used earlier in 2006 following a joint survey by WHO and the US Centres for Disease Control and Prevention (CDC) DrTVRao MD 51
How x-MDR generated
Acquired resistance is that which occurs as a result of specific previous treatment The level of primary resistance in the community is considered to reflect the efficacy of control measures in the past while the level of acquired resistance is a measure of on-going TB control measuresDrTVRao MD 52
Extreme Drug resistant Tuberculosis (XDR-TB)
Resistant to all first line drugs namely Isoniazid and Rifampin and Three or more second line drugs (SLDrsquoS) that are used to treat MDR-TB Thequinalones like Ofloaxin
Or Aminoglycosides like Capreomycin amp
Kanamycin
No third-line drugs available to treat XDR-TB since none has been developed in the last 40 years
DrTVRao MD 53
Background Extensively drug-resistant tuberculosis
Extensively drug-resistant tuberculosis has been reported in 45 countries including countries with limited resources and a high burden of tuberculosis
DrTVRao MD 54
DrTVRao MD 55
Transmissionof X -MDR
Like other forms of TB XDR-TB is spread through the air When a person with infectious TB coughs sneezes talks or spits they propel Mycobacterium into the air
DrTVRao MD 56
Best options to diagnoseX-MDR tuberculosis
To evaluate drug susceptibility the bacteria need to be cultivated and tested in a suitable laboratory Final diagnosis in this way for TB and especially for XDR-TB may take from 6 to 16 weeks To reduce the time needed for diagnosis new tools for rapid TB diagnosis are urgently needed
DrTVRao MD 57
When to suspect MDR TB
Patients not showing any reduction
in bacillary population after 3-
months of regular treatment with
Cat II regimen
Sputum positive patients who are
contacts of a known MDR TB
patient
DrTVRao MD 58
How to evaluate MDR TB
MDR TB is only a laboratory
proved HR resistance
Clinical suspicion should be
followed by lab Confirmation
Laboratories should be quality
controlledTRC
DrTVRao MD 59
Extreme Drug resistant Tuberculosis (XDR-TB) and AIDS
It can also be contracted without a patient receiving any previous treatment for TB
Mostly associated with HIV positive patients
HIV has the potential to fast tracking XDR-TB into an uncontrollable epidemic
Average survival period for patients infected with XDR-TB is 16 days
DrTVRao MD 60
Responding to MDRXDR-TB
Augment DOTS Program by
New diagnostics
New drugs New vaccines HIV incidence
reduction Advocacy1
A mathematical model projected by Basu and co-workers indicates that half of XDR-TB can be averted by 2012 by bringing synergistic effects through
Use of masks Reduced time as in-patient Improved ventilation Rapid resistance testing HIV treatment TB isolation facilities2
1Marteens and Wilkinson Lancet 20073702030-432Basu et al Quoted in Porco and Getz Lancet 20073701464-5
DrTVRao MD 61
Second Line Drug Treatment (SLDrsquos)
Less effective more costly and more toxic 50 cure rate
Four months intensive phase (5 drugs) Kanamycins Ethionamide Pyrazinamide Ofloxacin Cycloserine or Ethambutol DrTVRao MD 62
World Health Organisation (WHO) Guidelines for treatment
of MDR-TB
Strengthen basic TB care to prevent the emergence of drug-resistance
Ensure prompt diagnosis and treatment of drug resistant cases to cure existing cases and prevent further transmission
Increase collaboration between HIV and TB control programmes to provide necessary prevention and care to co-infected patients
Increase investment in laboratory infrastructures to enable better detection and management of resistant cases
DrTVRao MD 63
Treatment Guidelines
Sensitivity testing for all smear positive specimens
Patient Family and staff counselling amp education
Correct and thorough hand washing protocol and procedure
Personal protection is very important
DrTVRao MD 64
THE NEW MDR-TB Guidelines
A flexible framework approach combining both clinical and programmatic aspects of DOTS Plus based on essential programme conditions
But encouraging programs to tailor their case-finding and treatment strategies to the local epidemiological and Programme situation
Reflect GLC expert consensus and evidence and experience from GLC projects thus far
DrTVRao MD 65
Effective laboratory Diagnosis
Sputum smear examinations ndash rapid classification of species (atypical mycobacteria common in AIDS)
Culture examinations
Rapid drug sensitivity testingDrTVRao MD 66
MDR TB and HIV
MDR TB occurs with the same frequency in HIV
patients as in TB patients who are smear negative
Transmission of drug-resistant strains among HIV-
infected patients in congregate settings occurs
leading to lsquooutbreaksrsquo of MDR TB in such settings
Infection control measures absolutely essential in
settings where large number of HIV TB patients stay
togetherDrTVRao MD 67
Transmission is dependent on closeness and time of contact
In penitentiary care contacts are very close and prolonged ndash culture positive cases can also transmit TB especially to HIV positive population
DrTVRao MD 68
To Know more on MDR ndashTB Current Guidelines of WHO
Guidelines for the programmatic management of drug-resistant tuberculosis - 2011 update [pdf 904kb]
Visit helliphelliphellip WHOHTMTB20116DrTVRao MD 69
Are there any solutions for effective
Diagnosis in TB
DrTVRao MD 70
Programme Created by DrTVRao MD for Medical and Health Care
Workers in the Developing World Email
doctortvraogmailcom
DrTVRao MD 71
RifampinReduced binding to RNA polymeraseClusters of mutations at ldquoRifampin Resistance Determining Regionrdquo (RRDR)
Reduced Cell wall permeability
Mechanism of resistance
DrTVRao MD 26
Gene location associated Drug-Resistant
Mtuberculosis Drug Gene Isoniazid Kat G Inh A Kas
A Rifampicin rpo B Ethambutol emb B Streptomycin rps L Pyrazinamide pnc A Fluoroquinolones gyr A
Dubaniewicz A et al Molecular sub-type of the HLA-DR antigens in pulmonary tuberculosis Int J Infect Dis20004129-33
DrTVRao MD 27
Current Scientific Documentations on Drug Resistance in
Tuberculosis
DrTVRao MD 28
Alarming Rise of Resistant TuberculosisWHO Report on
Anti-TB Drug Resistance
490000 new cases of MDR-TB each year with gt110000 deaths1
Accounts for 5 of 9 million new cases of TB2
MDR-TB rates higher than ever (up to 223) particularly in former Soviet Union countries
XDR-TB reported by as many as 49 countries (by June 2008)3
Recent WHOIUATLD Global Surveillance report indicated 75 (3014012) of MDR TB to be XDR4
Around 40000 XDR-TB cases emerge every year1
1Tuberculosis MDR-TB amp XDR-TBmdashThe 2008 Report The Stop TB Department WHO2Hargreaves S httpinfectionthelancetcom Vol 8 April 2008 p2203Raviglione MC NEJM 2008359636-84Anti-TB Drug Resistance in the World Report No 4 The WHOIUATLD Global Project on Anti-Tuberculosis Drug Resistance Surveillance 2002-2007 World Health Organization 2008 (WHOHTMTB2008394)
DrTVRao MD 29
MDR-TB amp XDR-TBTHE 2008 REPORT
of MDR-TB among new TB cases 1994-2007
DrTVRao MD 30
MDR-TB rates higher than ever (up to 223) particularly in former Soviet Union countries
DrTVRao MD 31
Alarming Rise of Resistant TB
Resistant TB burden in countries of former Soviet Union about 50 of cases resistant to at least one drug about 20 MDR XDR-TB proportions also higher (as high as 24 in
Estonia)1
MDRXDR TB ndash essentially a man-made problem2
High numbers of resistant cases (gt400000 MDR-TB cases every year) due mainly to Underinvestment in basic TB control Poor management of anti-TB drugs Transmission of drug resistant strains1
1Anti-TB Drug Resistance in the World Report No 4 The WHOIUATLD Global Project on Anti-Tuberculosis Drug Resistance Surveillance 2002-2007 World Health Organization 2008 (WHOHTMTB2008394)
2Reichman The Lancet 20083711052-3
DrTVRao MD 32
The Much Discussed Article on XDR TB in the Lancet
Of the 221 multi-drug resistant (MDR-TB) cases 53 (24) were XDR
Almost all (52 of 53) of the XDR-TB patients died with a median survival of only 16 days from the time of diagnosis (in the 42 patients with confirmed dates of death)
All the 44 XDR TB patients who were tested for HIV were found co-infected
55 patents had never received anti-TB drugs suggesting primary transmission of XDR pathogen
67 patients had been admitted to the hospital in the preceding 2 years suggesting potential role of nosocomial transmission
Gandhi et al Lancet 20063681575-80DrTVRao MD 33
Poor mangement of infected lead to grwoing resistance
Resistance to anti-TB drugs in populations is a phenomenon that occurs primarily due to poorly managed TB care Problems include incorrect drug prescribing practices by providers poor quality drugs or erratic supply of drugs and also patient non-adherence DrTVRao MD 34
Susceptibility Testing
1048708 Direct and indirect testing1048708 Primary Drugs testing1048708 Isoniazid1048708 Rifampicin1048708 Ethambutol ()1048708 Pyrizinamide ()
DrTVRao MD 35
Drug susceptibility testing (DST)
DST is recommended for all new cases for all first line drugs with specimens taken before initiating treatment
Accuracy is more important than speed DST results should come from a small
number of well-equipped experienced laboratories who participate and perform well in an international DST quality control scheme
The WHO Supranational Laboratory Quality Control Network offers the greatest global coverage for this
DrTVRao MD 36
Drug susceptibility Testing
Assessment of growth inhibition on solid media containing various dilutions of the drug in comparison with the test strains
As the method depend observation of growth Results are not available until several weeks after isolation of the organism
DrTVRao MD 37
Other accredited Methods
Radiometric and Non radiometric methods
Nucleic acid technology ndash effective upto 95 in mutations to rifampicin resistance to gene rpoB gene
DrTVRao MD 38
Drug susceptibility testing (DST)
As a minimum laboratories supplying DST data should correctly identify resistance to isoniazid and rifampicin in over 90 of quality control samples in two out of the last three quality control roundsDrTVRao MD 39
Detection of Rifampicin Drug susceptibility testing (DST) is more important
Early identification of mycobacterial growth as M tuberculosis complex and the identification of rifampicin resistance should be the first priority as rifampicin resistance invalidates standard 6 month short-course chemotherapy and is a useful marker in most countries for MDR-TB
Laboratories should aim to identify isolates as M tuberculosis complex and perform rifampicin resistance in 90 of isolates within 1-2 working days This is technologically feasible
DrTVRao MD 40
Drug susceptibility testing
For DST laboratories modern molecular techniques permit the successful identification of isoniazid resistance in at least 75 of mycobacterial cultures within 1-2 working days and are useful preliminary screens for isoniazid resistance
DrTVRao MD 41
Secondary Drugs testing [lack of standardized
methods]
Ofloxacin quinolonesEthionamide KanamycinCapreomycin Ensure quality control and
quality assurance
DrTVRao MD 42
WHO Controls the Tuberculosis related work
The laboratory methods for anti-tuberculosis drug susceptibility testing should be selected from among those that are WHO-recommended and all laboratory processes should be quality-assured in cooperation with a partner Supranational Reference Laboratory (SRL)DrTVRao MD 43
Other WHO-Endorsed Tools
Liquid culture (eg MGIT BacTALERT)
Capilia TB Rapid strip test that detects a TB-
specific antigen from culture
Molecular line probe assays (eg GenoType MTBDRplus INNO-LiPA RifTB) Strip test for detection of TB and
drug-resistance conferring mutations
DrTVRao MD 44
BacTALERTreg
DrTVRao MD 45
CDC Updates Guidelines for Nucleic AcidAmplification Techniques to Diagnose
Tuberculosis
NAAT results should be interpreted in conjunction with the AFB smear results
NAAT and smear positive start Rx despite pending culture results PPV 95
Smear negative NAAT positive use clinical judgment to either treat or await culture
DrTVRao MD 46
Selection from automated systems for molecular and
bacteriological rapid diagnostics
PCRRocheCOBASreg Amplicorreg
amplification kitsRocheCOBASreg LightCyclerreg
(real-time-PCR)RocheCOBASreg TaqMan 48reg(increases the specificity of real-
time-PCR)
DrTVRao MD 47
Molecular Fingerprinting
26 of 30 (87) XDR TB isolates found to be genetically similar
Majority of patients had no previous history of TB treatment Suggestive of recent infection with drug-resistant strain
DrTVRao MD 48
Is PCR methods a solution
PCR cant yet replace neither microscopy culturing and competent clinical examination
DrTVRao MD 49
No testing method replaces Clinical assessment
DrTVRao MD 50
XDR-TBThe description
of XDR-TB was first used earlier in 2006 following a joint survey by WHO and the US Centres for Disease Control and Prevention (CDC) DrTVRao MD 51
How x-MDR generated
Acquired resistance is that which occurs as a result of specific previous treatment The level of primary resistance in the community is considered to reflect the efficacy of control measures in the past while the level of acquired resistance is a measure of on-going TB control measuresDrTVRao MD 52
Extreme Drug resistant Tuberculosis (XDR-TB)
Resistant to all first line drugs namely Isoniazid and Rifampin and Three or more second line drugs (SLDrsquoS) that are used to treat MDR-TB Thequinalones like Ofloaxin
Or Aminoglycosides like Capreomycin amp
Kanamycin
No third-line drugs available to treat XDR-TB since none has been developed in the last 40 years
DrTVRao MD 53
Background Extensively drug-resistant tuberculosis
Extensively drug-resistant tuberculosis has been reported in 45 countries including countries with limited resources and a high burden of tuberculosis
DrTVRao MD 54
DrTVRao MD 55
Transmissionof X -MDR
Like other forms of TB XDR-TB is spread through the air When a person with infectious TB coughs sneezes talks or spits they propel Mycobacterium into the air
DrTVRao MD 56
Best options to diagnoseX-MDR tuberculosis
To evaluate drug susceptibility the bacteria need to be cultivated and tested in a suitable laboratory Final diagnosis in this way for TB and especially for XDR-TB may take from 6 to 16 weeks To reduce the time needed for diagnosis new tools for rapid TB diagnosis are urgently needed
DrTVRao MD 57
When to suspect MDR TB
Patients not showing any reduction
in bacillary population after 3-
months of regular treatment with
Cat II regimen
Sputum positive patients who are
contacts of a known MDR TB
patient
DrTVRao MD 58
How to evaluate MDR TB
MDR TB is only a laboratory
proved HR resistance
Clinical suspicion should be
followed by lab Confirmation
Laboratories should be quality
controlledTRC
DrTVRao MD 59
Extreme Drug resistant Tuberculosis (XDR-TB) and AIDS
It can also be contracted without a patient receiving any previous treatment for TB
Mostly associated with HIV positive patients
HIV has the potential to fast tracking XDR-TB into an uncontrollable epidemic
Average survival period for patients infected with XDR-TB is 16 days
DrTVRao MD 60
Responding to MDRXDR-TB
Augment DOTS Program by
New diagnostics
New drugs New vaccines HIV incidence
reduction Advocacy1
A mathematical model projected by Basu and co-workers indicates that half of XDR-TB can be averted by 2012 by bringing synergistic effects through
Use of masks Reduced time as in-patient Improved ventilation Rapid resistance testing HIV treatment TB isolation facilities2
1Marteens and Wilkinson Lancet 20073702030-432Basu et al Quoted in Porco and Getz Lancet 20073701464-5
DrTVRao MD 61
Second Line Drug Treatment (SLDrsquos)
Less effective more costly and more toxic 50 cure rate
Four months intensive phase (5 drugs) Kanamycins Ethionamide Pyrazinamide Ofloxacin Cycloserine or Ethambutol DrTVRao MD 62
World Health Organisation (WHO) Guidelines for treatment
of MDR-TB
Strengthen basic TB care to prevent the emergence of drug-resistance
Ensure prompt diagnosis and treatment of drug resistant cases to cure existing cases and prevent further transmission
Increase collaboration between HIV and TB control programmes to provide necessary prevention and care to co-infected patients
Increase investment in laboratory infrastructures to enable better detection and management of resistant cases
DrTVRao MD 63
Treatment Guidelines
Sensitivity testing for all smear positive specimens
Patient Family and staff counselling amp education
Correct and thorough hand washing protocol and procedure
Personal protection is very important
DrTVRao MD 64
THE NEW MDR-TB Guidelines
A flexible framework approach combining both clinical and programmatic aspects of DOTS Plus based on essential programme conditions
But encouraging programs to tailor their case-finding and treatment strategies to the local epidemiological and Programme situation
Reflect GLC expert consensus and evidence and experience from GLC projects thus far
DrTVRao MD 65
Effective laboratory Diagnosis
Sputum smear examinations ndash rapid classification of species (atypical mycobacteria common in AIDS)
Culture examinations
Rapid drug sensitivity testingDrTVRao MD 66
MDR TB and HIV
MDR TB occurs with the same frequency in HIV
patients as in TB patients who are smear negative
Transmission of drug-resistant strains among HIV-
infected patients in congregate settings occurs
leading to lsquooutbreaksrsquo of MDR TB in such settings
Infection control measures absolutely essential in
settings where large number of HIV TB patients stay
togetherDrTVRao MD 67
Transmission is dependent on closeness and time of contact
In penitentiary care contacts are very close and prolonged ndash culture positive cases can also transmit TB especially to HIV positive population
DrTVRao MD 68
To Know more on MDR ndashTB Current Guidelines of WHO
Guidelines for the programmatic management of drug-resistant tuberculosis - 2011 update [pdf 904kb]
Visit helliphelliphellip WHOHTMTB20116DrTVRao MD 69
Are there any solutions for effective
Diagnosis in TB
DrTVRao MD 70
Programme Created by DrTVRao MD for Medical and Health Care
Workers in the Developing World Email
doctortvraogmailcom
DrTVRao MD 71
Gene location associated Drug-Resistant
Mtuberculosis Drug Gene Isoniazid Kat G Inh A Kas
A Rifampicin rpo B Ethambutol emb B Streptomycin rps L Pyrazinamide pnc A Fluoroquinolones gyr A
Dubaniewicz A et al Molecular sub-type of the HLA-DR antigens in pulmonary tuberculosis Int J Infect Dis20004129-33
DrTVRao MD 27
Current Scientific Documentations on Drug Resistance in
Tuberculosis
DrTVRao MD 28
Alarming Rise of Resistant TuberculosisWHO Report on
Anti-TB Drug Resistance
490000 new cases of MDR-TB each year with gt110000 deaths1
Accounts for 5 of 9 million new cases of TB2
MDR-TB rates higher than ever (up to 223) particularly in former Soviet Union countries
XDR-TB reported by as many as 49 countries (by June 2008)3
Recent WHOIUATLD Global Surveillance report indicated 75 (3014012) of MDR TB to be XDR4
Around 40000 XDR-TB cases emerge every year1
1Tuberculosis MDR-TB amp XDR-TBmdashThe 2008 Report The Stop TB Department WHO2Hargreaves S httpinfectionthelancetcom Vol 8 April 2008 p2203Raviglione MC NEJM 2008359636-84Anti-TB Drug Resistance in the World Report No 4 The WHOIUATLD Global Project on Anti-Tuberculosis Drug Resistance Surveillance 2002-2007 World Health Organization 2008 (WHOHTMTB2008394)
DrTVRao MD 29
MDR-TB amp XDR-TBTHE 2008 REPORT
of MDR-TB among new TB cases 1994-2007
DrTVRao MD 30
MDR-TB rates higher than ever (up to 223) particularly in former Soviet Union countries
DrTVRao MD 31
Alarming Rise of Resistant TB
Resistant TB burden in countries of former Soviet Union about 50 of cases resistant to at least one drug about 20 MDR XDR-TB proportions also higher (as high as 24 in
Estonia)1
MDRXDR TB ndash essentially a man-made problem2
High numbers of resistant cases (gt400000 MDR-TB cases every year) due mainly to Underinvestment in basic TB control Poor management of anti-TB drugs Transmission of drug resistant strains1
1Anti-TB Drug Resistance in the World Report No 4 The WHOIUATLD Global Project on Anti-Tuberculosis Drug Resistance Surveillance 2002-2007 World Health Organization 2008 (WHOHTMTB2008394)
2Reichman The Lancet 20083711052-3
DrTVRao MD 32
The Much Discussed Article on XDR TB in the Lancet
Of the 221 multi-drug resistant (MDR-TB) cases 53 (24) were XDR
Almost all (52 of 53) of the XDR-TB patients died with a median survival of only 16 days from the time of diagnosis (in the 42 patients with confirmed dates of death)
All the 44 XDR TB patients who were tested for HIV were found co-infected
55 patents had never received anti-TB drugs suggesting primary transmission of XDR pathogen
67 patients had been admitted to the hospital in the preceding 2 years suggesting potential role of nosocomial transmission
Gandhi et al Lancet 20063681575-80DrTVRao MD 33
Poor mangement of infected lead to grwoing resistance
Resistance to anti-TB drugs in populations is a phenomenon that occurs primarily due to poorly managed TB care Problems include incorrect drug prescribing practices by providers poor quality drugs or erratic supply of drugs and also patient non-adherence DrTVRao MD 34
Susceptibility Testing
1048708 Direct and indirect testing1048708 Primary Drugs testing1048708 Isoniazid1048708 Rifampicin1048708 Ethambutol ()1048708 Pyrizinamide ()
DrTVRao MD 35
Drug susceptibility testing (DST)
DST is recommended for all new cases for all first line drugs with specimens taken before initiating treatment
Accuracy is more important than speed DST results should come from a small
number of well-equipped experienced laboratories who participate and perform well in an international DST quality control scheme
The WHO Supranational Laboratory Quality Control Network offers the greatest global coverage for this
DrTVRao MD 36
Drug susceptibility Testing
Assessment of growth inhibition on solid media containing various dilutions of the drug in comparison with the test strains
As the method depend observation of growth Results are not available until several weeks after isolation of the organism
DrTVRao MD 37
Other accredited Methods
Radiometric and Non radiometric methods
Nucleic acid technology ndash effective upto 95 in mutations to rifampicin resistance to gene rpoB gene
DrTVRao MD 38
Drug susceptibility testing (DST)
As a minimum laboratories supplying DST data should correctly identify resistance to isoniazid and rifampicin in over 90 of quality control samples in two out of the last three quality control roundsDrTVRao MD 39
Detection of Rifampicin Drug susceptibility testing (DST) is more important
Early identification of mycobacterial growth as M tuberculosis complex and the identification of rifampicin resistance should be the first priority as rifampicin resistance invalidates standard 6 month short-course chemotherapy and is a useful marker in most countries for MDR-TB
Laboratories should aim to identify isolates as M tuberculosis complex and perform rifampicin resistance in 90 of isolates within 1-2 working days This is technologically feasible
DrTVRao MD 40
Drug susceptibility testing
For DST laboratories modern molecular techniques permit the successful identification of isoniazid resistance in at least 75 of mycobacterial cultures within 1-2 working days and are useful preliminary screens for isoniazid resistance
DrTVRao MD 41
Secondary Drugs testing [lack of standardized
methods]
Ofloxacin quinolonesEthionamide KanamycinCapreomycin Ensure quality control and
quality assurance
DrTVRao MD 42
WHO Controls the Tuberculosis related work
The laboratory methods for anti-tuberculosis drug susceptibility testing should be selected from among those that are WHO-recommended and all laboratory processes should be quality-assured in cooperation with a partner Supranational Reference Laboratory (SRL)DrTVRao MD 43
Other WHO-Endorsed Tools
Liquid culture (eg MGIT BacTALERT)
Capilia TB Rapid strip test that detects a TB-
specific antigen from culture
Molecular line probe assays (eg GenoType MTBDRplus INNO-LiPA RifTB) Strip test for detection of TB and
drug-resistance conferring mutations
DrTVRao MD 44
BacTALERTreg
DrTVRao MD 45
CDC Updates Guidelines for Nucleic AcidAmplification Techniques to Diagnose
Tuberculosis
NAAT results should be interpreted in conjunction with the AFB smear results
NAAT and smear positive start Rx despite pending culture results PPV 95
Smear negative NAAT positive use clinical judgment to either treat or await culture
DrTVRao MD 46
Selection from automated systems for molecular and
bacteriological rapid diagnostics
PCRRocheCOBASreg Amplicorreg
amplification kitsRocheCOBASreg LightCyclerreg
(real-time-PCR)RocheCOBASreg TaqMan 48reg(increases the specificity of real-
time-PCR)
DrTVRao MD 47
Molecular Fingerprinting
26 of 30 (87) XDR TB isolates found to be genetically similar
Majority of patients had no previous history of TB treatment Suggestive of recent infection with drug-resistant strain
DrTVRao MD 48
Is PCR methods a solution
PCR cant yet replace neither microscopy culturing and competent clinical examination
DrTVRao MD 49
No testing method replaces Clinical assessment
DrTVRao MD 50
XDR-TBThe description
of XDR-TB was first used earlier in 2006 following a joint survey by WHO and the US Centres for Disease Control and Prevention (CDC) DrTVRao MD 51
How x-MDR generated
Acquired resistance is that which occurs as a result of specific previous treatment The level of primary resistance in the community is considered to reflect the efficacy of control measures in the past while the level of acquired resistance is a measure of on-going TB control measuresDrTVRao MD 52
Extreme Drug resistant Tuberculosis (XDR-TB)
Resistant to all first line drugs namely Isoniazid and Rifampin and Three or more second line drugs (SLDrsquoS) that are used to treat MDR-TB Thequinalones like Ofloaxin
Or Aminoglycosides like Capreomycin amp
Kanamycin
No third-line drugs available to treat XDR-TB since none has been developed in the last 40 years
DrTVRao MD 53
Background Extensively drug-resistant tuberculosis
Extensively drug-resistant tuberculosis has been reported in 45 countries including countries with limited resources and a high burden of tuberculosis
DrTVRao MD 54
DrTVRao MD 55
Transmissionof X -MDR
Like other forms of TB XDR-TB is spread through the air When a person with infectious TB coughs sneezes talks or spits they propel Mycobacterium into the air
DrTVRao MD 56
Best options to diagnoseX-MDR tuberculosis
To evaluate drug susceptibility the bacteria need to be cultivated and tested in a suitable laboratory Final diagnosis in this way for TB and especially for XDR-TB may take from 6 to 16 weeks To reduce the time needed for diagnosis new tools for rapid TB diagnosis are urgently needed
DrTVRao MD 57
When to suspect MDR TB
Patients not showing any reduction
in bacillary population after 3-
months of regular treatment with
Cat II regimen
Sputum positive patients who are
contacts of a known MDR TB
patient
DrTVRao MD 58
How to evaluate MDR TB
MDR TB is only a laboratory
proved HR resistance
Clinical suspicion should be
followed by lab Confirmation
Laboratories should be quality
controlledTRC
DrTVRao MD 59
Extreme Drug resistant Tuberculosis (XDR-TB) and AIDS
It can also be contracted without a patient receiving any previous treatment for TB
Mostly associated with HIV positive patients
HIV has the potential to fast tracking XDR-TB into an uncontrollable epidemic
Average survival period for patients infected with XDR-TB is 16 days
DrTVRao MD 60
Responding to MDRXDR-TB
Augment DOTS Program by
New diagnostics
New drugs New vaccines HIV incidence
reduction Advocacy1
A mathematical model projected by Basu and co-workers indicates that half of XDR-TB can be averted by 2012 by bringing synergistic effects through
Use of masks Reduced time as in-patient Improved ventilation Rapid resistance testing HIV treatment TB isolation facilities2
1Marteens and Wilkinson Lancet 20073702030-432Basu et al Quoted in Porco and Getz Lancet 20073701464-5
DrTVRao MD 61
Second Line Drug Treatment (SLDrsquos)
Less effective more costly and more toxic 50 cure rate
Four months intensive phase (5 drugs) Kanamycins Ethionamide Pyrazinamide Ofloxacin Cycloserine or Ethambutol DrTVRao MD 62
World Health Organisation (WHO) Guidelines for treatment
of MDR-TB
Strengthen basic TB care to prevent the emergence of drug-resistance
Ensure prompt diagnosis and treatment of drug resistant cases to cure existing cases and prevent further transmission
Increase collaboration between HIV and TB control programmes to provide necessary prevention and care to co-infected patients
Increase investment in laboratory infrastructures to enable better detection and management of resistant cases
DrTVRao MD 63
Treatment Guidelines
Sensitivity testing for all smear positive specimens
Patient Family and staff counselling amp education
Correct and thorough hand washing protocol and procedure
Personal protection is very important
DrTVRao MD 64
THE NEW MDR-TB Guidelines
A flexible framework approach combining both clinical and programmatic aspects of DOTS Plus based on essential programme conditions
But encouraging programs to tailor their case-finding and treatment strategies to the local epidemiological and Programme situation
Reflect GLC expert consensus and evidence and experience from GLC projects thus far
DrTVRao MD 65
Effective laboratory Diagnosis
Sputum smear examinations ndash rapid classification of species (atypical mycobacteria common in AIDS)
Culture examinations
Rapid drug sensitivity testingDrTVRao MD 66
MDR TB and HIV
MDR TB occurs with the same frequency in HIV
patients as in TB patients who are smear negative
Transmission of drug-resistant strains among HIV-
infected patients in congregate settings occurs
leading to lsquooutbreaksrsquo of MDR TB in such settings
Infection control measures absolutely essential in
settings where large number of HIV TB patients stay
togetherDrTVRao MD 67
Transmission is dependent on closeness and time of contact
In penitentiary care contacts are very close and prolonged ndash culture positive cases can also transmit TB especially to HIV positive population
DrTVRao MD 68
To Know more on MDR ndashTB Current Guidelines of WHO
Guidelines for the programmatic management of drug-resistant tuberculosis - 2011 update [pdf 904kb]
Visit helliphelliphellip WHOHTMTB20116DrTVRao MD 69
Are there any solutions for effective
Diagnosis in TB
DrTVRao MD 70
Programme Created by DrTVRao MD for Medical and Health Care
Workers in the Developing World Email
doctortvraogmailcom
DrTVRao MD 71
Current Scientific Documentations on Drug Resistance in
Tuberculosis
DrTVRao MD 28
Alarming Rise of Resistant TuberculosisWHO Report on
Anti-TB Drug Resistance
490000 new cases of MDR-TB each year with gt110000 deaths1
Accounts for 5 of 9 million new cases of TB2
MDR-TB rates higher than ever (up to 223) particularly in former Soviet Union countries
XDR-TB reported by as many as 49 countries (by June 2008)3
Recent WHOIUATLD Global Surveillance report indicated 75 (3014012) of MDR TB to be XDR4
Around 40000 XDR-TB cases emerge every year1
1Tuberculosis MDR-TB amp XDR-TBmdashThe 2008 Report The Stop TB Department WHO2Hargreaves S httpinfectionthelancetcom Vol 8 April 2008 p2203Raviglione MC NEJM 2008359636-84Anti-TB Drug Resistance in the World Report No 4 The WHOIUATLD Global Project on Anti-Tuberculosis Drug Resistance Surveillance 2002-2007 World Health Organization 2008 (WHOHTMTB2008394)
DrTVRao MD 29
MDR-TB amp XDR-TBTHE 2008 REPORT
of MDR-TB among new TB cases 1994-2007
DrTVRao MD 30
MDR-TB rates higher than ever (up to 223) particularly in former Soviet Union countries
DrTVRao MD 31
Alarming Rise of Resistant TB
Resistant TB burden in countries of former Soviet Union about 50 of cases resistant to at least one drug about 20 MDR XDR-TB proportions also higher (as high as 24 in
Estonia)1
MDRXDR TB ndash essentially a man-made problem2
High numbers of resistant cases (gt400000 MDR-TB cases every year) due mainly to Underinvestment in basic TB control Poor management of anti-TB drugs Transmission of drug resistant strains1
1Anti-TB Drug Resistance in the World Report No 4 The WHOIUATLD Global Project on Anti-Tuberculosis Drug Resistance Surveillance 2002-2007 World Health Organization 2008 (WHOHTMTB2008394)
2Reichman The Lancet 20083711052-3
DrTVRao MD 32
The Much Discussed Article on XDR TB in the Lancet
Of the 221 multi-drug resistant (MDR-TB) cases 53 (24) were XDR
Almost all (52 of 53) of the XDR-TB patients died with a median survival of only 16 days from the time of diagnosis (in the 42 patients with confirmed dates of death)
All the 44 XDR TB patients who were tested for HIV were found co-infected
55 patents had never received anti-TB drugs suggesting primary transmission of XDR pathogen
67 patients had been admitted to the hospital in the preceding 2 years suggesting potential role of nosocomial transmission
Gandhi et al Lancet 20063681575-80DrTVRao MD 33
Poor mangement of infected lead to grwoing resistance
Resistance to anti-TB drugs in populations is a phenomenon that occurs primarily due to poorly managed TB care Problems include incorrect drug prescribing practices by providers poor quality drugs or erratic supply of drugs and also patient non-adherence DrTVRao MD 34
Susceptibility Testing
1048708 Direct and indirect testing1048708 Primary Drugs testing1048708 Isoniazid1048708 Rifampicin1048708 Ethambutol ()1048708 Pyrizinamide ()
DrTVRao MD 35
Drug susceptibility testing (DST)
DST is recommended for all new cases for all first line drugs with specimens taken before initiating treatment
Accuracy is more important than speed DST results should come from a small
number of well-equipped experienced laboratories who participate and perform well in an international DST quality control scheme
The WHO Supranational Laboratory Quality Control Network offers the greatest global coverage for this
DrTVRao MD 36
Drug susceptibility Testing
Assessment of growth inhibition on solid media containing various dilutions of the drug in comparison with the test strains
As the method depend observation of growth Results are not available until several weeks after isolation of the organism
DrTVRao MD 37
Other accredited Methods
Radiometric and Non radiometric methods
Nucleic acid technology ndash effective upto 95 in mutations to rifampicin resistance to gene rpoB gene
DrTVRao MD 38
Drug susceptibility testing (DST)
As a minimum laboratories supplying DST data should correctly identify resistance to isoniazid and rifampicin in over 90 of quality control samples in two out of the last three quality control roundsDrTVRao MD 39
Detection of Rifampicin Drug susceptibility testing (DST) is more important
Early identification of mycobacterial growth as M tuberculosis complex and the identification of rifampicin resistance should be the first priority as rifampicin resistance invalidates standard 6 month short-course chemotherapy and is a useful marker in most countries for MDR-TB
Laboratories should aim to identify isolates as M tuberculosis complex and perform rifampicin resistance in 90 of isolates within 1-2 working days This is technologically feasible
DrTVRao MD 40
Drug susceptibility testing
For DST laboratories modern molecular techniques permit the successful identification of isoniazid resistance in at least 75 of mycobacterial cultures within 1-2 working days and are useful preliminary screens for isoniazid resistance
DrTVRao MD 41
Secondary Drugs testing [lack of standardized
methods]
Ofloxacin quinolonesEthionamide KanamycinCapreomycin Ensure quality control and
quality assurance
DrTVRao MD 42
WHO Controls the Tuberculosis related work
The laboratory methods for anti-tuberculosis drug susceptibility testing should be selected from among those that are WHO-recommended and all laboratory processes should be quality-assured in cooperation with a partner Supranational Reference Laboratory (SRL)DrTVRao MD 43
Other WHO-Endorsed Tools
Liquid culture (eg MGIT BacTALERT)
Capilia TB Rapid strip test that detects a TB-
specific antigen from culture
Molecular line probe assays (eg GenoType MTBDRplus INNO-LiPA RifTB) Strip test for detection of TB and
drug-resistance conferring mutations
DrTVRao MD 44
BacTALERTreg
DrTVRao MD 45
CDC Updates Guidelines for Nucleic AcidAmplification Techniques to Diagnose
Tuberculosis
NAAT results should be interpreted in conjunction with the AFB smear results
NAAT and smear positive start Rx despite pending culture results PPV 95
Smear negative NAAT positive use clinical judgment to either treat or await culture
DrTVRao MD 46
Selection from automated systems for molecular and
bacteriological rapid diagnostics
PCRRocheCOBASreg Amplicorreg
amplification kitsRocheCOBASreg LightCyclerreg
(real-time-PCR)RocheCOBASreg TaqMan 48reg(increases the specificity of real-
time-PCR)
DrTVRao MD 47
Molecular Fingerprinting
26 of 30 (87) XDR TB isolates found to be genetically similar
Majority of patients had no previous history of TB treatment Suggestive of recent infection with drug-resistant strain
DrTVRao MD 48
Is PCR methods a solution
PCR cant yet replace neither microscopy culturing and competent clinical examination
DrTVRao MD 49
No testing method replaces Clinical assessment
DrTVRao MD 50
XDR-TBThe description
of XDR-TB was first used earlier in 2006 following a joint survey by WHO and the US Centres for Disease Control and Prevention (CDC) DrTVRao MD 51
How x-MDR generated
Acquired resistance is that which occurs as a result of specific previous treatment The level of primary resistance in the community is considered to reflect the efficacy of control measures in the past while the level of acquired resistance is a measure of on-going TB control measuresDrTVRao MD 52
Extreme Drug resistant Tuberculosis (XDR-TB)
Resistant to all first line drugs namely Isoniazid and Rifampin and Three or more second line drugs (SLDrsquoS) that are used to treat MDR-TB Thequinalones like Ofloaxin
Or Aminoglycosides like Capreomycin amp
Kanamycin
No third-line drugs available to treat XDR-TB since none has been developed in the last 40 years
DrTVRao MD 53
Background Extensively drug-resistant tuberculosis
Extensively drug-resistant tuberculosis has been reported in 45 countries including countries with limited resources and a high burden of tuberculosis
DrTVRao MD 54
DrTVRao MD 55
Transmissionof X -MDR
Like other forms of TB XDR-TB is spread through the air When a person with infectious TB coughs sneezes talks or spits they propel Mycobacterium into the air
DrTVRao MD 56
Best options to diagnoseX-MDR tuberculosis
To evaluate drug susceptibility the bacteria need to be cultivated and tested in a suitable laboratory Final diagnosis in this way for TB and especially for XDR-TB may take from 6 to 16 weeks To reduce the time needed for diagnosis new tools for rapid TB diagnosis are urgently needed
DrTVRao MD 57
When to suspect MDR TB
Patients not showing any reduction
in bacillary population after 3-
months of regular treatment with
Cat II regimen
Sputum positive patients who are
contacts of a known MDR TB
patient
DrTVRao MD 58
How to evaluate MDR TB
MDR TB is only a laboratory
proved HR resistance
Clinical suspicion should be
followed by lab Confirmation
Laboratories should be quality
controlledTRC
DrTVRao MD 59
Extreme Drug resistant Tuberculosis (XDR-TB) and AIDS
It can also be contracted without a patient receiving any previous treatment for TB
Mostly associated with HIV positive patients
HIV has the potential to fast tracking XDR-TB into an uncontrollable epidemic
Average survival period for patients infected with XDR-TB is 16 days
DrTVRao MD 60
Responding to MDRXDR-TB
Augment DOTS Program by
New diagnostics
New drugs New vaccines HIV incidence
reduction Advocacy1
A mathematical model projected by Basu and co-workers indicates that half of XDR-TB can be averted by 2012 by bringing synergistic effects through
Use of masks Reduced time as in-patient Improved ventilation Rapid resistance testing HIV treatment TB isolation facilities2
1Marteens and Wilkinson Lancet 20073702030-432Basu et al Quoted in Porco and Getz Lancet 20073701464-5
DrTVRao MD 61
Second Line Drug Treatment (SLDrsquos)
Less effective more costly and more toxic 50 cure rate
Four months intensive phase (5 drugs) Kanamycins Ethionamide Pyrazinamide Ofloxacin Cycloserine or Ethambutol DrTVRao MD 62
World Health Organisation (WHO) Guidelines for treatment
of MDR-TB
Strengthen basic TB care to prevent the emergence of drug-resistance
Ensure prompt diagnosis and treatment of drug resistant cases to cure existing cases and prevent further transmission
Increase collaboration between HIV and TB control programmes to provide necessary prevention and care to co-infected patients
Increase investment in laboratory infrastructures to enable better detection and management of resistant cases
DrTVRao MD 63
Treatment Guidelines
Sensitivity testing for all smear positive specimens
Patient Family and staff counselling amp education
Correct and thorough hand washing protocol and procedure
Personal protection is very important
DrTVRao MD 64
THE NEW MDR-TB Guidelines
A flexible framework approach combining both clinical and programmatic aspects of DOTS Plus based on essential programme conditions
But encouraging programs to tailor their case-finding and treatment strategies to the local epidemiological and Programme situation
Reflect GLC expert consensus and evidence and experience from GLC projects thus far
DrTVRao MD 65
Effective laboratory Diagnosis
Sputum smear examinations ndash rapid classification of species (atypical mycobacteria common in AIDS)
Culture examinations
Rapid drug sensitivity testingDrTVRao MD 66
MDR TB and HIV
MDR TB occurs with the same frequency in HIV
patients as in TB patients who are smear negative
Transmission of drug-resistant strains among HIV-
infected patients in congregate settings occurs
leading to lsquooutbreaksrsquo of MDR TB in such settings
Infection control measures absolutely essential in
settings where large number of HIV TB patients stay
togetherDrTVRao MD 67
Transmission is dependent on closeness and time of contact
In penitentiary care contacts are very close and prolonged ndash culture positive cases can also transmit TB especially to HIV positive population
DrTVRao MD 68
To Know more on MDR ndashTB Current Guidelines of WHO
Guidelines for the programmatic management of drug-resistant tuberculosis - 2011 update [pdf 904kb]
Visit helliphelliphellip WHOHTMTB20116DrTVRao MD 69
Are there any solutions for effective
Diagnosis in TB
DrTVRao MD 70
Programme Created by DrTVRao MD for Medical and Health Care
Workers in the Developing World Email
doctortvraogmailcom
DrTVRao MD 71
Alarming Rise of Resistant TuberculosisWHO Report on
Anti-TB Drug Resistance
490000 new cases of MDR-TB each year with gt110000 deaths1
Accounts for 5 of 9 million new cases of TB2
MDR-TB rates higher than ever (up to 223) particularly in former Soviet Union countries
XDR-TB reported by as many as 49 countries (by June 2008)3
Recent WHOIUATLD Global Surveillance report indicated 75 (3014012) of MDR TB to be XDR4
Around 40000 XDR-TB cases emerge every year1
1Tuberculosis MDR-TB amp XDR-TBmdashThe 2008 Report The Stop TB Department WHO2Hargreaves S httpinfectionthelancetcom Vol 8 April 2008 p2203Raviglione MC NEJM 2008359636-84Anti-TB Drug Resistance in the World Report No 4 The WHOIUATLD Global Project on Anti-Tuberculosis Drug Resistance Surveillance 2002-2007 World Health Organization 2008 (WHOHTMTB2008394)
DrTVRao MD 29
MDR-TB amp XDR-TBTHE 2008 REPORT
of MDR-TB among new TB cases 1994-2007
DrTVRao MD 30
MDR-TB rates higher than ever (up to 223) particularly in former Soviet Union countries
DrTVRao MD 31
Alarming Rise of Resistant TB
Resistant TB burden in countries of former Soviet Union about 50 of cases resistant to at least one drug about 20 MDR XDR-TB proportions also higher (as high as 24 in
Estonia)1
MDRXDR TB ndash essentially a man-made problem2
High numbers of resistant cases (gt400000 MDR-TB cases every year) due mainly to Underinvestment in basic TB control Poor management of anti-TB drugs Transmission of drug resistant strains1
1Anti-TB Drug Resistance in the World Report No 4 The WHOIUATLD Global Project on Anti-Tuberculosis Drug Resistance Surveillance 2002-2007 World Health Organization 2008 (WHOHTMTB2008394)
2Reichman The Lancet 20083711052-3
DrTVRao MD 32
The Much Discussed Article on XDR TB in the Lancet
Of the 221 multi-drug resistant (MDR-TB) cases 53 (24) were XDR
Almost all (52 of 53) of the XDR-TB patients died with a median survival of only 16 days from the time of diagnosis (in the 42 patients with confirmed dates of death)
All the 44 XDR TB patients who were tested for HIV were found co-infected
55 patents had never received anti-TB drugs suggesting primary transmission of XDR pathogen
67 patients had been admitted to the hospital in the preceding 2 years suggesting potential role of nosocomial transmission
Gandhi et al Lancet 20063681575-80DrTVRao MD 33
Poor mangement of infected lead to grwoing resistance
Resistance to anti-TB drugs in populations is a phenomenon that occurs primarily due to poorly managed TB care Problems include incorrect drug prescribing practices by providers poor quality drugs or erratic supply of drugs and also patient non-adherence DrTVRao MD 34
Susceptibility Testing
1048708 Direct and indirect testing1048708 Primary Drugs testing1048708 Isoniazid1048708 Rifampicin1048708 Ethambutol ()1048708 Pyrizinamide ()
DrTVRao MD 35
Drug susceptibility testing (DST)
DST is recommended for all new cases for all first line drugs with specimens taken before initiating treatment
Accuracy is more important than speed DST results should come from a small
number of well-equipped experienced laboratories who participate and perform well in an international DST quality control scheme
The WHO Supranational Laboratory Quality Control Network offers the greatest global coverage for this
DrTVRao MD 36
Drug susceptibility Testing
Assessment of growth inhibition on solid media containing various dilutions of the drug in comparison with the test strains
As the method depend observation of growth Results are not available until several weeks after isolation of the organism
DrTVRao MD 37
Other accredited Methods
Radiometric and Non radiometric methods
Nucleic acid technology ndash effective upto 95 in mutations to rifampicin resistance to gene rpoB gene
DrTVRao MD 38
Drug susceptibility testing (DST)
As a minimum laboratories supplying DST data should correctly identify resistance to isoniazid and rifampicin in over 90 of quality control samples in two out of the last three quality control roundsDrTVRao MD 39
Detection of Rifampicin Drug susceptibility testing (DST) is more important
Early identification of mycobacterial growth as M tuberculosis complex and the identification of rifampicin resistance should be the first priority as rifampicin resistance invalidates standard 6 month short-course chemotherapy and is a useful marker in most countries for MDR-TB
Laboratories should aim to identify isolates as M tuberculosis complex and perform rifampicin resistance in 90 of isolates within 1-2 working days This is technologically feasible
DrTVRao MD 40
Drug susceptibility testing
For DST laboratories modern molecular techniques permit the successful identification of isoniazid resistance in at least 75 of mycobacterial cultures within 1-2 working days and are useful preliminary screens for isoniazid resistance
DrTVRao MD 41
Secondary Drugs testing [lack of standardized
methods]
Ofloxacin quinolonesEthionamide KanamycinCapreomycin Ensure quality control and
quality assurance
DrTVRao MD 42
WHO Controls the Tuberculosis related work
The laboratory methods for anti-tuberculosis drug susceptibility testing should be selected from among those that are WHO-recommended and all laboratory processes should be quality-assured in cooperation with a partner Supranational Reference Laboratory (SRL)DrTVRao MD 43
Other WHO-Endorsed Tools
Liquid culture (eg MGIT BacTALERT)
Capilia TB Rapid strip test that detects a TB-
specific antigen from culture
Molecular line probe assays (eg GenoType MTBDRplus INNO-LiPA RifTB) Strip test for detection of TB and
drug-resistance conferring mutations
DrTVRao MD 44
BacTALERTreg
DrTVRao MD 45
CDC Updates Guidelines for Nucleic AcidAmplification Techniques to Diagnose
Tuberculosis
NAAT results should be interpreted in conjunction with the AFB smear results
NAAT and smear positive start Rx despite pending culture results PPV 95
Smear negative NAAT positive use clinical judgment to either treat or await culture
DrTVRao MD 46
Selection from automated systems for molecular and
bacteriological rapid diagnostics
PCRRocheCOBASreg Amplicorreg
amplification kitsRocheCOBASreg LightCyclerreg
(real-time-PCR)RocheCOBASreg TaqMan 48reg(increases the specificity of real-
time-PCR)
DrTVRao MD 47
Molecular Fingerprinting
26 of 30 (87) XDR TB isolates found to be genetically similar
Majority of patients had no previous history of TB treatment Suggestive of recent infection with drug-resistant strain
DrTVRao MD 48
Is PCR methods a solution
PCR cant yet replace neither microscopy culturing and competent clinical examination
DrTVRao MD 49
No testing method replaces Clinical assessment
DrTVRao MD 50
XDR-TBThe description
of XDR-TB was first used earlier in 2006 following a joint survey by WHO and the US Centres for Disease Control and Prevention (CDC) DrTVRao MD 51
How x-MDR generated
Acquired resistance is that which occurs as a result of specific previous treatment The level of primary resistance in the community is considered to reflect the efficacy of control measures in the past while the level of acquired resistance is a measure of on-going TB control measuresDrTVRao MD 52
Extreme Drug resistant Tuberculosis (XDR-TB)
Resistant to all first line drugs namely Isoniazid and Rifampin and Three or more second line drugs (SLDrsquoS) that are used to treat MDR-TB Thequinalones like Ofloaxin
Or Aminoglycosides like Capreomycin amp
Kanamycin
No third-line drugs available to treat XDR-TB since none has been developed in the last 40 years
DrTVRao MD 53
Background Extensively drug-resistant tuberculosis
Extensively drug-resistant tuberculosis has been reported in 45 countries including countries with limited resources and a high burden of tuberculosis
DrTVRao MD 54
DrTVRao MD 55
Transmissionof X -MDR
Like other forms of TB XDR-TB is spread through the air When a person with infectious TB coughs sneezes talks or spits they propel Mycobacterium into the air
DrTVRao MD 56
Best options to diagnoseX-MDR tuberculosis
To evaluate drug susceptibility the bacteria need to be cultivated and tested in a suitable laboratory Final diagnosis in this way for TB and especially for XDR-TB may take from 6 to 16 weeks To reduce the time needed for diagnosis new tools for rapid TB diagnosis are urgently needed
DrTVRao MD 57
When to suspect MDR TB
Patients not showing any reduction
in bacillary population after 3-
months of regular treatment with
Cat II regimen
Sputum positive patients who are
contacts of a known MDR TB
patient
DrTVRao MD 58
How to evaluate MDR TB
MDR TB is only a laboratory
proved HR resistance
Clinical suspicion should be
followed by lab Confirmation
Laboratories should be quality
controlledTRC
DrTVRao MD 59
Extreme Drug resistant Tuberculosis (XDR-TB) and AIDS
It can also be contracted without a patient receiving any previous treatment for TB
Mostly associated with HIV positive patients
HIV has the potential to fast tracking XDR-TB into an uncontrollable epidemic
Average survival period for patients infected with XDR-TB is 16 days
DrTVRao MD 60
Responding to MDRXDR-TB
Augment DOTS Program by
New diagnostics
New drugs New vaccines HIV incidence
reduction Advocacy1
A mathematical model projected by Basu and co-workers indicates that half of XDR-TB can be averted by 2012 by bringing synergistic effects through
Use of masks Reduced time as in-patient Improved ventilation Rapid resistance testing HIV treatment TB isolation facilities2
1Marteens and Wilkinson Lancet 20073702030-432Basu et al Quoted in Porco and Getz Lancet 20073701464-5
DrTVRao MD 61
Second Line Drug Treatment (SLDrsquos)
Less effective more costly and more toxic 50 cure rate
Four months intensive phase (5 drugs) Kanamycins Ethionamide Pyrazinamide Ofloxacin Cycloserine or Ethambutol DrTVRao MD 62
World Health Organisation (WHO) Guidelines for treatment
of MDR-TB
Strengthen basic TB care to prevent the emergence of drug-resistance
Ensure prompt diagnosis and treatment of drug resistant cases to cure existing cases and prevent further transmission
Increase collaboration between HIV and TB control programmes to provide necessary prevention and care to co-infected patients
Increase investment in laboratory infrastructures to enable better detection and management of resistant cases
DrTVRao MD 63
Treatment Guidelines
Sensitivity testing for all smear positive specimens
Patient Family and staff counselling amp education
Correct and thorough hand washing protocol and procedure
Personal protection is very important
DrTVRao MD 64
THE NEW MDR-TB Guidelines
A flexible framework approach combining both clinical and programmatic aspects of DOTS Plus based on essential programme conditions
But encouraging programs to tailor their case-finding and treatment strategies to the local epidemiological and Programme situation
Reflect GLC expert consensus and evidence and experience from GLC projects thus far
DrTVRao MD 65
Effective laboratory Diagnosis
Sputum smear examinations ndash rapid classification of species (atypical mycobacteria common in AIDS)
Culture examinations
Rapid drug sensitivity testingDrTVRao MD 66
MDR TB and HIV
MDR TB occurs with the same frequency in HIV
patients as in TB patients who are smear negative
Transmission of drug-resistant strains among HIV-
infected patients in congregate settings occurs
leading to lsquooutbreaksrsquo of MDR TB in such settings
Infection control measures absolutely essential in
settings where large number of HIV TB patients stay
togetherDrTVRao MD 67
Transmission is dependent on closeness and time of contact
In penitentiary care contacts are very close and prolonged ndash culture positive cases can also transmit TB especially to HIV positive population
DrTVRao MD 68
To Know more on MDR ndashTB Current Guidelines of WHO
Guidelines for the programmatic management of drug-resistant tuberculosis - 2011 update [pdf 904kb]
Visit helliphelliphellip WHOHTMTB20116DrTVRao MD 69
Are there any solutions for effective
Diagnosis in TB
DrTVRao MD 70
Programme Created by DrTVRao MD for Medical and Health Care
Workers in the Developing World Email
doctortvraogmailcom
DrTVRao MD 71
MDR-TB amp XDR-TBTHE 2008 REPORT
of MDR-TB among new TB cases 1994-2007
DrTVRao MD 30
MDR-TB rates higher than ever (up to 223) particularly in former Soviet Union countries
DrTVRao MD 31
Alarming Rise of Resistant TB
Resistant TB burden in countries of former Soviet Union about 50 of cases resistant to at least one drug about 20 MDR XDR-TB proportions also higher (as high as 24 in
Estonia)1
MDRXDR TB ndash essentially a man-made problem2
High numbers of resistant cases (gt400000 MDR-TB cases every year) due mainly to Underinvestment in basic TB control Poor management of anti-TB drugs Transmission of drug resistant strains1
1Anti-TB Drug Resistance in the World Report No 4 The WHOIUATLD Global Project on Anti-Tuberculosis Drug Resistance Surveillance 2002-2007 World Health Organization 2008 (WHOHTMTB2008394)
2Reichman The Lancet 20083711052-3
DrTVRao MD 32
The Much Discussed Article on XDR TB in the Lancet
Of the 221 multi-drug resistant (MDR-TB) cases 53 (24) were XDR
Almost all (52 of 53) of the XDR-TB patients died with a median survival of only 16 days from the time of diagnosis (in the 42 patients with confirmed dates of death)
All the 44 XDR TB patients who were tested for HIV were found co-infected
55 patents had never received anti-TB drugs suggesting primary transmission of XDR pathogen
67 patients had been admitted to the hospital in the preceding 2 years suggesting potential role of nosocomial transmission
Gandhi et al Lancet 20063681575-80DrTVRao MD 33
Poor mangement of infected lead to grwoing resistance
Resistance to anti-TB drugs in populations is a phenomenon that occurs primarily due to poorly managed TB care Problems include incorrect drug prescribing practices by providers poor quality drugs or erratic supply of drugs and also patient non-adherence DrTVRao MD 34
Susceptibility Testing
1048708 Direct and indirect testing1048708 Primary Drugs testing1048708 Isoniazid1048708 Rifampicin1048708 Ethambutol ()1048708 Pyrizinamide ()
DrTVRao MD 35
Drug susceptibility testing (DST)
DST is recommended for all new cases for all first line drugs with specimens taken before initiating treatment
Accuracy is more important than speed DST results should come from a small
number of well-equipped experienced laboratories who participate and perform well in an international DST quality control scheme
The WHO Supranational Laboratory Quality Control Network offers the greatest global coverage for this
DrTVRao MD 36
Drug susceptibility Testing
Assessment of growth inhibition on solid media containing various dilutions of the drug in comparison with the test strains
As the method depend observation of growth Results are not available until several weeks after isolation of the organism
DrTVRao MD 37
Other accredited Methods
Radiometric and Non radiometric methods
Nucleic acid technology ndash effective upto 95 in mutations to rifampicin resistance to gene rpoB gene
DrTVRao MD 38
Drug susceptibility testing (DST)
As a minimum laboratories supplying DST data should correctly identify resistance to isoniazid and rifampicin in over 90 of quality control samples in two out of the last three quality control roundsDrTVRao MD 39
Detection of Rifampicin Drug susceptibility testing (DST) is more important
Early identification of mycobacterial growth as M tuberculosis complex and the identification of rifampicin resistance should be the first priority as rifampicin resistance invalidates standard 6 month short-course chemotherapy and is a useful marker in most countries for MDR-TB
Laboratories should aim to identify isolates as M tuberculosis complex and perform rifampicin resistance in 90 of isolates within 1-2 working days This is technologically feasible
DrTVRao MD 40
Drug susceptibility testing
For DST laboratories modern molecular techniques permit the successful identification of isoniazid resistance in at least 75 of mycobacterial cultures within 1-2 working days and are useful preliminary screens for isoniazid resistance
DrTVRao MD 41
Secondary Drugs testing [lack of standardized
methods]
Ofloxacin quinolonesEthionamide KanamycinCapreomycin Ensure quality control and
quality assurance
DrTVRao MD 42
WHO Controls the Tuberculosis related work
The laboratory methods for anti-tuberculosis drug susceptibility testing should be selected from among those that are WHO-recommended and all laboratory processes should be quality-assured in cooperation with a partner Supranational Reference Laboratory (SRL)DrTVRao MD 43
Other WHO-Endorsed Tools
Liquid culture (eg MGIT BacTALERT)
Capilia TB Rapid strip test that detects a TB-
specific antigen from culture
Molecular line probe assays (eg GenoType MTBDRplus INNO-LiPA RifTB) Strip test for detection of TB and
drug-resistance conferring mutations
DrTVRao MD 44
BacTALERTreg
DrTVRao MD 45
CDC Updates Guidelines for Nucleic AcidAmplification Techniques to Diagnose
Tuberculosis
NAAT results should be interpreted in conjunction with the AFB smear results
NAAT and smear positive start Rx despite pending culture results PPV 95
Smear negative NAAT positive use clinical judgment to either treat or await culture
DrTVRao MD 46
Selection from automated systems for molecular and
bacteriological rapid diagnostics
PCRRocheCOBASreg Amplicorreg
amplification kitsRocheCOBASreg LightCyclerreg
(real-time-PCR)RocheCOBASreg TaqMan 48reg(increases the specificity of real-
time-PCR)
DrTVRao MD 47
Molecular Fingerprinting
26 of 30 (87) XDR TB isolates found to be genetically similar
Majority of patients had no previous history of TB treatment Suggestive of recent infection with drug-resistant strain
DrTVRao MD 48
Is PCR methods a solution
PCR cant yet replace neither microscopy culturing and competent clinical examination
DrTVRao MD 49
No testing method replaces Clinical assessment
DrTVRao MD 50
XDR-TBThe description
of XDR-TB was first used earlier in 2006 following a joint survey by WHO and the US Centres for Disease Control and Prevention (CDC) DrTVRao MD 51
How x-MDR generated
Acquired resistance is that which occurs as a result of specific previous treatment The level of primary resistance in the community is considered to reflect the efficacy of control measures in the past while the level of acquired resistance is a measure of on-going TB control measuresDrTVRao MD 52
Extreme Drug resistant Tuberculosis (XDR-TB)
Resistant to all first line drugs namely Isoniazid and Rifampin and Three or more second line drugs (SLDrsquoS) that are used to treat MDR-TB Thequinalones like Ofloaxin
Or Aminoglycosides like Capreomycin amp
Kanamycin
No third-line drugs available to treat XDR-TB since none has been developed in the last 40 years
DrTVRao MD 53
Background Extensively drug-resistant tuberculosis
Extensively drug-resistant tuberculosis has been reported in 45 countries including countries with limited resources and a high burden of tuberculosis
DrTVRao MD 54
DrTVRao MD 55
Transmissionof X -MDR
Like other forms of TB XDR-TB is spread through the air When a person with infectious TB coughs sneezes talks or spits they propel Mycobacterium into the air
DrTVRao MD 56
Best options to diagnoseX-MDR tuberculosis
To evaluate drug susceptibility the bacteria need to be cultivated and tested in a suitable laboratory Final diagnosis in this way for TB and especially for XDR-TB may take from 6 to 16 weeks To reduce the time needed for diagnosis new tools for rapid TB diagnosis are urgently needed
DrTVRao MD 57
When to suspect MDR TB
Patients not showing any reduction
in bacillary population after 3-
months of regular treatment with
Cat II regimen
Sputum positive patients who are
contacts of a known MDR TB
patient
DrTVRao MD 58
How to evaluate MDR TB
MDR TB is only a laboratory
proved HR resistance
Clinical suspicion should be
followed by lab Confirmation
Laboratories should be quality
controlledTRC
DrTVRao MD 59
Extreme Drug resistant Tuberculosis (XDR-TB) and AIDS
It can also be contracted without a patient receiving any previous treatment for TB
Mostly associated with HIV positive patients
HIV has the potential to fast tracking XDR-TB into an uncontrollable epidemic
Average survival period for patients infected with XDR-TB is 16 days
DrTVRao MD 60
Responding to MDRXDR-TB
Augment DOTS Program by
New diagnostics
New drugs New vaccines HIV incidence
reduction Advocacy1
A mathematical model projected by Basu and co-workers indicates that half of XDR-TB can be averted by 2012 by bringing synergistic effects through
Use of masks Reduced time as in-patient Improved ventilation Rapid resistance testing HIV treatment TB isolation facilities2
1Marteens and Wilkinson Lancet 20073702030-432Basu et al Quoted in Porco and Getz Lancet 20073701464-5
DrTVRao MD 61
Second Line Drug Treatment (SLDrsquos)
Less effective more costly and more toxic 50 cure rate
Four months intensive phase (5 drugs) Kanamycins Ethionamide Pyrazinamide Ofloxacin Cycloserine or Ethambutol DrTVRao MD 62
World Health Organisation (WHO) Guidelines for treatment
of MDR-TB
Strengthen basic TB care to prevent the emergence of drug-resistance
Ensure prompt diagnosis and treatment of drug resistant cases to cure existing cases and prevent further transmission
Increase collaboration between HIV and TB control programmes to provide necessary prevention and care to co-infected patients
Increase investment in laboratory infrastructures to enable better detection and management of resistant cases
DrTVRao MD 63
Treatment Guidelines
Sensitivity testing for all smear positive specimens
Patient Family and staff counselling amp education
Correct and thorough hand washing protocol and procedure
Personal protection is very important
DrTVRao MD 64
THE NEW MDR-TB Guidelines
A flexible framework approach combining both clinical and programmatic aspects of DOTS Plus based on essential programme conditions
But encouraging programs to tailor their case-finding and treatment strategies to the local epidemiological and Programme situation
Reflect GLC expert consensus and evidence and experience from GLC projects thus far
DrTVRao MD 65
Effective laboratory Diagnosis
Sputum smear examinations ndash rapid classification of species (atypical mycobacteria common in AIDS)
Culture examinations
Rapid drug sensitivity testingDrTVRao MD 66
MDR TB and HIV
MDR TB occurs with the same frequency in HIV
patients as in TB patients who are smear negative
Transmission of drug-resistant strains among HIV-
infected patients in congregate settings occurs
leading to lsquooutbreaksrsquo of MDR TB in such settings
Infection control measures absolutely essential in
settings where large number of HIV TB patients stay
togetherDrTVRao MD 67
Transmission is dependent on closeness and time of contact
In penitentiary care contacts are very close and prolonged ndash culture positive cases can also transmit TB especially to HIV positive population
DrTVRao MD 68
To Know more on MDR ndashTB Current Guidelines of WHO
Guidelines for the programmatic management of drug-resistant tuberculosis - 2011 update [pdf 904kb]
Visit helliphelliphellip WHOHTMTB20116DrTVRao MD 69
Are there any solutions for effective
Diagnosis in TB
DrTVRao MD 70
Programme Created by DrTVRao MD for Medical and Health Care
Workers in the Developing World Email
doctortvraogmailcom
DrTVRao MD 71
MDR-TB rates higher than ever (up to 223) particularly in former Soviet Union countries
DrTVRao MD 31
Alarming Rise of Resistant TB
Resistant TB burden in countries of former Soviet Union about 50 of cases resistant to at least one drug about 20 MDR XDR-TB proportions also higher (as high as 24 in
Estonia)1
MDRXDR TB ndash essentially a man-made problem2
High numbers of resistant cases (gt400000 MDR-TB cases every year) due mainly to Underinvestment in basic TB control Poor management of anti-TB drugs Transmission of drug resistant strains1
1Anti-TB Drug Resistance in the World Report No 4 The WHOIUATLD Global Project on Anti-Tuberculosis Drug Resistance Surveillance 2002-2007 World Health Organization 2008 (WHOHTMTB2008394)
2Reichman The Lancet 20083711052-3
DrTVRao MD 32
The Much Discussed Article on XDR TB in the Lancet
Of the 221 multi-drug resistant (MDR-TB) cases 53 (24) were XDR
Almost all (52 of 53) of the XDR-TB patients died with a median survival of only 16 days from the time of diagnosis (in the 42 patients with confirmed dates of death)
All the 44 XDR TB patients who were tested for HIV were found co-infected
55 patents had never received anti-TB drugs suggesting primary transmission of XDR pathogen
67 patients had been admitted to the hospital in the preceding 2 years suggesting potential role of nosocomial transmission
Gandhi et al Lancet 20063681575-80DrTVRao MD 33
Poor mangement of infected lead to grwoing resistance
Resistance to anti-TB drugs in populations is a phenomenon that occurs primarily due to poorly managed TB care Problems include incorrect drug prescribing practices by providers poor quality drugs or erratic supply of drugs and also patient non-adherence DrTVRao MD 34
Susceptibility Testing
1048708 Direct and indirect testing1048708 Primary Drugs testing1048708 Isoniazid1048708 Rifampicin1048708 Ethambutol ()1048708 Pyrizinamide ()
DrTVRao MD 35
Drug susceptibility testing (DST)
DST is recommended for all new cases for all first line drugs with specimens taken before initiating treatment
Accuracy is more important than speed DST results should come from a small
number of well-equipped experienced laboratories who participate and perform well in an international DST quality control scheme
The WHO Supranational Laboratory Quality Control Network offers the greatest global coverage for this
DrTVRao MD 36
Drug susceptibility Testing
Assessment of growth inhibition on solid media containing various dilutions of the drug in comparison with the test strains
As the method depend observation of growth Results are not available until several weeks after isolation of the organism
DrTVRao MD 37
Other accredited Methods
Radiometric and Non radiometric methods
Nucleic acid technology ndash effective upto 95 in mutations to rifampicin resistance to gene rpoB gene
DrTVRao MD 38
Drug susceptibility testing (DST)
As a minimum laboratories supplying DST data should correctly identify resistance to isoniazid and rifampicin in over 90 of quality control samples in two out of the last three quality control roundsDrTVRao MD 39
Detection of Rifampicin Drug susceptibility testing (DST) is more important
Early identification of mycobacterial growth as M tuberculosis complex and the identification of rifampicin resistance should be the first priority as rifampicin resistance invalidates standard 6 month short-course chemotherapy and is a useful marker in most countries for MDR-TB
Laboratories should aim to identify isolates as M tuberculosis complex and perform rifampicin resistance in 90 of isolates within 1-2 working days This is technologically feasible
DrTVRao MD 40
Drug susceptibility testing
For DST laboratories modern molecular techniques permit the successful identification of isoniazid resistance in at least 75 of mycobacterial cultures within 1-2 working days and are useful preliminary screens for isoniazid resistance
DrTVRao MD 41
Secondary Drugs testing [lack of standardized
methods]
Ofloxacin quinolonesEthionamide KanamycinCapreomycin Ensure quality control and
quality assurance
DrTVRao MD 42
WHO Controls the Tuberculosis related work
The laboratory methods for anti-tuberculosis drug susceptibility testing should be selected from among those that are WHO-recommended and all laboratory processes should be quality-assured in cooperation with a partner Supranational Reference Laboratory (SRL)DrTVRao MD 43
Other WHO-Endorsed Tools
Liquid culture (eg MGIT BacTALERT)
Capilia TB Rapid strip test that detects a TB-
specific antigen from culture
Molecular line probe assays (eg GenoType MTBDRplus INNO-LiPA RifTB) Strip test for detection of TB and
drug-resistance conferring mutations
DrTVRao MD 44
BacTALERTreg
DrTVRao MD 45
CDC Updates Guidelines for Nucleic AcidAmplification Techniques to Diagnose
Tuberculosis
NAAT results should be interpreted in conjunction with the AFB smear results
NAAT and smear positive start Rx despite pending culture results PPV 95
Smear negative NAAT positive use clinical judgment to either treat or await culture
DrTVRao MD 46
Selection from automated systems for molecular and
bacteriological rapid diagnostics
PCRRocheCOBASreg Amplicorreg
amplification kitsRocheCOBASreg LightCyclerreg
(real-time-PCR)RocheCOBASreg TaqMan 48reg(increases the specificity of real-
time-PCR)
DrTVRao MD 47
Molecular Fingerprinting
26 of 30 (87) XDR TB isolates found to be genetically similar
Majority of patients had no previous history of TB treatment Suggestive of recent infection with drug-resistant strain
DrTVRao MD 48
Is PCR methods a solution
PCR cant yet replace neither microscopy culturing and competent clinical examination
DrTVRao MD 49
No testing method replaces Clinical assessment
DrTVRao MD 50
XDR-TBThe description
of XDR-TB was first used earlier in 2006 following a joint survey by WHO and the US Centres for Disease Control and Prevention (CDC) DrTVRao MD 51
How x-MDR generated
Acquired resistance is that which occurs as a result of specific previous treatment The level of primary resistance in the community is considered to reflect the efficacy of control measures in the past while the level of acquired resistance is a measure of on-going TB control measuresDrTVRao MD 52
Extreme Drug resistant Tuberculosis (XDR-TB)
Resistant to all first line drugs namely Isoniazid and Rifampin and Three or more second line drugs (SLDrsquoS) that are used to treat MDR-TB Thequinalones like Ofloaxin
Or Aminoglycosides like Capreomycin amp
Kanamycin
No third-line drugs available to treat XDR-TB since none has been developed in the last 40 years
DrTVRao MD 53
Background Extensively drug-resistant tuberculosis
Extensively drug-resistant tuberculosis has been reported in 45 countries including countries with limited resources and a high burden of tuberculosis
DrTVRao MD 54
DrTVRao MD 55
Transmissionof X -MDR
Like other forms of TB XDR-TB is spread through the air When a person with infectious TB coughs sneezes talks or spits they propel Mycobacterium into the air
DrTVRao MD 56
Best options to diagnoseX-MDR tuberculosis
To evaluate drug susceptibility the bacteria need to be cultivated and tested in a suitable laboratory Final diagnosis in this way for TB and especially for XDR-TB may take from 6 to 16 weeks To reduce the time needed for diagnosis new tools for rapid TB diagnosis are urgently needed
DrTVRao MD 57
When to suspect MDR TB
Patients not showing any reduction
in bacillary population after 3-
months of regular treatment with
Cat II regimen
Sputum positive patients who are
contacts of a known MDR TB
patient
DrTVRao MD 58
How to evaluate MDR TB
MDR TB is only a laboratory
proved HR resistance
Clinical suspicion should be
followed by lab Confirmation
Laboratories should be quality
controlledTRC
DrTVRao MD 59
Extreme Drug resistant Tuberculosis (XDR-TB) and AIDS
It can also be contracted without a patient receiving any previous treatment for TB
Mostly associated with HIV positive patients
HIV has the potential to fast tracking XDR-TB into an uncontrollable epidemic
Average survival period for patients infected with XDR-TB is 16 days
DrTVRao MD 60
Responding to MDRXDR-TB
Augment DOTS Program by
New diagnostics
New drugs New vaccines HIV incidence
reduction Advocacy1
A mathematical model projected by Basu and co-workers indicates that half of XDR-TB can be averted by 2012 by bringing synergistic effects through
Use of masks Reduced time as in-patient Improved ventilation Rapid resistance testing HIV treatment TB isolation facilities2
1Marteens and Wilkinson Lancet 20073702030-432Basu et al Quoted in Porco and Getz Lancet 20073701464-5
DrTVRao MD 61
Second Line Drug Treatment (SLDrsquos)
Less effective more costly and more toxic 50 cure rate
Four months intensive phase (5 drugs) Kanamycins Ethionamide Pyrazinamide Ofloxacin Cycloserine or Ethambutol DrTVRao MD 62
World Health Organisation (WHO) Guidelines for treatment
of MDR-TB
Strengthen basic TB care to prevent the emergence of drug-resistance
Ensure prompt diagnosis and treatment of drug resistant cases to cure existing cases and prevent further transmission
Increase collaboration between HIV and TB control programmes to provide necessary prevention and care to co-infected patients
Increase investment in laboratory infrastructures to enable better detection and management of resistant cases
DrTVRao MD 63
Treatment Guidelines
Sensitivity testing for all smear positive specimens
Patient Family and staff counselling amp education
Correct and thorough hand washing protocol and procedure
Personal protection is very important
DrTVRao MD 64
THE NEW MDR-TB Guidelines
A flexible framework approach combining both clinical and programmatic aspects of DOTS Plus based on essential programme conditions
But encouraging programs to tailor their case-finding and treatment strategies to the local epidemiological and Programme situation
Reflect GLC expert consensus and evidence and experience from GLC projects thus far
DrTVRao MD 65
Effective laboratory Diagnosis
Sputum smear examinations ndash rapid classification of species (atypical mycobacteria common in AIDS)
Culture examinations
Rapid drug sensitivity testingDrTVRao MD 66
MDR TB and HIV
MDR TB occurs with the same frequency in HIV
patients as in TB patients who are smear negative
Transmission of drug-resistant strains among HIV-
infected patients in congregate settings occurs
leading to lsquooutbreaksrsquo of MDR TB in such settings
Infection control measures absolutely essential in
settings where large number of HIV TB patients stay
togetherDrTVRao MD 67
Transmission is dependent on closeness and time of contact
In penitentiary care contacts are very close and prolonged ndash culture positive cases can also transmit TB especially to HIV positive population
DrTVRao MD 68
To Know more on MDR ndashTB Current Guidelines of WHO
Guidelines for the programmatic management of drug-resistant tuberculosis - 2011 update [pdf 904kb]
Visit helliphelliphellip WHOHTMTB20116DrTVRao MD 69
Are there any solutions for effective
Diagnosis in TB
DrTVRao MD 70
Programme Created by DrTVRao MD for Medical and Health Care
Workers in the Developing World Email
doctortvraogmailcom
DrTVRao MD 71
Alarming Rise of Resistant TB
Resistant TB burden in countries of former Soviet Union about 50 of cases resistant to at least one drug about 20 MDR XDR-TB proportions also higher (as high as 24 in
Estonia)1
MDRXDR TB ndash essentially a man-made problem2
High numbers of resistant cases (gt400000 MDR-TB cases every year) due mainly to Underinvestment in basic TB control Poor management of anti-TB drugs Transmission of drug resistant strains1
1Anti-TB Drug Resistance in the World Report No 4 The WHOIUATLD Global Project on Anti-Tuberculosis Drug Resistance Surveillance 2002-2007 World Health Organization 2008 (WHOHTMTB2008394)
2Reichman The Lancet 20083711052-3
DrTVRao MD 32
The Much Discussed Article on XDR TB in the Lancet
Of the 221 multi-drug resistant (MDR-TB) cases 53 (24) were XDR
Almost all (52 of 53) of the XDR-TB patients died with a median survival of only 16 days from the time of diagnosis (in the 42 patients with confirmed dates of death)
All the 44 XDR TB patients who were tested for HIV were found co-infected
55 patents had never received anti-TB drugs suggesting primary transmission of XDR pathogen
67 patients had been admitted to the hospital in the preceding 2 years suggesting potential role of nosocomial transmission
Gandhi et al Lancet 20063681575-80DrTVRao MD 33
Poor mangement of infected lead to grwoing resistance
Resistance to anti-TB drugs in populations is a phenomenon that occurs primarily due to poorly managed TB care Problems include incorrect drug prescribing practices by providers poor quality drugs or erratic supply of drugs and also patient non-adherence DrTVRao MD 34
Susceptibility Testing
1048708 Direct and indirect testing1048708 Primary Drugs testing1048708 Isoniazid1048708 Rifampicin1048708 Ethambutol ()1048708 Pyrizinamide ()
DrTVRao MD 35
Drug susceptibility testing (DST)
DST is recommended for all new cases for all first line drugs with specimens taken before initiating treatment
Accuracy is more important than speed DST results should come from a small
number of well-equipped experienced laboratories who participate and perform well in an international DST quality control scheme
The WHO Supranational Laboratory Quality Control Network offers the greatest global coverage for this
DrTVRao MD 36
Drug susceptibility Testing
Assessment of growth inhibition on solid media containing various dilutions of the drug in comparison with the test strains
As the method depend observation of growth Results are not available until several weeks after isolation of the organism
DrTVRao MD 37
Other accredited Methods
Radiometric and Non radiometric methods
Nucleic acid technology ndash effective upto 95 in mutations to rifampicin resistance to gene rpoB gene
DrTVRao MD 38
Drug susceptibility testing (DST)
As a minimum laboratories supplying DST data should correctly identify resistance to isoniazid and rifampicin in over 90 of quality control samples in two out of the last three quality control roundsDrTVRao MD 39
Detection of Rifampicin Drug susceptibility testing (DST) is more important
Early identification of mycobacterial growth as M tuberculosis complex and the identification of rifampicin resistance should be the first priority as rifampicin resistance invalidates standard 6 month short-course chemotherapy and is a useful marker in most countries for MDR-TB
Laboratories should aim to identify isolates as M tuberculosis complex and perform rifampicin resistance in 90 of isolates within 1-2 working days This is technologically feasible
DrTVRao MD 40
Drug susceptibility testing
For DST laboratories modern molecular techniques permit the successful identification of isoniazid resistance in at least 75 of mycobacterial cultures within 1-2 working days and are useful preliminary screens for isoniazid resistance
DrTVRao MD 41
Secondary Drugs testing [lack of standardized
methods]
Ofloxacin quinolonesEthionamide KanamycinCapreomycin Ensure quality control and
quality assurance
DrTVRao MD 42
WHO Controls the Tuberculosis related work
The laboratory methods for anti-tuberculosis drug susceptibility testing should be selected from among those that are WHO-recommended and all laboratory processes should be quality-assured in cooperation with a partner Supranational Reference Laboratory (SRL)DrTVRao MD 43
Other WHO-Endorsed Tools
Liquid culture (eg MGIT BacTALERT)
Capilia TB Rapid strip test that detects a TB-
specific antigen from culture
Molecular line probe assays (eg GenoType MTBDRplus INNO-LiPA RifTB) Strip test for detection of TB and
drug-resistance conferring mutations
DrTVRao MD 44
BacTALERTreg
DrTVRao MD 45
CDC Updates Guidelines for Nucleic AcidAmplification Techniques to Diagnose
Tuberculosis
NAAT results should be interpreted in conjunction with the AFB smear results
NAAT and smear positive start Rx despite pending culture results PPV 95
Smear negative NAAT positive use clinical judgment to either treat or await culture
DrTVRao MD 46
Selection from automated systems for molecular and
bacteriological rapid diagnostics
PCRRocheCOBASreg Amplicorreg
amplification kitsRocheCOBASreg LightCyclerreg
(real-time-PCR)RocheCOBASreg TaqMan 48reg(increases the specificity of real-
time-PCR)
DrTVRao MD 47
Molecular Fingerprinting
26 of 30 (87) XDR TB isolates found to be genetically similar
Majority of patients had no previous history of TB treatment Suggestive of recent infection with drug-resistant strain
DrTVRao MD 48
Is PCR methods a solution
PCR cant yet replace neither microscopy culturing and competent clinical examination
DrTVRao MD 49
No testing method replaces Clinical assessment
DrTVRao MD 50
XDR-TBThe description
of XDR-TB was first used earlier in 2006 following a joint survey by WHO and the US Centres for Disease Control and Prevention (CDC) DrTVRao MD 51
How x-MDR generated
Acquired resistance is that which occurs as a result of specific previous treatment The level of primary resistance in the community is considered to reflect the efficacy of control measures in the past while the level of acquired resistance is a measure of on-going TB control measuresDrTVRao MD 52
Extreme Drug resistant Tuberculosis (XDR-TB)
Resistant to all first line drugs namely Isoniazid and Rifampin and Three or more second line drugs (SLDrsquoS) that are used to treat MDR-TB Thequinalones like Ofloaxin
Or Aminoglycosides like Capreomycin amp
Kanamycin
No third-line drugs available to treat XDR-TB since none has been developed in the last 40 years
DrTVRao MD 53
Background Extensively drug-resistant tuberculosis
Extensively drug-resistant tuberculosis has been reported in 45 countries including countries with limited resources and a high burden of tuberculosis
DrTVRao MD 54
DrTVRao MD 55
Transmissionof X -MDR
Like other forms of TB XDR-TB is spread through the air When a person with infectious TB coughs sneezes talks or spits they propel Mycobacterium into the air
DrTVRao MD 56
Best options to diagnoseX-MDR tuberculosis
To evaluate drug susceptibility the bacteria need to be cultivated and tested in a suitable laboratory Final diagnosis in this way for TB and especially for XDR-TB may take from 6 to 16 weeks To reduce the time needed for diagnosis new tools for rapid TB diagnosis are urgently needed
DrTVRao MD 57
When to suspect MDR TB
Patients not showing any reduction
in bacillary population after 3-
months of regular treatment with
Cat II regimen
Sputum positive patients who are
contacts of a known MDR TB
patient
DrTVRao MD 58
How to evaluate MDR TB
MDR TB is only a laboratory
proved HR resistance
Clinical suspicion should be
followed by lab Confirmation
Laboratories should be quality
controlledTRC
DrTVRao MD 59
Extreme Drug resistant Tuberculosis (XDR-TB) and AIDS
It can also be contracted without a patient receiving any previous treatment for TB
Mostly associated with HIV positive patients
HIV has the potential to fast tracking XDR-TB into an uncontrollable epidemic
Average survival period for patients infected with XDR-TB is 16 days
DrTVRao MD 60
Responding to MDRXDR-TB
Augment DOTS Program by
New diagnostics
New drugs New vaccines HIV incidence
reduction Advocacy1
A mathematical model projected by Basu and co-workers indicates that half of XDR-TB can be averted by 2012 by bringing synergistic effects through
Use of masks Reduced time as in-patient Improved ventilation Rapid resistance testing HIV treatment TB isolation facilities2
1Marteens and Wilkinson Lancet 20073702030-432Basu et al Quoted in Porco and Getz Lancet 20073701464-5
DrTVRao MD 61
Second Line Drug Treatment (SLDrsquos)
Less effective more costly and more toxic 50 cure rate
Four months intensive phase (5 drugs) Kanamycins Ethionamide Pyrazinamide Ofloxacin Cycloserine or Ethambutol DrTVRao MD 62
World Health Organisation (WHO) Guidelines for treatment
of MDR-TB
Strengthen basic TB care to prevent the emergence of drug-resistance
Ensure prompt diagnosis and treatment of drug resistant cases to cure existing cases and prevent further transmission
Increase collaboration between HIV and TB control programmes to provide necessary prevention and care to co-infected patients
Increase investment in laboratory infrastructures to enable better detection and management of resistant cases
DrTVRao MD 63
Treatment Guidelines
Sensitivity testing for all smear positive specimens
Patient Family and staff counselling amp education
Correct and thorough hand washing protocol and procedure
Personal protection is very important
DrTVRao MD 64
THE NEW MDR-TB Guidelines
A flexible framework approach combining both clinical and programmatic aspects of DOTS Plus based on essential programme conditions
But encouraging programs to tailor their case-finding and treatment strategies to the local epidemiological and Programme situation
Reflect GLC expert consensus and evidence and experience from GLC projects thus far
DrTVRao MD 65
Effective laboratory Diagnosis
Sputum smear examinations ndash rapid classification of species (atypical mycobacteria common in AIDS)
Culture examinations
Rapid drug sensitivity testingDrTVRao MD 66
MDR TB and HIV
MDR TB occurs with the same frequency in HIV
patients as in TB patients who are smear negative
Transmission of drug-resistant strains among HIV-
infected patients in congregate settings occurs
leading to lsquooutbreaksrsquo of MDR TB in such settings
Infection control measures absolutely essential in
settings where large number of HIV TB patients stay
togetherDrTVRao MD 67
Transmission is dependent on closeness and time of contact
In penitentiary care contacts are very close and prolonged ndash culture positive cases can also transmit TB especially to HIV positive population
DrTVRao MD 68
To Know more on MDR ndashTB Current Guidelines of WHO
Guidelines for the programmatic management of drug-resistant tuberculosis - 2011 update [pdf 904kb]
Visit helliphelliphellip WHOHTMTB20116DrTVRao MD 69
Are there any solutions for effective
Diagnosis in TB
DrTVRao MD 70
Programme Created by DrTVRao MD for Medical and Health Care
Workers in the Developing World Email
doctortvraogmailcom
DrTVRao MD 71
The Much Discussed Article on XDR TB in the Lancet
Of the 221 multi-drug resistant (MDR-TB) cases 53 (24) were XDR
Almost all (52 of 53) of the XDR-TB patients died with a median survival of only 16 days from the time of diagnosis (in the 42 patients with confirmed dates of death)
All the 44 XDR TB patients who were tested for HIV were found co-infected
55 patents had never received anti-TB drugs suggesting primary transmission of XDR pathogen
67 patients had been admitted to the hospital in the preceding 2 years suggesting potential role of nosocomial transmission
Gandhi et al Lancet 20063681575-80DrTVRao MD 33
Poor mangement of infected lead to grwoing resistance
Resistance to anti-TB drugs in populations is a phenomenon that occurs primarily due to poorly managed TB care Problems include incorrect drug prescribing practices by providers poor quality drugs or erratic supply of drugs and also patient non-adherence DrTVRao MD 34
Susceptibility Testing
1048708 Direct and indirect testing1048708 Primary Drugs testing1048708 Isoniazid1048708 Rifampicin1048708 Ethambutol ()1048708 Pyrizinamide ()
DrTVRao MD 35
Drug susceptibility testing (DST)
DST is recommended for all new cases for all first line drugs with specimens taken before initiating treatment
Accuracy is more important than speed DST results should come from a small
number of well-equipped experienced laboratories who participate and perform well in an international DST quality control scheme
The WHO Supranational Laboratory Quality Control Network offers the greatest global coverage for this
DrTVRao MD 36
Drug susceptibility Testing
Assessment of growth inhibition on solid media containing various dilutions of the drug in comparison with the test strains
As the method depend observation of growth Results are not available until several weeks after isolation of the organism
DrTVRao MD 37
Other accredited Methods
Radiometric and Non radiometric methods
Nucleic acid technology ndash effective upto 95 in mutations to rifampicin resistance to gene rpoB gene
DrTVRao MD 38
Drug susceptibility testing (DST)
As a minimum laboratories supplying DST data should correctly identify resistance to isoniazid and rifampicin in over 90 of quality control samples in two out of the last three quality control roundsDrTVRao MD 39
Detection of Rifampicin Drug susceptibility testing (DST) is more important
Early identification of mycobacterial growth as M tuberculosis complex and the identification of rifampicin resistance should be the first priority as rifampicin resistance invalidates standard 6 month short-course chemotherapy and is a useful marker in most countries for MDR-TB
Laboratories should aim to identify isolates as M tuberculosis complex and perform rifampicin resistance in 90 of isolates within 1-2 working days This is technologically feasible
DrTVRao MD 40
Drug susceptibility testing
For DST laboratories modern molecular techniques permit the successful identification of isoniazid resistance in at least 75 of mycobacterial cultures within 1-2 working days and are useful preliminary screens for isoniazid resistance
DrTVRao MD 41
Secondary Drugs testing [lack of standardized
methods]
Ofloxacin quinolonesEthionamide KanamycinCapreomycin Ensure quality control and
quality assurance
DrTVRao MD 42
WHO Controls the Tuberculosis related work
The laboratory methods for anti-tuberculosis drug susceptibility testing should be selected from among those that are WHO-recommended and all laboratory processes should be quality-assured in cooperation with a partner Supranational Reference Laboratory (SRL)DrTVRao MD 43
Other WHO-Endorsed Tools
Liquid culture (eg MGIT BacTALERT)
Capilia TB Rapid strip test that detects a TB-
specific antigen from culture
Molecular line probe assays (eg GenoType MTBDRplus INNO-LiPA RifTB) Strip test for detection of TB and
drug-resistance conferring mutations
DrTVRao MD 44
BacTALERTreg
DrTVRao MD 45
CDC Updates Guidelines for Nucleic AcidAmplification Techniques to Diagnose
Tuberculosis
NAAT results should be interpreted in conjunction with the AFB smear results
NAAT and smear positive start Rx despite pending culture results PPV 95
Smear negative NAAT positive use clinical judgment to either treat or await culture
DrTVRao MD 46
Selection from automated systems for molecular and
bacteriological rapid diagnostics
PCRRocheCOBASreg Amplicorreg
amplification kitsRocheCOBASreg LightCyclerreg
(real-time-PCR)RocheCOBASreg TaqMan 48reg(increases the specificity of real-
time-PCR)
DrTVRao MD 47
Molecular Fingerprinting
26 of 30 (87) XDR TB isolates found to be genetically similar
Majority of patients had no previous history of TB treatment Suggestive of recent infection with drug-resistant strain
DrTVRao MD 48
Is PCR methods a solution
PCR cant yet replace neither microscopy culturing and competent clinical examination
DrTVRao MD 49
No testing method replaces Clinical assessment
DrTVRao MD 50
XDR-TBThe description
of XDR-TB was first used earlier in 2006 following a joint survey by WHO and the US Centres for Disease Control and Prevention (CDC) DrTVRao MD 51
How x-MDR generated
Acquired resistance is that which occurs as a result of specific previous treatment The level of primary resistance in the community is considered to reflect the efficacy of control measures in the past while the level of acquired resistance is a measure of on-going TB control measuresDrTVRao MD 52
Extreme Drug resistant Tuberculosis (XDR-TB)
Resistant to all first line drugs namely Isoniazid and Rifampin and Three or more second line drugs (SLDrsquoS) that are used to treat MDR-TB Thequinalones like Ofloaxin
Or Aminoglycosides like Capreomycin amp
Kanamycin
No third-line drugs available to treat XDR-TB since none has been developed in the last 40 years
DrTVRao MD 53
Background Extensively drug-resistant tuberculosis
Extensively drug-resistant tuberculosis has been reported in 45 countries including countries with limited resources and a high burden of tuberculosis
DrTVRao MD 54
DrTVRao MD 55
Transmissionof X -MDR
Like other forms of TB XDR-TB is spread through the air When a person with infectious TB coughs sneezes talks or spits they propel Mycobacterium into the air
DrTVRao MD 56
Best options to diagnoseX-MDR tuberculosis
To evaluate drug susceptibility the bacteria need to be cultivated and tested in a suitable laboratory Final diagnosis in this way for TB and especially for XDR-TB may take from 6 to 16 weeks To reduce the time needed for diagnosis new tools for rapid TB diagnosis are urgently needed
DrTVRao MD 57
When to suspect MDR TB
Patients not showing any reduction
in bacillary population after 3-
months of regular treatment with
Cat II regimen
Sputum positive patients who are
contacts of a known MDR TB
patient
DrTVRao MD 58
How to evaluate MDR TB
MDR TB is only a laboratory
proved HR resistance
Clinical suspicion should be
followed by lab Confirmation
Laboratories should be quality
controlledTRC
DrTVRao MD 59
Extreme Drug resistant Tuberculosis (XDR-TB) and AIDS
It can also be contracted without a patient receiving any previous treatment for TB
Mostly associated with HIV positive patients
HIV has the potential to fast tracking XDR-TB into an uncontrollable epidemic
Average survival period for patients infected with XDR-TB is 16 days
DrTVRao MD 60
Responding to MDRXDR-TB
Augment DOTS Program by
New diagnostics
New drugs New vaccines HIV incidence
reduction Advocacy1
A mathematical model projected by Basu and co-workers indicates that half of XDR-TB can be averted by 2012 by bringing synergistic effects through
Use of masks Reduced time as in-patient Improved ventilation Rapid resistance testing HIV treatment TB isolation facilities2
1Marteens and Wilkinson Lancet 20073702030-432Basu et al Quoted in Porco and Getz Lancet 20073701464-5
DrTVRao MD 61
Second Line Drug Treatment (SLDrsquos)
Less effective more costly and more toxic 50 cure rate
Four months intensive phase (5 drugs) Kanamycins Ethionamide Pyrazinamide Ofloxacin Cycloserine or Ethambutol DrTVRao MD 62
World Health Organisation (WHO) Guidelines for treatment
of MDR-TB
Strengthen basic TB care to prevent the emergence of drug-resistance
Ensure prompt diagnosis and treatment of drug resistant cases to cure existing cases and prevent further transmission
Increase collaboration between HIV and TB control programmes to provide necessary prevention and care to co-infected patients
Increase investment in laboratory infrastructures to enable better detection and management of resistant cases
DrTVRao MD 63
Treatment Guidelines
Sensitivity testing for all smear positive specimens
Patient Family and staff counselling amp education
Correct and thorough hand washing protocol and procedure
Personal protection is very important
DrTVRao MD 64
THE NEW MDR-TB Guidelines
A flexible framework approach combining both clinical and programmatic aspects of DOTS Plus based on essential programme conditions
But encouraging programs to tailor their case-finding and treatment strategies to the local epidemiological and Programme situation
Reflect GLC expert consensus and evidence and experience from GLC projects thus far
DrTVRao MD 65
Effective laboratory Diagnosis
Sputum smear examinations ndash rapid classification of species (atypical mycobacteria common in AIDS)
Culture examinations
Rapid drug sensitivity testingDrTVRao MD 66
MDR TB and HIV
MDR TB occurs with the same frequency in HIV
patients as in TB patients who are smear negative
Transmission of drug-resistant strains among HIV-
infected patients in congregate settings occurs
leading to lsquooutbreaksrsquo of MDR TB in such settings
Infection control measures absolutely essential in
settings where large number of HIV TB patients stay
togetherDrTVRao MD 67
Transmission is dependent on closeness and time of contact
In penitentiary care contacts are very close and prolonged ndash culture positive cases can also transmit TB especially to HIV positive population
DrTVRao MD 68
To Know more on MDR ndashTB Current Guidelines of WHO
Guidelines for the programmatic management of drug-resistant tuberculosis - 2011 update [pdf 904kb]
Visit helliphelliphellip WHOHTMTB20116DrTVRao MD 69
Are there any solutions for effective
Diagnosis in TB
DrTVRao MD 70
Programme Created by DrTVRao MD for Medical and Health Care
Workers in the Developing World Email
doctortvraogmailcom
DrTVRao MD 71
Poor mangement of infected lead to grwoing resistance
Resistance to anti-TB drugs in populations is a phenomenon that occurs primarily due to poorly managed TB care Problems include incorrect drug prescribing practices by providers poor quality drugs or erratic supply of drugs and also patient non-adherence DrTVRao MD 34
Susceptibility Testing
1048708 Direct and indirect testing1048708 Primary Drugs testing1048708 Isoniazid1048708 Rifampicin1048708 Ethambutol ()1048708 Pyrizinamide ()
DrTVRao MD 35
Drug susceptibility testing (DST)
DST is recommended for all new cases for all first line drugs with specimens taken before initiating treatment
Accuracy is more important than speed DST results should come from a small
number of well-equipped experienced laboratories who participate and perform well in an international DST quality control scheme
The WHO Supranational Laboratory Quality Control Network offers the greatest global coverage for this
DrTVRao MD 36
Drug susceptibility Testing
Assessment of growth inhibition on solid media containing various dilutions of the drug in comparison with the test strains
As the method depend observation of growth Results are not available until several weeks after isolation of the organism
DrTVRao MD 37
Other accredited Methods
Radiometric and Non radiometric methods
Nucleic acid technology ndash effective upto 95 in mutations to rifampicin resistance to gene rpoB gene
DrTVRao MD 38
Drug susceptibility testing (DST)
As a minimum laboratories supplying DST data should correctly identify resistance to isoniazid and rifampicin in over 90 of quality control samples in two out of the last three quality control roundsDrTVRao MD 39
Detection of Rifampicin Drug susceptibility testing (DST) is more important
Early identification of mycobacterial growth as M tuberculosis complex and the identification of rifampicin resistance should be the first priority as rifampicin resistance invalidates standard 6 month short-course chemotherapy and is a useful marker in most countries for MDR-TB
Laboratories should aim to identify isolates as M tuberculosis complex and perform rifampicin resistance in 90 of isolates within 1-2 working days This is technologically feasible
DrTVRao MD 40
Drug susceptibility testing
For DST laboratories modern molecular techniques permit the successful identification of isoniazid resistance in at least 75 of mycobacterial cultures within 1-2 working days and are useful preliminary screens for isoniazid resistance
DrTVRao MD 41
Secondary Drugs testing [lack of standardized
methods]
Ofloxacin quinolonesEthionamide KanamycinCapreomycin Ensure quality control and
quality assurance
DrTVRao MD 42
WHO Controls the Tuberculosis related work
The laboratory methods for anti-tuberculosis drug susceptibility testing should be selected from among those that are WHO-recommended and all laboratory processes should be quality-assured in cooperation with a partner Supranational Reference Laboratory (SRL)DrTVRao MD 43
Other WHO-Endorsed Tools
Liquid culture (eg MGIT BacTALERT)
Capilia TB Rapid strip test that detects a TB-
specific antigen from culture
Molecular line probe assays (eg GenoType MTBDRplus INNO-LiPA RifTB) Strip test for detection of TB and
drug-resistance conferring mutations
DrTVRao MD 44
BacTALERTreg
DrTVRao MD 45
CDC Updates Guidelines for Nucleic AcidAmplification Techniques to Diagnose
Tuberculosis
NAAT results should be interpreted in conjunction with the AFB smear results
NAAT and smear positive start Rx despite pending culture results PPV 95
Smear negative NAAT positive use clinical judgment to either treat or await culture
DrTVRao MD 46
Selection from automated systems for molecular and
bacteriological rapid diagnostics
PCRRocheCOBASreg Amplicorreg
amplification kitsRocheCOBASreg LightCyclerreg
(real-time-PCR)RocheCOBASreg TaqMan 48reg(increases the specificity of real-
time-PCR)
DrTVRao MD 47
Molecular Fingerprinting
26 of 30 (87) XDR TB isolates found to be genetically similar
Majority of patients had no previous history of TB treatment Suggestive of recent infection with drug-resistant strain
DrTVRao MD 48
Is PCR methods a solution
PCR cant yet replace neither microscopy culturing and competent clinical examination
DrTVRao MD 49
No testing method replaces Clinical assessment
DrTVRao MD 50
XDR-TBThe description
of XDR-TB was first used earlier in 2006 following a joint survey by WHO and the US Centres for Disease Control and Prevention (CDC) DrTVRao MD 51
How x-MDR generated
Acquired resistance is that which occurs as a result of specific previous treatment The level of primary resistance in the community is considered to reflect the efficacy of control measures in the past while the level of acquired resistance is a measure of on-going TB control measuresDrTVRao MD 52
Extreme Drug resistant Tuberculosis (XDR-TB)
Resistant to all first line drugs namely Isoniazid and Rifampin and Three or more second line drugs (SLDrsquoS) that are used to treat MDR-TB Thequinalones like Ofloaxin
Or Aminoglycosides like Capreomycin amp
Kanamycin
No third-line drugs available to treat XDR-TB since none has been developed in the last 40 years
DrTVRao MD 53
Background Extensively drug-resistant tuberculosis
Extensively drug-resistant tuberculosis has been reported in 45 countries including countries with limited resources and a high burden of tuberculosis
DrTVRao MD 54
DrTVRao MD 55
Transmissionof X -MDR
Like other forms of TB XDR-TB is spread through the air When a person with infectious TB coughs sneezes talks or spits they propel Mycobacterium into the air
DrTVRao MD 56
Best options to diagnoseX-MDR tuberculosis
To evaluate drug susceptibility the bacteria need to be cultivated and tested in a suitable laboratory Final diagnosis in this way for TB and especially for XDR-TB may take from 6 to 16 weeks To reduce the time needed for diagnosis new tools for rapid TB diagnosis are urgently needed
DrTVRao MD 57
When to suspect MDR TB
Patients not showing any reduction
in bacillary population after 3-
months of regular treatment with
Cat II regimen
Sputum positive patients who are
contacts of a known MDR TB
patient
DrTVRao MD 58
How to evaluate MDR TB
MDR TB is only a laboratory
proved HR resistance
Clinical suspicion should be
followed by lab Confirmation
Laboratories should be quality
controlledTRC
DrTVRao MD 59
Extreme Drug resistant Tuberculosis (XDR-TB) and AIDS
It can also be contracted without a patient receiving any previous treatment for TB
Mostly associated with HIV positive patients
HIV has the potential to fast tracking XDR-TB into an uncontrollable epidemic
Average survival period for patients infected with XDR-TB is 16 days
DrTVRao MD 60
Responding to MDRXDR-TB
Augment DOTS Program by
New diagnostics
New drugs New vaccines HIV incidence
reduction Advocacy1
A mathematical model projected by Basu and co-workers indicates that half of XDR-TB can be averted by 2012 by bringing synergistic effects through
Use of masks Reduced time as in-patient Improved ventilation Rapid resistance testing HIV treatment TB isolation facilities2
1Marteens and Wilkinson Lancet 20073702030-432Basu et al Quoted in Porco and Getz Lancet 20073701464-5
DrTVRao MD 61
Second Line Drug Treatment (SLDrsquos)
Less effective more costly and more toxic 50 cure rate
Four months intensive phase (5 drugs) Kanamycins Ethionamide Pyrazinamide Ofloxacin Cycloserine or Ethambutol DrTVRao MD 62
World Health Organisation (WHO) Guidelines for treatment
of MDR-TB
Strengthen basic TB care to prevent the emergence of drug-resistance
Ensure prompt diagnosis and treatment of drug resistant cases to cure existing cases and prevent further transmission
Increase collaboration between HIV and TB control programmes to provide necessary prevention and care to co-infected patients
Increase investment in laboratory infrastructures to enable better detection and management of resistant cases
DrTVRao MD 63
Treatment Guidelines
Sensitivity testing for all smear positive specimens
Patient Family and staff counselling amp education
Correct and thorough hand washing protocol and procedure
Personal protection is very important
DrTVRao MD 64
THE NEW MDR-TB Guidelines
A flexible framework approach combining both clinical and programmatic aspects of DOTS Plus based on essential programme conditions
But encouraging programs to tailor their case-finding and treatment strategies to the local epidemiological and Programme situation
Reflect GLC expert consensus and evidence and experience from GLC projects thus far
DrTVRao MD 65
Effective laboratory Diagnosis
Sputum smear examinations ndash rapid classification of species (atypical mycobacteria common in AIDS)
Culture examinations
Rapid drug sensitivity testingDrTVRao MD 66
MDR TB and HIV
MDR TB occurs with the same frequency in HIV
patients as in TB patients who are smear negative
Transmission of drug-resistant strains among HIV-
infected patients in congregate settings occurs
leading to lsquooutbreaksrsquo of MDR TB in such settings
Infection control measures absolutely essential in
settings where large number of HIV TB patients stay
togetherDrTVRao MD 67
Transmission is dependent on closeness and time of contact
In penitentiary care contacts are very close and prolonged ndash culture positive cases can also transmit TB especially to HIV positive population
DrTVRao MD 68
To Know more on MDR ndashTB Current Guidelines of WHO
Guidelines for the programmatic management of drug-resistant tuberculosis - 2011 update [pdf 904kb]
Visit helliphelliphellip WHOHTMTB20116DrTVRao MD 69
Are there any solutions for effective
Diagnosis in TB
DrTVRao MD 70
Programme Created by DrTVRao MD for Medical and Health Care
Workers in the Developing World Email
doctortvraogmailcom
DrTVRao MD 71
Susceptibility Testing
1048708 Direct and indirect testing1048708 Primary Drugs testing1048708 Isoniazid1048708 Rifampicin1048708 Ethambutol ()1048708 Pyrizinamide ()
DrTVRao MD 35
Drug susceptibility testing (DST)
DST is recommended for all new cases for all first line drugs with specimens taken before initiating treatment
Accuracy is more important than speed DST results should come from a small
number of well-equipped experienced laboratories who participate and perform well in an international DST quality control scheme
The WHO Supranational Laboratory Quality Control Network offers the greatest global coverage for this
DrTVRao MD 36
Drug susceptibility Testing
Assessment of growth inhibition on solid media containing various dilutions of the drug in comparison with the test strains
As the method depend observation of growth Results are not available until several weeks after isolation of the organism
DrTVRao MD 37
Other accredited Methods
Radiometric and Non radiometric methods
Nucleic acid technology ndash effective upto 95 in mutations to rifampicin resistance to gene rpoB gene
DrTVRao MD 38
Drug susceptibility testing (DST)
As a minimum laboratories supplying DST data should correctly identify resistance to isoniazid and rifampicin in over 90 of quality control samples in two out of the last three quality control roundsDrTVRao MD 39
Detection of Rifampicin Drug susceptibility testing (DST) is more important
Early identification of mycobacterial growth as M tuberculosis complex and the identification of rifampicin resistance should be the first priority as rifampicin resistance invalidates standard 6 month short-course chemotherapy and is a useful marker in most countries for MDR-TB
Laboratories should aim to identify isolates as M tuberculosis complex and perform rifampicin resistance in 90 of isolates within 1-2 working days This is technologically feasible
DrTVRao MD 40
Drug susceptibility testing
For DST laboratories modern molecular techniques permit the successful identification of isoniazid resistance in at least 75 of mycobacterial cultures within 1-2 working days and are useful preliminary screens for isoniazid resistance
DrTVRao MD 41
Secondary Drugs testing [lack of standardized
methods]
Ofloxacin quinolonesEthionamide KanamycinCapreomycin Ensure quality control and
quality assurance
DrTVRao MD 42
WHO Controls the Tuberculosis related work
The laboratory methods for anti-tuberculosis drug susceptibility testing should be selected from among those that are WHO-recommended and all laboratory processes should be quality-assured in cooperation with a partner Supranational Reference Laboratory (SRL)DrTVRao MD 43
Other WHO-Endorsed Tools
Liquid culture (eg MGIT BacTALERT)
Capilia TB Rapid strip test that detects a TB-
specific antigen from culture
Molecular line probe assays (eg GenoType MTBDRplus INNO-LiPA RifTB) Strip test for detection of TB and
drug-resistance conferring mutations
DrTVRao MD 44
BacTALERTreg
DrTVRao MD 45
CDC Updates Guidelines for Nucleic AcidAmplification Techniques to Diagnose
Tuberculosis
NAAT results should be interpreted in conjunction with the AFB smear results
NAAT and smear positive start Rx despite pending culture results PPV 95
Smear negative NAAT positive use clinical judgment to either treat or await culture
DrTVRao MD 46
Selection from automated systems for molecular and
bacteriological rapid diagnostics
PCRRocheCOBASreg Amplicorreg
amplification kitsRocheCOBASreg LightCyclerreg
(real-time-PCR)RocheCOBASreg TaqMan 48reg(increases the specificity of real-
time-PCR)
DrTVRao MD 47
Molecular Fingerprinting
26 of 30 (87) XDR TB isolates found to be genetically similar
Majority of patients had no previous history of TB treatment Suggestive of recent infection with drug-resistant strain
DrTVRao MD 48
Is PCR methods a solution
PCR cant yet replace neither microscopy culturing and competent clinical examination
DrTVRao MD 49
No testing method replaces Clinical assessment
DrTVRao MD 50
XDR-TBThe description
of XDR-TB was first used earlier in 2006 following a joint survey by WHO and the US Centres for Disease Control and Prevention (CDC) DrTVRao MD 51
How x-MDR generated
Acquired resistance is that which occurs as a result of specific previous treatment The level of primary resistance in the community is considered to reflect the efficacy of control measures in the past while the level of acquired resistance is a measure of on-going TB control measuresDrTVRao MD 52
Extreme Drug resistant Tuberculosis (XDR-TB)
Resistant to all first line drugs namely Isoniazid and Rifampin and Three or more second line drugs (SLDrsquoS) that are used to treat MDR-TB Thequinalones like Ofloaxin
Or Aminoglycosides like Capreomycin amp
Kanamycin
No third-line drugs available to treat XDR-TB since none has been developed in the last 40 years
DrTVRao MD 53
Background Extensively drug-resistant tuberculosis
Extensively drug-resistant tuberculosis has been reported in 45 countries including countries with limited resources and a high burden of tuberculosis
DrTVRao MD 54
DrTVRao MD 55
Transmissionof X -MDR
Like other forms of TB XDR-TB is spread through the air When a person with infectious TB coughs sneezes talks or spits they propel Mycobacterium into the air
DrTVRao MD 56
Best options to diagnoseX-MDR tuberculosis
To evaluate drug susceptibility the bacteria need to be cultivated and tested in a suitable laboratory Final diagnosis in this way for TB and especially for XDR-TB may take from 6 to 16 weeks To reduce the time needed for diagnosis new tools for rapid TB diagnosis are urgently needed
DrTVRao MD 57
When to suspect MDR TB
Patients not showing any reduction
in bacillary population after 3-
months of regular treatment with
Cat II regimen
Sputum positive patients who are
contacts of a known MDR TB
patient
DrTVRao MD 58
How to evaluate MDR TB
MDR TB is only a laboratory
proved HR resistance
Clinical suspicion should be
followed by lab Confirmation
Laboratories should be quality
controlledTRC
DrTVRao MD 59
Extreme Drug resistant Tuberculosis (XDR-TB) and AIDS
It can also be contracted without a patient receiving any previous treatment for TB
Mostly associated with HIV positive patients
HIV has the potential to fast tracking XDR-TB into an uncontrollable epidemic
Average survival period for patients infected with XDR-TB is 16 days
DrTVRao MD 60
Responding to MDRXDR-TB
Augment DOTS Program by
New diagnostics
New drugs New vaccines HIV incidence
reduction Advocacy1
A mathematical model projected by Basu and co-workers indicates that half of XDR-TB can be averted by 2012 by bringing synergistic effects through
Use of masks Reduced time as in-patient Improved ventilation Rapid resistance testing HIV treatment TB isolation facilities2
1Marteens and Wilkinson Lancet 20073702030-432Basu et al Quoted in Porco and Getz Lancet 20073701464-5
DrTVRao MD 61
Second Line Drug Treatment (SLDrsquos)
Less effective more costly and more toxic 50 cure rate
Four months intensive phase (5 drugs) Kanamycins Ethionamide Pyrazinamide Ofloxacin Cycloserine or Ethambutol DrTVRao MD 62
World Health Organisation (WHO) Guidelines for treatment
of MDR-TB
Strengthen basic TB care to prevent the emergence of drug-resistance
Ensure prompt diagnosis and treatment of drug resistant cases to cure existing cases and prevent further transmission
Increase collaboration between HIV and TB control programmes to provide necessary prevention and care to co-infected patients
Increase investment in laboratory infrastructures to enable better detection and management of resistant cases
DrTVRao MD 63
Treatment Guidelines
Sensitivity testing for all smear positive specimens
Patient Family and staff counselling amp education
Correct and thorough hand washing protocol and procedure
Personal protection is very important
DrTVRao MD 64
THE NEW MDR-TB Guidelines
A flexible framework approach combining both clinical and programmatic aspects of DOTS Plus based on essential programme conditions
But encouraging programs to tailor their case-finding and treatment strategies to the local epidemiological and Programme situation
Reflect GLC expert consensus and evidence and experience from GLC projects thus far
DrTVRao MD 65
Effective laboratory Diagnosis
Sputum smear examinations ndash rapid classification of species (atypical mycobacteria common in AIDS)
Culture examinations
Rapid drug sensitivity testingDrTVRao MD 66
MDR TB and HIV
MDR TB occurs with the same frequency in HIV
patients as in TB patients who are smear negative
Transmission of drug-resistant strains among HIV-
infected patients in congregate settings occurs
leading to lsquooutbreaksrsquo of MDR TB in such settings
Infection control measures absolutely essential in
settings where large number of HIV TB patients stay
togetherDrTVRao MD 67
Transmission is dependent on closeness and time of contact
In penitentiary care contacts are very close and prolonged ndash culture positive cases can also transmit TB especially to HIV positive population
DrTVRao MD 68
To Know more on MDR ndashTB Current Guidelines of WHO
Guidelines for the programmatic management of drug-resistant tuberculosis - 2011 update [pdf 904kb]
Visit helliphelliphellip WHOHTMTB20116DrTVRao MD 69
Are there any solutions for effective
Diagnosis in TB
DrTVRao MD 70
Programme Created by DrTVRao MD for Medical and Health Care
Workers in the Developing World Email
doctortvraogmailcom
DrTVRao MD 71
Drug susceptibility testing (DST)
DST is recommended for all new cases for all first line drugs with specimens taken before initiating treatment
Accuracy is more important than speed DST results should come from a small
number of well-equipped experienced laboratories who participate and perform well in an international DST quality control scheme
The WHO Supranational Laboratory Quality Control Network offers the greatest global coverage for this
DrTVRao MD 36
Drug susceptibility Testing
Assessment of growth inhibition on solid media containing various dilutions of the drug in comparison with the test strains
As the method depend observation of growth Results are not available until several weeks after isolation of the organism
DrTVRao MD 37
Other accredited Methods
Radiometric and Non radiometric methods
Nucleic acid technology ndash effective upto 95 in mutations to rifampicin resistance to gene rpoB gene
DrTVRao MD 38
Drug susceptibility testing (DST)
As a minimum laboratories supplying DST data should correctly identify resistance to isoniazid and rifampicin in over 90 of quality control samples in two out of the last three quality control roundsDrTVRao MD 39
Detection of Rifampicin Drug susceptibility testing (DST) is more important
Early identification of mycobacterial growth as M tuberculosis complex and the identification of rifampicin resistance should be the first priority as rifampicin resistance invalidates standard 6 month short-course chemotherapy and is a useful marker in most countries for MDR-TB
Laboratories should aim to identify isolates as M tuberculosis complex and perform rifampicin resistance in 90 of isolates within 1-2 working days This is technologically feasible
DrTVRao MD 40
Drug susceptibility testing
For DST laboratories modern molecular techniques permit the successful identification of isoniazid resistance in at least 75 of mycobacterial cultures within 1-2 working days and are useful preliminary screens for isoniazid resistance
DrTVRao MD 41
Secondary Drugs testing [lack of standardized
methods]
Ofloxacin quinolonesEthionamide KanamycinCapreomycin Ensure quality control and
quality assurance
DrTVRao MD 42
WHO Controls the Tuberculosis related work
The laboratory methods for anti-tuberculosis drug susceptibility testing should be selected from among those that are WHO-recommended and all laboratory processes should be quality-assured in cooperation with a partner Supranational Reference Laboratory (SRL)DrTVRao MD 43
Other WHO-Endorsed Tools
Liquid culture (eg MGIT BacTALERT)
Capilia TB Rapid strip test that detects a TB-
specific antigen from culture
Molecular line probe assays (eg GenoType MTBDRplus INNO-LiPA RifTB) Strip test for detection of TB and
drug-resistance conferring mutations
DrTVRao MD 44
BacTALERTreg
DrTVRao MD 45
CDC Updates Guidelines for Nucleic AcidAmplification Techniques to Diagnose
Tuberculosis
NAAT results should be interpreted in conjunction with the AFB smear results
NAAT and smear positive start Rx despite pending culture results PPV 95
Smear negative NAAT positive use clinical judgment to either treat or await culture
DrTVRao MD 46
Selection from automated systems for molecular and
bacteriological rapid diagnostics
PCRRocheCOBASreg Amplicorreg
amplification kitsRocheCOBASreg LightCyclerreg
(real-time-PCR)RocheCOBASreg TaqMan 48reg(increases the specificity of real-
time-PCR)
DrTVRao MD 47
Molecular Fingerprinting
26 of 30 (87) XDR TB isolates found to be genetically similar
Majority of patients had no previous history of TB treatment Suggestive of recent infection with drug-resistant strain
DrTVRao MD 48
Is PCR methods a solution
PCR cant yet replace neither microscopy culturing and competent clinical examination
DrTVRao MD 49
No testing method replaces Clinical assessment
DrTVRao MD 50
XDR-TBThe description
of XDR-TB was first used earlier in 2006 following a joint survey by WHO and the US Centres for Disease Control and Prevention (CDC) DrTVRao MD 51
How x-MDR generated
Acquired resistance is that which occurs as a result of specific previous treatment The level of primary resistance in the community is considered to reflect the efficacy of control measures in the past while the level of acquired resistance is a measure of on-going TB control measuresDrTVRao MD 52
Extreme Drug resistant Tuberculosis (XDR-TB)
Resistant to all first line drugs namely Isoniazid and Rifampin and Three or more second line drugs (SLDrsquoS) that are used to treat MDR-TB Thequinalones like Ofloaxin
Or Aminoglycosides like Capreomycin amp
Kanamycin
No third-line drugs available to treat XDR-TB since none has been developed in the last 40 years
DrTVRao MD 53
Background Extensively drug-resistant tuberculosis
Extensively drug-resistant tuberculosis has been reported in 45 countries including countries with limited resources and a high burden of tuberculosis
DrTVRao MD 54
DrTVRao MD 55
Transmissionof X -MDR
Like other forms of TB XDR-TB is spread through the air When a person with infectious TB coughs sneezes talks or spits they propel Mycobacterium into the air
DrTVRao MD 56
Best options to diagnoseX-MDR tuberculosis
To evaluate drug susceptibility the bacteria need to be cultivated and tested in a suitable laboratory Final diagnosis in this way for TB and especially for XDR-TB may take from 6 to 16 weeks To reduce the time needed for diagnosis new tools for rapid TB diagnosis are urgently needed
DrTVRao MD 57
When to suspect MDR TB
Patients not showing any reduction
in bacillary population after 3-
months of regular treatment with
Cat II regimen
Sputum positive patients who are
contacts of a known MDR TB
patient
DrTVRao MD 58
How to evaluate MDR TB
MDR TB is only a laboratory
proved HR resistance
Clinical suspicion should be
followed by lab Confirmation
Laboratories should be quality
controlledTRC
DrTVRao MD 59
Extreme Drug resistant Tuberculosis (XDR-TB) and AIDS
It can also be contracted without a patient receiving any previous treatment for TB
Mostly associated with HIV positive patients
HIV has the potential to fast tracking XDR-TB into an uncontrollable epidemic
Average survival period for patients infected with XDR-TB is 16 days
DrTVRao MD 60
Responding to MDRXDR-TB
Augment DOTS Program by
New diagnostics
New drugs New vaccines HIV incidence
reduction Advocacy1
A mathematical model projected by Basu and co-workers indicates that half of XDR-TB can be averted by 2012 by bringing synergistic effects through
Use of masks Reduced time as in-patient Improved ventilation Rapid resistance testing HIV treatment TB isolation facilities2
1Marteens and Wilkinson Lancet 20073702030-432Basu et al Quoted in Porco and Getz Lancet 20073701464-5
DrTVRao MD 61
Second Line Drug Treatment (SLDrsquos)
Less effective more costly and more toxic 50 cure rate
Four months intensive phase (5 drugs) Kanamycins Ethionamide Pyrazinamide Ofloxacin Cycloserine or Ethambutol DrTVRao MD 62
World Health Organisation (WHO) Guidelines for treatment
of MDR-TB
Strengthen basic TB care to prevent the emergence of drug-resistance
Ensure prompt diagnosis and treatment of drug resistant cases to cure existing cases and prevent further transmission
Increase collaboration between HIV and TB control programmes to provide necessary prevention and care to co-infected patients
Increase investment in laboratory infrastructures to enable better detection and management of resistant cases
DrTVRao MD 63
Treatment Guidelines
Sensitivity testing for all smear positive specimens
Patient Family and staff counselling amp education
Correct and thorough hand washing protocol and procedure
Personal protection is very important
DrTVRao MD 64
THE NEW MDR-TB Guidelines
A flexible framework approach combining both clinical and programmatic aspects of DOTS Plus based on essential programme conditions
But encouraging programs to tailor their case-finding and treatment strategies to the local epidemiological and Programme situation
Reflect GLC expert consensus and evidence and experience from GLC projects thus far
DrTVRao MD 65
Effective laboratory Diagnosis
Sputum smear examinations ndash rapid classification of species (atypical mycobacteria common in AIDS)
Culture examinations
Rapid drug sensitivity testingDrTVRao MD 66
MDR TB and HIV
MDR TB occurs with the same frequency in HIV
patients as in TB patients who are smear negative
Transmission of drug-resistant strains among HIV-
infected patients in congregate settings occurs
leading to lsquooutbreaksrsquo of MDR TB in such settings
Infection control measures absolutely essential in
settings where large number of HIV TB patients stay
togetherDrTVRao MD 67
Transmission is dependent on closeness and time of contact
In penitentiary care contacts are very close and prolonged ndash culture positive cases can also transmit TB especially to HIV positive population
DrTVRao MD 68
To Know more on MDR ndashTB Current Guidelines of WHO
Guidelines for the programmatic management of drug-resistant tuberculosis - 2011 update [pdf 904kb]
Visit helliphelliphellip WHOHTMTB20116DrTVRao MD 69
Are there any solutions for effective
Diagnosis in TB
DrTVRao MD 70
Programme Created by DrTVRao MD for Medical and Health Care
Workers in the Developing World Email
doctortvraogmailcom
DrTVRao MD 71
Drug susceptibility Testing
Assessment of growth inhibition on solid media containing various dilutions of the drug in comparison with the test strains
As the method depend observation of growth Results are not available until several weeks after isolation of the organism
DrTVRao MD 37
Other accredited Methods
Radiometric and Non radiometric methods
Nucleic acid technology ndash effective upto 95 in mutations to rifampicin resistance to gene rpoB gene
DrTVRao MD 38
Drug susceptibility testing (DST)
As a minimum laboratories supplying DST data should correctly identify resistance to isoniazid and rifampicin in over 90 of quality control samples in two out of the last three quality control roundsDrTVRao MD 39
Detection of Rifampicin Drug susceptibility testing (DST) is more important
Early identification of mycobacterial growth as M tuberculosis complex and the identification of rifampicin resistance should be the first priority as rifampicin resistance invalidates standard 6 month short-course chemotherapy and is a useful marker in most countries for MDR-TB
Laboratories should aim to identify isolates as M tuberculosis complex and perform rifampicin resistance in 90 of isolates within 1-2 working days This is technologically feasible
DrTVRao MD 40
Drug susceptibility testing
For DST laboratories modern molecular techniques permit the successful identification of isoniazid resistance in at least 75 of mycobacterial cultures within 1-2 working days and are useful preliminary screens for isoniazid resistance
DrTVRao MD 41
Secondary Drugs testing [lack of standardized
methods]
Ofloxacin quinolonesEthionamide KanamycinCapreomycin Ensure quality control and
quality assurance
DrTVRao MD 42
WHO Controls the Tuberculosis related work
The laboratory methods for anti-tuberculosis drug susceptibility testing should be selected from among those that are WHO-recommended and all laboratory processes should be quality-assured in cooperation with a partner Supranational Reference Laboratory (SRL)DrTVRao MD 43
Other WHO-Endorsed Tools
Liquid culture (eg MGIT BacTALERT)
Capilia TB Rapid strip test that detects a TB-
specific antigen from culture
Molecular line probe assays (eg GenoType MTBDRplus INNO-LiPA RifTB) Strip test for detection of TB and
drug-resistance conferring mutations
DrTVRao MD 44
BacTALERTreg
DrTVRao MD 45
CDC Updates Guidelines for Nucleic AcidAmplification Techniques to Diagnose
Tuberculosis
NAAT results should be interpreted in conjunction with the AFB smear results
NAAT and smear positive start Rx despite pending culture results PPV 95
Smear negative NAAT positive use clinical judgment to either treat or await culture
DrTVRao MD 46
Selection from automated systems for molecular and
bacteriological rapid diagnostics
PCRRocheCOBASreg Amplicorreg
amplification kitsRocheCOBASreg LightCyclerreg
(real-time-PCR)RocheCOBASreg TaqMan 48reg(increases the specificity of real-
time-PCR)
DrTVRao MD 47
Molecular Fingerprinting
26 of 30 (87) XDR TB isolates found to be genetically similar
Majority of patients had no previous history of TB treatment Suggestive of recent infection with drug-resistant strain
DrTVRao MD 48
Is PCR methods a solution
PCR cant yet replace neither microscopy culturing and competent clinical examination
DrTVRao MD 49
No testing method replaces Clinical assessment
DrTVRao MD 50
XDR-TBThe description
of XDR-TB was first used earlier in 2006 following a joint survey by WHO and the US Centres for Disease Control and Prevention (CDC) DrTVRao MD 51
How x-MDR generated
Acquired resistance is that which occurs as a result of specific previous treatment The level of primary resistance in the community is considered to reflect the efficacy of control measures in the past while the level of acquired resistance is a measure of on-going TB control measuresDrTVRao MD 52
Extreme Drug resistant Tuberculosis (XDR-TB)
Resistant to all first line drugs namely Isoniazid and Rifampin and Three or more second line drugs (SLDrsquoS) that are used to treat MDR-TB Thequinalones like Ofloaxin
Or Aminoglycosides like Capreomycin amp
Kanamycin
No third-line drugs available to treat XDR-TB since none has been developed in the last 40 years
DrTVRao MD 53
Background Extensively drug-resistant tuberculosis
Extensively drug-resistant tuberculosis has been reported in 45 countries including countries with limited resources and a high burden of tuberculosis
DrTVRao MD 54
DrTVRao MD 55
Transmissionof X -MDR
Like other forms of TB XDR-TB is spread through the air When a person with infectious TB coughs sneezes talks or spits they propel Mycobacterium into the air
DrTVRao MD 56
Best options to diagnoseX-MDR tuberculosis
To evaluate drug susceptibility the bacteria need to be cultivated and tested in a suitable laboratory Final diagnosis in this way for TB and especially for XDR-TB may take from 6 to 16 weeks To reduce the time needed for diagnosis new tools for rapid TB diagnosis are urgently needed
DrTVRao MD 57
When to suspect MDR TB
Patients not showing any reduction
in bacillary population after 3-
months of regular treatment with
Cat II regimen
Sputum positive patients who are
contacts of a known MDR TB
patient
DrTVRao MD 58
How to evaluate MDR TB
MDR TB is only a laboratory
proved HR resistance
Clinical suspicion should be
followed by lab Confirmation
Laboratories should be quality
controlledTRC
DrTVRao MD 59
Extreme Drug resistant Tuberculosis (XDR-TB) and AIDS
It can also be contracted without a patient receiving any previous treatment for TB
Mostly associated with HIV positive patients
HIV has the potential to fast tracking XDR-TB into an uncontrollable epidemic
Average survival period for patients infected with XDR-TB is 16 days
DrTVRao MD 60
Responding to MDRXDR-TB
Augment DOTS Program by
New diagnostics
New drugs New vaccines HIV incidence
reduction Advocacy1
A mathematical model projected by Basu and co-workers indicates that half of XDR-TB can be averted by 2012 by bringing synergistic effects through
Use of masks Reduced time as in-patient Improved ventilation Rapid resistance testing HIV treatment TB isolation facilities2
1Marteens and Wilkinson Lancet 20073702030-432Basu et al Quoted in Porco and Getz Lancet 20073701464-5
DrTVRao MD 61
Second Line Drug Treatment (SLDrsquos)
Less effective more costly and more toxic 50 cure rate
Four months intensive phase (5 drugs) Kanamycins Ethionamide Pyrazinamide Ofloxacin Cycloserine or Ethambutol DrTVRao MD 62
World Health Organisation (WHO) Guidelines for treatment
of MDR-TB
Strengthen basic TB care to prevent the emergence of drug-resistance
Ensure prompt diagnosis and treatment of drug resistant cases to cure existing cases and prevent further transmission
Increase collaboration between HIV and TB control programmes to provide necessary prevention and care to co-infected patients
Increase investment in laboratory infrastructures to enable better detection and management of resistant cases
DrTVRao MD 63
Treatment Guidelines
Sensitivity testing for all smear positive specimens
Patient Family and staff counselling amp education
Correct and thorough hand washing protocol and procedure
Personal protection is very important
DrTVRao MD 64
THE NEW MDR-TB Guidelines
A flexible framework approach combining both clinical and programmatic aspects of DOTS Plus based on essential programme conditions
But encouraging programs to tailor their case-finding and treatment strategies to the local epidemiological and Programme situation
Reflect GLC expert consensus and evidence and experience from GLC projects thus far
DrTVRao MD 65
Effective laboratory Diagnosis
Sputum smear examinations ndash rapid classification of species (atypical mycobacteria common in AIDS)
Culture examinations
Rapid drug sensitivity testingDrTVRao MD 66
MDR TB and HIV
MDR TB occurs with the same frequency in HIV
patients as in TB patients who are smear negative
Transmission of drug-resistant strains among HIV-
infected patients in congregate settings occurs
leading to lsquooutbreaksrsquo of MDR TB in such settings
Infection control measures absolutely essential in
settings where large number of HIV TB patients stay
togetherDrTVRao MD 67
Transmission is dependent on closeness and time of contact
In penitentiary care contacts are very close and prolonged ndash culture positive cases can also transmit TB especially to HIV positive population
DrTVRao MD 68
To Know more on MDR ndashTB Current Guidelines of WHO
Guidelines for the programmatic management of drug-resistant tuberculosis - 2011 update [pdf 904kb]
Visit helliphelliphellip WHOHTMTB20116DrTVRao MD 69
Are there any solutions for effective
Diagnosis in TB
DrTVRao MD 70
Programme Created by DrTVRao MD for Medical and Health Care
Workers in the Developing World Email
doctortvraogmailcom
DrTVRao MD 71
Other accredited Methods
Radiometric and Non radiometric methods
Nucleic acid technology ndash effective upto 95 in mutations to rifampicin resistance to gene rpoB gene
DrTVRao MD 38
Drug susceptibility testing (DST)
As a minimum laboratories supplying DST data should correctly identify resistance to isoniazid and rifampicin in over 90 of quality control samples in two out of the last three quality control roundsDrTVRao MD 39
Detection of Rifampicin Drug susceptibility testing (DST) is more important
Early identification of mycobacterial growth as M tuberculosis complex and the identification of rifampicin resistance should be the first priority as rifampicin resistance invalidates standard 6 month short-course chemotherapy and is a useful marker in most countries for MDR-TB
Laboratories should aim to identify isolates as M tuberculosis complex and perform rifampicin resistance in 90 of isolates within 1-2 working days This is technologically feasible
DrTVRao MD 40
Drug susceptibility testing
For DST laboratories modern molecular techniques permit the successful identification of isoniazid resistance in at least 75 of mycobacterial cultures within 1-2 working days and are useful preliminary screens for isoniazid resistance
DrTVRao MD 41
Secondary Drugs testing [lack of standardized
methods]
Ofloxacin quinolonesEthionamide KanamycinCapreomycin Ensure quality control and
quality assurance
DrTVRao MD 42
WHO Controls the Tuberculosis related work
The laboratory methods for anti-tuberculosis drug susceptibility testing should be selected from among those that are WHO-recommended and all laboratory processes should be quality-assured in cooperation with a partner Supranational Reference Laboratory (SRL)DrTVRao MD 43
Other WHO-Endorsed Tools
Liquid culture (eg MGIT BacTALERT)
Capilia TB Rapid strip test that detects a TB-
specific antigen from culture
Molecular line probe assays (eg GenoType MTBDRplus INNO-LiPA RifTB) Strip test for detection of TB and
drug-resistance conferring mutations
DrTVRao MD 44
BacTALERTreg
DrTVRao MD 45
CDC Updates Guidelines for Nucleic AcidAmplification Techniques to Diagnose
Tuberculosis
NAAT results should be interpreted in conjunction with the AFB smear results
NAAT and smear positive start Rx despite pending culture results PPV 95
Smear negative NAAT positive use clinical judgment to either treat or await culture
DrTVRao MD 46
Selection from automated systems for molecular and
bacteriological rapid diagnostics
PCRRocheCOBASreg Amplicorreg
amplification kitsRocheCOBASreg LightCyclerreg
(real-time-PCR)RocheCOBASreg TaqMan 48reg(increases the specificity of real-
time-PCR)
DrTVRao MD 47
Molecular Fingerprinting
26 of 30 (87) XDR TB isolates found to be genetically similar
Majority of patients had no previous history of TB treatment Suggestive of recent infection with drug-resistant strain
DrTVRao MD 48
Is PCR methods a solution
PCR cant yet replace neither microscopy culturing and competent clinical examination
DrTVRao MD 49
No testing method replaces Clinical assessment
DrTVRao MD 50
XDR-TBThe description
of XDR-TB was first used earlier in 2006 following a joint survey by WHO and the US Centres for Disease Control and Prevention (CDC) DrTVRao MD 51
How x-MDR generated
Acquired resistance is that which occurs as a result of specific previous treatment The level of primary resistance in the community is considered to reflect the efficacy of control measures in the past while the level of acquired resistance is a measure of on-going TB control measuresDrTVRao MD 52
Extreme Drug resistant Tuberculosis (XDR-TB)
Resistant to all first line drugs namely Isoniazid and Rifampin and Three or more second line drugs (SLDrsquoS) that are used to treat MDR-TB Thequinalones like Ofloaxin
Or Aminoglycosides like Capreomycin amp
Kanamycin
No third-line drugs available to treat XDR-TB since none has been developed in the last 40 years
DrTVRao MD 53
Background Extensively drug-resistant tuberculosis
Extensively drug-resistant tuberculosis has been reported in 45 countries including countries with limited resources and a high burden of tuberculosis
DrTVRao MD 54
DrTVRao MD 55
Transmissionof X -MDR
Like other forms of TB XDR-TB is spread through the air When a person with infectious TB coughs sneezes talks or spits they propel Mycobacterium into the air
DrTVRao MD 56
Best options to diagnoseX-MDR tuberculosis
To evaluate drug susceptibility the bacteria need to be cultivated and tested in a suitable laboratory Final diagnosis in this way for TB and especially for XDR-TB may take from 6 to 16 weeks To reduce the time needed for diagnosis new tools for rapid TB diagnosis are urgently needed
DrTVRao MD 57
When to suspect MDR TB
Patients not showing any reduction
in bacillary population after 3-
months of regular treatment with
Cat II regimen
Sputum positive patients who are
contacts of a known MDR TB
patient
DrTVRao MD 58
How to evaluate MDR TB
MDR TB is only a laboratory
proved HR resistance
Clinical suspicion should be
followed by lab Confirmation
Laboratories should be quality
controlledTRC
DrTVRao MD 59
Extreme Drug resistant Tuberculosis (XDR-TB) and AIDS
It can also be contracted without a patient receiving any previous treatment for TB
Mostly associated with HIV positive patients
HIV has the potential to fast tracking XDR-TB into an uncontrollable epidemic
Average survival period for patients infected with XDR-TB is 16 days
DrTVRao MD 60
Responding to MDRXDR-TB
Augment DOTS Program by
New diagnostics
New drugs New vaccines HIV incidence
reduction Advocacy1
A mathematical model projected by Basu and co-workers indicates that half of XDR-TB can be averted by 2012 by bringing synergistic effects through
Use of masks Reduced time as in-patient Improved ventilation Rapid resistance testing HIV treatment TB isolation facilities2
1Marteens and Wilkinson Lancet 20073702030-432Basu et al Quoted in Porco and Getz Lancet 20073701464-5
DrTVRao MD 61
Second Line Drug Treatment (SLDrsquos)
Less effective more costly and more toxic 50 cure rate
Four months intensive phase (5 drugs) Kanamycins Ethionamide Pyrazinamide Ofloxacin Cycloserine or Ethambutol DrTVRao MD 62
World Health Organisation (WHO) Guidelines for treatment
of MDR-TB
Strengthen basic TB care to prevent the emergence of drug-resistance
Ensure prompt diagnosis and treatment of drug resistant cases to cure existing cases and prevent further transmission
Increase collaboration between HIV and TB control programmes to provide necessary prevention and care to co-infected patients
Increase investment in laboratory infrastructures to enable better detection and management of resistant cases
DrTVRao MD 63
Treatment Guidelines
Sensitivity testing for all smear positive specimens
Patient Family and staff counselling amp education
Correct and thorough hand washing protocol and procedure
Personal protection is very important
DrTVRao MD 64
THE NEW MDR-TB Guidelines
A flexible framework approach combining both clinical and programmatic aspects of DOTS Plus based on essential programme conditions
But encouraging programs to tailor their case-finding and treatment strategies to the local epidemiological and Programme situation
Reflect GLC expert consensus and evidence and experience from GLC projects thus far
DrTVRao MD 65
Effective laboratory Diagnosis
Sputum smear examinations ndash rapid classification of species (atypical mycobacteria common in AIDS)
Culture examinations
Rapid drug sensitivity testingDrTVRao MD 66
MDR TB and HIV
MDR TB occurs with the same frequency in HIV
patients as in TB patients who are smear negative
Transmission of drug-resistant strains among HIV-
infected patients in congregate settings occurs
leading to lsquooutbreaksrsquo of MDR TB in such settings
Infection control measures absolutely essential in
settings where large number of HIV TB patients stay
togetherDrTVRao MD 67
Transmission is dependent on closeness and time of contact
In penitentiary care contacts are very close and prolonged ndash culture positive cases can also transmit TB especially to HIV positive population
DrTVRao MD 68
To Know more on MDR ndashTB Current Guidelines of WHO
Guidelines for the programmatic management of drug-resistant tuberculosis - 2011 update [pdf 904kb]
Visit helliphelliphellip WHOHTMTB20116DrTVRao MD 69
Are there any solutions for effective
Diagnosis in TB
DrTVRao MD 70
Programme Created by DrTVRao MD for Medical and Health Care
Workers in the Developing World Email
doctortvraogmailcom
DrTVRao MD 71
Drug susceptibility testing (DST)
As a minimum laboratories supplying DST data should correctly identify resistance to isoniazid and rifampicin in over 90 of quality control samples in two out of the last three quality control roundsDrTVRao MD 39
Detection of Rifampicin Drug susceptibility testing (DST) is more important
Early identification of mycobacterial growth as M tuberculosis complex and the identification of rifampicin resistance should be the first priority as rifampicin resistance invalidates standard 6 month short-course chemotherapy and is a useful marker in most countries for MDR-TB
Laboratories should aim to identify isolates as M tuberculosis complex and perform rifampicin resistance in 90 of isolates within 1-2 working days This is technologically feasible
DrTVRao MD 40
Drug susceptibility testing
For DST laboratories modern molecular techniques permit the successful identification of isoniazid resistance in at least 75 of mycobacterial cultures within 1-2 working days and are useful preliminary screens for isoniazid resistance
DrTVRao MD 41
Secondary Drugs testing [lack of standardized
methods]
Ofloxacin quinolonesEthionamide KanamycinCapreomycin Ensure quality control and
quality assurance
DrTVRao MD 42
WHO Controls the Tuberculosis related work
The laboratory methods for anti-tuberculosis drug susceptibility testing should be selected from among those that are WHO-recommended and all laboratory processes should be quality-assured in cooperation with a partner Supranational Reference Laboratory (SRL)DrTVRao MD 43
Other WHO-Endorsed Tools
Liquid culture (eg MGIT BacTALERT)
Capilia TB Rapid strip test that detects a TB-
specific antigen from culture
Molecular line probe assays (eg GenoType MTBDRplus INNO-LiPA RifTB) Strip test for detection of TB and
drug-resistance conferring mutations
DrTVRao MD 44
BacTALERTreg
DrTVRao MD 45
CDC Updates Guidelines for Nucleic AcidAmplification Techniques to Diagnose
Tuberculosis
NAAT results should be interpreted in conjunction with the AFB smear results
NAAT and smear positive start Rx despite pending culture results PPV 95
Smear negative NAAT positive use clinical judgment to either treat or await culture
DrTVRao MD 46
Selection from automated systems for molecular and
bacteriological rapid diagnostics
PCRRocheCOBASreg Amplicorreg
amplification kitsRocheCOBASreg LightCyclerreg
(real-time-PCR)RocheCOBASreg TaqMan 48reg(increases the specificity of real-
time-PCR)
DrTVRao MD 47
Molecular Fingerprinting
26 of 30 (87) XDR TB isolates found to be genetically similar
Majority of patients had no previous history of TB treatment Suggestive of recent infection with drug-resistant strain
DrTVRao MD 48
Is PCR methods a solution
PCR cant yet replace neither microscopy culturing and competent clinical examination
DrTVRao MD 49
No testing method replaces Clinical assessment
DrTVRao MD 50
XDR-TBThe description
of XDR-TB was first used earlier in 2006 following a joint survey by WHO and the US Centres for Disease Control and Prevention (CDC) DrTVRao MD 51
How x-MDR generated
Acquired resistance is that which occurs as a result of specific previous treatment The level of primary resistance in the community is considered to reflect the efficacy of control measures in the past while the level of acquired resistance is a measure of on-going TB control measuresDrTVRao MD 52
Extreme Drug resistant Tuberculosis (XDR-TB)
Resistant to all first line drugs namely Isoniazid and Rifampin and Three or more second line drugs (SLDrsquoS) that are used to treat MDR-TB Thequinalones like Ofloaxin
Or Aminoglycosides like Capreomycin amp
Kanamycin
No third-line drugs available to treat XDR-TB since none has been developed in the last 40 years
DrTVRao MD 53
Background Extensively drug-resistant tuberculosis
Extensively drug-resistant tuberculosis has been reported in 45 countries including countries with limited resources and a high burden of tuberculosis
DrTVRao MD 54
DrTVRao MD 55
Transmissionof X -MDR
Like other forms of TB XDR-TB is spread through the air When a person with infectious TB coughs sneezes talks or spits they propel Mycobacterium into the air
DrTVRao MD 56
Best options to diagnoseX-MDR tuberculosis
To evaluate drug susceptibility the bacteria need to be cultivated and tested in a suitable laboratory Final diagnosis in this way for TB and especially for XDR-TB may take from 6 to 16 weeks To reduce the time needed for diagnosis new tools for rapid TB diagnosis are urgently needed
DrTVRao MD 57
When to suspect MDR TB
Patients not showing any reduction
in bacillary population after 3-
months of regular treatment with
Cat II regimen
Sputum positive patients who are
contacts of a known MDR TB
patient
DrTVRao MD 58
How to evaluate MDR TB
MDR TB is only a laboratory
proved HR resistance
Clinical suspicion should be
followed by lab Confirmation
Laboratories should be quality
controlledTRC
DrTVRao MD 59
Extreme Drug resistant Tuberculosis (XDR-TB) and AIDS
It can also be contracted without a patient receiving any previous treatment for TB
Mostly associated with HIV positive patients
HIV has the potential to fast tracking XDR-TB into an uncontrollable epidemic
Average survival period for patients infected with XDR-TB is 16 days
DrTVRao MD 60
Responding to MDRXDR-TB
Augment DOTS Program by
New diagnostics
New drugs New vaccines HIV incidence
reduction Advocacy1
A mathematical model projected by Basu and co-workers indicates that half of XDR-TB can be averted by 2012 by bringing synergistic effects through
Use of masks Reduced time as in-patient Improved ventilation Rapid resistance testing HIV treatment TB isolation facilities2
1Marteens and Wilkinson Lancet 20073702030-432Basu et al Quoted in Porco and Getz Lancet 20073701464-5
DrTVRao MD 61
Second Line Drug Treatment (SLDrsquos)
Less effective more costly and more toxic 50 cure rate
Four months intensive phase (5 drugs) Kanamycins Ethionamide Pyrazinamide Ofloxacin Cycloserine or Ethambutol DrTVRao MD 62
World Health Organisation (WHO) Guidelines for treatment
of MDR-TB
Strengthen basic TB care to prevent the emergence of drug-resistance
Ensure prompt diagnosis and treatment of drug resistant cases to cure existing cases and prevent further transmission
Increase collaboration between HIV and TB control programmes to provide necessary prevention and care to co-infected patients
Increase investment in laboratory infrastructures to enable better detection and management of resistant cases
DrTVRao MD 63
Treatment Guidelines
Sensitivity testing for all smear positive specimens
Patient Family and staff counselling amp education
Correct and thorough hand washing protocol and procedure
Personal protection is very important
DrTVRao MD 64
THE NEW MDR-TB Guidelines
A flexible framework approach combining both clinical and programmatic aspects of DOTS Plus based on essential programme conditions
But encouraging programs to tailor their case-finding and treatment strategies to the local epidemiological and Programme situation
Reflect GLC expert consensus and evidence and experience from GLC projects thus far
DrTVRao MD 65
Effective laboratory Diagnosis
Sputum smear examinations ndash rapid classification of species (atypical mycobacteria common in AIDS)
Culture examinations
Rapid drug sensitivity testingDrTVRao MD 66
MDR TB and HIV
MDR TB occurs with the same frequency in HIV
patients as in TB patients who are smear negative
Transmission of drug-resistant strains among HIV-
infected patients in congregate settings occurs
leading to lsquooutbreaksrsquo of MDR TB in such settings
Infection control measures absolutely essential in
settings where large number of HIV TB patients stay
togetherDrTVRao MD 67
Transmission is dependent on closeness and time of contact
In penitentiary care contacts are very close and prolonged ndash culture positive cases can also transmit TB especially to HIV positive population
DrTVRao MD 68
To Know more on MDR ndashTB Current Guidelines of WHO
Guidelines for the programmatic management of drug-resistant tuberculosis - 2011 update [pdf 904kb]
Visit helliphelliphellip WHOHTMTB20116DrTVRao MD 69
Are there any solutions for effective
Diagnosis in TB
DrTVRao MD 70
Programme Created by DrTVRao MD for Medical and Health Care
Workers in the Developing World Email
doctortvraogmailcom
DrTVRao MD 71
Detection of Rifampicin Drug susceptibility testing (DST) is more important
Early identification of mycobacterial growth as M tuberculosis complex and the identification of rifampicin resistance should be the first priority as rifampicin resistance invalidates standard 6 month short-course chemotherapy and is a useful marker in most countries for MDR-TB
Laboratories should aim to identify isolates as M tuberculosis complex and perform rifampicin resistance in 90 of isolates within 1-2 working days This is technologically feasible
DrTVRao MD 40
Drug susceptibility testing
For DST laboratories modern molecular techniques permit the successful identification of isoniazid resistance in at least 75 of mycobacterial cultures within 1-2 working days and are useful preliminary screens for isoniazid resistance
DrTVRao MD 41
Secondary Drugs testing [lack of standardized
methods]
Ofloxacin quinolonesEthionamide KanamycinCapreomycin Ensure quality control and
quality assurance
DrTVRao MD 42
WHO Controls the Tuberculosis related work
The laboratory methods for anti-tuberculosis drug susceptibility testing should be selected from among those that are WHO-recommended and all laboratory processes should be quality-assured in cooperation with a partner Supranational Reference Laboratory (SRL)DrTVRao MD 43
Other WHO-Endorsed Tools
Liquid culture (eg MGIT BacTALERT)
Capilia TB Rapid strip test that detects a TB-
specific antigen from culture
Molecular line probe assays (eg GenoType MTBDRplus INNO-LiPA RifTB) Strip test for detection of TB and
drug-resistance conferring mutations
DrTVRao MD 44
BacTALERTreg
DrTVRao MD 45
CDC Updates Guidelines for Nucleic AcidAmplification Techniques to Diagnose
Tuberculosis
NAAT results should be interpreted in conjunction with the AFB smear results
NAAT and smear positive start Rx despite pending culture results PPV 95
Smear negative NAAT positive use clinical judgment to either treat or await culture
DrTVRao MD 46
Selection from automated systems for molecular and
bacteriological rapid diagnostics
PCRRocheCOBASreg Amplicorreg
amplification kitsRocheCOBASreg LightCyclerreg
(real-time-PCR)RocheCOBASreg TaqMan 48reg(increases the specificity of real-
time-PCR)
DrTVRao MD 47
Molecular Fingerprinting
26 of 30 (87) XDR TB isolates found to be genetically similar
Majority of patients had no previous history of TB treatment Suggestive of recent infection with drug-resistant strain
DrTVRao MD 48
Is PCR methods a solution
PCR cant yet replace neither microscopy culturing and competent clinical examination
DrTVRao MD 49
No testing method replaces Clinical assessment
DrTVRao MD 50
XDR-TBThe description
of XDR-TB was first used earlier in 2006 following a joint survey by WHO and the US Centres for Disease Control and Prevention (CDC) DrTVRao MD 51
How x-MDR generated
Acquired resistance is that which occurs as a result of specific previous treatment The level of primary resistance in the community is considered to reflect the efficacy of control measures in the past while the level of acquired resistance is a measure of on-going TB control measuresDrTVRao MD 52
Extreme Drug resistant Tuberculosis (XDR-TB)
Resistant to all first line drugs namely Isoniazid and Rifampin and Three or more second line drugs (SLDrsquoS) that are used to treat MDR-TB Thequinalones like Ofloaxin
Or Aminoglycosides like Capreomycin amp
Kanamycin
No third-line drugs available to treat XDR-TB since none has been developed in the last 40 years
DrTVRao MD 53
Background Extensively drug-resistant tuberculosis
Extensively drug-resistant tuberculosis has been reported in 45 countries including countries with limited resources and a high burden of tuberculosis
DrTVRao MD 54
DrTVRao MD 55
Transmissionof X -MDR
Like other forms of TB XDR-TB is spread through the air When a person with infectious TB coughs sneezes talks or spits they propel Mycobacterium into the air
DrTVRao MD 56
Best options to diagnoseX-MDR tuberculosis
To evaluate drug susceptibility the bacteria need to be cultivated and tested in a suitable laboratory Final diagnosis in this way for TB and especially for XDR-TB may take from 6 to 16 weeks To reduce the time needed for diagnosis new tools for rapid TB diagnosis are urgently needed
DrTVRao MD 57
When to suspect MDR TB
Patients not showing any reduction
in bacillary population after 3-
months of regular treatment with
Cat II regimen
Sputum positive patients who are
contacts of a known MDR TB
patient
DrTVRao MD 58
How to evaluate MDR TB
MDR TB is only a laboratory
proved HR resistance
Clinical suspicion should be
followed by lab Confirmation
Laboratories should be quality
controlledTRC
DrTVRao MD 59
Extreme Drug resistant Tuberculosis (XDR-TB) and AIDS
It can also be contracted without a patient receiving any previous treatment for TB
Mostly associated with HIV positive patients
HIV has the potential to fast tracking XDR-TB into an uncontrollable epidemic
Average survival period for patients infected with XDR-TB is 16 days
DrTVRao MD 60
Responding to MDRXDR-TB
Augment DOTS Program by
New diagnostics
New drugs New vaccines HIV incidence
reduction Advocacy1
A mathematical model projected by Basu and co-workers indicates that half of XDR-TB can be averted by 2012 by bringing synergistic effects through
Use of masks Reduced time as in-patient Improved ventilation Rapid resistance testing HIV treatment TB isolation facilities2
1Marteens and Wilkinson Lancet 20073702030-432Basu et al Quoted in Porco and Getz Lancet 20073701464-5
DrTVRao MD 61
Second Line Drug Treatment (SLDrsquos)
Less effective more costly and more toxic 50 cure rate
Four months intensive phase (5 drugs) Kanamycins Ethionamide Pyrazinamide Ofloxacin Cycloserine or Ethambutol DrTVRao MD 62
World Health Organisation (WHO) Guidelines for treatment
of MDR-TB
Strengthen basic TB care to prevent the emergence of drug-resistance
Ensure prompt diagnosis and treatment of drug resistant cases to cure existing cases and prevent further transmission
Increase collaboration between HIV and TB control programmes to provide necessary prevention and care to co-infected patients
Increase investment in laboratory infrastructures to enable better detection and management of resistant cases
DrTVRao MD 63
Treatment Guidelines
Sensitivity testing for all smear positive specimens
Patient Family and staff counselling amp education
Correct and thorough hand washing protocol and procedure
Personal protection is very important
DrTVRao MD 64
THE NEW MDR-TB Guidelines
A flexible framework approach combining both clinical and programmatic aspects of DOTS Plus based on essential programme conditions
But encouraging programs to tailor their case-finding and treatment strategies to the local epidemiological and Programme situation
Reflect GLC expert consensus and evidence and experience from GLC projects thus far
DrTVRao MD 65
Effective laboratory Diagnosis
Sputum smear examinations ndash rapid classification of species (atypical mycobacteria common in AIDS)
Culture examinations
Rapid drug sensitivity testingDrTVRao MD 66
MDR TB and HIV
MDR TB occurs with the same frequency in HIV
patients as in TB patients who are smear negative
Transmission of drug-resistant strains among HIV-
infected patients in congregate settings occurs
leading to lsquooutbreaksrsquo of MDR TB in such settings
Infection control measures absolutely essential in
settings where large number of HIV TB patients stay
togetherDrTVRao MD 67
Transmission is dependent on closeness and time of contact
In penitentiary care contacts are very close and prolonged ndash culture positive cases can also transmit TB especially to HIV positive population
DrTVRao MD 68
To Know more on MDR ndashTB Current Guidelines of WHO
Guidelines for the programmatic management of drug-resistant tuberculosis - 2011 update [pdf 904kb]
Visit helliphelliphellip WHOHTMTB20116DrTVRao MD 69
Are there any solutions for effective
Diagnosis in TB
DrTVRao MD 70
Programme Created by DrTVRao MD for Medical and Health Care
Workers in the Developing World Email
doctortvraogmailcom
DrTVRao MD 71
Drug susceptibility testing
For DST laboratories modern molecular techniques permit the successful identification of isoniazid resistance in at least 75 of mycobacterial cultures within 1-2 working days and are useful preliminary screens for isoniazid resistance
DrTVRao MD 41
Secondary Drugs testing [lack of standardized
methods]
Ofloxacin quinolonesEthionamide KanamycinCapreomycin Ensure quality control and
quality assurance
DrTVRao MD 42
WHO Controls the Tuberculosis related work
The laboratory methods for anti-tuberculosis drug susceptibility testing should be selected from among those that are WHO-recommended and all laboratory processes should be quality-assured in cooperation with a partner Supranational Reference Laboratory (SRL)DrTVRao MD 43
Other WHO-Endorsed Tools
Liquid culture (eg MGIT BacTALERT)
Capilia TB Rapid strip test that detects a TB-
specific antigen from culture
Molecular line probe assays (eg GenoType MTBDRplus INNO-LiPA RifTB) Strip test for detection of TB and
drug-resistance conferring mutations
DrTVRao MD 44
BacTALERTreg
DrTVRao MD 45
CDC Updates Guidelines for Nucleic AcidAmplification Techniques to Diagnose
Tuberculosis
NAAT results should be interpreted in conjunction with the AFB smear results
NAAT and smear positive start Rx despite pending culture results PPV 95
Smear negative NAAT positive use clinical judgment to either treat or await culture
DrTVRao MD 46
Selection from automated systems for molecular and
bacteriological rapid diagnostics
PCRRocheCOBASreg Amplicorreg
amplification kitsRocheCOBASreg LightCyclerreg
(real-time-PCR)RocheCOBASreg TaqMan 48reg(increases the specificity of real-
time-PCR)
DrTVRao MD 47
Molecular Fingerprinting
26 of 30 (87) XDR TB isolates found to be genetically similar
Majority of patients had no previous history of TB treatment Suggestive of recent infection with drug-resistant strain
DrTVRao MD 48
Is PCR methods a solution
PCR cant yet replace neither microscopy culturing and competent clinical examination
DrTVRao MD 49
No testing method replaces Clinical assessment
DrTVRao MD 50
XDR-TBThe description
of XDR-TB was first used earlier in 2006 following a joint survey by WHO and the US Centres for Disease Control and Prevention (CDC) DrTVRao MD 51
How x-MDR generated
Acquired resistance is that which occurs as a result of specific previous treatment The level of primary resistance in the community is considered to reflect the efficacy of control measures in the past while the level of acquired resistance is a measure of on-going TB control measuresDrTVRao MD 52
Extreme Drug resistant Tuberculosis (XDR-TB)
Resistant to all first line drugs namely Isoniazid and Rifampin and Three or more second line drugs (SLDrsquoS) that are used to treat MDR-TB Thequinalones like Ofloaxin
Or Aminoglycosides like Capreomycin amp
Kanamycin
No third-line drugs available to treat XDR-TB since none has been developed in the last 40 years
DrTVRao MD 53
Background Extensively drug-resistant tuberculosis
Extensively drug-resistant tuberculosis has been reported in 45 countries including countries with limited resources and a high burden of tuberculosis
DrTVRao MD 54
DrTVRao MD 55
Transmissionof X -MDR
Like other forms of TB XDR-TB is spread through the air When a person with infectious TB coughs sneezes talks or spits they propel Mycobacterium into the air
DrTVRao MD 56
Best options to diagnoseX-MDR tuberculosis
To evaluate drug susceptibility the bacteria need to be cultivated and tested in a suitable laboratory Final diagnosis in this way for TB and especially for XDR-TB may take from 6 to 16 weeks To reduce the time needed for diagnosis new tools for rapid TB diagnosis are urgently needed
DrTVRao MD 57
When to suspect MDR TB
Patients not showing any reduction
in bacillary population after 3-
months of regular treatment with
Cat II regimen
Sputum positive patients who are
contacts of a known MDR TB
patient
DrTVRao MD 58
How to evaluate MDR TB
MDR TB is only a laboratory
proved HR resistance
Clinical suspicion should be
followed by lab Confirmation
Laboratories should be quality
controlledTRC
DrTVRao MD 59
Extreme Drug resistant Tuberculosis (XDR-TB) and AIDS
It can also be contracted without a patient receiving any previous treatment for TB
Mostly associated with HIV positive patients
HIV has the potential to fast tracking XDR-TB into an uncontrollable epidemic
Average survival period for patients infected with XDR-TB is 16 days
DrTVRao MD 60
Responding to MDRXDR-TB
Augment DOTS Program by
New diagnostics
New drugs New vaccines HIV incidence
reduction Advocacy1
A mathematical model projected by Basu and co-workers indicates that half of XDR-TB can be averted by 2012 by bringing synergistic effects through
Use of masks Reduced time as in-patient Improved ventilation Rapid resistance testing HIV treatment TB isolation facilities2
1Marteens and Wilkinson Lancet 20073702030-432Basu et al Quoted in Porco and Getz Lancet 20073701464-5
DrTVRao MD 61
Second Line Drug Treatment (SLDrsquos)
Less effective more costly and more toxic 50 cure rate
Four months intensive phase (5 drugs) Kanamycins Ethionamide Pyrazinamide Ofloxacin Cycloserine or Ethambutol DrTVRao MD 62
World Health Organisation (WHO) Guidelines for treatment
of MDR-TB
Strengthen basic TB care to prevent the emergence of drug-resistance
Ensure prompt diagnosis and treatment of drug resistant cases to cure existing cases and prevent further transmission
Increase collaboration between HIV and TB control programmes to provide necessary prevention and care to co-infected patients
Increase investment in laboratory infrastructures to enable better detection and management of resistant cases
DrTVRao MD 63
Treatment Guidelines
Sensitivity testing for all smear positive specimens
Patient Family and staff counselling amp education
Correct and thorough hand washing protocol and procedure
Personal protection is very important
DrTVRao MD 64
THE NEW MDR-TB Guidelines
A flexible framework approach combining both clinical and programmatic aspects of DOTS Plus based on essential programme conditions
But encouraging programs to tailor their case-finding and treatment strategies to the local epidemiological and Programme situation
Reflect GLC expert consensus and evidence and experience from GLC projects thus far
DrTVRao MD 65
Effective laboratory Diagnosis
Sputum smear examinations ndash rapid classification of species (atypical mycobacteria common in AIDS)
Culture examinations
Rapid drug sensitivity testingDrTVRao MD 66
MDR TB and HIV
MDR TB occurs with the same frequency in HIV
patients as in TB patients who are smear negative
Transmission of drug-resistant strains among HIV-
infected patients in congregate settings occurs
leading to lsquooutbreaksrsquo of MDR TB in such settings
Infection control measures absolutely essential in
settings where large number of HIV TB patients stay
togetherDrTVRao MD 67
Transmission is dependent on closeness and time of contact
In penitentiary care contacts are very close and prolonged ndash culture positive cases can also transmit TB especially to HIV positive population
DrTVRao MD 68
To Know more on MDR ndashTB Current Guidelines of WHO
Guidelines for the programmatic management of drug-resistant tuberculosis - 2011 update [pdf 904kb]
Visit helliphelliphellip WHOHTMTB20116DrTVRao MD 69
Are there any solutions for effective
Diagnosis in TB
DrTVRao MD 70
Programme Created by DrTVRao MD for Medical and Health Care
Workers in the Developing World Email
doctortvraogmailcom
DrTVRao MD 71
Secondary Drugs testing [lack of standardized
methods]
Ofloxacin quinolonesEthionamide KanamycinCapreomycin Ensure quality control and
quality assurance
DrTVRao MD 42
WHO Controls the Tuberculosis related work
The laboratory methods for anti-tuberculosis drug susceptibility testing should be selected from among those that are WHO-recommended and all laboratory processes should be quality-assured in cooperation with a partner Supranational Reference Laboratory (SRL)DrTVRao MD 43
Other WHO-Endorsed Tools
Liquid culture (eg MGIT BacTALERT)
Capilia TB Rapid strip test that detects a TB-
specific antigen from culture
Molecular line probe assays (eg GenoType MTBDRplus INNO-LiPA RifTB) Strip test for detection of TB and
drug-resistance conferring mutations
DrTVRao MD 44
BacTALERTreg
DrTVRao MD 45
CDC Updates Guidelines for Nucleic AcidAmplification Techniques to Diagnose
Tuberculosis
NAAT results should be interpreted in conjunction with the AFB smear results
NAAT and smear positive start Rx despite pending culture results PPV 95
Smear negative NAAT positive use clinical judgment to either treat or await culture
DrTVRao MD 46
Selection from automated systems for molecular and
bacteriological rapid diagnostics
PCRRocheCOBASreg Amplicorreg
amplification kitsRocheCOBASreg LightCyclerreg
(real-time-PCR)RocheCOBASreg TaqMan 48reg(increases the specificity of real-
time-PCR)
DrTVRao MD 47
Molecular Fingerprinting
26 of 30 (87) XDR TB isolates found to be genetically similar
Majority of patients had no previous history of TB treatment Suggestive of recent infection with drug-resistant strain
DrTVRao MD 48
Is PCR methods a solution
PCR cant yet replace neither microscopy culturing and competent clinical examination
DrTVRao MD 49
No testing method replaces Clinical assessment
DrTVRao MD 50
XDR-TBThe description
of XDR-TB was first used earlier in 2006 following a joint survey by WHO and the US Centres for Disease Control and Prevention (CDC) DrTVRao MD 51
How x-MDR generated
Acquired resistance is that which occurs as a result of specific previous treatment The level of primary resistance in the community is considered to reflect the efficacy of control measures in the past while the level of acquired resistance is a measure of on-going TB control measuresDrTVRao MD 52
Extreme Drug resistant Tuberculosis (XDR-TB)
Resistant to all first line drugs namely Isoniazid and Rifampin and Three or more second line drugs (SLDrsquoS) that are used to treat MDR-TB Thequinalones like Ofloaxin
Or Aminoglycosides like Capreomycin amp
Kanamycin
No third-line drugs available to treat XDR-TB since none has been developed in the last 40 years
DrTVRao MD 53
Background Extensively drug-resistant tuberculosis
Extensively drug-resistant tuberculosis has been reported in 45 countries including countries with limited resources and a high burden of tuberculosis
DrTVRao MD 54
DrTVRao MD 55
Transmissionof X -MDR
Like other forms of TB XDR-TB is spread through the air When a person with infectious TB coughs sneezes talks or spits they propel Mycobacterium into the air
DrTVRao MD 56
Best options to diagnoseX-MDR tuberculosis
To evaluate drug susceptibility the bacteria need to be cultivated and tested in a suitable laboratory Final diagnosis in this way for TB and especially for XDR-TB may take from 6 to 16 weeks To reduce the time needed for diagnosis new tools for rapid TB diagnosis are urgently needed
DrTVRao MD 57
When to suspect MDR TB
Patients not showing any reduction
in bacillary population after 3-
months of regular treatment with
Cat II regimen
Sputum positive patients who are
contacts of a known MDR TB
patient
DrTVRao MD 58
How to evaluate MDR TB
MDR TB is only a laboratory
proved HR resistance
Clinical suspicion should be
followed by lab Confirmation
Laboratories should be quality
controlledTRC
DrTVRao MD 59
Extreme Drug resistant Tuberculosis (XDR-TB) and AIDS
It can also be contracted without a patient receiving any previous treatment for TB
Mostly associated with HIV positive patients
HIV has the potential to fast tracking XDR-TB into an uncontrollable epidemic
Average survival period for patients infected with XDR-TB is 16 days
DrTVRao MD 60
Responding to MDRXDR-TB
Augment DOTS Program by
New diagnostics
New drugs New vaccines HIV incidence
reduction Advocacy1
A mathematical model projected by Basu and co-workers indicates that half of XDR-TB can be averted by 2012 by bringing synergistic effects through
Use of masks Reduced time as in-patient Improved ventilation Rapid resistance testing HIV treatment TB isolation facilities2
1Marteens and Wilkinson Lancet 20073702030-432Basu et al Quoted in Porco and Getz Lancet 20073701464-5
DrTVRao MD 61
Second Line Drug Treatment (SLDrsquos)
Less effective more costly and more toxic 50 cure rate
Four months intensive phase (5 drugs) Kanamycins Ethionamide Pyrazinamide Ofloxacin Cycloserine or Ethambutol DrTVRao MD 62
World Health Organisation (WHO) Guidelines for treatment
of MDR-TB
Strengthen basic TB care to prevent the emergence of drug-resistance
Ensure prompt diagnosis and treatment of drug resistant cases to cure existing cases and prevent further transmission
Increase collaboration between HIV and TB control programmes to provide necessary prevention and care to co-infected patients
Increase investment in laboratory infrastructures to enable better detection and management of resistant cases
DrTVRao MD 63
Treatment Guidelines
Sensitivity testing for all smear positive specimens
Patient Family and staff counselling amp education
Correct and thorough hand washing protocol and procedure
Personal protection is very important
DrTVRao MD 64
THE NEW MDR-TB Guidelines
A flexible framework approach combining both clinical and programmatic aspects of DOTS Plus based on essential programme conditions
But encouraging programs to tailor their case-finding and treatment strategies to the local epidemiological and Programme situation
Reflect GLC expert consensus and evidence and experience from GLC projects thus far
DrTVRao MD 65
Effective laboratory Diagnosis
Sputum smear examinations ndash rapid classification of species (atypical mycobacteria common in AIDS)
Culture examinations
Rapid drug sensitivity testingDrTVRao MD 66
MDR TB and HIV
MDR TB occurs with the same frequency in HIV
patients as in TB patients who are smear negative
Transmission of drug-resistant strains among HIV-
infected patients in congregate settings occurs
leading to lsquooutbreaksrsquo of MDR TB in such settings
Infection control measures absolutely essential in
settings where large number of HIV TB patients stay
togetherDrTVRao MD 67
Transmission is dependent on closeness and time of contact
In penitentiary care contacts are very close and prolonged ndash culture positive cases can also transmit TB especially to HIV positive population
DrTVRao MD 68
To Know more on MDR ndashTB Current Guidelines of WHO
Guidelines for the programmatic management of drug-resistant tuberculosis - 2011 update [pdf 904kb]
Visit helliphelliphellip WHOHTMTB20116DrTVRao MD 69
Are there any solutions for effective
Diagnosis in TB
DrTVRao MD 70
Programme Created by DrTVRao MD for Medical and Health Care
Workers in the Developing World Email
doctortvraogmailcom
DrTVRao MD 71
WHO Controls the Tuberculosis related work
The laboratory methods for anti-tuberculosis drug susceptibility testing should be selected from among those that are WHO-recommended and all laboratory processes should be quality-assured in cooperation with a partner Supranational Reference Laboratory (SRL)DrTVRao MD 43
Other WHO-Endorsed Tools
Liquid culture (eg MGIT BacTALERT)
Capilia TB Rapid strip test that detects a TB-
specific antigen from culture
Molecular line probe assays (eg GenoType MTBDRplus INNO-LiPA RifTB) Strip test for detection of TB and
drug-resistance conferring mutations
DrTVRao MD 44
BacTALERTreg
DrTVRao MD 45
CDC Updates Guidelines for Nucleic AcidAmplification Techniques to Diagnose
Tuberculosis
NAAT results should be interpreted in conjunction with the AFB smear results
NAAT and smear positive start Rx despite pending culture results PPV 95
Smear negative NAAT positive use clinical judgment to either treat or await culture
DrTVRao MD 46
Selection from automated systems for molecular and
bacteriological rapid diagnostics
PCRRocheCOBASreg Amplicorreg
amplification kitsRocheCOBASreg LightCyclerreg
(real-time-PCR)RocheCOBASreg TaqMan 48reg(increases the specificity of real-
time-PCR)
DrTVRao MD 47
Molecular Fingerprinting
26 of 30 (87) XDR TB isolates found to be genetically similar
Majority of patients had no previous history of TB treatment Suggestive of recent infection with drug-resistant strain
DrTVRao MD 48
Is PCR methods a solution
PCR cant yet replace neither microscopy culturing and competent clinical examination
DrTVRao MD 49
No testing method replaces Clinical assessment
DrTVRao MD 50
XDR-TBThe description
of XDR-TB was first used earlier in 2006 following a joint survey by WHO and the US Centres for Disease Control and Prevention (CDC) DrTVRao MD 51
How x-MDR generated
Acquired resistance is that which occurs as a result of specific previous treatment The level of primary resistance in the community is considered to reflect the efficacy of control measures in the past while the level of acquired resistance is a measure of on-going TB control measuresDrTVRao MD 52
Extreme Drug resistant Tuberculosis (XDR-TB)
Resistant to all first line drugs namely Isoniazid and Rifampin and Three or more second line drugs (SLDrsquoS) that are used to treat MDR-TB Thequinalones like Ofloaxin
Or Aminoglycosides like Capreomycin amp
Kanamycin
No third-line drugs available to treat XDR-TB since none has been developed in the last 40 years
DrTVRao MD 53
Background Extensively drug-resistant tuberculosis
Extensively drug-resistant tuberculosis has been reported in 45 countries including countries with limited resources and a high burden of tuberculosis
DrTVRao MD 54
DrTVRao MD 55
Transmissionof X -MDR
Like other forms of TB XDR-TB is spread through the air When a person with infectious TB coughs sneezes talks or spits they propel Mycobacterium into the air
DrTVRao MD 56
Best options to diagnoseX-MDR tuberculosis
To evaluate drug susceptibility the bacteria need to be cultivated and tested in a suitable laboratory Final diagnosis in this way for TB and especially for XDR-TB may take from 6 to 16 weeks To reduce the time needed for diagnosis new tools for rapid TB diagnosis are urgently needed
DrTVRao MD 57
When to suspect MDR TB
Patients not showing any reduction
in bacillary population after 3-
months of regular treatment with
Cat II regimen
Sputum positive patients who are
contacts of a known MDR TB
patient
DrTVRao MD 58
How to evaluate MDR TB
MDR TB is only a laboratory
proved HR resistance
Clinical suspicion should be
followed by lab Confirmation
Laboratories should be quality
controlledTRC
DrTVRao MD 59
Extreme Drug resistant Tuberculosis (XDR-TB) and AIDS
It can also be contracted without a patient receiving any previous treatment for TB
Mostly associated with HIV positive patients
HIV has the potential to fast tracking XDR-TB into an uncontrollable epidemic
Average survival period for patients infected with XDR-TB is 16 days
DrTVRao MD 60
Responding to MDRXDR-TB
Augment DOTS Program by
New diagnostics
New drugs New vaccines HIV incidence
reduction Advocacy1
A mathematical model projected by Basu and co-workers indicates that half of XDR-TB can be averted by 2012 by bringing synergistic effects through
Use of masks Reduced time as in-patient Improved ventilation Rapid resistance testing HIV treatment TB isolation facilities2
1Marteens and Wilkinson Lancet 20073702030-432Basu et al Quoted in Porco and Getz Lancet 20073701464-5
DrTVRao MD 61
Second Line Drug Treatment (SLDrsquos)
Less effective more costly and more toxic 50 cure rate
Four months intensive phase (5 drugs) Kanamycins Ethionamide Pyrazinamide Ofloxacin Cycloserine or Ethambutol DrTVRao MD 62
World Health Organisation (WHO) Guidelines for treatment
of MDR-TB
Strengthen basic TB care to prevent the emergence of drug-resistance
Ensure prompt diagnosis and treatment of drug resistant cases to cure existing cases and prevent further transmission
Increase collaboration between HIV and TB control programmes to provide necessary prevention and care to co-infected patients
Increase investment in laboratory infrastructures to enable better detection and management of resistant cases
DrTVRao MD 63
Treatment Guidelines
Sensitivity testing for all smear positive specimens
Patient Family and staff counselling amp education
Correct and thorough hand washing protocol and procedure
Personal protection is very important
DrTVRao MD 64
THE NEW MDR-TB Guidelines
A flexible framework approach combining both clinical and programmatic aspects of DOTS Plus based on essential programme conditions
But encouraging programs to tailor their case-finding and treatment strategies to the local epidemiological and Programme situation
Reflect GLC expert consensus and evidence and experience from GLC projects thus far
DrTVRao MD 65
Effective laboratory Diagnosis
Sputum smear examinations ndash rapid classification of species (atypical mycobacteria common in AIDS)
Culture examinations
Rapid drug sensitivity testingDrTVRao MD 66
MDR TB and HIV
MDR TB occurs with the same frequency in HIV
patients as in TB patients who are smear negative
Transmission of drug-resistant strains among HIV-
infected patients in congregate settings occurs
leading to lsquooutbreaksrsquo of MDR TB in such settings
Infection control measures absolutely essential in
settings where large number of HIV TB patients stay
togetherDrTVRao MD 67
Transmission is dependent on closeness and time of contact
In penitentiary care contacts are very close and prolonged ndash culture positive cases can also transmit TB especially to HIV positive population
DrTVRao MD 68
To Know more on MDR ndashTB Current Guidelines of WHO
Guidelines for the programmatic management of drug-resistant tuberculosis - 2011 update [pdf 904kb]
Visit helliphelliphellip WHOHTMTB20116DrTVRao MD 69
Are there any solutions for effective
Diagnosis in TB
DrTVRao MD 70
Programme Created by DrTVRao MD for Medical and Health Care
Workers in the Developing World Email
doctortvraogmailcom
DrTVRao MD 71
Other WHO-Endorsed Tools
Liquid culture (eg MGIT BacTALERT)
Capilia TB Rapid strip test that detects a TB-
specific antigen from culture
Molecular line probe assays (eg GenoType MTBDRplus INNO-LiPA RifTB) Strip test for detection of TB and
drug-resistance conferring mutations
DrTVRao MD 44
BacTALERTreg
DrTVRao MD 45
CDC Updates Guidelines for Nucleic AcidAmplification Techniques to Diagnose
Tuberculosis
NAAT results should be interpreted in conjunction with the AFB smear results
NAAT and smear positive start Rx despite pending culture results PPV 95
Smear negative NAAT positive use clinical judgment to either treat or await culture
DrTVRao MD 46
Selection from automated systems for molecular and
bacteriological rapid diagnostics
PCRRocheCOBASreg Amplicorreg
amplification kitsRocheCOBASreg LightCyclerreg
(real-time-PCR)RocheCOBASreg TaqMan 48reg(increases the specificity of real-
time-PCR)
DrTVRao MD 47
Molecular Fingerprinting
26 of 30 (87) XDR TB isolates found to be genetically similar
Majority of patients had no previous history of TB treatment Suggestive of recent infection with drug-resistant strain
DrTVRao MD 48
Is PCR methods a solution
PCR cant yet replace neither microscopy culturing and competent clinical examination
DrTVRao MD 49
No testing method replaces Clinical assessment
DrTVRao MD 50
XDR-TBThe description
of XDR-TB was first used earlier in 2006 following a joint survey by WHO and the US Centres for Disease Control and Prevention (CDC) DrTVRao MD 51
How x-MDR generated
Acquired resistance is that which occurs as a result of specific previous treatment The level of primary resistance in the community is considered to reflect the efficacy of control measures in the past while the level of acquired resistance is a measure of on-going TB control measuresDrTVRao MD 52
Extreme Drug resistant Tuberculosis (XDR-TB)
Resistant to all first line drugs namely Isoniazid and Rifampin and Three or more second line drugs (SLDrsquoS) that are used to treat MDR-TB Thequinalones like Ofloaxin
Or Aminoglycosides like Capreomycin amp
Kanamycin
No third-line drugs available to treat XDR-TB since none has been developed in the last 40 years
DrTVRao MD 53
Background Extensively drug-resistant tuberculosis
Extensively drug-resistant tuberculosis has been reported in 45 countries including countries with limited resources and a high burden of tuberculosis
DrTVRao MD 54
DrTVRao MD 55
Transmissionof X -MDR
Like other forms of TB XDR-TB is spread through the air When a person with infectious TB coughs sneezes talks or spits they propel Mycobacterium into the air
DrTVRao MD 56
Best options to diagnoseX-MDR tuberculosis
To evaluate drug susceptibility the bacteria need to be cultivated and tested in a suitable laboratory Final diagnosis in this way for TB and especially for XDR-TB may take from 6 to 16 weeks To reduce the time needed for diagnosis new tools for rapid TB diagnosis are urgently needed
DrTVRao MD 57
When to suspect MDR TB
Patients not showing any reduction
in bacillary population after 3-
months of regular treatment with
Cat II regimen
Sputum positive patients who are
contacts of a known MDR TB
patient
DrTVRao MD 58
How to evaluate MDR TB
MDR TB is only a laboratory
proved HR resistance
Clinical suspicion should be
followed by lab Confirmation
Laboratories should be quality
controlledTRC
DrTVRao MD 59
Extreme Drug resistant Tuberculosis (XDR-TB) and AIDS
It can also be contracted without a patient receiving any previous treatment for TB
Mostly associated with HIV positive patients
HIV has the potential to fast tracking XDR-TB into an uncontrollable epidemic
Average survival period for patients infected with XDR-TB is 16 days
DrTVRao MD 60
Responding to MDRXDR-TB
Augment DOTS Program by
New diagnostics
New drugs New vaccines HIV incidence
reduction Advocacy1
A mathematical model projected by Basu and co-workers indicates that half of XDR-TB can be averted by 2012 by bringing synergistic effects through
Use of masks Reduced time as in-patient Improved ventilation Rapid resistance testing HIV treatment TB isolation facilities2
1Marteens and Wilkinson Lancet 20073702030-432Basu et al Quoted in Porco and Getz Lancet 20073701464-5
DrTVRao MD 61
Second Line Drug Treatment (SLDrsquos)
Less effective more costly and more toxic 50 cure rate
Four months intensive phase (5 drugs) Kanamycins Ethionamide Pyrazinamide Ofloxacin Cycloserine or Ethambutol DrTVRao MD 62
World Health Organisation (WHO) Guidelines for treatment
of MDR-TB
Strengthen basic TB care to prevent the emergence of drug-resistance
Ensure prompt diagnosis and treatment of drug resistant cases to cure existing cases and prevent further transmission
Increase collaboration between HIV and TB control programmes to provide necessary prevention and care to co-infected patients
Increase investment in laboratory infrastructures to enable better detection and management of resistant cases
DrTVRao MD 63
Treatment Guidelines
Sensitivity testing for all smear positive specimens
Patient Family and staff counselling amp education
Correct and thorough hand washing protocol and procedure
Personal protection is very important
DrTVRao MD 64
THE NEW MDR-TB Guidelines
A flexible framework approach combining both clinical and programmatic aspects of DOTS Plus based on essential programme conditions
But encouraging programs to tailor their case-finding and treatment strategies to the local epidemiological and Programme situation
Reflect GLC expert consensus and evidence and experience from GLC projects thus far
DrTVRao MD 65
Effective laboratory Diagnosis
Sputum smear examinations ndash rapid classification of species (atypical mycobacteria common in AIDS)
Culture examinations
Rapid drug sensitivity testingDrTVRao MD 66
MDR TB and HIV
MDR TB occurs with the same frequency in HIV
patients as in TB patients who are smear negative
Transmission of drug-resistant strains among HIV-
infected patients in congregate settings occurs
leading to lsquooutbreaksrsquo of MDR TB in such settings
Infection control measures absolutely essential in
settings where large number of HIV TB patients stay
togetherDrTVRao MD 67
Transmission is dependent on closeness and time of contact
In penitentiary care contacts are very close and prolonged ndash culture positive cases can also transmit TB especially to HIV positive population
DrTVRao MD 68
To Know more on MDR ndashTB Current Guidelines of WHO
Guidelines for the programmatic management of drug-resistant tuberculosis - 2011 update [pdf 904kb]
Visit helliphelliphellip WHOHTMTB20116DrTVRao MD 69
Are there any solutions for effective
Diagnosis in TB
DrTVRao MD 70
Programme Created by DrTVRao MD for Medical and Health Care
Workers in the Developing World Email
doctortvraogmailcom
DrTVRao MD 71
BacTALERTreg
DrTVRao MD 45
CDC Updates Guidelines for Nucleic AcidAmplification Techniques to Diagnose
Tuberculosis
NAAT results should be interpreted in conjunction with the AFB smear results
NAAT and smear positive start Rx despite pending culture results PPV 95
Smear negative NAAT positive use clinical judgment to either treat or await culture
DrTVRao MD 46
Selection from automated systems for molecular and
bacteriological rapid diagnostics
PCRRocheCOBASreg Amplicorreg
amplification kitsRocheCOBASreg LightCyclerreg
(real-time-PCR)RocheCOBASreg TaqMan 48reg(increases the specificity of real-
time-PCR)
DrTVRao MD 47
Molecular Fingerprinting
26 of 30 (87) XDR TB isolates found to be genetically similar
Majority of patients had no previous history of TB treatment Suggestive of recent infection with drug-resistant strain
DrTVRao MD 48
Is PCR methods a solution
PCR cant yet replace neither microscopy culturing and competent clinical examination
DrTVRao MD 49
No testing method replaces Clinical assessment
DrTVRao MD 50
XDR-TBThe description
of XDR-TB was first used earlier in 2006 following a joint survey by WHO and the US Centres for Disease Control and Prevention (CDC) DrTVRao MD 51
How x-MDR generated
Acquired resistance is that which occurs as a result of specific previous treatment The level of primary resistance in the community is considered to reflect the efficacy of control measures in the past while the level of acquired resistance is a measure of on-going TB control measuresDrTVRao MD 52
Extreme Drug resistant Tuberculosis (XDR-TB)
Resistant to all first line drugs namely Isoniazid and Rifampin and Three or more second line drugs (SLDrsquoS) that are used to treat MDR-TB Thequinalones like Ofloaxin
Or Aminoglycosides like Capreomycin amp
Kanamycin
No third-line drugs available to treat XDR-TB since none has been developed in the last 40 years
DrTVRao MD 53
Background Extensively drug-resistant tuberculosis
Extensively drug-resistant tuberculosis has been reported in 45 countries including countries with limited resources and a high burden of tuberculosis
DrTVRao MD 54
DrTVRao MD 55
Transmissionof X -MDR
Like other forms of TB XDR-TB is spread through the air When a person with infectious TB coughs sneezes talks or spits they propel Mycobacterium into the air
DrTVRao MD 56
Best options to diagnoseX-MDR tuberculosis
To evaluate drug susceptibility the bacteria need to be cultivated and tested in a suitable laboratory Final diagnosis in this way for TB and especially for XDR-TB may take from 6 to 16 weeks To reduce the time needed for diagnosis new tools for rapid TB diagnosis are urgently needed
DrTVRao MD 57
When to suspect MDR TB
Patients not showing any reduction
in bacillary population after 3-
months of regular treatment with
Cat II regimen
Sputum positive patients who are
contacts of a known MDR TB
patient
DrTVRao MD 58
How to evaluate MDR TB
MDR TB is only a laboratory
proved HR resistance
Clinical suspicion should be
followed by lab Confirmation
Laboratories should be quality
controlledTRC
DrTVRao MD 59
Extreme Drug resistant Tuberculosis (XDR-TB) and AIDS
It can also be contracted without a patient receiving any previous treatment for TB
Mostly associated with HIV positive patients
HIV has the potential to fast tracking XDR-TB into an uncontrollable epidemic
Average survival period for patients infected with XDR-TB is 16 days
DrTVRao MD 60
Responding to MDRXDR-TB
Augment DOTS Program by
New diagnostics
New drugs New vaccines HIV incidence
reduction Advocacy1
A mathematical model projected by Basu and co-workers indicates that half of XDR-TB can be averted by 2012 by bringing synergistic effects through
Use of masks Reduced time as in-patient Improved ventilation Rapid resistance testing HIV treatment TB isolation facilities2
1Marteens and Wilkinson Lancet 20073702030-432Basu et al Quoted in Porco and Getz Lancet 20073701464-5
DrTVRao MD 61
Second Line Drug Treatment (SLDrsquos)
Less effective more costly and more toxic 50 cure rate
Four months intensive phase (5 drugs) Kanamycins Ethionamide Pyrazinamide Ofloxacin Cycloserine or Ethambutol DrTVRao MD 62
World Health Organisation (WHO) Guidelines for treatment
of MDR-TB
Strengthen basic TB care to prevent the emergence of drug-resistance
Ensure prompt diagnosis and treatment of drug resistant cases to cure existing cases and prevent further transmission
Increase collaboration between HIV and TB control programmes to provide necessary prevention and care to co-infected patients
Increase investment in laboratory infrastructures to enable better detection and management of resistant cases
DrTVRao MD 63
Treatment Guidelines
Sensitivity testing for all smear positive specimens
Patient Family and staff counselling amp education
Correct and thorough hand washing protocol and procedure
Personal protection is very important
DrTVRao MD 64
THE NEW MDR-TB Guidelines
A flexible framework approach combining both clinical and programmatic aspects of DOTS Plus based on essential programme conditions
But encouraging programs to tailor their case-finding and treatment strategies to the local epidemiological and Programme situation
Reflect GLC expert consensus and evidence and experience from GLC projects thus far
DrTVRao MD 65
Effective laboratory Diagnosis
Sputum smear examinations ndash rapid classification of species (atypical mycobacteria common in AIDS)
Culture examinations
Rapid drug sensitivity testingDrTVRao MD 66
MDR TB and HIV
MDR TB occurs with the same frequency in HIV
patients as in TB patients who are smear negative
Transmission of drug-resistant strains among HIV-
infected patients in congregate settings occurs
leading to lsquooutbreaksrsquo of MDR TB in such settings
Infection control measures absolutely essential in
settings where large number of HIV TB patients stay
togetherDrTVRao MD 67
Transmission is dependent on closeness and time of contact
In penitentiary care contacts are very close and prolonged ndash culture positive cases can also transmit TB especially to HIV positive population
DrTVRao MD 68
To Know more on MDR ndashTB Current Guidelines of WHO
Guidelines for the programmatic management of drug-resistant tuberculosis - 2011 update [pdf 904kb]
Visit helliphelliphellip WHOHTMTB20116DrTVRao MD 69
Are there any solutions for effective
Diagnosis in TB
DrTVRao MD 70
Programme Created by DrTVRao MD for Medical and Health Care
Workers in the Developing World Email
doctortvraogmailcom
DrTVRao MD 71
CDC Updates Guidelines for Nucleic AcidAmplification Techniques to Diagnose
Tuberculosis
NAAT results should be interpreted in conjunction with the AFB smear results
NAAT and smear positive start Rx despite pending culture results PPV 95
Smear negative NAAT positive use clinical judgment to either treat or await culture
DrTVRao MD 46
Selection from automated systems for molecular and
bacteriological rapid diagnostics
PCRRocheCOBASreg Amplicorreg
amplification kitsRocheCOBASreg LightCyclerreg
(real-time-PCR)RocheCOBASreg TaqMan 48reg(increases the specificity of real-
time-PCR)
DrTVRao MD 47
Molecular Fingerprinting
26 of 30 (87) XDR TB isolates found to be genetically similar
Majority of patients had no previous history of TB treatment Suggestive of recent infection with drug-resistant strain
DrTVRao MD 48
Is PCR methods a solution
PCR cant yet replace neither microscopy culturing and competent clinical examination
DrTVRao MD 49
No testing method replaces Clinical assessment
DrTVRao MD 50
XDR-TBThe description
of XDR-TB was first used earlier in 2006 following a joint survey by WHO and the US Centres for Disease Control and Prevention (CDC) DrTVRao MD 51
How x-MDR generated
Acquired resistance is that which occurs as a result of specific previous treatment The level of primary resistance in the community is considered to reflect the efficacy of control measures in the past while the level of acquired resistance is a measure of on-going TB control measuresDrTVRao MD 52
Extreme Drug resistant Tuberculosis (XDR-TB)
Resistant to all first line drugs namely Isoniazid and Rifampin and Three or more second line drugs (SLDrsquoS) that are used to treat MDR-TB Thequinalones like Ofloaxin
Or Aminoglycosides like Capreomycin amp
Kanamycin
No third-line drugs available to treat XDR-TB since none has been developed in the last 40 years
DrTVRao MD 53
Background Extensively drug-resistant tuberculosis
Extensively drug-resistant tuberculosis has been reported in 45 countries including countries with limited resources and a high burden of tuberculosis
DrTVRao MD 54
DrTVRao MD 55
Transmissionof X -MDR
Like other forms of TB XDR-TB is spread through the air When a person with infectious TB coughs sneezes talks or spits they propel Mycobacterium into the air
DrTVRao MD 56
Best options to diagnoseX-MDR tuberculosis
To evaluate drug susceptibility the bacteria need to be cultivated and tested in a suitable laboratory Final diagnosis in this way for TB and especially for XDR-TB may take from 6 to 16 weeks To reduce the time needed for diagnosis new tools for rapid TB diagnosis are urgently needed
DrTVRao MD 57
When to suspect MDR TB
Patients not showing any reduction
in bacillary population after 3-
months of regular treatment with
Cat II regimen
Sputum positive patients who are
contacts of a known MDR TB
patient
DrTVRao MD 58
How to evaluate MDR TB
MDR TB is only a laboratory
proved HR resistance
Clinical suspicion should be
followed by lab Confirmation
Laboratories should be quality
controlledTRC
DrTVRao MD 59
Extreme Drug resistant Tuberculosis (XDR-TB) and AIDS
It can also be contracted without a patient receiving any previous treatment for TB
Mostly associated with HIV positive patients
HIV has the potential to fast tracking XDR-TB into an uncontrollable epidemic
Average survival period for patients infected with XDR-TB is 16 days
DrTVRao MD 60
Responding to MDRXDR-TB
Augment DOTS Program by
New diagnostics
New drugs New vaccines HIV incidence
reduction Advocacy1
A mathematical model projected by Basu and co-workers indicates that half of XDR-TB can be averted by 2012 by bringing synergistic effects through
Use of masks Reduced time as in-patient Improved ventilation Rapid resistance testing HIV treatment TB isolation facilities2
1Marteens and Wilkinson Lancet 20073702030-432Basu et al Quoted in Porco and Getz Lancet 20073701464-5
DrTVRao MD 61
Second Line Drug Treatment (SLDrsquos)
Less effective more costly and more toxic 50 cure rate
Four months intensive phase (5 drugs) Kanamycins Ethionamide Pyrazinamide Ofloxacin Cycloserine or Ethambutol DrTVRao MD 62
World Health Organisation (WHO) Guidelines for treatment
of MDR-TB
Strengthen basic TB care to prevent the emergence of drug-resistance
Ensure prompt diagnosis and treatment of drug resistant cases to cure existing cases and prevent further transmission
Increase collaboration between HIV and TB control programmes to provide necessary prevention and care to co-infected patients
Increase investment in laboratory infrastructures to enable better detection and management of resistant cases
DrTVRao MD 63
Treatment Guidelines
Sensitivity testing for all smear positive specimens
Patient Family and staff counselling amp education
Correct and thorough hand washing protocol and procedure
Personal protection is very important
DrTVRao MD 64
THE NEW MDR-TB Guidelines
A flexible framework approach combining both clinical and programmatic aspects of DOTS Plus based on essential programme conditions
But encouraging programs to tailor their case-finding and treatment strategies to the local epidemiological and Programme situation
Reflect GLC expert consensus and evidence and experience from GLC projects thus far
DrTVRao MD 65
Effective laboratory Diagnosis
Sputum smear examinations ndash rapid classification of species (atypical mycobacteria common in AIDS)
Culture examinations
Rapid drug sensitivity testingDrTVRao MD 66
MDR TB and HIV
MDR TB occurs with the same frequency in HIV
patients as in TB patients who are smear negative
Transmission of drug-resistant strains among HIV-
infected patients in congregate settings occurs
leading to lsquooutbreaksrsquo of MDR TB in such settings
Infection control measures absolutely essential in
settings where large number of HIV TB patients stay
togetherDrTVRao MD 67
Transmission is dependent on closeness and time of contact
In penitentiary care contacts are very close and prolonged ndash culture positive cases can also transmit TB especially to HIV positive population
DrTVRao MD 68
To Know more on MDR ndashTB Current Guidelines of WHO
Guidelines for the programmatic management of drug-resistant tuberculosis - 2011 update [pdf 904kb]
Visit helliphelliphellip WHOHTMTB20116DrTVRao MD 69
Are there any solutions for effective
Diagnosis in TB
DrTVRao MD 70
Programme Created by DrTVRao MD for Medical and Health Care
Workers in the Developing World Email
doctortvraogmailcom
DrTVRao MD 71
Selection from automated systems for molecular and
bacteriological rapid diagnostics
PCRRocheCOBASreg Amplicorreg
amplification kitsRocheCOBASreg LightCyclerreg
(real-time-PCR)RocheCOBASreg TaqMan 48reg(increases the specificity of real-
time-PCR)
DrTVRao MD 47
Molecular Fingerprinting
26 of 30 (87) XDR TB isolates found to be genetically similar
Majority of patients had no previous history of TB treatment Suggestive of recent infection with drug-resistant strain
DrTVRao MD 48
Is PCR methods a solution
PCR cant yet replace neither microscopy culturing and competent clinical examination
DrTVRao MD 49
No testing method replaces Clinical assessment
DrTVRao MD 50
XDR-TBThe description
of XDR-TB was first used earlier in 2006 following a joint survey by WHO and the US Centres for Disease Control and Prevention (CDC) DrTVRao MD 51
How x-MDR generated
Acquired resistance is that which occurs as a result of specific previous treatment The level of primary resistance in the community is considered to reflect the efficacy of control measures in the past while the level of acquired resistance is a measure of on-going TB control measuresDrTVRao MD 52
Extreme Drug resistant Tuberculosis (XDR-TB)
Resistant to all first line drugs namely Isoniazid and Rifampin and Three or more second line drugs (SLDrsquoS) that are used to treat MDR-TB Thequinalones like Ofloaxin
Or Aminoglycosides like Capreomycin amp
Kanamycin
No third-line drugs available to treat XDR-TB since none has been developed in the last 40 years
DrTVRao MD 53
Background Extensively drug-resistant tuberculosis
Extensively drug-resistant tuberculosis has been reported in 45 countries including countries with limited resources and a high burden of tuberculosis
DrTVRao MD 54
DrTVRao MD 55
Transmissionof X -MDR
Like other forms of TB XDR-TB is spread through the air When a person with infectious TB coughs sneezes talks or spits they propel Mycobacterium into the air
DrTVRao MD 56
Best options to diagnoseX-MDR tuberculosis
To evaluate drug susceptibility the bacteria need to be cultivated and tested in a suitable laboratory Final diagnosis in this way for TB and especially for XDR-TB may take from 6 to 16 weeks To reduce the time needed for diagnosis new tools for rapid TB diagnosis are urgently needed
DrTVRao MD 57
When to suspect MDR TB
Patients not showing any reduction
in bacillary population after 3-
months of regular treatment with
Cat II regimen
Sputum positive patients who are
contacts of a known MDR TB
patient
DrTVRao MD 58
How to evaluate MDR TB
MDR TB is only a laboratory
proved HR resistance
Clinical suspicion should be
followed by lab Confirmation
Laboratories should be quality
controlledTRC
DrTVRao MD 59
Extreme Drug resistant Tuberculosis (XDR-TB) and AIDS
It can also be contracted without a patient receiving any previous treatment for TB
Mostly associated with HIV positive patients
HIV has the potential to fast tracking XDR-TB into an uncontrollable epidemic
Average survival period for patients infected with XDR-TB is 16 days
DrTVRao MD 60
Responding to MDRXDR-TB
Augment DOTS Program by
New diagnostics
New drugs New vaccines HIV incidence
reduction Advocacy1
A mathematical model projected by Basu and co-workers indicates that half of XDR-TB can be averted by 2012 by bringing synergistic effects through
Use of masks Reduced time as in-patient Improved ventilation Rapid resistance testing HIV treatment TB isolation facilities2
1Marteens and Wilkinson Lancet 20073702030-432Basu et al Quoted in Porco and Getz Lancet 20073701464-5
DrTVRao MD 61
Second Line Drug Treatment (SLDrsquos)
Less effective more costly and more toxic 50 cure rate
Four months intensive phase (5 drugs) Kanamycins Ethionamide Pyrazinamide Ofloxacin Cycloserine or Ethambutol DrTVRao MD 62
World Health Organisation (WHO) Guidelines for treatment
of MDR-TB
Strengthen basic TB care to prevent the emergence of drug-resistance
Ensure prompt diagnosis and treatment of drug resistant cases to cure existing cases and prevent further transmission
Increase collaboration between HIV and TB control programmes to provide necessary prevention and care to co-infected patients
Increase investment in laboratory infrastructures to enable better detection and management of resistant cases
DrTVRao MD 63
Treatment Guidelines
Sensitivity testing for all smear positive specimens
Patient Family and staff counselling amp education
Correct and thorough hand washing protocol and procedure
Personal protection is very important
DrTVRao MD 64
THE NEW MDR-TB Guidelines
A flexible framework approach combining both clinical and programmatic aspects of DOTS Plus based on essential programme conditions
But encouraging programs to tailor their case-finding and treatment strategies to the local epidemiological and Programme situation
Reflect GLC expert consensus and evidence and experience from GLC projects thus far
DrTVRao MD 65
Effective laboratory Diagnosis
Sputum smear examinations ndash rapid classification of species (atypical mycobacteria common in AIDS)
Culture examinations
Rapid drug sensitivity testingDrTVRao MD 66
MDR TB and HIV
MDR TB occurs with the same frequency in HIV
patients as in TB patients who are smear negative
Transmission of drug-resistant strains among HIV-
infected patients in congregate settings occurs
leading to lsquooutbreaksrsquo of MDR TB in such settings
Infection control measures absolutely essential in
settings where large number of HIV TB patients stay
togetherDrTVRao MD 67
Transmission is dependent on closeness and time of contact
In penitentiary care contacts are very close and prolonged ndash culture positive cases can also transmit TB especially to HIV positive population
DrTVRao MD 68
To Know more on MDR ndashTB Current Guidelines of WHO
Guidelines for the programmatic management of drug-resistant tuberculosis - 2011 update [pdf 904kb]
Visit helliphelliphellip WHOHTMTB20116DrTVRao MD 69
Are there any solutions for effective
Diagnosis in TB
DrTVRao MD 70
Programme Created by DrTVRao MD for Medical and Health Care
Workers in the Developing World Email
doctortvraogmailcom
DrTVRao MD 71
Molecular Fingerprinting
26 of 30 (87) XDR TB isolates found to be genetically similar
Majority of patients had no previous history of TB treatment Suggestive of recent infection with drug-resistant strain
DrTVRao MD 48
Is PCR methods a solution
PCR cant yet replace neither microscopy culturing and competent clinical examination
DrTVRao MD 49
No testing method replaces Clinical assessment
DrTVRao MD 50
XDR-TBThe description
of XDR-TB was first used earlier in 2006 following a joint survey by WHO and the US Centres for Disease Control and Prevention (CDC) DrTVRao MD 51
How x-MDR generated
Acquired resistance is that which occurs as a result of specific previous treatment The level of primary resistance in the community is considered to reflect the efficacy of control measures in the past while the level of acquired resistance is a measure of on-going TB control measuresDrTVRao MD 52
Extreme Drug resistant Tuberculosis (XDR-TB)
Resistant to all first line drugs namely Isoniazid and Rifampin and Three or more second line drugs (SLDrsquoS) that are used to treat MDR-TB Thequinalones like Ofloaxin
Or Aminoglycosides like Capreomycin amp
Kanamycin
No third-line drugs available to treat XDR-TB since none has been developed in the last 40 years
DrTVRao MD 53
Background Extensively drug-resistant tuberculosis
Extensively drug-resistant tuberculosis has been reported in 45 countries including countries with limited resources and a high burden of tuberculosis
DrTVRao MD 54
DrTVRao MD 55
Transmissionof X -MDR
Like other forms of TB XDR-TB is spread through the air When a person with infectious TB coughs sneezes talks or spits they propel Mycobacterium into the air
DrTVRao MD 56
Best options to diagnoseX-MDR tuberculosis
To evaluate drug susceptibility the bacteria need to be cultivated and tested in a suitable laboratory Final diagnosis in this way for TB and especially for XDR-TB may take from 6 to 16 weeks To reduce the time needed for diagnosis new tools for rapid TB diagnosis are urgently needed
DrTVRao MD 57
When to suspect MDR TB
Patients not showing any reduction
in bacillary population after 3-
months of regular treatment with
Cat II regimen
Sputum positive patients who are
contacts of a known MDR TB
patient
DrTVRao MD 58
How to evaluate MDR TB
MDR TB is only a laboratory
proved HR resistance
Clinical suspicion should be
followed by lab Confirmation
Laboratories should be quality
controlledTRC
DrTVRao MD 59
Extreme Drug resistant Tuberculosis (XDR-TB) and AIDS
It can also be contracted without a patient receiving any previous treatment for TB
Mostly associated with HIV positive patients
HIV has the potential to fast tracking XDR-TB into an uncontrollable epidemic
Average survival period for patients infected with XDR-TB is 16 days
DrTVRao MD 60
Responding to MDRXDR-TB
Augment DOTS Program by
New diagnostics
New drugs New vaccines HIV incidence
reduction Advocacy1
A mathematical model projected by Basu and co-workers indicates that half of XDR-TB can be averted by 2012 by bringing synergistic effects through
Use of masks Reduced time as in-patient Improved ventilation Rapid resistance testing HIV treatment TB isolation facilities2
1Marteens and Wilkinson Lancet 20073702030-432Basu et al Quoted in Porco and Getz Lancet 20073701464-5
DrTVRao MD 61
Second Line Drug Treatment (SLDrsquos)
Less effective more costly and more toxic 50 cure rate
Four months intensive phase (5 drugs) Kanamycins Ethionamide Pyrazinamide Ofloxacin Cycloserine or Ethambutol DrTVRao MD 62
World Health Organisation (WHO) Guidelines for treatment
of MDR-TB
Strengthen basic TB care to prevent the emergence of drug-resistance
Ensure prompt diagnosis and treatment of drug resistant cases to cure existing cases and prevent further transmission
Increase collaboration between HIV and TB control programmes to provide necessary prevention and care to co-infected patients
Increase investment in laboratory infrastructures to enable better detection and management of resistant cases
DrTVRao MD 63
Treatment Guidelines
Sensitivity testing for all smear positive specimens
Patient Family and staff counselling amp education
Correct and thorough hand washing protocol and procedure
Personal protection is very important
DrTVRao MD 64
THE NEW MDR-TB Guidelines
A flexible framework approach combining both clinical and programmatic aspects of DOTS Plus based on essential programme conditions
But encouraging programs to tailor their case-finding and treatment strategies to the local epidemiological and Programme situation
Reflect GLC expert consensus and evidence and experience from GLC projects thus far
DrTVRao MD 65
Effective laboratory Diagnosis
Sputum smear examinations ndash rapid classification of species (atypical mycobacteria common in AIDS)
Culture examinations
Rapid drug sensitivity testingDrTVRao MD 66
MDR TB and HIV
MDR TB occurs with the same frequency in HIV
patients as in TB patients who are smear negative
Transmission of drug-resistant strains among HIV-
infected patients in congregate settings occurs
leading to lsquooutbreaksrsquo of MDR TB in such settings
Infection control measures absolutely essential in
settings where large number of HIV TB patients stay
togetherDrTVRao MD 67
Transmission is dependent on closeness and time of contact
In penitentiary care contacts are very close and prolonged ndash culture positive cases can also transmit TB especially to HIV positive population
DrTVRao MD 68
To Know more on MDR ndashTB Current Guidelines of WHO
Guidelines for the programmatic management of drug-resistant tuberculosis - 2011 update [pdf 904kb]
Visit helliphelliphellip WHOHTMTB20116DrTVRao MD 69
Are there any solutions for effective
Diagnosis in TB
DrTVRao MD 70
Programme Created by DrTVRao MD for Medical and Health Care
Workers in the Developing World Email
doctortvraogmailcom
DrTVRao MD 71
Is PCR methods a solution
PCR cant yet replace neither microscopy culturing and competent clinical examination
DrTVRao MD 49
No testing method replaces Clinical assessment
DrTVRao MD 50
XDR-TBThe description
of XDR-TB was first used earlier in 2006 following a joint survey by WHO and the US Centres for Disease Control and Prevention (CDC) DrTVRao MD 51
How x-MDR generated
Acquired resistance is that which occurs as a result of specific previous treatment The level of primary resistance in the community is considered to reflect the efficacy of control measures in the past while the level of acquired resistance is a measure of on-going TB control measuresDrTVRao MD 52
Extreme Drug resistant Tuberculosis (XDR-TB)
Resistant to all first line drugs namely Isoniazid and Rifampin and Three or more second line drugs (SLDrsquoS) that are used to treat MDR-TB Thequinalones like Ofloaxin
Or Aminoglycosides like Capreomycin amp
Kanamycin
No third-line drugs available to treat XDR-TB since none has been developed in the last 40 years
DrTVRao MD 53
Background Extensively drug-resistant tuberculosis
Extensively drug-resistant tuberculosis has been reported in 45 countries including countries with limited resources and a high burden of tuberculosis
DrTVRao MD 54
DrTVRao MD 55
Transmissionof X -MDR
Like other forms of TB XDR-TB is spread through the air When a person with infectious TB coughs sneezes talks or spits they propel Mycobacterium into the air
DrTVRao MD 56
Best options to diagnoseX-MDR tuberculosis
To evaluate drug susceptibility the bacteria need to be cultivated and tested in a suitable laboratory Final diagnosis in this way for TB and especially for XDR-TB may take from 6 to 16 weeks To reduce the time needed for diagnosis new tools for rapid TB diagnosis are urgently needed
DrTVRao MD 57
When to suspect MDR TB
Patients not showing any reduction
in bacillary population after 3-
months of regular treatment with
Cat II regimen
Sputum positive patients who are
contacts of a known MDR TB
patient
DrTVRao MD 58
How to evaluate MDR TB
MDR TB is only a laboratory
proved HR resistance
Clinical suspicion should be
followed by lab Confirmation
Laboratories should be quality
controlledTRC
DrTVRao MD 59
Extreme Drug resistant Tuberculosis (XDR-TB) and AIDS
It can also be contracted without a patient receiving any previous treatment for TB
Mostly associated with HIV positive patients
HIV has the potential to fast tracking XDR-TB into an uncontrollable epidemic
Average survival period for patients infected with XDR-TB is 16 days
DrTVRao MD 60
Responding to MDRXDR-TB
Augment DOTS Program by
New diagnostics
New drugs New vaccines HIV incidence
reduction Advocacy1
A mathematical model projected by Basu and co-workers indicates that half of XDR-TB can be averted by 2012 by bringing synergistic effects through
Use of masks Reduced time as in-patient Improved ventilation Rapid resistance testing HIV treatment TB isolation facilities2
1Marteens and Wilkinson Lancet 20073702030-432Basu et al Quoted in Porco and Getz Lancet 20073701464-5
DrTVRao MD 61
Second Line Drug Treatment (SLDrsquos)
Less effective more costly and more toxic 50 cure rate
Four months intensive phase (5 drugs) Kanamycins Ethionamide Pyrazinamide Ofloxacin Cycloserine or Ethambutol DrTVRao MD 62
World Health Organisation (WHO) Guidelines for treatment
of MDR-TB
Strengthen basic TB care to prevent the emergence of drug-resistance
Ensure prompt diagnosis and treatment of drug resistant cases to cure existing cases and prevent further transmission
Increase collaboration between HIV and TB control programmes to provide necessary prevention and care to co-infected patients
Increase investment in laboratory infrastructures to enable better detection and management of resistant cases
DrTVRao MD 63
Treatment Guidelines
Sensitivity testing for all smear positive specimens
Patient Family and staff counselling amp education
Correct and thorough hand washing protocol and procedure
Personal protection is very important
DrTVRao MD 64
THE NEW MDR-TB Guidelines
A flexible framework approach combining both clinical and programmatic aspects of DOTS Plus based on essential programme conditions
But encouraging programs to tailor their case-finding and treatment strategies to the local epidemiological and Programme situation
Reflect GLC expert consensus and evidence and experience from GLC projects thus far
DrTVRao MD 65
Effective laboratory Diagnosis
Sputum smear examinations ndash rapid classification of species (atypical mycobacteria common in AIDS)
Culture examinations
Rapid drug sensitivity testingDrTVRao MD 66
MDR TB and HIV
MDR TB occurs with the same frequency in HIV
patients as in TB patients who are smear negative
Transmission of drug-resistant strains among HIV-
infected patients in congregate settings occurs
leading to lsquooutbreaksrsquo of MDR TB in such settings
Infection control measures absolutely essential in
settings where large number of HIV TB patients stay
togetherDrTVRao MD 67
Transmission is dependent on closeness and time of contact
In penitentiary care contacts are very close and prolonged ndash culture positive cases can also transmit TB especially to HIV positive population
DrTVRao MD 68
To Know more on MDR ndashTB Current Guidelines of WHO
Guidelines for the programmatic management of drug-resistant tuberculosis - 2011 update [pdf 904kb]
Visit helliphelliphellip WHOHTMTB20116DrTVRao MD 69
Are there any solutions for effective
Diagnosis in TB
DrTVRao MD 70
Programme Created by DrTVRao MD for Medical and Health Care
Workers in the Developing World Email
doctortvraogmailcom
DrTVRao MD 71
No testing method replaces Clinical assessment
DrTVRao MD 50
XDR-TBThe description
of XDR-TB was first used earlier in 2006 following a joint survey by WHO and the US Centres for Disease Control and Prevention (CDC) DrTVRao MD 51
How x-MDR generated
Acquired resistance is that which occurs as a result of specific previous treatment The level of primary resistance in the community is considered to reflect the efficacy of control measures in the past while the level of acquired resistance is a measure of on-going TB control measuresDrTVRao MD 52
Extreme Drug resistant Tuberculosis (XDR-TB)
Resistant to all first line drugs namely Isoniazid and Rifampin and Three or more second line drugs (SLDrsquoS) that are used to treat MDR-TB Thequinalones like Ofloaxin
Or Aminoglycosides like Capreomycin amp
Kanamycin
No third-line drugs available to treat XDR-TB since none has been developed in the last 40 years
DrTVRao MD 53
Background Extensively drug-resistant tuberculosis
Extensively drug-resistant tuberculosis has been reported in 45 countries including countries with limited resources and a high burden of tuberculosis
DrTVRao MD 54
DrTVRao MD 55
Transmissionof X -MDR
Like other forms of TB XDR-TB is spread through the air When a person with infectious TB coughs sneezes talks or spits they propel Mycobacterium into the air
DrTVRao MD 56
Best options to diagnoseX-MDR tuberculosis
To evaluate drug susceptibility the bacteria need to be cultivated and tested in a suitable laboratory Final diagnosis in this way for TB and especially for XDR-TB may take from 6 to 16 weeks To reduce the time needed for diagnosis new tools for rapid TB diagnosis are urgently needed
DrTVRao MD 57
When to suspect MDR TB
Patients not showing any reduction
in bacillary population after 3-
months of regular treatment with
Cat II regimen
Sputum positive patients who are
contacts of a known MDR TB
patient
DrTVRao MD 58
How to evaluate MDR TB
MDR TB is only a laboratory
proved HR resistance
Clinical suspicion should be
followed by lab Confirmation
Laboratories should be quality
controlledTRC
DrTVRao MD 59
Extreme Drug resistant Tuberculosis (XDR-TB) and AIDS
It can also be contracted without a patient receiving any previous treatment for TB
Mostly associated with HIV positive patients
HIV has the potential to fast tracking XDR-TB into an uncontrollable epidemic
Average survival period for patients infected with XDR-TB is 16 days
DrTVRao MD 60
Responding to MDRXDR-TB
Augment DOTS Program by
New diagnostics
New drugs New vaccines HIV incidence
reduction Advocacy1
A mathematical model projected by Basu and co-workers indicates that half of XDR-TB can be averted by 2012 by bringing synergistic effects through
Use of masks Reduced time as in-patient Improved ventilation Rapid resistance testing HIV treatment TB isolation facilities2
1Marteens and Wilkinson Lancet 20073702030-432Basu et al Quoted in Porco and Getz Lancet 20073701464-5
DrTVRao MD 61
Second Line Drug Treatment (SLDrsquos)
Less effective more costly and more toxic 50 cure rate
Four months intensive phase (5 drugs) Kanamycins Ethionamide Pyrazinamide Ofloxacin Cycloserine or Ethambutol DrTVRao MD 62
World Health Organisation (WHO) Guidelines for treatment
of MDR-TB
Strengthen basic TB care to prevent the emergence of drug-resistance
Ensure prompt diagnosis and treatment of drug resistant cases to cure existing cases and prevent further transmission
Increase collaboration between HIV and TB control programmes to provide necessary prevention and care to co-infected patients
Increase investment in laboratory infrastructures to enable better detection and management of resistant cases
DrTVRao MD 63
Treatment Guidelines
Sensitivity testing for all smear positive specimens
Patient Family and staff counselling amp education
Correct and thorough hand washing protocol and procedure
Personal protection is very important
DrTVRao MD 64
THE NEW MDR-TB Guidelines
A flexible framework approach combining both clinical and programmatic aspects of DOTS Plus based on essential programme conditions
But encouraging programs to tailor their case-finding and treatment strategies to the local epidemiological and Programme situation
Reflect GLC expert consensus and evidence and experience from GLC projects thus far
DrTVRao MD 65
Effective laboratory Diagnosis
Sputum smear examinations ndash rapid classification of species (atypical mycobacteria common in AIDS)
Culture examinations
Rapid drug sensitivity testingDrTVRao MD 66
MDR TB and HIV
MDR TB occurs with the same frequency in HIV
patients as in TB patients who are smear negative
Transmission of drug-resistant strains among HIV-
infected patients in congregate settings occurs
leading to lsquooutbreaksrsquo of MDR TB in such settings
Infection control measures absolutely essential in
settings where large number of HIV TB patients stay
togetherDrTVRao MD 67
Transmission is dependent on closeness and time of contact
In penitentiary care contacts are very close and prolonged ndash culture positive cases can also transmit TB especially to HIV positive population
DrTVRao MD 68
To Know more on MDR ndashTB Current Guidelines of WHO
Guidelines for the programmatic management of drug-resistant tuberculosis - 2011 update [pdf 904kb]
Visit helliphelliphellip WHOHTMTB20116DrTVRao MD 69
Are there any solutions for effective
Diagnosis in TB
DrTVRao MD 70
Programme Created by DrTVRao MD for Medical and Health Care
Workers in the Developing World Email
doctortvraogmailcom
DrTVRao MD 71
XDR-TBThe description
of XDR-TB was first used earlier in 2006 following a joint survey by WHO and the US Centres for Disease Control and Prevention (CDC) DrTVRao MD 51
How x-MDR generated
Acquired resistance is that which occurs as a result of specific previous treatment The level of primary resistance in the community is considered to reflect the efficacy of control measures in the past while the level of acquired resistance is a measure of on-going TB control measuresDrTVRao MD 52
Extreme Drug resistant Tuberculosis (XDR-TB)
Resistant to all first line drugs namely Isoniazid and Rifampin and Three or more second line drugs (SLDrsquoS) that are used to treat MDR-TB Thequinalones like Ofloaxin
Or Aminoglycosides like Capreomycin amp
Kanamycin
No third-line drugs available to treat XDR-TB since none has been developed in the last 40 years
DrTVRao MD 53
Background Extensively drug-resistant tuberculosis
Extensively drug-resistant tuberculosis has been reported in 45 countries including countries with limited resources and a high burden of tuberculosis
DrTVRao MD 54
DrTVRao MD 55
Transmissionof X -MDR
Like other forms of TB XDR-TB is spread through the air When a person with infectious TB coughs sneezes talks or spits they propel Mycobacterium into the air
DrTVRao MD 56
Best options to diagnoseX-MDR tuberculosis
To evaluate drug susceptibility the bacteria need to be cultivated and tested in a suitable laboratory Final diagnosis in this way for TB and especially for XDR-TB may take from 6 to 16 weeks To reduce the time needed for diagnosis new tools for rapid TB diagnosis are urgently needed
DrTVRao MD 57
When to suspect MDR TB
Patients not showing any reduction
in bacillary population after 3-
months of regular treatment with
Cat II regimen
Sputum positive patients who are
contacts of a known MDR TB
patient
DrTVRao MD 58
How to evaluate MDR TB
MDR TB is only a laboratory
proved HR resistance
Clinical suspicion should be
followed by lab Confirmation
Laboratories should be quality
controlledTRC
DrTVRao MD 59
Extreme Drug resistant Tuberculosis (XDR-TB) and AIDS
It can also be contracted without a patient receiving any previous treatment for TB
Mostly associated with HIV positive patients
HIV has the potential to fast tracking XDR-TB into an uncontrollable epidemic
Average survival period for patients infected with XDR-TB is 16 days
DrTVRao MD 60
Responding to MDRXDR-TB
Augment DOTS Program by
New diagnostics
New drugs New vaccines HIV incidence
reduction Advocacy1
A mathematical model projected by Basu and co-workers indicates that half of XDR-TB can be averted by 2012 by bringing synergistic effects through
Use of masks Reduced time as in-patient Improved ventilation Rapid resistance testing HIV treatment TB isolation facilities2
1Marteens and Wilkinson Lancet 20073702030-432Basu et al Quoted in Porco and Getz Lancet 20073701464-5
DrTVRao MD 61
Second Line Drug Treatment (SLDrsquos)
Less effective more costly and more toxic 50 cure rate
Four months intensive phase (5 drugs) Kanamycins Ethionamide Pyrazinamide Ofloxacin Cycloserine or Ethambutol DrTVRao MD 62
World Health Organisation (WHO) Guidelines for treatment
of MDR-TB
Strengthen basic TB care to prevent the emergence of drug-resistance
Ensure prompt diagnosis and treatment of drug resistant cases to cure existing cases and prevent further transmission
Increase collaboration between HIV and TB control programmes to provide necessary prevention and care to co-infected patients
Increase investment in laboratory infrastructures to enable better detection and management of resistant cases
DrTVRao MD 63
Treatment Guidelines
Sensitivity testing for all smear positive specimens
Patient Family and staff counselling amp education
Correct and thorough hand washing protocol and procedure
Personal protection is very important
DrTVRao MD 64
THE NEW MDR-TB Guidelines
A flexible framework approach combining both clinical and programmatic aspects of DOTS Plus based on essential programme conditions
But encouraging programs to tailor their case-finding and treatment strategies to the local epidemiological and Programme situation
Reflect GLC expert consensus and evidence and experience from GLC projects thus far
DrTVRao MD 65
Effective laboratory Diagnosis
Sputum smear examinations ndash rapid classification of species (atypical mycobacteria common in AIDS)
Culture examinations
Rapid drug sensitivity testingDrTVRao MD 66
MDR TB and HIV
MDR TB occurs with the same frequency in HIV
patients as in TB patients who are smear negative
Transmission of drug-resistant strains among HIV-
infected patients in congregate settings occurs
leading to lsquooutbreaksrsquo of MDR TB in such settings
Infection control measures absolutely essential in
settings where large number of HIV TB patients stay
togetherDrTVRao MD 67
Transmission is dependent on closeness and time of contact
In penitentiary care contacts are very close and prolonged ndash culture positive cases can also transmit TB especially to HIV positive population
DrTVRao MD 68
To Know more on MDR ndashTB Current Guidelines of WHO
Guidelines for the programmatic management of drug-resistant tuberculosis - 2011 update [pdf 904kb]
Visit helliphelliphellip WHOHTMTB20116DrTVRao MD 69
Are there any solutions for effective
Diagnosis in TB
DrTVRao MD 70
Programme Created by DrTVRao MD for Medical and Health Care
Workers in the Developing World Email
doctortvraogmailcom
DrTVRao MD 71
How x-MDR generated
Acquired resistance is that which occurs as a result of specific previous treatment The level of primary resistance in the community is considered to reflect the efficacy of control measures in the past while the level of acquired resistance is a measure of on-going TB control measuresDrTVRao MD 52
Extreme Drug resistant Tuberculosis (XDR-TB)
Resistant to all first line drugs namely Isoniazid and Rifampin and Three or more second line drugs (SLDrsquoS) that are used to treat MDR-TB Thequinalones like Ofloaxin
Or Aminoglycosides like Capreomycin amp
Kanamycin
No third-line drugs available to treat XDR-TB since none has been developed in the last 40 years
DrTVRao MD 53
Background Extensively drug-resistant tuberculosis
Extensively drug-resistant tuberculosis has been reported in 45 countries including countries with limited resources and a high burden of tuberculosis
DrTVRao MD 54
DrTVRao MD 55
Transmissionof X -MDR
Like other forms of TB XDR-TB is spread through the air When a person with infectious TB coughs sneezes talks or spits they propel Mycobacterium into the air
DrTVRao MD 56
Best options to diagnoseX-MDR tuberculosis
To evaluate drug susceptibility the bacteria need to be cultivated and tested in a suitable laboratory Final diagnosis in this way for TB and especially for XDR-TB may take from 6 to 16 weeks To reduce the time needed for diagnosis new tools for rapid TB diagnosis are urgently needed
DrTVRao MD 57
When to suspect MDR TB
Patients not showing any reduction
in bacillary population after 3-
months of regular treatment with
Cat II regimen
Sputum positive patients who are
contacts of a known MDR TB
patient
DrTVRao MD 58
How to evaluate MDR TB
MDR TB is only a laboratory
proved HR resistance
Clinical suspicion should be
followed by lab Confirmation
Laboratories should be quality
controlledTRC
DrTVRao MD 59
Extreme Drug resistant Tuberculosis (XDR-TB) and AIDS
It can also be contracted without a patient receiving any previous treatment for TB
Mostly associated with HIV positive patients
HIV has the potential to fast tracking XDR-TB into an uncontrollable epidemic
Average survival period for patients infected with XDR-TB is 16 days
DrTVRao MD 60
Responding to MDRXDR-TB
Augment DOTS Program by
New diagnostics
New drugs New vaccines HIV incidence
reduction Advocacy1
A mathematical model projected by Basu and co-workers indicates that half of XDR-TB can be averted by 2012 by bringing synergistic effects through
Use of masks Reduced time as in-patient Improved ventilation Rapid resistance testing HIV treatment TB isolation facilities2
1Marteens and Wilkinson Lancet 20073702030-432Basu et al Quoted in Porco and Getz Lancet 20073701464-5
DrTVRao MD 61
Second Line Drug Treatment (SLDrsquos)
Less effective more costly and more toxic 50 cure rate
Four months intensive phase (5 drugs) Kanamycins Ethionamide Pyrazinamide Ofloxacin Cycloserine or Ethambutol DrTVRao MD 62
World Health Organisation (WHO) Guidelines for treatment
of MDR-TB
Strengthen basic TB care to prevent the emergence of drug-resistance
Ensure prompt diagnosis and treatment of drug resistant cases to cure existing cases and prevent further transmission
Increase collaboration between HIV and TB control programmes to provide necessary prevention and care to co-infected patients
Increase investment in laboratory infrastructures to enable better detection and management of resistant cases
DrTVRao MD 63
Treatment Guidelines
Sensitivity testing for all smear positive specimens
Patient Family and staff counselling amp education
Correct and thorough hand washing protocol and procedure
Personal protection is very important
DrTVRao MD 64
THE NEW MDR-TB Guidelines
A flexible framework approach combining both clinical and programmatic aspects of DOTS Plus based on essential programme conditions
But encouraging programs to tailor their case-finding and treatment strategies to the local epidemiological and Programme situation
Reflect GLC expert consensus and evidence and experience from GLC projects thus far
DrTVRao MD 65
Effective laboratory Diagnosis
Sputum smear examinations ndash rapid classification of species (atypical mycobacteria common in AIDS)
Culture examinations
Rapid drug sensitivity testingDrTVRao MD 66
MDR TB and HIV
MDR TB occurs with the same frequency in HIV
patients as in TB patients who are smear negative
Transmission of drug-resistant strains among HIV-
infected patients in congregate settings occurs
leading to lsquooutbreaksrsquo of MDR TB in such settings
Infection control measures absolutely essential in
settings where large number of HIV TB patients stay
togetherDrTVRao MD 67
Transmission is dependent on closeness and time of contact
In penitentiary care contacts are very close and prolonged ndash culture positive cases can also transmit TB especially to HIV positive population
DrTVRao MD 68
To Know more on MDR ndashTB Current Guidelines of WHO
Guidelines for the programmatic management of drug-resistant tuberculosis - 2011 update [pdf 904kb]
Visit helliphelliphellip WHOHTMTB20116DrTVRao MD 69
Are there any solutions for effective
Diagnosis in TB
DrTVRao MD 70
Programme Created by DrTVRao MD for Medical and Health Care
Workers in the Developing World Email
doctortvraogmailcom
DrTVRao MD 71
Extreme Drug resistant Tuberculosis (XDR-TB)
Resistant to all first line drugs namely Isoniazid and Rifampin and Three or more second line drugs (SLDrsquoS) that are used to treat MDR-TB Thequinalones like Ofloaxin
Or Aminoglycosides like Capreomycin amp
Kanamycin
No third-line drugs available to treat XDR-TB since none has been developed in the last 40 years
DrTVRao MD 53
Background Extensively drug-resistant tuberculosis
Extensively drug-resistant tuberculosis has been reported in 45 countries including countries with limited resources and a high burden of tuberculosis
DrTVRao MD 54
DrTVRao MD 55
Transmissionof X -MDR
Like other forms of TB XDR-TB is spread through the air When a person with infectious TB coughs sneezes talks or spits they propel Mycobacterium into the air
DrTVRao MD 56
Best options to diagnoseX-MDR tuberculosis
To evaluate drug susceptibility the bacteria need to be cultivated and tested in a suitable laboratory Final diagnosis in this way for TB and especially for XDR-TB may take from 6 to 16 weeks To reduce the time needed for diagnosis new tools for rapid TB diagnosis are urgently needed
DrTVRao MD 57
When to suspect MDR TB
Patients not showing any reduction
in bacillary population after 3-
months of regular treatment with
Cat II regimen
Sputum positive patients who are
contacts of a known MDR TB
patient
DrTVRao MD 58
How to evaluate MDR TB
MDR TB is only a laboratory
proved HR resistance
Clinical suspicion should be
followed by lab Confirmation
Laboratories should be quality
controlledTRC
DrTVRao MD 59
Extreme Drug resistant Tuberculosis (XDR-TB) and AIDS
It can also be contracted without a patient receiving any previous treatment for TB
Mostly associated with HIV positive patients
HIV has the potential to fast tracking XDR-TB into an uncontrollable epidemic
Average survival period for patients infected with XDR-TB is 16 days
DrTVRao MD 60
Responding to MDRXDR-TB
Augment DOTS Program by
New diagnostics
New drugs New vaccines HIV incidence
reduction Advocacy1
A mathematical model projected by Basu and co-workers indicates that half of XDR-TB can be averted by 2012 by bringing synergistic effects through
Use of masks Reduced time as in-patient Improved ventilation Rapid resistance testing HIV treatment TB isolation facilities2
1Marteens and Wilkinson Lancet 20073702030-432Basu et al Quoted in Porco and Getz Lancet 20073701464-5
DrTVRao MD 61
Second Line Drug Treatment (SLDrsquos)
Less effective more costly and more toxic 50 cure rate
Four months intensive phase (5 drugs) Kanamycins Ethionamide Pyrazinamide Ofloxacin Cycloserine or Ethambutol DrTVRao MD 62
World Health Organisation (WHO) Guidelines for treatment
of MDR-TB
Strengthen basic TB care to prevent the emergence of drug-resistance
Ensure prompt diagnosis and treatment of drug resistant cases to cure existing cases and prevent further transmission
Increase collaboration between HIV and TB control programmes to provide necessary prevention and care to co-infected patients
Increase investment in laboratory infrastructures to enable better detection and management of resistant cases
DrTVRao MD 63
Treatment Guidelines
Sensitivity testing for all smear positive specimens
Patient Family and staff counselling amp education
Correct and thorough hand washing protocol and procedure
Personal protection is very important
DrTVRao MD 64
THE NEW MDR-TB Guidelines
A flexible framework approach combining both clinical and programmatic aspects of DOTS Plus based on essential programme conditions
But encouraging programs to tailor their case-finding and treatment strategies to the local epidemiological and Programme situation
Reflect GLC expert consensus and evidence and experience from GLC projects thus far
DrTVRao MD 65
Effective laboratory Diagnosis
Sputum smear examinations ndash rapid classification of species (atypical mycobacteria common in AIDS)
Culture examinations
Rapid drug sensitivity testingDrTVRao MD 66
MDR TB and HIV
MDR TB occurs with the same frequency in HIV
patients as in TB patients who are smear negative
Transmission of drug-resistant strains among HIV-
infected patients in congregate settings occurs
leading to lsquooutbreaksrsquo of MDR TB in such settings
Infection control measures absolutely essential in
settings where large number of HIV TB patients stay
togetherDrTVRao MD 67
Transmission is dependent on closeness and time of contact
In penitentiary care contacts are very close and prolonged ndash culture positive cases can also transmit TB especially to HIV positive population
DrTVRao MD 68
To Know more on MDR ndashTB Current Guidelines of WHO
Guidelines for the programmatic management of drug-resistant tuberculosis - 2011 update [pdf 904kb]
Visit helliphelliphellip WHOHTMTB20116DrTVRao MD 69
Are there any solutions for effective
Diagnosis in TB
DrTVRao MD 70
Programme Created by DrTVRao MD for Medical and Health Care
Workers in the Developing World Email
doctortvraogmailcom
DrTVRao MD 71
Background Extensively drug-resistant tuberculosis
Extensively drug-resistant tuberculosis has been reported in 45 countries including countries with limited resources and a high burden of tuberculosis
DrTVRao MD 54
DrTVRao MD 55
Transmissionof X -MDR
Like other forms of TB XDR-TB is spread through the air When a person with infectious TB coughs sneezes talks or spits they propel Mycobacterium into the air
DrTVRao MD 56
Best options to diagnoseX-MDR tuberculosis
To evaluate drug susceptibility the bacteria need to be cultivated and tested in a suitable laboratory Final diagnosis in this way for TB and especially for XDR-TB may take from 6 to 16 weeks To reduce the time needed for diagnosis new tools for rapid TB diagnosis are urgently needed
DrTVRao MD 57
When to suspect MDR TB
Patients not showing any reduction
in bacillary population after 3-
months of regular treatment with
Cat II regimen
Sputum positive patients who are
contacts of a known MDR TB
patient
DrTVRao MD 58
How to evaluate MDR TB
MDR TB is only a laboratory
proved HR resistance
Clinical suspicion should be
followed by lab Confirmation
Laboratories should be quality
controlledTRC
DrTVRao MD 59
Extreme Drug resistant Tuberculosis (XDR-TB) and AIDS
It can also be contracted without a patient receiving any previous treatment for TB
Mostly associated with HIV positive patients
HIV has the potential to fast tracking XDR-TB into an uncontrollable epidemic
Average survival period for patients infected with XDR-TB is 16 days
DrTVRao MD 60
Responding to MDRXDR-TB
Augment DOTS Program by
New diagnostics
New drugs New vaccines HIV incidence
reduction Advocacy1
A mathematical model projected by Basu and co-workers indicates that half of XDR-TB can be averted by 2012 by bringing synergistic effects through
Use of masks Reduced time as in-patient Improved ventilation Rapid resistance testing HIV treatment TB isolation facilities2
1Marteens and Wilkinson Lancet 20073702030-432Basu et al Quoted in Porco and Getz Lancet 20073701464-5
DrTVRao MD 61
Second Line Drug Treatment (SLDrsquos)
Less effective more costly and more toxic 50 cure rate
Four months intensive phase (5 drugs) Kanamycins Ethionamide Pyrazinamide Ofloxacin Cycloserine or Ethambutol DrTVRao MD 62
World Health Organisation (WHO) Guidelines for treatment
of MDR-TB
Strengthen basic TB care to prevent the emergence of drug-resistance
Ensure prompt diagnosis and treatment of drug resistant cases to cure existing cases and prevent further transmission
Increase collaboration between HIV and TB control programmes to provide necessary prevention and care to co-infected patients
Increase investment in laboratory infrastructures to enable better detection and management of resistant cases
DrTVRao MD 63
Treatment Guidelines
Sensitivity testing for all smear positive specimens
Patient Family and staff counselling amp education
Correct and thorough hand washing protocol and procedure
Personal protection is very important
DrTVRao MD 64
THE NEW MDR-TB Guidelines
A flexible framework approach combining both clinical and programmatic aspects of DOTS Plus based on essential programme conditions
But encouraging programs to tailor their case-finding and treatment strategies to the local epidemiological and Programme situation
Reflect GLC expert consensus and evidence and experience from GLC projects thus far
DrTVRao MD 65
Effective laboratory Diagnosis
Sputum smear examinations ndash rapid classification of species (atypical mycobacteria common in AIDS)
Culture examinations
Rapid drug sensitivity testingDrTVRao MD 66
MDR TB and HIV
MDR TB occurs with the same frequency in HIV
patients as in TB patients who are smear negative
Transmission of drug-resistant strains among HIV-
infected patients in congregate settings occurs
leading to lsquooutbreaksrsquo of MDR TB in such settings
Infection control measures absolutely essential in
settings where large number of HIV TB patients stay
togetherDrTVRao MD 67
Transmission is dependent on closeness and time of contact
In penitentiary care contacts are very close and prolonged ndash culture positive cases can also transmit TB especially to HIV positive population
DrTVRao MD 68
To Know more on MDR ndashTB Current Guidelines of WHO
Guidelines for the programmatic management of drug-resistant tuberculosis - 2011 update [pdf 904kb]
Visit helliphelliphellip WHOHTMTB20116DrTVRao MD 69
Are there any solutions for effective
Diagnosis in TB
DrTVRao MD 70
Programme Created by DrTVRao MD for Medical and Health Care
Workers in the Developing World Email
doctortvraogmailcom
DrTVRao MD 71
DrTVRao MD 55
Transmissionof X -MDR
Like other forms of TB XDR-TB is spread through the air When a person with infectious TB coughs sneezes talks or spits they propel Mycobacterium into the air
DrTVRao MD 56
Best options to diagnoseX-MDR tuberculosis
To evaluate drug susceptibility the bacteria need to be cultivated and tested in a suitable laboratory Final diagnosis in this way for TB and especially for XDR-TB may take from 6 to 16 weeks To reduce the time needed for diagnosis new tools for rapid TB diagnosis are urgently needed
DrTVRao MD 57
When to suspect MDR TB
Patients not showing any reduction
in bacillary population after 3-
months of regular treatment with
Cat II regimen
Sputum positive patients who are
contacts of a known MDR TB
patient
DrTVRao MD 58
How to evaluate MDR TB
MDR TB is only a laboratory
proved HR resistance
Clinical suspicion should be
followed by lab Confirmation
Laboratories should be quality
controlledTRC
DrTVRao MD 59
Extreme Drug resistant Tuberculosis (XDR-TB) and AIDS
It can also be contracted without a patient receiving any previous treatment for TB
Mostly associated with HIV positive patients
HIV has the potential to fast tracking XDR-TB into an uncontrollable epidemic
Average survival period for patients infected with XDR-TB is 16 days
DrTVRao MD 60
Responding to MDRXDR-TB
Augment DOTS Program by
New diagnostics
New drugs New vaccines HIV incidence
reduction Advocacy1
A mathematical model projected by Basu and co-workers indicates that half of XDR-TB can be averted by 2012 by bringing synergistic effects through
Use of masks Reduced time as in-patient Improved ventilation Rapid resistance testing HIV treatment TB isolation facilities2
1Marteens and Wilkinson Lancet 20073702030-432Basu et al Quoted in Porco and Getz Lancet 20073701464-5
DrTVRao MD 61
Second Line Drug Treatment (SLDrsquos)
Less effective more costly and more toxic 50 cure rate
Four months intensive phase (5 drugs) Kanamycins Ethionamide Pyrazinamide Ofloxacin Cycloserine or Ethambutol DrTVRao MD 62
World Health Organisation (WHO) Guidelines for treatment
of MDR-TB
Strengthen basic TB care to prevent the emergence of drug-resistance
Ensure prompt diagnosis and treatment of drug resistant cases to cure existing cases and prevent further transmission
Increase collaboration between HIV and TB control programmes to provide necessary prevention and care to co-infected patients
Increase investment in laboratory infrastructures to enable better detection and management of resistant cases
DrTVRao MD 63
Treatment Guidelines
Sensitivity testing for all smear positive specimens
Patient Family and staff counselling amp education
Correct and thorough hand washing protocol and procedure
Personal protection is very important
DrTVRao MD 64
THE NEW MDR-TB Guidelines
A flexible framework approach combining both clinical and programmatic aspects of DOTS Plus based on essential programme conditions
But encouraging programs to tailor their case-finding and treatment strategies to the local epidemiological and Programme situation
Reflect GLC expert consensus and evidence and experience from GLC projects thus far
DrTVRao MD 65
Effective laboratory Diagnosis
Sputum smear examinations ndash rapid classification of species (atypical mycobacteria common in AIDS)
Culture examinations
Rapid drug sensitivity testingDrTVRao MD 66
MDR TB and HIV
MDR TB occurs with the same frequency in HIV
patients as in TB patients who are smear negative
Transmission of drug-resistant strains among HIV-
infected patients in congregate settings occurs
leading to lsquooutbreaksrsquo of MDR TB in such settings
Infection control measures absolutely essential in
settings where large number of HIV TB patients stay
togetherDrTVRao MD 67
Transmission is dependent on closeness and time of contact
In penitentiary care contacts are very close and prolonged ndash culture positive cases can also transmit TB especially to HIV positive population
DrTVRao MD 68
To Know more on MDR ndashTB Current Guidelines of WHO
Guidelines for the programmatic management of drug-resistant tuberculosis - 2011 update [pdf 904kb]
Visit helliphelliphellip WHOHTMTB20116DrTVRao MD 69
Are there any solutions for effective
Diagnosis in TB
DrTVRao MD 70
Programme Created by DrTVRao MD for Medical and Health Care
Workers in the Developing World Email
doctortvraogmailcom
DrTVRao MD 71
Transmissionof X -MDR
Like other forms of TB XDR-TB is spread through the air When a person with infectious TB coughs sneezes talks or spits they propel Mycobacterium into the air
DrTVRao MD 56
Best options to diagnoseX-MDR tuberculosis
To evaluate drug susceptibility the bacteria need to be cultivated and tested in a suitable laboratory Final diagnosis in this way for TB and especially for XDR-TB may take from 6 to 16 weeks To reduce the time needed for diagnosis new tools for rapid TB diagnosis are urgently needed
DrTVRao MD 57
When to suspect MDR TB
Patients not showing any reduction
in bacillary population after 3-
months of regular treatment with
Cat II regimen
Sputum positive patients who are
contacts of a known MDR TB
patient
DrTVRao MD 58
How to evaluate MDR TB
MDR TB is only a laboratory
proved HR resistance
Clinical suspicion should be
followed by lab Confirmation
Laboratories should be quality
controlledTRC
DrTVRao MD 59
Extreme Drug resistant Tuberculosis (XDR-TB) and AIDS
It can also be contracted without a patient receiving any previous treatment for TB
Mostly associated with HIV positive patients
HIV has the potential to fast tracking XDR-TB into an uncontrollable epidemic
Average survival period for patients infected with XDR-TB is 16 days
DrTVRao MD 60
Responding to MDRXDR-TB
Augment DOTS Program by
New diagnostics
New drugs New vaccines HIV incidence
reduction Advocacy1
A mathematical model projected by Basu and co-workers indicates that half of XDR-TB can be averted by 2012 by bringing synergistic effects through
Use of masks Reduced time as in-patient Improved ventilation Rapid resistance testing HIV treatment TB isolation facilities2
1Marteens and Wilkinson Lancet 20073702030-432Basu et al Quoted in Porco and Getz Lancet 20073701464-5
DrTVRao MD 61
Second Line Drug Treatment (SLDrsquos)
Less effective more costly and more toxic 50 cure rate
Four months intensive phase (5 drugs) Kanamycins Ethionamide Pyrazinamide Ofloxacin Cycloserine or Ethambutol DrTVRao MD 62
World Health Organisation (WHO) Guidelines for treatment
of MDR-TB
Strengthen basic TB care to prevent the emergence of drug-resistance
Ensure prompt diagnosis and treatment of drug resistant cases to cure existing cases and prevent further transmission
Increase collaboration between HIV and TB control programmes to provide necessary prevention and care to co-infected patients
Increase investment in laboratory infrastructures to enable better detection and management of resistant cases
DrTVRao MD 63
Treatment Guidelines
Sensitivity testing for all smear positive specimens
Patient Family and staff counselling amp education
Correct and thorough hand washing protocol and procedure
Personal protection is very important
DrTVRao MD 64
THE NEW MDR-TB Guidelines
A flexible framework approach combining both clinical and programmatic aspects of DOTS Plus based on essential programme conditions
But encouraging programs to tailor their case-finding and treatment strategies to the local epidemiological and Programme situation
Reflect GLC expert consensus and evidence and experience from GLC projects thus far
DrTVRao MD 65
Effective laboratory Diagnosis
Sputum smear examinations ndash rapid classification of species (atypical mycobacteria common in AIDS)
Culture examinations
Rapid drug sensitivity testingDrTVRao MD 66
MDR TB and HIV
MDR TB occurs with the same frequency in HIV
patients as in TB patients who are smear negative
Transmission of drug-resistant strains among HIV-
infected patients in congregate settings occurs
leading to lsquooutbreaksrsquo of MDR TB in such settings
Infection control measures absolutely essential in
settings where large number of HIV TB patients stay
togetherDrTVRao MD 67
Transmission is dependent on closeness and time of contact
In penitentiary care contacts are very close and prolonged ndash culture positive cases can also transmit TB especially to HIV positive population
DrTVRao MD 68
To Know more on MDR ndashTB Current Guidelines of WHO
Guidelines for the programmatic management of drug-resistant tuberculosis - 2011 update [pdf 904kb]
Visit helliphelliphellip WHOHTMTB20116DrTVRao MD 69
Are there any solutions for effective
Diagnosis in TB
DrTVRao MD 70
Programme Created by DrTVRao MD for Medical and Health Care
Workers in the Developing World Email
doctortvraogmailcom
DrTVRao MD 71
Best options to diagnoseX-MDR tuberculosis
To evaluate drug susceptibility the bacteria need to be cultivated and tested in a suitable laboratory Final diagnosis in this way for TB and especially for XDR-TB may take from 6 to 16 weeks To reduce the time needed for diagnosis new tools for rapid TB diagnosis are urgently needed
DrTVRao MD 57
When to suspect MDR TB
Patients not showing any reduction
in bacillary population after 3-
months of regular treatment with
Cat II regimen
Sputum positive patients who are
contacts of a known MDR TB
patient
DrTVRao MD 58
How to evaluate MDR TB
MDR TB is only a laboratory
proved HR resistance
Clinical suspicion should be
followed by lab Confirmation
Laboratories should be quality
controlledTRC
DrTVRao MD 59
Extreme Drug resistant Tuberculosis (XDR-TB) and AIDS
It can also be contracted without a patient receiving any previous treatment for TB
Mostly associated with HIV positive patients
HIV has the potential to fast tracking XDR-TB into an uncontrollable epidemic
Average survival period for patients infected with XDR-TB is 16 days
DrTVRao MD 60
Responding to MDRXDR-TB
Augment DOTS Program by
New diagnostics
New drugs New vaccines HIV incidence
reduction Advocacy1
A mathematical model projected by Basu and co-workers indicates that half of XDR-TB can be averted by 2012 by bringing synergistic effects through
Use of masks Reduced time as in-patient Improved ventilation Rapid resistance testing HIV treatment TB isolation facilities2
1Marteens and Wilkinson Lancet 20073702030-432Basu et al Quoted in Porco and Getz Lancet 20073701464-5
DrTVRao MD 61
Second Line Drug Treatment (SLDrsquos)
Less effective more costly and more toxic 50 cure rate
Four months intensive phase (5 drugs) Kanamycins Ethionamide Pyrazinamide Ofloxacin Cycloserine or Ethambutol DrTVRao MD 62
World Health Organisation (WHO) Guidelines for treatment
of MDR-TB
Strengthen basic TB care to prevent the emergence of drug-resistance
Ensure prompt diagnosis and treatment of drug resistant cases to cure existing cases and prevent further transmission
Increase collaboration between HIV and TB control programmes to provide necessary prevention and care to co-infected patients
Increase investment in laboratory infrastructures to enable better detection and management of resistant cases
DrTVRao MD 63
Treatment Guidelines
Sensitivity testing for all smear positive specimens
Patient Family and staff counselling amp education
Correct and thorough hand washing protocol and procedure
Personal protection is very important
DrTVRao MD 64
THE NEW MDR-TB Guidelines
A flexible framework approach combining both clinical and programmatic aspects of DOTS Plus based on essential programme conditions
But encouraging programs to tailor their case-finding and treatment strategies to the local epidemiological and Programme situation
Reflect GLC expert consensus and evidence and experience from GLC projects thus far
DrTVRao MD 65
Effective laboratory Diagnosis
Sputum smear examinations ndash rapid classification of species (atypical mycobacteria common in AIDS)
Culture examinations
Rapid drug sensitivity testingDrTVRao MD 66
MDR TB and HIV
MDR TB occurs with the same frequency in HIV
patients as in TB patients who are smear negative
Transmission of drug-resistant strains among HIV-
infected patients in congregate settings occurs
leading to lsquooutbreaksrsquo of MDR TB in such settings
Infection control measures absolutely essential in
settings where large number of HIV TB patients stay
togetherDrTVRao MD 67
Transmission is dependent on closeness and time of contact
In penitentiary care contacts are very close and prolonged ndash culture positive cases can also transmit TB especially to HIV positive population
DrTVRao MD 68
To Know more on MDR ndashTB Current Guidelines of WHO
Guidelines for the programmatic management of drug-resistant tuberculosis - 2011 update [pdf 904kb]
Visit helliphelliphellip WHOHTMTB20116DrTVRao MD 69
Are there any solutions for effective
Diagnosis in TB
DrTVRao MD 70
Programme Created by DrTVRao MD for Medical and Health Care
Workers in the Developing World Email
doctortvraogmailcom
DrTVRao MD 71
When to suspect MDR TB
Patients not showing any reduction
in bacillary population after 3-
months of regular treatment with
Cat II regimen
Sputum positive patients who are
contacts of a known MDR TB
patient
DrTVRao MD 58
How to evaluate MDR TB
MDR TB is only a laboratory
proved HR resistance
Clinical suspicion should be
followed by lab Confirmation
Laboratories should be quality
controlledTRC
DrTVRao MD 59
Extreme Drug resistant Tuberculosis (XDR-TB) and AIDS
It can also be contracted without a patient receiving any previous treatment for TB
Mostly associated with HIV positive patients
HIV has the potential to fast tracking XDR-TB into an uncontrollable epidemic
Average survival period for patients infected with XDR-TB is 16 days
DrTVRao MD 60
Responding to MDRXDR-TB
Augment DOTS Program by
New diagnostics
New drugs New vaccines HIV incidence
reduction Advocacy1
A mathematical model projected by Basu and co-workers indicates that half of XDR-TB can be averted by 2012 by bringing synergistic effects through
Use of masks Reduced time as in-patient Improved ventilation Rapid resistance testing HIV treatment TB isolation facilities2
1Marteens and Wilkinson Lancet 20073702030-432Basu et al Quoted in Porco and Getz Lancet 20073701464-5
DrTVRao MD 61
Second Line Drug Treatment (SLDrsquos)
Less effective more costly and more toxic 50 cure rate
Four months intensive phase (5 drugs) Kanamycins Ethionamide Pyrazinamide Ofloxacin Cycloserine or Ethambutol DrTVRao MD 62
World Health Organisation (WHO) Guidelines for treatment
of MDR-TB
Strengthen basic TB care to prevent the emergence of drug-resistance
Ensure prompt diagnosis and treatment of drug resistant cases to cure existing cases and prevent further transmission
Increase collaboration between HIV and TB control programmes to provide necessary prevention and care to co-infected patients
Increase investment in laboratory infrastructures to enable better detection and management of resistant cases
DrTVRao MD 63
Treatment Guidelines
Sensitivity testing for all smear positive specimens
Patient Family and staff counselling amp education
Correct and thorough hand washing protocol and procedure
Personal protection is very important
DrTVRao MD 64
THE NEW MDR-TB Guidelines
A flexible framework approach combining both clinical and programmatic aspects of DOTS Plus based on essential programme conditions
But encouraging programs to tailor their case-finding and treatment strategies to the local epidemiological and Programme situation
Reflect GLC expert consensus and evidence and experience from GLC projects thus far
DrTVRao MD 65
Effective laboratory Diagnosis
Sputum smear examinations ndash rapid classification of species (atypical mycobacteria common in AIDS)
Culture examinations
Rapid drug sensitivity testingDrTVRao MD 66
MDR TB and HIV
MDR TB occurs with the same frequency in HIV
patients as in TB patients who are smear negative
Transmission of drug-resistant strains among HIV-
infected patients in congregate settings occurs
leading to lsquooutbreaksrsquo of MDR TB in such settings
Infection control measures absolutely essential in
settings where large number of HIV TB patients stay
togetherDrTVRao MD 67
Transmission is dependent on closeness and time of contact
In penitentiary care contacts are very close and prolonged ndash culture positive cases can also transmit TB especially to HIV positive population
DrTVRao MD 68
To Know more on MDR ndashTB Current Guidelines of WHO
Guidelines for the programmatic management of drug-resistant tuberculosis - 2011 update [pdf 904kb]
Visit helliphelliphellip WHOHTMTB20116DrTVRao MD 69
Are there any solutions for effective
Diagnosis in TB
DrTVRao MD 70
Programme Created by DrTVRao MD for Medical and Health Care
Workers in the Developing World Email
doctortvraogmailcom
DrTVRao MD 71
How to evaluate MDR TB
MDR TB is only a laboratory
proved HR resistance
Clinical suspicion should be
followed by lab Confirmation
Laboratories should be quality
controlledTRC
DrTVRao MD 59
Extreme Drug resistant Tuberculosis (XDR-TB) and AIDS
It can also be contracted without a patient receiving any previous treatment for TB
Mostly associated with HIV positive patients
HIV has the potential to fast tracking XDR-TB into an uncontrollable epidemic
Average survival period for patients infected with XDR-TB is 16 days
DrTVRao MD 60
Responding to MDRXDR-TB
Augment DOTS Program by
New diagnostics
New drugs New vaccines HIV incidence
reduction Advocacy1
A mathematical model projected by Basu and co-workers indicates that half of XDR-TB can be averted by 2012 by bringing synergistic effects through
Use of masks Reduced time as in-patient Improved ventilation Rapid resistance testing HIV treatment TB isolation facilities2
1Marteens and Wilkinson Lancet 20073702030-432Basu et al Quoted in Porco and Getz Lancet 20073701464-5
DrTVRao MD 61
Second Line Drug Treatment (SLDrsquos)
Less effective more costly and more toxic 50 cure rate
Four months intensive phase (5 drugs) Kanamycins Ethionamide Pyrazinamide Ofloxacin Cycloserine or Ethambutol DrTVRao MD 62
World Health Organisation (WHO) Guidelines for treatment
of MDR-TB
Strengthen basic TB care to prevent the emergence of drug-resistance
Ensure prompt diagnosis and treatment of drug resistant cases to cure existing cases and prevent further transmission
Increase collaboration between HIV and TB control programmes to provide necessary prevention and care to co-infected patients
Increase investment in laboratory infrastructures to enable better detection and management of resistant cases
DrTVRao MD 63
Treatment Guidelines
Sensitivity testing for all smear positive specimens
Patient Family and staff counselling amp education
Correct and thorough hand washing protocol and procedure
Personal protection is very important
DrTVRao MD 64
THE NEW MDR-TB Guidelines
A flexible framework approach combining both clinical and programmatic aspects of DOTS Plus based on essential programme conditions
But encouraging programs to tailor their case-finding and treatment strategies to the local epidemiological and Programme situation
Reflect GLC expert consensus and evidence and experience from GLC projects thus far
DrTVRao MD 65
Effective laboratory Diagnosis
Sputum smear examinations ndash rapid classification of species (atypical mycobacteria common in AIDS)
Culture examinations
Rapid drug sensitivity testingDrTVRao MD 66
MDR TB and HIV
MDR TB occurs with the same frequency in HIV
patients as in TB patients who are smear negative
Transmission of drug-resistant strains among HIV-
infected patients in congregate settings occurs
leading to lsquooutbreaksrsquo of MDR TB in such settings
Infection control measures absolutely essential in
settings where large number of HIV TB patients stay
togetherDrTVRao MD 67
Transmission is dependent on closeness and time of contact
In penitentiary care contacts are very close and prolonged ndash culture positive cases can also transmit TB especially to HIV positive population
DrTVRao MD 68
To Know more on MDR ndashTB Current Guidelines of WHO
Guidelines for the programmatic management of drug-resistant tuberculosis - 2011 update [pdf 904kb]
Visit helliphelliphellip WHOHTMTB20116DrTVRao MD 69
Are there any solutions for effective
Diagnosis in TB
DrTVRao MD 70
Programme Created by DrTVRao MD for Medical and Health Care
Workers in the Developing World Email
doctortvraogmailcom
DrTVRao MD 71
Extreme Drug resistant Tuberculosis (XDR-TB) and AIDS
It can also be contracted without a patient receiving any previous treatment for TB
Mostly associated with HIV positive patients
HIV has the potential to fast tracking XDR-TB into an uncontrollable epidemic
Average survival period for patients infected with XDR-TB is 16 days
DrTVRao MD 60
Responding to MDRXDR-TB
Augment DOTS Program by
New diagnostics
New drugs New vaccines HIV incidence
reduction Advocacy1
A mathematical model projected by Basu and co-workers indicates that half of XDR-TB can be averted by 2012 by bringing synergistic effects through
Use of masks Reduced time as in-patient Improved ventilation Rapid resistance testing HIV treatment TB isolation facilities2
1Marteens and Wilkinson Lancet 20073702030-432Basu et al Quoted in Porco and Getz Lancet 20073701464-5
DrTVRao MD 61
Second Line Drug Treatment (SLDrsquos)
Less effective more costly and more toxic 50 cure rate
Four months intensive phase (5 drugs) Kanamycins Ethionamide Pyrazinamide Ofloxacin Cycloserine or Ethambutol DrTVRao MD 62
World Health Organisation (WHO) Guidelines for treatment
of MDR-TB
Strengthen basic TB care to prevent the emergence of drug-resistance
Ensure prompt diagnosis and treatment of drug resistant cases to cure existing cases and prevent further transmission
Increase collaboration between HIV and TB control programmes to provide necessary prevention and care to co-infected patients
Increase investment in laboratory infrastructures to enable better detection and management of resistant cases
DrTVRao MD 63
Treatment Guidelines
Sensitivity testing for all smear positive specimens
Patient Family and staff counselling amp education
Correct and thorough hand washing protocol and procedure
Personal protection is very important
DrTVRao MD 64
THE NEW MDR-TB Guidelines
A flexible framework approach combining both clinical and programmatic aspects of DOTS Plus based on essential programme conditions
But encouraging programs to tailor their case-finding and treatment strategies to the local epidemiological and Programme situation
Reflect GLC expert consensus and evidence and experience from GLC projects thus far
DrTVRao MD 65
Effective laboratory Diagnosis
Sputum smear examinations ndash rapid classification of species (atypical mycobacteria common in AIDS)
Culture examinations
Rapid drug sensitivity testingDrTVRao MD 66
MDR TB and HIV
MDR TB occurs with the same frequency in HIV
patients as in TB patients who are smear negative
Transmission of drug-resistant strains among HIV-
infected patients in congregate settings occurs
leading to lsquooutbreaksrsquo of MDR TB in such settings
Infection control measures absolutely essential in
settings where large number of HIV TB patients stay
togetherDrTVRao MD 67
Transmission is dependent on closeness and time of contact
In penitentiary care contacts are very close and prolonged ndash culture positive cases can also transmit TB especially to HIV positive population
DrTVRao MD 68
To Know more on MDR ndashTB Current Guidelines of WHO
Guidelines for the programmatic management of drug-resistant tuberculosis - 2011 update [pdf 904kb]
Visit helliphelliphellip WHOHTMTB20116DrTVRao MD 69
Are there any solutions for effective
Diagnosis in TB
DrTVRao MD 70
Programme Created by DrTVRao MD for Medical and Health Care
Workers in the Developing World Email
doctortvraogmailcom
DrTVRao MD 71
Responding to MDRXDR-TB
Augment DOTS Program by
New diagnostics
New drugs New vaccines HIV incidence
reduction Advocacy1
A mathematical model projected by Basu and co-workers indicates that half of XDR-TB can be averted by 2012 by bringing synergistic effects through
Use of masks Reduced time as in-patient Improved ventilation Rapid resistance testing HIV treatment TB isolation facilities2
1Marteens and Wilkinson Lancet 20073702030-432Basu et al Quoted in Porco and Getz Lancet 20073701464-5
DrTVRao MD 61
Second Line Drug Treatment (SLDrsquos)
Less effective more costly and more toxic 50 cure rate
Four months intensive phase (5 drugs) Kanamycins Ethionamide Pyrazinamide Ofloxacin Cycloserine or Ethambutol DrTVRao MD 62
World Health Organisation (WHO) Guidelines for treatment
of MDR-TB
Strengthen basic TB care to prevent the emergence of drug-resistance
Ensure prompt diagnosis and treatment of drug resistant cases to cure existing cases and prevent further transmission
Increase collaboration between HIV and TB control programmes to provide necessary prevention and care to co-infected patients
Increase investment in laboratory infrastructures to enable better detection and management of resistant cases
DrTVRao MD 63
Treatment Guidelines
Sensitivity testing for all smear positive specimens
Patient Family and staff counselling amp education
Correct and thorough hand washing protocol and procedure
Personal protection is very important
DrTVRao MD 64
THE NEW MDR-TB Guidelines
A flexible framework approach combining both clinical and programmatic aspects of DOTS Plus based on essential programme conditions
But encouraging programs to tailor their case-finding and treatment strategies to the local epidemiological and Programme situation
Reflect GLC expert consensus and evidence and experience from GLC projects thus far
DrTVRao MD 65
Effective laboratory Diagnosis
Sputum smear examinations ndash rapid classification of species (atypical mycobacteria common in AIDS)
Culture examinations
Rapid drug sensitivity testingDrTVRao MD 66
MDR TB and HIV
MDR TB occurs with the same frequency in HIV
patients as in TB patients who are smear negative
Transmission of drug-resistant strains among HIV-
infected patients in congregate settings occurs
leading to lsquooutbreaksrsquo of MDR TB in such settings
Infection control measures absolutely essential in
settings where large number of HIV TB patients stay
togetherDrTVRao MD 67
Transmission is dependent on closeness and time of contact
In penitentiary care contacts are very close and prolonged ndash culture positive cases can also transmit TB especially to HIV positive population
DrTVRao MD 68
To Know more on MDR ndashTB Current Guidelines of WHO
Guidelines for the programmatic management of drug-resistant tuberculosis - 2011 update [pdf 904kb]
Visit helliphelliphellip WHOHTMTB20116DrTVRao MD 69
Are there any solutions for effective
Diagnosis in TB
DrTVRao MD 70
Programme Created by DrTVRao MD for Medical and Health Care
Workers in the Developing World Email
doctortvraogmailcom
DrTVRao MD 71
Second Line Drug Treatment (SLDrsquos)
Less effective more costly and more toxic 50 cure rate
Four months intensive phase (5 drugs) Kanamycins Ethionamide Pyrazinamide Ofloxacin Cycloserine or Ethambutol DrTVRao MD 62
World Health Organisation (WHO) Guidelines for treatment
of MDR-TB
Strengthen basic TB care to prevent the emergence of drug-resistance
Ensure prompt diagnosis and treatment of drug resistant cases to cure existing cases and prevent further transmission
Increase collaboration between HIV and TB control programmes to provide necessary prevention and care to co-infected patients
Increase investment in laboratory infrastructures to enable better detection and management of resistant cases
DrTVRao MD 63
Treatment Guidelines
Sensitivity testing for all smear positive specimens
Patient Family and staff counselling amp education
Correct and thorough hand washing protocol and procedure
Personal protection is very important
DrTVRao MD 64
THE NEW MDR-TB Guidelines
A flexible framework approach combining both clinical and programmatic aspects of DOTS Plus based on essential programme conditions
But encouraging programs to tailor their case-finding and treatment strategies to the local epidemiological and Programme situation
Reflect GLC expert consensus and evidence and experience from GLC projects thus far
DrTVRao MD 65
Effective laboratory Diagnosis
Sputum smear examinations ndash rapid classification of species (atypical mycobacteria common in AIDS)
Culture examinations
Rapid drug sensitivity testingDrTVRao MD 66
MDR TB and HIV
MDR TB occurs with the same frequency in HIV
patients as in TB patients who are smear negative
Transmission of drug-resistant strains among HIV-
infected patients in congregate settings occurs
leading to lsquooutbreaksrsquo of MDR TB in such settings
Infection control measures absolutely essential in
settings where large number of HIV TB patients stay
togetherDrTVRao MD 67
Transmission is dependent on closeness and time of contact
In penitentiary care contacts are very close and prolonged ndash culture positive cases can also transmit TB especially to HIV positive population
DrTVRao MD 68
To Know more on MDR ndashTB Current Guidelines of WHO
Guidelines for the programmatic management of drug-resistant tuberculosis - 2011 update [pdf 904kb]
Visit helliphelliphellip WHOHTMTB20116DrTVRao MD 69
Are there any solutions for effective
Diagnosis in TB
DrTVRao MD 70
Programme Created by DrTVRao MD for Medical and Health Care
Workers in the Developing World Email
doctortvraogmailcom
DrTVRao MD 71
World Health Organisation (WHO) Guidelines for treatment
of MDR-TB
Strengthen basic TB care to prevent the emergence of drug-resistance
Ensure prompt diagnosis and treatment of drug resistant cases to cure existing cases and prevent further transmission
Increase collaboration between HIV and TB control programmes to provide necessary prevention and care to co-infected patients
Increase investment in laboratory infrastructures to enable better detection and management of resistant cases
DrTVRao MD 63
Treatment Guidelines
Sensitivity testing for all smear positive specimens
Patient Family and staff counselling amp education
Correct and thorough hand washing protocol and procedure
Personal protection is very important
DrTVRao MD 64
THE NEW MDR-TB Guidelines
A flexible framework approach combining both clinical and programmatic aspects of DOTS Plus based on essential programme conditions
But encouraging programs to tailor their case-finding and treatment strategies to the local epidemiological and Programme situation
Reflect GLC expert consensus and evidence and experience from GLC projects thus far
DrTVRao MD 65
Effective laboratory Diagnosis
Sputum smear examinations ndash rapid classification of species (atypical mycobacteria common in AIDS)
Culture examinations
Rapid drug sensitivity testingDrTVRao MD 66
MDR TB and HIV
MDR TB occurs with the same frequency in HIV
patients as in TB patients who are smear negative
Transmission of drug-resistant strains among HIV-
infected patients in congregate settings occurs
leading to lsquooutbreaksrsquo of MDR TB in such settings
Infection control measures absolutely essential in
settings where large number of HIV TB patients stay
togetherDrTVRao MD 67
Transmission is dependent on closeness and time of contact
In penitentiary care contacts are very close and prolonged ndash culture positive cases can also transmit TB especially to HIV positive population
DrTVRao MD 68
To Know more on MDR ndashTB Current Guidelines of WHO
Guidelines for the programmatic management of drug-resistant tuberculosis - 2011 update [pdf 904kb]
Visit helliphelliphellip WHOHTMTB20116DrTVRao MD 69
Are there any solutions for effective
Diagnosis in TB
DrTVRao MD 70
Programme Created by DrTVRao MD for Medical and Health Care
Workers in the Developing World Email
doctortvraogmailcom
DrTVRao MD 71
Treatment Guidelines
Sensitivity testing for all smear positive specimens
Patient Family and staff counselling amp education
Correct and thorough hand washing protocol and procedure
Personal protection is very important
DrTVRao MD 64
THE NEW MDR-TB Guidelines
A flexible framework approach combining both clinical and programmatic aspects of DOTS Plus based on essential programme conditions
But encouraging programs to tailor their case-finding and treatment strategies to the local epidemiological and Programme situation
Reflect GLC expert consensus and evidence and experience from GLC projects thus far
DrTVRao MD 65
Effective laboratory Diagnosis
Sputum smear examinations ndash rapid classification of species (atypical mycobacteria common in AIDS)
Culture examinations
Rapid drug sensitivity testingDrTVRao MD 66
MDR TB and HIV
MDR TB occurs with the same frequency in HIV
patients as in TB patients who are smear negative
Transmission of drug-resistant strains among HIV-
infected patients in congregate settings occurs
leading to lsquooutbreaksrsquo of MDR TB in such settings
Infection control measures absolutely essential in
settings where large number of HIV TB patients stay
togetherDrTVRao MD 67
Transmission is dependent on closeness and time of contact
In penitentiary care contacts are very close and prolonged ndash culture positive cases can also transmit TB especially to HIV positive population
DrTVRao MD 68
To Know more on MDR ndashTB Current Guidelines of WHO
Guidelines for the programmatic management of drug-resistant tuberculosis - 2011 update [pdf 904kb]
Visit helliphelliphellip WHOHTMTB20116DrTVRao MD 69
Are there any solutions for effective
Diagnosis in TB
DrTVRao MD 70
Programme Created by DrTVRao MD for Medical and Health Care
Workers in the Developing World Email
doctortvraogmailcom
DrTVRao MD 71
THE NEW MDR-TB Guidelines
A flexible framework approach combining both clinical and programmatic aspects of DOTS Plus based on essential programme conditions
But encouraging programs to tailor their case-finding and treatment strategies to the local epidemiological and Programme situation
Reflect GLC expert consensus and evidence and experience from GLC projects thus far
DrTVRao MD 65
Effective laboratory Diagnosis
Sputum smear examinations ndash rapid classification of species (atypical mycobacteria common in AIDS)
Culture examinations
Rapid drug sensitivity testingDrTVRao MD 66
MDR TB and HIV
MDR TB occurs with the same frequency in HIV
patients as in TB patients who are smear negative
Transmission of drug-resistant strains among HIV-
infected patients in congregate settings occurs
leading to lsquooutbreaksrsquo of MDR TB in such settings
Infection control measures absolutely essential in
settings where large number of HIV TB patients stay
togetherDrTVRao MD 67
Transmission is dependent on closeness and time of contact
In penitentiary care contacts are very close and prolonged ndash culture positive cases can also transmit TB especially to HIV positive population
DrTVRao MD 68
To Know more on MDR ndashTB Current Guidelines of WHO
Guidelines for the programmatic management of drug-resistant tuberculosis - 2011 update [pdf 904kb]
Visit helliphelliphellip WHOHTMTB20116DrTVRao MD 69
Are there any solutions for effective
Diagnosis in TB
DrTVRao MD 70
Programme Created by DrTVRao MD for Medical and Health Care
Workers in the Developing World Email
doctortvraogmailcom
DrTVRao MD 71
Effective laboratory Diagnosis
Sputum smear examinations ndash rapid classification of species (atypical mycobacteria common in AIDS)
Culture examinations
Rapid drug sensitivity testingDrTVRao MD 66
MDR TB and HIV
MDR TB occurs with the same frequency in HIV
patients as in TB patients who are smear negative
Transmission of drug-resistant strains among HIV-
infected patients in congregate settings occurs
leading to lsquooutbreaksrsquo of MDR TB in such settings
Infection control measures absolutely essential in
settings where large number of HIV TB patients stay
togetherDrTVRao MD 67
Transmission is dependent on closeness and time of contact
In penitentiary care contacts are very close and prolonged ndash culture positive cases can also transmit TB especially to HIV positive population
DrTVRao MD 68
To Know more on MDR ndashTB Current Guidelines of WHO
Guidelines for the programmatic management of drug-resistant tuberculosis - 2011 update [pdf 904kb]
Visit helliphelliphellip WHOHTMTB20116DrTVRao MD 69
Are there any solutions for effective
Diagnosis in TB
DrTVRao MD 70
Programme Created by DrTVRao MD for Medical and Health Care
Workers in the Developing World Email
doctortvraogmailcom
DrTVRao MD 71
MDR TB and HIV
MDR TB occurs with the same frequency in HIV
patients as in TB patients who are smear negative
Transmission of drug-resistant strains among HIV-
infected patients in congregate settings occurs
leading to lsquooutbreaksrsquo of MDR TB in such settings
Infection control measures absolutely essential in
settings where large number of HIV TB patients stay
togetherDrTVRao MD 67
Transmission is dependent on closeness and time of contact
In penitentiary care contacts are very close and prolonged ndash culture positive cases can also transmit TB especially to HIV positive population
DrTVRao MD 68
To Know more on MDR ndashTB Current Guidelines of WHO
Guidelines for the programmatic management of drug-resistant tuberculosis - 2011 update [pdf 904kb]
Visit helliphelliphellip WHOHTMTB20116DrTVRao MD 69
Are there any solutions for effective
Diagnosis in TB
DrTVRao MD 70
Programme Created by DrTVRao MD for Medical and Health Care
Workers in the Developing World Email
doctortvraogmailcom
DrTVRao MD 71
Transmission is dependent on closeness and time of contact
In penitentiary care contacts are very close and prolonged ndash culture positive cases can also transmit TB especially to HIV positive population
DrTVRao MD 68
To Know more on MDR ndashTB Current Guidelines of WHO
Guidelines for the programmatic management of drug-resistant tuberculosis - 2011 update [pdf 904kb]
Visit helliphelliphellip WHOHTMTB20116DrTVRao MD 69
Are there any solutions for effective
Diagnosis in TB
DrTVRao MD 70
Programme Created by DrTVRao MD for Medical and Health Care
Workers in the Developing World Email
doctortvraogmailcom
DrTVRao MD 71
To Know more on MDR ndashTB Current Guidelines of WHO
Guidelines for the programmatic management of drug-resistant tuberculosis - 2011 update [pdf 904kb]
Visit helliphelliphellip WHOHTMTB20116DrTVRao MD 69
Are there any solutions for effective
Diagnosis in TB
DrTVRao MD 70
Programme Created by DrTVRao MD for Medical and Health Care
Workers in the Developing World Email
doctortvraogmailcom
DrTVRao MD 71
Are there any solutions for effective
Diagnosis in TB
DrTVRao MD 70
Programme Created by DrTVRao MD for Medical and Health Care
Workers in the Developing World Email
doctortvraogmailcom
DrTVRao MD 71
Programme Created by DrTVRao MD for Medical and Health Care
Workers in the Developing World Email
doctortvraogmailcom
DrTVRao MD 71