MULTI-DRUG RESISTANT TUBERCULOSIS

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INTRODUCTION

Multi drug resistance is a condition enabling a disease causing organism to resist distinct drugs or chemicals of a wide variety of structure & function targeted at eradicating the organism

Organism that display multi drug resistance can be pathologic cells including bacterial and neoplastic (tumor) cells

Main mechanism of drug resistance of tumor cells

SEVERAL MECHANISM EMPLOYED BY THESE MICROORGANISM TO ATTAIN MDR

• No longer relying on a glycoprotein cell wall

• Enzymatic deactivation of antibiotics • Decreased cell wall permeability to antibiotics

• Altered target sites of antibiotic

• Efflux mechanism to remove antibiotics • Increased mutation rate as a stress response

TO LIMIT THE DEVELOPMENT OF ANTIBIOTIC RESISTANCE

• Use antibiotics only for bacterial infection• Identify the causative organism if possible• Use the right antibiotic do not rely on

broad range of antibiotic• Not stop antibiotic as soon as symptoms

improve finish the full course• No use of antibiotic for most cold,

coughs,bronchitis,sinus infections and eye infection which are caused by viruses

SOME IMPORTANT INFORMATION ABOUT DRUG RESISTANCE Drug resistance strains of pathogen may arise

from seemingly innocent activities such as tooth-brushing, hand washing, application of deodrants and any cosmetic or health-care products

Dipping of pets and farm animals or the use of disinfectants and detergent

The chemicals contained in these preparation may intentionally or inadvertently target organisms that have the potential to develop resistance &there by become problematic

WHAT WHO SAYS ABOUT DRUG RESISTANCE

“The use and misuse of antimicrobials in human medicine and animal husbandry over the past 70 years led to a relentless rise in the number and types of microorganism resistant to these medicine leading to death, increased suffering & disability and higher health care cost”

PRESENTATION OUTLINE

Definition of MDR TB Epidemiology of MDR TB Genesis of MDR Mechanism of resistance Treatment Chemoprophylaxis for MDR TB

exposure

DEFINITION OF MDR TB

1950s-1970s: M. tb resistant to INH, streptomycin and/or

PAS 1980s-current:

M. tb resistant to at least INH and Rifampin

WHY INH AND RIFAMPIN Most potent and bacteriocidal Tb can be treated effectively with INH+Rif

alone Mono-resistance to one of them can be

treated effectively with a regimen containing the other agent with very low failure rate (2.5-5%)

Failure rate when INH+Rif resistant is 44% in non-HIV and 70% in HIV patients

Duration required for cure doubles to triples.

EPIDEMIOLOGY OF MDR TB

85,008 (4.5)Western Pacific

75,062 (2.5)Southeast Asia

45,964 (7.9)Eastern Mediterranean

25,199 (1.8)Africa, high HIV

15,014 (1.9)Africa, low HIV

17,269 (5.5)Eastern Europe

8508 (2.2)Latin America

882 (0.7)Established market economies

272,906 (3.2)All countries (n = 136)

No. of MDR TB cases (% of all new cases)Geographic region

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WHO SURVEILLANCE AND INCIDENCE OF MDR TB

Country % MDR TB of all new cases

Estonia 14.1

Latvia 9.0

China (non-DOTS) 7.7

China (DOTS) 2.8

Russia 6.0

India 3.4

Iran 5.8

Dominican 6.6

Ivory Cost 5.3

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WHO ESTIMATES OF MDR TB IN SOME ARABIAN COUNTRIES

Country % MDR TB of all new cases

Morocco* 2.2

Oman* 0.8

Algeria 0.7

Egypt 5.6

Jordan 2.8

Kuwait 3.3

Lebanon 3.4

Saudi Arabia 3.0

Sudan 10.1

Syria 6.7

Yemen 12.4.

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.

Strains with genetic drug resistance

Wild M. TB strain

Acquired drug resistance

Primary drug resistance

Spontaneous mutation

Selection: inadequate treatment

Transmission

Development of anti-tuberculosis drug resistance

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CLINICAL FACTORS PROMOTING RESISTANCE

Delayed diagnosis and isolation Inappropriate drug regimen.

Inadequate initial therapy Incomplete course of treatment Inappropriate treatment modifications Adding single drug to a failing regimen Inappropriate use of chemoprophylaxis

Poor adherence and incomplete F/U Failure to isolate MDR TB patients Failure to employ DOT Over the counter anti TB Faked drugs

MECHANISM OF RESISTANCE

TB specific drugs INH, PZA, ETH

Antibiotics with activity against TB RIF Aminogycosides Flouroquinolones

MECHANISM OF RESISTANCE

INH Chromosomally mediated Loss of catalase/peroxidase Mutation in mycolic acid synthesis Regulators of peroxide response

MECHANISM OF RESISTANCE

Rifampin Reduced binding to RNA polymerase

Clusters of mutations at “Rifampin Resistance Determining Region” (RRDR)

Reduced Cell wall permeability

TREATMENT OF MDR TB

Factors determining Success Culture of MDR TB Reliable susceptibility Reliable history of previous drug regimens Program to assure delivery of prescribed

drugs (DOT) Correct choice of modified treatment

regimen Reliable follow up

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NEW CHEMOTHERAPEUTIC AGENTS Not many. Low interest from industry Derivatives of Rifamycin

Rifabutin: Sensitive subset of Rifampin resistant strains Rifapentine: Extended half-life but more mono-resistance

to rifamycins KRM-1648. benzoxazinorifamycin. In vitro and animal

models. New flouroquinolones

Gatifloxacin, Moxifloxacin, levofloxacin, sparfloxacin Nitroimidazoles

related to metronidazole. May work better against latent bacilli

Avoiding pro-drug problems

CHEMOPROPHYLAXIS

Determinants of intervention Likelihood of infection with MDR TB

Low Intermediate High

Likelihood of developing MDR TB Immune suppression

Likelihood of infection with MDR TB

Intermediate to highLow

High possibility for disease

YesNo

Consider Multidrug prophylaxis

Confirmed R to INH+RIF

Standard recommendation For non-MDR TB contacts

DEVELOPMENT OF DRUG RESISTANCEFROM THE PERSPECTIVE OF THE PATIENT:

The presence of drug resistant strains results from simple Darwinian pressures, brought out by the presence of antibiotics

Multiple drug resistant strains result from the step-wise accumulation of individual resistance elements therefore MDR-TB is MAN-MADE

History Elements that place a patient at-risk for MDR-TB or drug resistance1. Previous TB treatment with multiple drugs

2. Failed TB Treatment that is documented

3. A known chronic TB case

4. Default from previous TB treatment or erratic use of TB drugs

5. Exposure to a known MDR case

6. Use of TB drugs of poor or unknown quality

7. Prior use of an inadequate regimen

8. Conditions associated with drug malabsorption or severe diarrhea

THE BASIS OF ANTI-TB THERAPY AND MDR-TB: HDL -- A COMPREHENSIVE APPROACH AND UNIFIED SYSTEM OF CARE

Drugs

Case management

Surgery

Smear/Culture

DST & QC

Private Physiciansand Hospitals

Government HealthServices

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

EXPECTED OUTCOMES OF DRS

Level and pattern of resistance to first-line anti-TB drugs among new sputum smear positive cases and among previously treated TB cases in Central Java.

The outcome of treatment of patients with different resistance patterns.

A model protocol for surveillance of drug resistance in Indonesia

DOTS-PLUS

A comprehensive strategy of the WHO Stop TB Partnership, developed by the DOTS-Plus Working Group, for the diagnosis and management of MDR-TB and other forms of drug resistant TB

1. Sustained Political commitment

5. Recording and reporting system designed for DOTS-Plus programs.

4. Uninterrupted supply of quality assured second-line anti-tuberculosis drugs.

3. Appropriate treatment strategies that utilize second line drugs under proper management conditions.

2.Diagnosis of MDR-TB through quality-assured culture and drug susceptibility testing (DST).

THE DOTS-Plus Framework

MAINSTREAMING DOTS-PLUS INTO DOTS

• Referral from DOTS-programme: failures, chronics

• Same (reference) laboratory

• Same treatment delivery system

• Drug-procurement and R&R: adapted but integrated!

PRELIMINARY RESULTS OF DOTS-PLUS PROJECTS

In Estonia and Latvia a large proportion of cases enrolled on MDR-TB treatment are new while in Peru, Philippines and Tomsk the majority are chronic

Treatment success rates range from 61-82% Only 2% of patients have stopped treatment

due to adverse events Future plans: Case-based data is being

collected from these pilot sites to serve as evidence for MDR-TB policy development

PARAMETERS TO CONSIDER WHEN DESIGNING A DOTS-PLUS STRATEGY

Government and NTP commitment Well performing basic DOTS Program is able to implement the 5

components of DOTS-Plus Rational case-finding strategy using quality

assured smear, culture and DST ( concordance with a SRL)

Representative DRS data for rational country/area-specific treatment design and planning of procurement

Reliable DOT throughout treatment Free effective side-effect management Regular supply of ALL drugs involved!

MDR TB PATIENTS MANAGEMENT Individual Treatment regimen:

IP: Minimum of 4 in Abkhazia, 5 in Nukus, 2nd Line TB drugs to which patient is susceptible, including an injectable for 4 to 6 months after culture conversion

CP: Same regimen but the injectable for 18 months

DOT Comprehensive management of side-effects Infection control measures in the hospital:

UV lights Ventilation (difficult in the winter time) High filtration masks for staff and visitors Separation of the patients

MDR TREATMENT OUTCOMES

Treatment outcomes are reported according to WHO and international definitions: Cure Treatment completed Death Failure Default Still on treatment

OPERATIONAL IMPLICATIONS

If super-infection between patients during the stay in the hospital: Urgent needs to improve infection control within

the hospital Consider ambulatory treatment from the

beginning? If family clusters

Aggressive active screening in all family members? If true amplification

Use more aggressive treatment regimen, including 3rd Line TB drugs

Call for research on new drugs

TRANSMISSION & PATHOGENESIS

DIAGNOSIS OF TB DISEASE

• Clinical suspicion (Think TB)• PPD skin test results (BCG status not used)• Chest x-ray• AFB smears of 3 sputum specimens• Culture identification (confirmation)• Other procedures as needed

DRUG SUSCEPTIBILITY TESTING (DST)

To identify drug-resistant strains. To specify pattern of resistance.

Implications for therapy and protocols Results obtained 1-2 weeks after

culture growth. New molecular methods rapid but

expensive.

• Primary Resistance– Drug resistance among new cases.

• Never received TB drugs or received them for < 1 month.

• Initial culture.

• Secondary (Acquired) Resistance – Drug resistance in a patient who

previously received at least 1 month of TB therapy.

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