Drug Resistant Tuberculosis: An Overview

/fli6«o Ifo/f]u sfo{qmdNational Tuberculosis Center

Drug Resistant Tuberculosis: An Overview

July 14, 2014, Pokhara, Nepal

Dr. Sharat Chandra VermaChief Consultant Chest Physician

National TB CentreNepal


Some definitions• Multi-Drug Resistant (MDR) TB: MDR-TB is defined

as TB caused by bacteria resistance to isoniazid and rifampicin, with or without resistance to other first-line drugs (FLD).

• Extensive Drug Resistant (XDR) TB: XDR-TB is caused by bacteria that are resistant to rifampicin and isoniazid as well as resistant to any one of the fluoroquinolones (e.g. ofloxacin and moxifloxacin) and to at least one of the injectable second-line drugs (capreomycin, kanamycin or amikacin).


Why is MDR-TB a problem?

• Possibility of resistance to all major anti-TB drugs

• Treatable, but requires extensive therapy: up to 2 yrs of treatment

• Expensive• Treatment could be toxic to patients


How is DR-TB transmitted?

• TB bacilli with different levels of resistance spread in the same way and with the same risk of infection as fully drug susceptible strains.– Person-to-person through inhalation of

droplet nucleii– Infected person usually coughs or sneezes

and projected infected droplet nucleii into the air


Pathogenesis ofDrug Resistance


INH = 1 in 106

RIF = 1 in 108

EMB = 1 in 106

Strep = 1 in 106

INH + RIF = 1 in 1014

Frequency of Resistance Mutations


Development of Drug Resistance

1 2

3

Multiple Drugs vs. Monotherapy

I = INH resistant, R = RIF resistant, P = PZA resistant

INH

I

R P

RIFPZA

INH II

I I

I

I


Development of Drug Resistance (2)

I = INH resistant, R = RIF resistant, P = PZA resistant

Further acquired resistance after single drug added

II

I I

I

I

IR IRIR

IRIR

IR

IR

IR

IRIR IR

IRIR

IRP

III

I

II

I

II

I II

IIP

IRI

INHRIFINH


Months of Rx 0 5 7 9

INH

RIF

EMB

Smear + + + +

Culture + + + +

Susceptibility

INH R* R R R

RIF S* R R R

EMB S* S S R

* Results not known to clinician

Unintended Monotherapy and Resistance


Factors that Lead to Drug Resistance

Causes of inadequate treatment:• Patient-related factors• Healthcare provider-related factors• Healthcare system-related factors



Patient-related factors:• Non-adherence, default

• Malabsorption of drugs

• Adverse drug reactions

• Lack of information, transportation, money

• Social barriers to treatment adherence

• Substance dependency disorders



Healthcare provider-related factors:• Inadequate initial treatment regimen: Wrong

combination or doses, guideline noncompliance• Treatment “in the dark” for retreatment cases:

no drug susceptibility testing available, or results delayed

• Clinical errors: Adding a single drug to a failing regimen

• Lack of proper monitoring• Lack of proper provider awareness


Factors that Lead to Drug ResistanceHealthcare programme-related factors:• Unavailability of drugs (stock-outs or delivery

disruptions)

• Poor drug quality, poor storage conditions

• Poorly organized or under-funded TB-control programmes

• Inappropriate or no guidelines

• Lack of appropriate or timely laboratory testing


Epidemiology

• In practice, MDR-TB develops either because the person is infected initially with a:– Drug-resistant strain (primary), or– Susceptible strain that becomes resistant

(secondary)


Epidemiology cont.

• Reasons for secondary resistance are numerous and complex:– Wrong drugs used in an improper way– Failure to assess drug susceptibility patterns of the

organism– A large bacterial load, especially in the case of

cavitation– Poor adherence to the treatment regimen


Epidemiology cont.

• TB (including MDR-TB) and HIV co-infections are relatively common globally and each condition adversely affects the other.


WHO Region 2012Estimated Reported Ratio

African 38,000 18,129 48%

American 7,100 2,967 42%

East Med. 18,000 2,236 12%

European 74,000 36,708 50%

S-E Asian 90,000 19,202 21%

West Pacific 74,000 4,473 6%

Global 300,000 83,715 28%

MDR-TB notification and enrolment MDR cases reported vs estimated among notified TB, 2012: WHO 2013


XDR-TB

• In 2006, the first reports of extensively drug-resistant tuberculosis (XDR-TB) began to appear.

• About 9.6% (8.1-11.2%) of MDR-TB cases in countries with representative surveillance data have XDR-TB. By October 2013, 92 countries had reported one or more XDR-TB cases. (WHO Report 2013)


Development of extensive drug resistance in Multi-Drug resistant tuberculosis patients

• XDR-TB emerges like MDR-TB through mismanagement of treatment.

• It is however believed that many cases of XDR TB are never diagnosed due to a lack of laboratory capacity to test for resistance to second line drugs.


Clinical Manifestations

• MDR-TB are not clinically distinguishable from drug-susceptible TB at the outset.

• Signs, symptoms, and radiological findings are similar initially to drug-susceptible TB.


Reasons to suspect drug resistance are:

• A history of previously treated TB in a person presenting with active TB

• High community rates of drug resistant TB• Positive HIV status• High likelihood of exposure to nosocomial, prison or

community sources of MDR-TB• The infected person is from a country with a high MDR-TB

rates• Contacts with persons with MDR-TB• Infected person has received inadequate treatment regimens

for >2 weeks• Smears or cultures remain positive despite 2 months of

treatment for TB


Symptoms of Dr-TB is no different from ordinary TB

• Cough (usually productive and maybe bloody)

• Low-grade fever• Sweating• Chills at night• Fatigue• Malaise• Anorexia• Shortness of breath

• Weight loss• Dull, aching chest pain

or tightness

• Symptoms of extrapulmonary TB depend on the organ system involved but may include systemic symptoms.


Early identification and prompt treatment of DR-TB

• Prevents the spread of disease,• Helps stop development of further

amplification of resistance,• Reduces the progression to permanent lung

damage, and • Results in higher cure rates.


Thank You

Documents

Drug Resistant Tuberculosis: An Overview