Drug Resistant Tuberculosis: An Overview

1. Drug Resistant Tuberculosis: An Overview July 14, 2014, Pokhara, Nepal Dr. Sharat Chandra Verma Chief Consultant Chest Physician National TB Centre Nepal

2. 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).

3. 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

4. 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

5. Pathogenesis of Drug Resistance

6. 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

7. Development of Drug Resistance Multiple Drugs vs. Monotherapy 1 2 3 I = INH resistant, R = RIF resistant, P = PZA resistant

8. Development of Drug Resistance (2) Further acquired resistance after single drug added I = INH resistant, R = RIF resistant, P = PZA resistant

9. Unintended Monotherapy and Resistance * Results not known to clinician

10. Factors that Lead to Drug Resistance Causes of inadequate treatment: • Patient-related factors • Healthcare provider-related factors • Healthcare system-related factors

11. Factors that Lead to Drug Resistance 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

12. Factors that Lead to Drug Resistance 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

13. Factors that Lead to Drug Resistance Healthcare 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

14. 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)

15. 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

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

17. MDR-TB notification and enrolment MDR cases reported vs estimatedamongnotified TB, 2012: WHO 2013

18. 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)

19. 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.

20. 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.

21. 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

22. 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. Symptoms of Dr-TB is no different from ordinary TB

23. 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.

24. Thank You