1. Introduction to Drug-Resistant TB Session 2

2. Classification of drug-resistant TB “Drug-resistant TB” is a general term to describe a strain of M. tuberculosis that is resistant to one or more anti-TB drugs.

3. What is drug resistance? “When we say that a strain of tubercle bacilli is drug-resistant we usually mean that a patient yielding such organisms would fail to respond to treatment with the drug concerned in normal dosage, i.e. a dosage that will cause a response in patients infected with sensitive organisms.” – Mitchison DA. “What is drug resistance?” TubercleSuppl 1969; 50: 44-47.

4. How is drug resistant TB created? “…any sensitive strain of tubercle bacilli contains a few organisms which are naturally resistant, sometimes to high drug concentrations. They have arisen by a process of mutation and are called mutants…When this population comes into contact with the therapeutic concentrations of either streptomycin or isoniazid, the sensitive bacilli are killed, whereas the few resistant mutants can multiply and eventually constitute the whole strain…” – Mitchison DA. “Problems of drug resistance,” British Medical Bulletin 1954; 10: 115-124.

5. Selecting for drug resistance streptomycin treatment S S R S H S S S S S

6. “Fall and rise” phenomenon International Union Against Tuberculosis.”Theclinical significance of bacterial resistance tests.” Bull Int Un Tuberc 1957; 27: 214-79.

7. Average mutation rates inM. tuberculosis

8. Development of resistance during treatment with a single drug Mitchison DA.” Problems of drug resistance”. British Medical Bulletin 1954; 10: 115-124.

9. Development of resistance during treatment with two drugs Mitchison DA. “Problems of drug resistance”. British Medical Bulletin 1954; 10: 115-124.

10. “Effective” monotherapy during treatment of DR-TB with SCC

11. Drug resistance can increase after failed SCC Quy HTW, Lan NTN, Borgdorff MW, et al. “Drug resistance among failure and relapse cases of tuberculosis: is the standard re-treatment regimen adequate?” Int J Tuberc Lung Dis 2003; 7: 631-6.

12. Amplifier effect of short-course chemotherapy 2HREZ/4HR (Category I) 2SHREZ/1HREZ/5HRE (Category II) 2SHREZ/1HREZ/5HRE (Category II) Resistance Patterns HS HRS HREZ S

13. The impact of resistance amplification on the DR TB epidemic • Drug resistance • Inadequate treatment • Resistance amplification • Nosocomial or community transmission

14. Category II is no longer acceptable “With the availability of funding from international financial partners, lack of resources for MDR-TB treatment is no longer an acceptable rationale for providing the 8-month retreatment regimen with first-line regimen drugs (formerly called the ‘Category II’) to patients with a high likelihood of MDR; this regimen is ineffective in treating MDR-TB and may result in amplification of drug resistance.” – World Health Organization (WHO). Treatment of Tuberculosis: Guidelines. Fourth Edition. Geneva: WHO, 2010.

15. Principles of MDR-TB management What improves outcomes: • Early identification (and treatment) of MDR-TB; • Use of an "effective" regimen (at least 4 susceptible second line drugs plus Z); • Adequate patient support: • Directly Observed Treatment (DOT) • Prompt treatment of side-effects • Social economic support