1. Multi-drug Resistant Tuberculosis Hail M. Al-Abdely Consultant, Infectious Diseases, KFSH&RC

2. Presentation Outline  Definition of MDR TB  Epidemiology of MDR TB  Genesis of MDR  Mechanism of resistance  Treatment  Chemoprophylaxis for MDR TB exposure

3. 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

4. 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.

5. Tuberculosis notification rates, 2000 25 - 49 50 - 99 100 or more 0 - 9 10 - 24 No report Rate per 100 000 The boundaries and names shown and the designations used on this map do not imply the expression of any opinion whatsoever on the part of the World Health Organization concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted lines on maps represent approximate border lines for which there may not yet be full agreement. Global Tuberculosis Control. WHO Report 2002. WHO/CDS/TB/2002.295 25 - 49 50 - 99 100 or more 0 - 9 10 - 24 No report Rate per 100 000 The boundaries and names shown and the designations used on this map do not imply the expression of any opinion whatsoever on the part of the World Health Organization concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted lines on maps represent approximate border lines for which there may not yet be full agreement. Global Tuberculosis Control. WHO Report 2002. WHO/CDS/TB/2002.295

6. 25 - 49 50 - 99 100 - 300 0 - 9 10 - 24 300 or more No estimate Rate per 100 000 Estimated TB incidence rates, 2000 The boundaries and names shown and the designations used on this map do not imply the expression of any opinion whatsoever on the part of the World Health Organization concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted lines on maps represent approximate border lines for which there may not yet be full agreement. Global Tuberculosis Control. WHO Report 2002. WHO/CDS/TB/2002.295

7. 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 Dye et al. Global Burden of Multidrug-Resistant TB. JID 185(8), 2002

8. WHO Surveillance and Incidence of MDR TB Country% MDR TB of all new cases Estonia14.1 Latvia9.0 China (non-DOTS)7.7 China (DOTS)2.8 Russia6.0 India3.4 Iran5.8 Dominican6.6 Ivory Cost5.3 Dye et al. Global Burden of Multidrug-Resistant TB. JID 185(8), 2002

9. 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 Egypt5.6 Jordan2.8 Kuwait3.3 Lebanon3.4 Saudi Arabia3.0 Sudan10.1 Syria6.7 Yemen12.4 Dye et al. Global Burden of Multidrug-Resistant TB. JID 185(8), 2002 * Surveyed

10. 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.

11. 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 Pablos-Mendez et al. WHO, 1997

12. 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

13. Mechanism of Resistance  TB specific drugs –INH, PZA, ETH  Antibiotics with activity against TB –RIF –Aminogycosides –Flouroquinolones

14.  INH –Chromosomally mediated –Loss of catalase/peroxidase –Mutation in mycolic acid synthesis –Regulators of peroxide response Mechanism of resistance

15.  Rifampin –Reduced binding to RNA polymerase  Clusters of mutations at “Rifampin Resistance Determining Region” (RRDR) –Reduced Cell wall permeability Mechanism of resistance

16. 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

17. Iseman M. NEJM, 329:784, 1993

18. 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

19. Chemoprophylaxis  Determinants of intervention –Likelihood of infection with MDR TB  Low  Intermediate  High –Likelihood of developing MDR TB  Immune suppression

20. Likelihood of infection with MDR TB Intermediate to highLow High possibility for disease Yes No Consider Multidrug prophylaxis Confirmed R to INH+RIF Standard recommendation For non-MDR TB contacts