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Multi-drug Resistant Tuberculosis Hail M. Al-Abdely Consultant, Infectious Diseases, KFSH&RC 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. Tuberculosis notification rates, 2000 Rate per 100 000 0-9 10 - 24 25 - 49 50 - 99 100 or more No report 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 Estimated TB incidence rates, 2000 Rate per 100 000 0-9 10 - 24 25 - 49 50 - 99 100 - 300 300 or more No estimate 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 Epidemiology of MDR TB Geographic region No. of MDR TB cases (% of all new cases) All countries (n = 136) 272,906 (3.2) Established market economies 882 (0.7) Latin America 8508 (2.2) Eastern Europe 17,269 (5.5) Africa, low HIV 15,014 (1.9) Africa, high HIV 25,199 (1.8) Eastern Mediterranean 45,964 (7.9) Southeast Asia 75,062 (2.5) Western Pacific 85,008 (4.5) Dye et al. Global Burden of Multidrug-Resistant TB. JID 185(8), 2002 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 Dye et al. Global Burden of Multidrug-Resistant TB. JID 185(8), 2002 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 * Surveyed Dye et al. Global Burden of Multidrug-Resistant TB. JID 185(8), 2002 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. Development of anti-tuberculosis drug resistance Wild M. TB strain Spontaneous mutation Strains with genetic drug resistance Selection: inadequate treatment Acquired drug resistance Transmission Primary drug resistance Pablos-Mendez et al. WHO, 1997 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 Iseman M. NEJM, 329:784, 1993 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 monoresistance 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 Low Intermediate to high High possibility for disease No Yes Confirmed R to INH+RIF Standard recommendation For non-MDR TB contacts Consider Multidrug prophylaxis