2. INTRODUCTION Multi drug resistance is a condition enabling a disease causing organism to resist distinct drugs or chemicals of a wide variety of structure & function targeted at eradicating the organism Organism that display multi drug resistance can be pathologic cells including bacterial and neoplastic (tumor) cells
14. What WHO says about Drug resistance “The use and misuse of antimicrobials in human medicine and animal husbandry over the past 70 years led to a relentless rise in the number and types of microorganism resistant to these medicine leading to death, increased suffering & disability and higher health care cost”
15. Presentation Outline Definition of MDR TB Epidemiology of MDR TB Genesis of MDR Mechanism of resistance Treatment Chemoprophylaxis for MDR TB exposure
16. 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
17. 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.
18. Epidemiology of MDR TB No. of MDR TB cases (% of all new cases) Geographic region 272,906 (3.2) All countries (n = 136) 882 (0.7) Established market economies 8508 (2.2) Latin America 17,269 (5.5) Eastern Europe 15,014 (1.9) Africa, low HIV 25,199 (1.8) Africa, high HIV 45,964 (7.9) Eastern Mediterranean 75,062 (2.5) Southeast Asia 85,008 (4.5) Western Pacific .
21. 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.
22. 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 .
23. 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
24. Mechanism of Resistance TB specific drugs INH, PZA, ETH Antibiotics with activity against TB RIF Aminogycosides Flouroquinolones
25. Mechanism of resistance INH Chromosomally mediated Loss of catalase/peroxidase Mutation in mycolic acid synthesis Regulators of peroxide response
26. Mechanism of resistance Rifampin Reduced binding to RNA polymerase Clusters of mutations at “Rifampin Resistance Determining Region” (RRDR) Reduced Cell wall permeability
27. 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
29. 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
30. Chemoprophylaxis Determinants of intervention Likelihood of infection with MDR TB Low Intermediate High Likelihood of developing MDR TB Immune suppression
31. Likelihood of infection with MDR TB Intermediate to high Low High possibility for disease No Yes Confirmed R to INH+RIF Standard recommendation For non-MDR TB contacts Consider Multidrug prophylaxis
32. Development of Drug Resistancefrom the perspective of the patient: The presence of drug resistant strains results from simple Darwinian pressures, brought out by the presence of antibiotics Multiple drug resistant strains result from the step-wise accumulation of individual resistance elements therefore MDR-TB is MAN-MADE
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34. The basis of anti-TB therapy and MDR-TB: HDL -- a comprehensive approach and unified system of care Drugs Smear/Culture Case management DST & QC Surgery Government Health Services Private Physicians and Hospitals
35. THE NEW MDR-TB Guidelines a flexible framework approach combining both clinical and programmatic aspects of DOTS Plus based on essential programme conditions But encouraging programs to tailor their case-finding and treatment strategies to the local epidemiological and programme situation Reflect GLC expert consensus and evidence and experience from GLC projects thus far
36. EXPECTED OUTCOMES of DRS Level and pattern of resistance to first-line anti-TB drugs among new sputum smear positive cases and among previously treated TB cases in Central Java. The outcome of treatment of patients with different resistance patterns. A model protocol for surveillance of drug resistance in Indonesia
37. DOTS-Plus A comprehensive strategy of the WHO Stop TB Partnership, developed by the DOTS-Plus Working Group, for the diagnosis and management of MDR-TB and other forms of drug resistant TB
38. THE DOTS-Plus Framework 1. Sustained Political commitment 2.Diagnosis of MDR-TB through quality-assured culture and drug susceptibility testing (DST). 3. Appropriate treatment strategies that utilize second line drugs under proper management conditions. 4. Uninterrupted supply of quality assured second-line anti-tuberculosis drugs. 5. Recording and reporting system designed for DOTS-Plus programs.
51. MDR treatment outcomes Treatment outcomes are reported according to WHO and international definitions: Cure Treatment completed Death Failure Default Still on treatment
