Multi-drug Resistant 		Tuberculosis<br />.<br />
INTRODUCTION<br />Multi drug resistance is a condition enabling a disease causing organism to resist distinct drugs or che...
Main mechanism of drug resistance of tumor cells<br />
Several mechanism employed by these microorganism to attain MDR<br /><ul><li>No longer relying on a glycoprotein cell wall
Enzymatic deactivation of antibiotics
Decreased cell wall permeability to antibiotics
Altered target sites of antibiotic
Efflux mechanism to remove antibiotics
Increased mutation rate as a stress response</li></li></ul><li>To limit the development of antibiotic resistance<br /><ul>...
Identify the causative organism if possible
Use the right antibiotic do not rely on broad range of antibiotic
Not stop antibiotic as soon as symptoms improve finish the full course
No use of antibiotic for most cold,  coughs,bronchitis,sinus infections and eye infection which are caused by viruses</li>...
What WHO says about Drug resistance<br />“The use and misuse of antimicrobials in human medicine and animal husbandry over...
Presentation Outline<br />Definition of MDR TB<br />Epidemiology of MDR TB<br />Genesis of MDR<br />Mechanism of resistanc...
Definition of MDR TB<br />1950s-1970s: <br />M. tb resistant to INH, streptomycin and/or PAS<br />1980s-current: <br />M. ...
Why INH and Rifampin<br />Most potent and bacteriocidal<br />Tb can be treated effectively with INH+Rif alone<br />Mono-re...
Epidemiology of MDR TB<br />No. of MDR TB cases (% of all new cases)<br />Geographic region<br />272,906 (3.2)<br />All co...
WHO Surveillance and Incidence of MDR TB<br />.<br />
WHO Estimates of MDR TB in Some Arabian Countries<br />.<br />
Genesis of MDR TB<br />Resistance is a man-made amplification of a natural phenomenon.<br />Inadequate drug delivery is ma...
Development of anti-tuberculosis drug resistance<br />   Wild M. TB strain<br />Spontaneous mutation<br />Strains with gen...
Clinical factors promoting resistance<br />Delayed diagnosis and isolation<br />Inappropriate drug regimen.<br />Inadequat...
Mechanism of Resistance<br />TB specific drugs<br />INH, PZA, ETH<br />Antibiotics with activity against TB<br />RIF<br />...
Mechanism of resistance<br />INH<br />Chromosomally mediated<br />Loss of catalase/peroxidase<br />Mutation in mycolic aci...
Mechanism of resistance<br />Rifampin<br />Reduced binding to RNA polymerase<br />Clusters of mutations at “Rifampin Resis...
Treatment of MDR TB<br />Factors determining Success<br />Culture of MDR TB<br />Reliable susceptibility<br />Reliable his...
.<br />
New Chemotherapeutic Agents<br />Not many. Low interest from industry<br />Derivatives of Rifamycin<br />Rifabutin: Sensit...
Chemoprophylaxis<br />Determinants of intervention<br />Likelihood of infection with MDR TB<br />Low<br />Intermediate<br ...
Likelihood of infection with MDR TB<br />Intermediate to high<br />Low<br />High possibility<br /> for disease<br />No<br ...
Development of Drug Resistancefrom the perspective of the patient:<br />The presence of drug resistant strains results fro...
The basis of anti-TB therapy and MDR-TB: HDL -- a comprehensive approach and unified system of care<br />Drugs<br />Smear/...
THE NEW MDR-TB Guidelines<br />a flexible framework approach combining both clinical and programmatic aspects of DOTS Plus...
EXPECTED  OUTCOMES of DRS<br />Level and pattern of resistance to first-line anti-TB drugs among new sputum smear positive...
DOTS-Plus<br />A comprehensive strategy of the WHO Stop TB Partnership, developed by the DOTS-Plus Working Group, for the ...
THE DOTS-Plus Framework<br />1. Sustained Political commitment<br />2.Diagnosis of MDR-TB through quality-assured culture ...
Mainstreaming DOTS-Plus into DOTS<br /><ul><li>Referral from DOTS-programme:  failures, chronics
Same (reference) laboratory
Same treatment delivery system
Drug-procurement and R&R:  adapted but integrated!</li></li></ul><li>Preliminary results of DOTS-Plus projects<br />In Est...
Parameters to consider when designing a DOTS-Plus strategy <br /><ul><li>Government and NTP commitment
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Multi drug resistant

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Multi drug resistant

  1. 1. Multi-drug Resistant Tuberculosis<br />.<br />
  2. 2. INTRODUCTION<br />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<br />Organism that display multi drug resistance can be pathologic cells including bacterial and neoplastic (tumor) cells <br />
  3. 3. Main mechanism of drug resistance of tumor cells<br />
  4. 4. Several mechanism employed by these microorganism to attain MDR<br /><ul><li>No longer relying on a glycoprotein cell wall
  5. 5. Enzymatic deactivation of antibiotics
  6. 6. Decreased cell wall permeability to antibiotics
  7. 7. Altered target sites of antibiotic
  8. 8. Efflux mechanism to remove antibiotics
  9. 9. Increased mutation rate as a stress response</li></li></ul><li>To limit the development of antibiotic resistance<br /><ul><li>Use antibiotics only for bacterial infection
  10. 10. Identify the causative organism if possible
  11. 11. Use the right antibiotic do not rely on broad range of antibiotic
  12. 12. Not stop antibiotic as soon as symptoms improve finish the full course
  13. 13. No use of antibiotic for most cold, coughs,bronchitis,sinus infections and eye infection which are caused by viruses</li></li></ul><li>Some important information about Drug Resistance<br />Drug resistance strains of pathogen may arise from seemingly innocent activities such as tooth-brushing, hand washing, application of deodrants and any cosmetic or health-care products<br />Dipping of pets and farm animals or the use of disinfectants and detergent<br />The chemicals contained in these preparation may intentionally or inadvertently target organisms that have the potential to develop resistance &there by become problematic<br />
  14. 14. What WHO says about Drug resistance<br />“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”<br />
  15. 15. Presentation Outline<br />Definition of MDR TB<br />Epidemiology of MDR TB<br />Genesis of MDR<br />Mechanism of resistance<br />Treatment<br />Chemoprophylaxis for MDR TB exposure<br />
  16. 16. Definition of MDR TB<br />1950s-1970s: <br />M. tb resistant to INH, streptomycin and/or PAS<br />1980s-current: <br />M. tb resistant to at least INH and Rifampin<br />
  17. 17. Why INH and Rifampin<br />Most potent and bacteriocidal<br />Tb can be treated effectively with INH+Rif alone<br />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%)<br />Failure rate when INH+Rif resistant is 44% in non-HIV and 70% in HIV patients<br />Duration required for cure doubles to triples.<br />
  18. 18. Epidemiology of MDR TB<br />No. of MDR TB cases (% of all new cases)<br />Geographic region<br />272,906 (3.2)<br />All countries (n = 136)<br />882 (0.7)<br />Established market economies<br />8508 (2.2)<br />Latin America<br />17,269 (5.5)<br />Eastern Europe<br />15,014 (1.9)<br />Africa, low HIV<br />25,199 (1.8)<br />Africa, high HIV<br />45,964 (7.9)<br />Eastern Mediterranean<br />75,062 (2.5)<br />Southeast Asia<br />85,008 (4.5)<br />Western Pacific<br />.<br />
  19. 19. WHO Surveillance and Incidence of MDR TB<br />.<br />
  20. 20. WHO Estimates of MDR TB in Some Arabian Countries<br />.<br />
  21. 21. Genesis of MDR TB<br />Resistance is a man-made amplification of a natural phenomenon.<br />Inadequate drug delivery is main cause of secondary drug resistance.<br />Secondary drug resistance is the main cause of primary drug resistance due to transmission of resistant strains.<br />MDR due to spontaneous mutations is not possible as the genes encoding resistance for anti TB are unlinked.<br />
  22. 22. Development of anti-tuberculosis drug resistance<br /> Wild M. TB strain<br />Spontaneous mutation<br />Strains with genetic <br />drug resistance<br />Selection: inadequate treatment<br />Acquired drug <br />resistance<br />Transmission<br />Primary drug <br />resistance<br />.<br />
  23. 23. Clinical factors promoting resistance<br />Delayed diagnosis and isolation<br />Inappropriate drug regimen.<br />Inadequate initial therapy<br />Incomplete course of treatment<br />Inappropriate treatment modifications<br />Adding single drug to a failing regimen<br />Inappropriate use of chemoprophylaxis<br />Poor adherence and incomplete F/U<br />Failure to isolate MDR TB patients<br />Failure to employ DOT<br />Over the counter anti TB<br />Faked drugs<br />
  24. 24. Mechanism of Resistance<br />TB specific drugs<br />INH, PZA, ETH<br />Antibiotics with activity against TB<br />RIF<br />Aminogycosides<br />Flouroquinolones<br />
  25. 25. Mechanism of resistance<br />INH<br />Chromosomally mediated<br />Loss of catalase/peroxidase<br />Mutation in mycolic acid synthesis<br />Regulators of peroxide response<br />
  26. 26. Mechanism of resistance<br />Rifampin<br />Reduced binding to RNA polymerase<br />Clusters of mutations at “Rifampin Resistance Determining Region” (RRDR)<br />Reduced Cell wall permeability<br />
  27. 27. Treatment of MDR TB<br />Factors determining Success<br />Culture of MDR TB<br />Reliable susceptibility<br />Reliable history of previous drug regimens<br />Program to assure delivery of prescribed drugs (DOT)<br />Correct choice of modified treatment regimen<br />Reliable follow up<br />
  28. 28. .<br />
  29. 29. New Chemotherapeutic Agents<br />Not many. Low interest from industry<br />Derivatives of Rifamycin<br />Rifabutin: Sensitive subset of Rifampin resistant strains<br />Rifapentine: Extended half-life but more mono-resistance to rifamycins<br />KRM-1648. benzoxazinorifamycin. In vitro and animal models.<br />New flouroquinolones<br />Gatifloxacin, Moxifloxacin, levofloxacin, sparfloxacin<br />Nitroimidazoles<br />related to metronidazole. May work better against latent bacilli<br />Avoiding pro-drug problems<br />
  30. 30. Chemoprophylaxis<br />Determinants of intervention<br />Likelihood of infection with MDR TB<br />Low<br />Intermediate<br />High<br />Likelihood of developing MDR TB<br />Immune suppression<br />
  31. 31. Likelihood of infection with MDR TB<br />Intermediate to high<br />Low<br />High possibility<br /> for disease<br />No<br />Yes<br />Confirmed R <br />to INH+RIF<br />Standard <br />recommendation <br />For non-MDR TB contacts<br />Consider Multidrug <br />prophylaxis<br />
  32. 32. Development of Drug Resistancefrom the perspective of the patient:<br />The presence of drug resistant strains results from simple Darwinian pressures, brought out by the presence of antibiotics<br />Multiple drug resistant strains result from the step-wise accumulation of individual resistance elements therefore MDR-TB is MAN-MADE<br />
  33. 33.
  34. 34. The basis of anti-TB therapy and MDR-TB: HDL -- a comprehensive approach and unified system of care<br />Drugs<br />Smear/Culture<br />Case management<br />DST & QC<br />Surgery<br />Government Health<br />Services<br />Private Physicians<br />and Hospitals<br />
  35. 35. THE NEW MDR-TB Guidelines<br />a flexible framework approach combining both clinical and programmatic aspects of DOTS Plus<br />based on essential programme conditions<br />But encouraging programs to tailor their case-finding and treatment strategies to the local epidemiological and programme situation <br />Reflect GLC expert consensus and evidence and experience from GLC projects thus far<br />
  36. 36. EXPECTED OUTCOMES of DRS<br />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.<br />The outcome of treatment of patients with different resistance patterns.<br />A model protocol for surveillance of drug resistance in Indonesia <br />
  37. 37. DOTS-Plus<br />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<br />
  38. 38. THE DOTS-Plus Framework<br />1. Sustained Political commitment<br />2.Diagnosis of MDR-TB through quality-assured culture and drug susceptibility testing (DST).<br />3. Appropriate treatment strategies that utilize second line drugs under proper management conditions. <br />4. Uninterrupted supply of quality assured second-line anti-tuberculosis drugs. <br />5. Recording and reporting system designed for DOTS-Plus programs.<br />
  39. 39. Mainstreaming DOTS-Plus into DOTS<br /><ul><li>Referral from DOTS-programme: failures, chronics
  40. 40. Same (reference) laboratory
  41. 41. Same treatment delivery system
  42. 42. Drug-procurement and R&R: adapted but integrated!</li></li></ul><li>Preliminary results of DOTS-Plus projects<br />In Estonia and Latvia a large proportion of cases enrolled on MDR-TB treatment are new while in Peru, Philippines and Tomsk the majority are chronic<br />Treatment success rates range from 61-82%<br />Only 2% of patients have stopped treatment due to adverse events<br />Future plans: Case-based data is being collected from these pilot sites to serve as evidence for MDR-TB policy development<br />
  43. 43. Parameters to consider when designing a DOTS-Plus strategy <br /><ul><li>Government and NTP commitment
  44. 44. Well performing basic DOTS
  45. 45. Program is able to implement the 5 components of DOTS-Plus
  46. 46. Rational case-finding strategy using quality assured smear, culture and DST ( concordance with a SRL)
  47. 47. Representative DRS data for rational country/area-specific treatment design and planning of procurement
  48. 48. Reliable DOT throughout treatment
  49. 49. Free effective side-effect management
  50. 50. Regular supply of ALL drugs involved! </li></li></ul><li>MDR TB patients management<br />Individual Treatment regimen:<br />IP: Minimum of 4 in Abkhazia, 5 in Nukus, 2nd Line TB drugs to which patient is susceptible, including an injectable for 4 to 6 months after culture conversion<br />CP: Same regimen but the injectable for 18 months<br />DOT<br />Comprehensive management of side-effects<br />Infection control measures in the hospital:<br />UV lights<br />Ventilation (difficult in the winter time)<br />High filtration masks for staff and visitors<br />Separation of the patients<br />
  51. 51. MDR treatment outcomes<br />Treatment outcomes are reported according to WHO and international definitions:<br />Cure<br />Treatment completed<br />Death<br />Failure<br />Default<br />Still on treatment<br />
  52. 52. Operational implications<br /><ul><li>If super-infection between patients during the stay in the hospital:</li></ul>Urgent needs to improve infection control within the hospital<br />Consider ambulatory treatment from the beginning?<br />If family clusters<br />Aggressive active screening in all family members?<br />If true amplification<br />Use more aggressive treatment regimen, including 3rd Line TB drugs<br />Call for research on new drugs<br />
  53. 53. Transmission & Pathogenesis<br />
  54. 54. Diagnosis of TB Disease<br /><ul><li>Clinical suspicion (Think TB)
  55. 55. PPD skin test results (BCG status not used)
  56. 56. Chest x-ray
  57. 57. AFB smears of 3 sputum specimens
  58. 58. Culture identification (confirmation)
  59. 59. Other procedures as needed</li></li></ul><li>Drug Susceptibility Testing (DST)<br />To identify drug-resistant strains. <br />To specify pattern of resistance.<br />Implications for therapy and protocols<br />Results obtained 1-2 weeks after culture growth.<br />New molecular methods rapid but expensive.<br />
  60. 60. <ul><li>Primary Resistance
  61. 61. Drug resistance among new cases.
  62. 62. Never received TB drugs or received them for < 1 month.
  63. 63. Initial culture.
  64. 64. Secondary (Acquired) Resistance
  65. 65. Drug resistance in a patient who previously</li></ul> received at least 1 month of TB therapy.<br />.<br />
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