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3.0 drug resistance

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3.0 drug resistance

  1. 1. Module 3: Drug-Resistant TB
  2. 2. Learning Objectives • Describe how drug resistance emerges • Explain the difference between primary and secondary resistance • Explain indications for drug susceptibility testing • Name 6 ways to prevent MDR TB
  3. 3. Types of TB Resistance • Confirmed mono-resistance: Tuberculosis in patients whose infecting isolates of M. tuberculosis are confirmed to be resistant in vitro to one first line anti- tuberculosis drug • Confirmed poly-resistance: Tuberculosis in patients whose infecting isolates are resistant in vitro to two or more first line anti- tuberculosis drug other than both isoniazid and rifampicin. • Confirmed MDR-TB: Tuberculosis in patients whose infecting isolates are resistant in vitro to at least both isoniazid and rifampicin.
  4. 4. Multi-Drug Resistant TB • MDR TB does not simply mean resistance to more than one drug, it specifically means resistance to at least both isoniazid (H) and rifampin (R)
  5. 5. Drug Resistance Patterns • Predicted by (mis)use of drugs over time • Influenced by – Dates drug first used in humans – Penetration into local marketplace (changes in cost, regulatory approval) – Evolution of National TB Program (NTP) regimens – Introduction of free-of-charge Rx – Availability as OTCs
  6. 6. • (H) Isoniazid • (R) Rifampin • (Z) Pyrazinamide • (E) Ethambutol First-Line Second-Line Anti-TB Drugs • Streptomycin • Cycloserine • Ethionamide • Amikacin • Ciprofloxacin
  7. 7. Drug-Resistant TB •Drug-resistant TB is transmitted the same way as drug-susceptible TB •Drug resistance is divided into two types: - Primary resistance refers to cases initially infected with resistant organisms - Acquired resistance develops during TB therapy
  8. 8. Persons at Increased Risk for Drug Resistance •History of treatment with TB drugs •Contacts of persons with drug-resistant TB •Smears or cultures remain positive despite 2 months of TB treatment •Received inadequate treatment regimens for >2 weeks
  9. 9. “Inadequate Treatment” • Multi-factorial – Lack of adherence/intermittent or interrupted therapy – Malabsorption – Inappropriate regimens; to properly treat TB one must always add at least two drugs to a failing regimen – Sub-therapeutic dosing – Expired or substandard drugs
  10. 10. Example of Management Errors Resulting in Acquired Drug Resistance • 35 MDR TB cases referred to US TB specialty hospital • Average 3.9 errors per patient – Inadequate primary regimen – Addition of single drug to failing regimen – Failure to address non-adherence • Isoniazid alone used for misdiagnosed LTBI – i.e., active TB patients on monotherapy Mahmoudi A, Iseman MD. JAMA 1993;270:65-68
  11. 11. Biologic Basis of Drug Resistant M. tuberculosis
  12. 12. Selected Spontaneous Mutations Drug Frequency Isoniazid 1/1,000,000 Pyrazinamide 1/1,000,000 Streptomycin 1/1,000,000 Ethambutol 1/100,000 Rifampin 1/100,000,000 H and R resistance mutation frequency = 1:1014
  13. 13. Pathogenesis • Susceptible bacilli are killed • Resistant bacilli grow and become dominant • Further sequential selection can produce multi-drug resistance
  14. 14. INH RIF PZA INH Spontaneous drug- resistant mutations in bacterial population Selection of INH-resistant bacterial population
  15. 15. INH RIF INH Additional spontaneous mutations Selection and establishment of MDR
  16. 16. Indications for DST • Drug susceptibility testing indicated for – all retreatment cases prior to initiation of treatment – Any patient who does not respond to therapy • Conduct culture and DST for patients who – Have positive smears despite 2 months of therapy
  17. 17. Consequences of MDR • Delay in diagnosis • Treatment duration extended – 18 to 24 mo. • Second line drugs – Effectiveness decreases – Toxicity increases • Expensive to treat • Community transmission
  18. 18. How we can prevent MDR TB • Initial treatment with standardized regimens (HRZE) • Directly observed therapy (DOT) • Drug susceptibility testing for all retreatment cases • Infection control precautions • Monitor drug resistance through surveys • Effective contact management

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