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Module 3: Drug-Resistant TB

Module 3: Drug-Resistant TB. 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. Types of TB Resistance.

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Module 3: Drug-Resistant TB

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  1. Module 3: Drug-Resistant TB

  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. 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. 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. 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. (H) Isoniazid (R) Rifampin (Z) Pyrazinamide (E) Ethambutol Streptomycin Cycloserine Ethionamide Amikacin Ciprofloxacin Anti-TB Drugs Second-Line First-Line

  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. 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. “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. 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. Biologic Basis of Drug Resistant M. tuberculosis

  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. Pathogenesis • Susceptible bacilli are killed • Resistant bacilli grow and become dominant • Further sequential selection can produce multi-drug resistance

  14. Spontaneous drug-resistant mutations in bacterial population INH RIF PZA INH Selection of INH-resistant bacterial population

  15. Additional spontaneous mutations INH INH RIF Selection and establishment of MDR

  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. 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. 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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