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Anti-TB Agents

Anti-TB Agents. Dr. Jeff Hobden MIP. Mycobacterium tuberculosis. TB is hard to kill with antibiotics Slow growth Fortified cell wall Intracellular growth Very good at developing resistance to single agents. Treatment of TB – Old School. Surgical collapse of infected lung

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Anti-TB Agents

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  1. Anti-TB Agents Dr. Jeff Hobden MIP

  2. Mycobacterium tuberculosis • TB is hard to kill with antibiotics • Slow growth • Fortified cell wall • Intracellular growth • Very good at developing resistance to single agents

  3. Treatment of TB – Old School • Surgical collapse of infected lung • Vitamin D & heliotherapy (can you say “melanoma” • Bed rest and fresh air

  4. Modern Treatment of TB – A Rigorous Course of Multiple Antibiotics • First line drugs • Isoniazid • Rifampin • Ethambutol • Streptomycin • Pyrazinomide • Second line drugs • Moxi-or gatifloxacin • Ethionamide • Aminosalicylic acid • Cycloserine • Amikacin and kanamycin • Capreomycin • linezolid 6 months of taking a handful of pills!

  5. Multi-Drug Resistant TB

  6. Isoniazid (INH) • Synthetic hydrazide of isonicotinic acid • Requires catalase-peroxidase for activation • Bacteriocidal for growing cells, static for resting cells • Prevents synthesis of mycolic acids

  7. Isoniazid (INH) • Oral or parental • Water soluble, penetrates into caseous material of granuloma • Acetylated and secreted into urine • Rate of secretion has racial component • Toxicity • Rash and fever (UC) • Jaundice (rare) • Peripheral neuritis (rare)

  8. Rifamycins • Natural and semi-derived from filamentous soil bacteria • Complex macrocyclic antibiotics • Members of the class • Rifabutin (for HIV+) • Rifapentine • Rifampin = rifampicin (for everyone else)

  9. Rifamycins • Broad spectrum, bactericidal • Inhibit DNA-dependent RNA polymerase • Resistance generated by altering target

  10. Rifamycins • Administered orally • Absorbed in GI tract • Asprin will interfere with its absorbance • Wide distribution • Can discolor body waste, saliva, tears orange-red • Acetylated and then excreted into bile and ultimately pooped out

  11. Uses of Select Rifamycins • Rifampicin • Treatment of TB • Prophylaxis against meningocccus • Staph infections • Rifabutin and rifapentine • TB therapy for HIV+ patients • MAC infections

  12. Toxicity/Contraindications of Rifamycins • Rifampicin • Flu-like illness (common) • Decreases half life of many drugs by inducing CYPs • HIV protease inhibitors and non-nucleoside RT inhibitors • Corticosteroids • Oral contraceptives • Rifambutin • Induces CYPs but not to the same degree as rifampicin • Rash, red pee, neutropenia, leukopenia (common)

  13. Ethambutol • Inhibits arabinosyl transferases involved in cell wall synthesis • Given orally and excreted mostly unchanged in the urine • Dose dependent diminished visual acuity

  14. Pyrazinamide • Synthetic pyrazine analog of nicotinamide • Bactericidal at weak pH, where TB can be found in MF • Inhibits fatty acid synthase I gene

  15. Pyrazinamide • Oral administration • Excellent penetration • Hydrolyzed and hydroxylated before being excreted by kidneys • Hepatotoxicity (uncommon) • Hyperuricermia – gout (rare)

  16. Mechanisms of Action

  17. Mechanisms of Resistance

  18. The End! Finally…

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