Anti-TB Agents Dr. Jeff Hobden MIP

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

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

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

Multi-Drug Resistant TB

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

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

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

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

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

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

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

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

Pyrazinamide Synthetic pyrazine analog of nicotinamide Synthetic pyrazine analog of nicotinamide Bactericidal at weak pH, where TB can be found in M  Bactericidal at weak pH, where TB can be found in M  Inhibits fatty acid synthase I gene Inhibits fatty acid synthase I gene

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

Mechanisms of Action

Mechanisms of Resistance

The End! Finally…