24. Antimycobacterial Agents Flashcards
rod shaped, may form filaments, lipid rich cell walls, gram stain poorly or not at all, acid fast stain, can replicate in macrophages
mycobacterium tuberculosis
inhibits DNA synthesis and supercoiling by targeting topoisomerase
fluoroquinoles
inhbits RNA synthesis by targeting 30s ribosomal subunit
rifamyacine and related compounds
inhbits protein sythesis by targeting 30S ribosomal subunit
streptomycin
target 23S ribosomal RNA, inhibiting peptidyl transferase
macrolides
inhibit mycolic acid synthesis
isoniazid and ethionamide
inhibit cell wall synthesis
ethanbutol
inhbit cell membrane synthesis
pyrazinamide
inhibit ATP synthase
TMC-207
inhibits mycolic acid and protein biosynthesis, possible action by generation of toxic radicals
PA-324
inactive, tubercle bacilli in the body, TST or blood test with IFN-y release usually positive, normal chest x-ray, negative sputum smear and cultures, no symptoms, not infectious, not a case of TB
latent TB infection
active, multiplying tubercle bacilli, TST or IFN-y test usually positive, sputum and cultures positive, have cough, fever, weight loss, often infectious before treatment
active TB
isoniazid, rifampin, pyrazinamide, and ethambutol, drops to isoniazid and rifampin after 2 months
recommended regimen for treatment of active tuberculosis infection
isoniazid and rifapentine for 3 months, no drugs are dropped
current recommendation for treatment of latent TB
bactericidal for actively growing bacilli, penetrates into macrophages and is active against extracellular and intracellular organisms, less effective against atypical mycobacterial infections, shares structural similarity to vitamin B6 pyridoxine, inhibits synthesis fo mycolic acid, delivered as a prodrug which is activated by mycobacterial catalase peroxidase enzyme, one of the safest and most effective antimyobacterial agents, primary drug for almost all TB infections, preferred treatment used in treatment of TB infections, resistance by mutation of Kat G gene prventing prodrug activation or ever expression of Inh A protein involved in cell wall synthesis, resistance to prodrugs are increasing so is always given with a second drug, readily absorbed from GI tract, peak plasma concentration in 2 hours, diffused into all body fluids and tissues including CNS, is acetylated to INH in the liver, bowel, and kidney but doesn’t affect clinical effectiveness, slow acetylators are more prone to develop toxicity like peripheral neuropathy due to structural similarity to vitamin B6 pyridoxine, can also cause hepatitis with risk of tthis increasing with age, peripheral neuropathy is more frequent in malnourished, alcoholic, diabetic, or suffering from AIDS
isoniazid
also active against gram positive and negative bugs, inhibits RNA synthesis, binds to bacterial DNA dependent RNA polymerase, is first line drug in the treatment of active tuberculosis infection, alternative to INH in latent tuberculosis, resistance is by point mutations in the bacterial RNA polymerase gene, arises at a rate of approximately 1x10^6, need to combined with other antituberculosis drugs, well absorbed from GI tract, peak absorption, causes nausea, vomiting, headache, dizziness, fatigue, hepatitis, harmless red orange color to urine/feces/sweat/tears, strong inducer of CYP450s, increases elimination of many drugs and classes such as antiretroviral protease inhibitors and nonucleoside reverse transcriptase inhibitors, substitute rifabutin for HIV infected patients
rifampin
synthetic analogue of nicotinamide, unknown mechanism of action, almost always used in combination therapy, possible inhibition of mycolic acid synthesis, prodrug is converted to active form by bacterial prazinamiase enzyme, antimicrobial activity is dependent on acidic environment, essential component of multidrug regiments used in treating active tuberculosis infections, resistance by mutation to pyrazinadimase to active form, well absorbed from GI tract, widely distributed throughout the body, enters macrophages and tuberculosis cavities, can cause hepatotoxicity and hyperuricemia/gout
pyrazinamide
almost exclusively used as part of 4 drug combinations used in treating active TB or mycobacterium avium infection, inhibits arabinosyl transferase involved in mycobacterial cell wall synthesis, component of multidrug therapies, point mutations in genes encoding arabinosyl transferases, should always be given in combination with other drugs, well absorbed from the gut, peak serum concentration in 4 hours, can cause retrobulbar neuritis which are reversible following discontinuation, rare and dose dependent with impaired visual acuity and red/green colorblindness, hyperuricemia also possible but less frequent and dramatic than pyrazinamide, small percentage have gouty arthritis
ethambutol
aminoglycodie antibiotic, one of the first used in the treatment of TB, interferes with bacterial protein synthesis, works against m tuberculosis, m avium complex species, penetrates poorly, resistance to point mutations in ribosomal proteins, delivered as injectable and has poor penetration into cells and tissues, causes ototoxicity and nephrotic side effects
streptomycin
related to rifampin, shares mechanism of action by inhibition of RNA polymerases, active against M tuberculosis and avium complex species, greater activity against MAC organisms than rifampin, less potent inducer of cytochrome P450 enzymes, commonly substituted for rifampin in treatment of tuberculosis infected HIV patients
rifabutin
include m. avium and intracellulare and others, can cause pulmonary disease in immunocompetent individuals and disseminated disease in AIDS patient, transmitted by respiratory droplets, treatment for MAC pulmonary infections are with macrolide antibiotic like clarithromycin or azithromycin, rifampin, ethambutol, sometimes streptomycin, combination therapy with MAC disseminated disease are the first three, prophylaxis in HIV patients is with clarithromycin and azithromycin
myobacterium avium complex
rare, less than 100 cases in the U.S. each year, develops over decades, disfiguring skin lesions with nodules and plaques, treatment with dapsone, clofazimine, and rifampin, therapy is 1-2 for tuberculoid and 5 years for lepromatous
leprosy/m. leprae
folic acid synthesis inhibitor, analog of PABA, can induce anemia
dapsone
bactericidal dye with unknown mechanism of action, changes skin to red/black
clofazimine
