antimycobacterials Flashcards
challenges of antimycobacterial therapy
difficult to kill, slow growth, lengthy therapy, intracellular forms, chronic disease
first-line drugs used in TB therapy
isoniazid, rifampin, ethambutol, pyrazinamide, streptomycin
cidal, inhibits synthesis of mycolic acids. activated by KatG protein, targets enoyl-acyl carrier protein reductase (InhA protein)
isoniazid
isoniazid resistance due to
mutations in KatG, mutations in InhA
isoniazid use
for all infected with INH-sensitive strains. given in combination for active TB treatment (alone for latent)
genetic polymorphism associated with INH
N-acetyltransferase-2: can be fast and slow acetylators
INH side effects
neurotoxicity, especially peripheral neuritis (slow acetylators), improves with B6 administration. hepatotoxicity (acetylhydrazine. esp with increased age)
inhibits DNA-dependent RNA polymerase, suppressing RNA synthesis. cidal.
rifampin. spontaneous mutation in RNA pol B subunit
Rifampin side effects
hepatotoxicity, potent CYP inducer –> increased metabolism of other drugs (3A4, 2C9, 2C19, etc). orange red color to tears, urine, saliva, etc.
interferes with arabinosyl transferase, blocking cell wall synthesis (prevents arabinoglycan polymerization). tuberculostatic when used alone.
ethambutol
ethambutol side effects
generally well tolerated but optic neuritis possible. (decreased visual acuity, red/green color blindness, often reversible) not hepatotoxic.
blocks mycolic acid synthesis by inhibiting fatty acid synthase I. cidal. important component of short-term therapy. helpful for CNS involvement.
pyrazinamide
pyrazinamide side effects
hepatic damage, especially when combined with rifampin
aminoglycoside, binds to several ribosomal sites to stop initiation and cause mRNA misreading. used for most serious TB forms
streptomycin
streptomycin side effects
ototoxicity, nephrotoxicity
short-course TB treatment
isoniazid + rifampin (6 mo) + pyrazinamide (first 2 months)
disseminated TB treatment
isoniazid + rifampin (9-24 mo) + pyrazinamide + ethambutol (1st 2 mo)
cidal, intracellular and extracellular treatment of conventional TB strains
isoniazid, rifampin, pyrazinamide
atypical mycopacterial infections + treatment
MAC. less fatal than TB so use anti-TB regimen until agent ID’d
single-agent prophylaxis of MAC in AIDS patients, alternate to rifampin for multi-drug treatment
rifabutin
rifabutin adverse effects
similar to rifampin but less frequent. drug interactions also similar to rifampin but to a lesser extent (less potent CYP inducer)
part of multi-drug treatment for MAC in AIDS patients, also for MAC prophylaxis. cidal in this case.
clarithromycin (avoids CYP induction)
MAC treatment regimens
clarithromycin + rifabutin, rifabutin synergistic in vitro with clarithromycin
for leprosy. structural analog of para-aminobenzoic acid, inhibits synthesis of folic acid, bacteriostatic. used in combination. alternative for prophylaxis and treatment of pneumocystis jiroveci in AIDS patients. slow & fast acetylators
dapsone
dapsone adverse effects
hemolytic anemia, methemoglobinemia
leprosy drug. binds to DNA, interfering with reproduction and growth, only used in combination therapy. no cross resistance.
clofazimine
clofazimine side effects
red-brown pigmentation of skin, eyes, urine
antibiotic used for leprosy treatment
rifampin. hepatotoxicity!
lepromatous disease treatment
dapsone + clofazimine + rifampin (2 yr)
tuberculoid disease treatment
dapsone + rifampin (1 yr)
