51-Antimycobacterial Drugs Flashcards
Recommended Treatment regimen for active TB?
Preferred regimen: Daily INH, RIF, PZA, and EMB for 8 weeks then either daily or twice weekly INH and RIF for 18 weeks
Alternative treatments for active TB
Alternative #1: Daily INH, RIF, PZA, and EMB for two weeks then twice weekly for six weeks. Then INH and RIF twice weekly for 18 weeks.
Alternative #2: Thrice-weekly INH, RIF, PZA, and EMB for 8 weeks. Then INH and RIF thrice weekly for 18 weeks.
What is the most active drug in the treatment of TB (active and latent)?
Isoniazid (INH)
Recommended treatment regimen for latent TB?
Isoniazid for 9 months (either daily or twice weekly)
What makes Isoniazid particularly potent against TB infections?
It penetrates macrophages so it is effective against extracellular and intracellular organisms.
It also readily penetrates CNS.
Isoniazid mechanism of action?
resistance?
Inhibits synthesis of mycolic acid for cell wall. Prodrug is activated by mycobacterial Kat G enzyme.
Resistance if mutation in Kat G or overexpression of Inh A protein involved in mycolic acid synthesis
When does Isoniazid pose a toxicity threat?
In people that are slow acetylators (inactivators). It is acetylated in the liver, bowel, and kidney
What are the most significant adverse effects of Isoniazid?
Liver toxicity causing hepatitis. People at an increased risk are older or alcohol dependants.
Peripheral neuropathy can occur in slow acetylators and patients who are malnourished, alcoholic, diabetic, or AIDS
Rifampin mechanism of action?
inhibits RNA synthesis by binding bacterial DNA dependent RNA polymerase. (also effective at killing intracellular bacteria)
Resistance to Rifampin?
point mutations in the bacterial RNA polymerase gene are very common (1 in 10^6)
Adverse effects of Rifampin?
GI, nervous system.
Hepatitis (most common with underlying liver disease and slow INH acetylators (combo therapy).
Also red-orange color in secretions (harmless)
Rifampin drug-drug interactions?
Induces Cytochrome P450 which metabolizes many drugs including antiretroviral drugs. Thus, in HIV infected patients use rifabutin as a substitute!
Pyrazinamide mechanism of action?
Prodrug is converted by bacterial enzyme and inhibits mycolic acid synthesis. Requires an acidic environment so works well against intracellular bacteria in macrophage lysosomes.
Resistance to Pyrazinamide?
mutation in the pyrazinamidase enzyme
Adverse effects of Pyrazinamide?
Hepatotoxicity, hyperuricemia (small percent gouty arthritis)
Ethambutol to treat what?
Used for active TB and M. avium bacteria.
Ethambutol mechanism of action?
Inhibits cell wall synthesis by arabinosyl transferases. Resistance with point mutations in genes encoding arabinosyl transferases.
Adverse reactions to Ethambutol?
Retrobulbar neuritis or red-green colorblindness (both reversible) and hyperuricemia
Streptomycin
(mechanism)
(resistance)
(adverse)
injectable that interferes with bacterial protein synthesis at 30S ribosome
point mutations in ribosome proteins
ototoxic/nephrotic
Rifabutin
used in the treatment of HIV infected patients because it doesn’t induce the CYP450 metabolism as much as rifampin.
Also has a greater efficacy against MAC organisms than rifampin
M. avium complex (MAC) treatment
Macrolide antibiotic
rifampin
ethambutol
streptomycin (+ or -)
for disseminated just top 3, pulmonary consider adding streptomycin
Treatment of leprosy
dapsone, clofazimine, and rifampin multidrug therapy. 1-2 years for tuberculoid, 5 years for lepromatous!
Dapsone mechanism and adverse
competitive inhibitor of folic acid synthesis (PABA analog)
can induce non-hemolytic anemias in some, and acute hemolytic anemia in people with G-6-P deficiency
(half-life 1-2 days, but high concentrations can remain in skin, liver and kidney for weeks after discontinuation)
Clofazamine
bactericidal dye
causes skin discoloration
