Antimycobacterial Drugs Flashcards
90 pct of primary tb infections lead to latent, asymptomatic tb. What causes this to happen?
Development of cell-mediated immunity (which keeps the Tb in check)
Are pts with latent Tb contagious?
No
How large does the induration have to be for a PPD test to be positive?
Immunocompromised pts or suspicion of Tb - gt 5 mm, Low risk populations - gt 15 mm, All others - gt 10 mm
There is an alternative to PPD for testing for Tb. What is the alternative and for whom is it recommended?
T cell-based inteferon gamma testing. Recommended for those who received BCG vaccine or those unlikely to return for PPD reading
List first line drugs for Mycobacterium tuberculosis
Isoniazid, Rifampin, Ethambutol, Pyrazinamide, Streptomycin
List second line drugs for Mycobacterium tuberculosis
Ethionamide, Capreomycin, Cycloserine, Aminosalicylic acid (PAS), Kanamycin, Amikacin, Quinolones (cipro, levofloxacin, moxifloxacin)
One anti-tb drug is recommended for use during entire duration of therapy due to efficacy, tolerability, and low cost. Which drug?
Isoniazid
Is isoniazid bactericidal or bacteriostatic?
Bactericidal
What is the mechanism of isoniazid (INH)?
Prodrug, converted by mycobacteria to active form, inhibits mycolic acids, which mycobacteria need for cell wall
AEs of isoniazid
Peripheral neuropathy (due to altered vit B6 metabolism) and Hepatitis (can be fatal)
When treating tb is rifampin bactericidal or bacteriostatic?
Bactericidal
Mechanism of rifampin
Binds to beta subunit of bacteria DNA-dependent RNA pol
AEs of rifampin
Drug-drug interactions (CYPs), imparts orange color to urine, sweat and tears. Also GI upset
Is pyrazinamide bactericidal or bacteriostatic?
Bactericidal in acid environments (such as where tb lives, in phagosomes of macrophages)
Mechanism of pyrazinamide
Inhibits mycolic acid biosynthesis by targeting fatty acid synthase I gene
AEs of pyrazinamide
Hepatotoxicity and hyperuricemia (may induce gout)
Is ethambutol bactericidal or bacteriostatic?
Bacteriostatic
echanism of ethambutol
Disrupts polymerization of cell wall
What effect does ethambutol administration have on rifampin and ofloxacin activity
Increases their anti-tb activity by disrupting the cell wall (they are lipophilic)
AEs of ethambutol
Decrease in visual acuity and loss of discrimination between green and red (dose-dependent)
To what does streptomycin bind
The S12 subunit of ribosomal proteins (different target than other aminoglycosides)
Is the effect of streptomycin on tb bactericidal or bacteriostatic?
Bacteriostatic (has bactericidal effects in vitro, but not enough reaches the tb to be cidal)
When is streptomycin primarily used in tb cases now?
For drug-resistant TB or when pts are unable to take oral meds (its only available IM and IV)
Compared to rifampin, rifabutin has more AEs and slightly worse tb activity. In what cases of tb would it be preferred over rifampin despite this?
In HIV positive patients also taking protease inhibitors, clarithromycin and azole antifungals, because it has far fewer drug-drug interactions
Rifampin is a first line drug for tb. What two other first line anti-tb drugs are similar to rifampin
Rifabutin - same MoA and resistance, Rifapentine - same efficacy and side effect profile (but longer half-life)
Ethionamide is a 2nd line drug for tb. What is its mechanism and what are its AEs?
Inhibits mycolic acid synthesis. Intense GI irritation, postural hypotension, mental depression, asthenia
Para-aminosalicylic Acid (PAS) is a 2nd line anti-tb drug. What is its mechanism and what are its AEs?
Folate synthesis antagonist (similar to sulfonamides). Severe gastric irritation (limits compliance) and hypersensitivity reactions
Which second line tb drug is associated with high incidence of ototoxicity and nephrotoxicity?
Capreomycin
Cycloserine is a second line anti-tb drug. Give the mechanism and AEs of cycloserine
Inhibits incorporation of d-alanine into bacterial cell walls. AEs are neuologic (somnolence, vertigo, confusion, psychosis). Only used in treatment failures
Which drugs of the same class as streptomycin are used as second line anti-tb agents?
Amikacin and Kanamycin (are both proper aminoglycosides) and capreomycin (is often grouped with the aminoglycosides)
What drugs are typically used in the initial phase (2 months) and the follow up phase (4 or 7 months) for treating Tb?
Initial - Isoniazid, Rifampin, Pyrazinamide, Ethambutol (or streptomycin in children), Follow up - just Isoniazid and Rifampin
What drugs are used to treat leprosy?
Dapsone, Rifampin and Clofazimine. Also ofloxacin, minocycline, thalidomide, and ethionamide
Dapsone is used to treat leprosy. What are the mechanism and AEs of dapsone?
Mechanism similar to sulfonamides. AEs include hemolysis (high doses) and Jarish-Herxheimer reaction (immune response to sudden increase in bacterial kill products)
What is ROM therapy?
Rofampin-Ofloxacin-Minocycline. Advocated by WHO as single dose therapy for a single paucibacillary (tuberculoid leprosy) skin lesion
Treatment of mycobacterium avium-intracellulare complex (MAC) in HIV-negative patients
Clarithromycin (or azithromycin), Ethambutol, and Rifampin for one year after cultures are negative
Treatment for mycobacterium kansasii
INH, rifampin, and ethambutol for 12-18 months
Treatment for mycobacterium marinum
Clarithromycin or doxycycline or trimethoprim-sulfamethoxazole or rifampin and ethambutol
