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amphotericin B
- polyene antibiotics - bind ergosterol, compromise fungal cell membrane
- broadest spectrum antifungal
- drug of choice for rx most life-threatening systemic fungal infections
- usually fungicidal
- pore former
- selective toxicity: mammalian cholesterol (lower affinity) vs ergosterol (higher affinity)
- resistance: rare, but observed in Candida; when used with inhibitors of ergosterol synthesis (azole); ergosterol reduced affinity for amphotericin B
- pharmacokinetics: oral (poor absorption), topical, parenterally (systemic infections) w/ deoxycholate (significant factor for toxicity)
- extensively metabolized, many metabolites
- adverse effects: oral / topical = irritation
- - IV immediate rxns are fever, chills, spasms, vomiting, HA, hypotension, anaphylaxis, thrombophlebitis; can be offset by decreasing dose and slowing infusion rate
- - IV slower toxicities are nephrotoxicity*** - potentially irreversible and anemia (reduced EPO)
- drug interactions: digitalis (hypokalemia), azoles, nephrotoxic agents
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Nystatin
- polyene antibiotics - bind ergosterol, compromise fungal cell membrane
- topical use for rx of candidal infection of oral cavity/vaginal mucosa - too toxic to be used parenterally
- not well absorbed from skin, mucous membranes, or GI tract
- adverse: bitter/unpleasant taste
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Griseofulvin
- associates with polymerized MTs, disrupts fungal mitosis
- fungistatic
- induces various CYP isoforms = alters pharmacologic effectiveness of drugs
- fetal harm and negative effects on sperm
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Flucytosine
- antimetabolite - cytosine derivative that inhibits DNA and RNA synthesis
- reduces protein synthesis
- fungistatic
- targets candida and cryptococcus
- poor therapeutic window when used alone (resistance common)
- use: in combination with amphotericin B to yield synergistic effect
- pharmacokinetics: good CNS penetration (meningitis)
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miconazole
- azoles - inhibits ergosterol synthesis by blocking fungal CYP enzyme (lanosterol 14-α-demethylase)
- imidazole
- fungistatic
- resistance: reduced drug (active efflux pump), reduced affinity for target enzyme, up-regulation of target enzyme
- selective toxicity: affect fungal CYP to greater extent than mammalian; imidazole much less specific for fungal CYP vs triazoles
- interactions: numerous drug interactions
- use: effective against local (topically used) fungal infections
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clotrimazole
- azoles - inhibits ergosterol synthesis by blocking fungal CYP enzyme (lanosterol 14-α-demethylase)
- imidazole
- fungistatic
- resistance: reduced drug (active efflux pump), reduced affinity for target enzyme, up-regulation of target enzyme
- selective toxicity: affect fungal CYP to greater extent than mammalian; imidazole much less specific for fungal CYP vs triazoles
- interactions: numerous drug interactions
- use: oral / topical administration for local distribution; drug of choice for oropharyngeal candidiasis in AIDs pts
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itraconazole
- azoles - inhibits ergosterol synthesis by blocking fungal CYP enzyme (lanosterol 14-α-demethylase)
- triazole
- fungistatic
- resistance: reduced drug (active efflux pump), reduced affinity for target enzyme, up-regulation of target enzyme
- selective toxicity: affect fungal CYP to greater extent than mammalian; imidazole much less specific for fungal CYP vs triazoles
- interactions: numerous drug interactions
- use: can be given systemically; treat aspergillus and fluconazole-resistant candida sp. (esophageal candidiasis); largely supplanted by voriconazole
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fluconazole
- azoles - inhibits ergosterol synthesis by blocking fungal CYP enzyme (lanosterol 14-α-demethylase)
- triazole
- fungistatic
- resistance: reduced drug (active efflux pump), reduced affinity for target enzyme, up-regulation of target enzyme
- selective toxicity: affect fungal CYP to greater extent than mammalian; imidazole much less specific for fungal CYP vs triazoles
- interactions: numerous drug interactions
- use: better CNS penetration than other azoles (rx cryptococcal meningitis), NOT active against aspergillus; 1st line agent for invasive infections by Candida (except C. krusei) and refractory mucocutaneous candidiasis
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voriconazole
- azoles - inhibits ergosterol synthesis by blocking fungal CYP enzyme (lanosterol 14-α-demethylase)
- triazole
- fungistatic
- resistance: reduced drug (active efflux pump), reduced affinity for target enzyme, up-regulation of target enzyme
- selective toxicity: affect fungal CYP to greater extent than mammalian; imidazole much less specific for fungal CYP vs triazoles
- interactions: numerous drug interactions
- use: same spectrum as itraconazole but more potent in vitro against yeast and molds (largely supplanted itraconazole); new standard of care for aspergillosis (**CIDAL effect against aspergillus)
- adverse effects: dose-related transient visual side effects (20-30%)
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posaconazole
- azoles - inhibits ergosterol synthesis by blocking fungal CYP enzyme (lanosterol 14-α-demethylase)
- triazole
- fungistatic
- resistance: reduced drug (active efflux pump), reduced affinity for target enzyme, up-regulation of target enzyme
- selective toxicity: affect fungal CYP to greater extent than mammalian; imidazole much less specific for fungal CYP vs triazoles
- interactions: numerous drug interactions
- use: only azole with significant activity against zygomycoses (rhizopus, mucor, rhizomucor); prophylaxis of invasive fungal infections in hematologic malignancy and prolonged neutropenia
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efinaconazole
- azoles - inhibits ergosterol synthesis by blocking fungal CYP enzyme (lanosterol 14-α-demethylase)
- triazole
- fungistatic
- resistance: reduced drug (active efflux pump), reduced affinity for target enzyme, up-regulation of target enzyme
- selective toxicity: affect fungal CYP to greater extent than mammalian; imidazole much less specific for fungal CYP vs triazoles
- interactions: numerous drug interactions
- use: monotherapy topical rx of onychomycosis (fungal toenail infection)
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terbinafine
- allyamine - inhibits ergosterol synthesis by blocking activity of squalene epoxidase
- fungicidal
- activity: effective against dermatophytes (largely replaced griseofulvin)
- pharmacokinetics: accumulates in skin, nails, and fatty tissues
- use: mainstay for skin/nail infections, used to treat unusual or refractory mold infections
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caspofungin and micafungin
- echinocandins - inhibits glucan synthesis leading to lysis (CIDAL)
- use: invasive candidiasis resistant to other antifungals, invasive aspergillosis / mold infections
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