23. Antifungal Chemotherapy Flashcards
histoplasma, blastomyces, coccidoides, sporothrix
dimophic systemic fungi
candida, aspergillus, cryptococcus
opportuninistic fungi
sporothrix schenkii, dermatophytes trichophyton, epidermophyton, microsporum, ringworm, athletes foot, onchymycosis
cutaneous/subcutaneous fungi
ergosterol and ergosterol synthesis, glucans, DNA and RNA synthesis, cell division
targets for antifungal therapy
targets membrane function
amphotericin B
target ergosterol synthesis
fluconazole, ibraconazole, voriconazole, naftiline, terbinafine
target nucleic acid synthesis
5-fluorocytosine
target cell wall synthesis
caspofungin
most widely used drug to treat fungal infections, broad spectrum, significant toxicity, binds to ergosterol in the fungal cell membrane, forms amp B containing pores, alterative treatment for candia or cryptococcus, or molds like aspergillus, histoplasma, coccidiodes, blastomyces, sporothrix, mucormycoses, resistance by decreasing ergosterol in the membrane, nearly insoluble in water, complexed with a bile saly for IV infusion, widely distributed into most tissues, most serious toxicity is nephrotoxicity, also fever, chills, muscle spasm, vomiting, headache, hyper/hypotension, also renal tubule injury and dysfunction, new formulations are packaged in a liposome to prevent binding to human cell membranes to reduce toxicity
amophotericin B
bind to enzyme converting lanosterol to ergosterol, used on pathogenic yeast like candida and cryptococcus, used on systemic myocoses like histoplasmosis, blastomyocosis, coccidioidomycosis, and dermatophytes like onychomycosis, resistance is increasing due to efflux pumps, mutations in the target enzyme, and decreased ergosterol content in the cell membrane, causes minor gastrointestinal disturbances, interacts with CYP450s, rarely used
azoles
oral or IV, water soluble and widely distributed, lowest level of interaction with P450s of all azoles with the widest therapeutic index, used for candidiasis, cryptococcus, coccidiomycosis, second line for histoplasmosis, blastomycosis, and sporotrichosis
flucanzole
broader spectrum of activity than fluconazole, worse bioavailability and therapeutic index, requires low gastric pH so is impaired bt antacids, proton pump inhibitors, and H2 blockers, interaccts with CYPs so interacts with rifampin, digoxin, cyclosporine, hypoglycemic agents, coumadin, drug of choice for blastomycosis, coccidiomycosis, histoplasmosis, sporotrichosis, dermatophytes/ onychomycosis
itraconazole
similar bioavailability to fluconazole, broad spectrum of activity, used in candida infection, endemic dimorphic fungi, replaced amphotericin B for treatment of aspergillosis, causes transient visual disturbances, blurred vision, photophobia, altered perception of color
voriconazole
broadest spectrum activity of all azoles, treats most species of candida, aspergillus, and the agents of mucormycoses, also active against cryptococcus and dimorphic fungi, given orally, absorption improved with fatty meals, rapidly distrubtedinto tissues, high tissue but low serum levels, strong inhibitor of CYP450s
posoconazole
greater solubility, administered as a prodrug and needs to cleaved, adminstered orally, unaffected pH, alternative treatment for invasive aspergillosis and mucormycosis
isavuconazole
fluorinated pyrimidine analog, combination therapy for some systemic infections like cryptoccocus, candida, transported by cytosine permease into the fungal cell, incorportated into RNA disrupting protein synthesis or is converted into deoxynucleosides and inhibits DNA synthesis, used almost exclusively as part of combination therapy like cryptococcal infections, given orally, rapidly distributed throughout tissues, can cause bone marrow toxicity leading to anemia, leukopenia, and thrombocytopenia
flucytosine
newest class of antifungal drugs, inhibit cell wall synthesis, lipopeptides linked to long fatty acids, -fungin, high selective degree of toxicity due to lack of B-glucans in mammalian cells, blockade weakens fungal cell walls causing greater osmotic stress on the fungal cell, however also limited to presence of B-glucans in cell wall, all given IV, distrubted through all major organs, poor penetration of CNS
echinocandins
griseofulvin, allylamines/terbinafine
oral systemic medications for cutaneous and mucocutaneous infections
very insoluble crystal, absorption improved with fatty meals, unclear mechanism of action, possibly interferes with microtubule function, largely replaced by newer drugs, second line agent in treatment of dermatophyte infections, can cause headache, hepatotoxicity, and GI stress, drug interaction by increasing warfarin effectiveness and decreasing effectiveness of oral contraceptives
griseofulvin
inhibitors of ergosterol synthesis, inhibit enzyme squalene epoxidase, susceptible fungi have defective or damaged cell membranes, available in both topical and oral forumlations, keratophillic like griseofulvin in skin, hair, and nails, good for nail infections
allylamines/terbinafine
polyenes like nystatin, azoles like efinaconazole, clotrimazole, miconazole, allylamines like terbinafine and nafitine, and others like ciclopirox
topical antifungal agents
first topical triazole used to treat onychomycosis, low affinity for keratin so penetrates into nail bed, minimal systemic absorption, cure rate of 50%
efinaconazole
blocks membrane transport, alters membrane permeability, binds iron, broad activity against yeast and molds, minimal absorption beyond the nail, little information on adverse reactions
ciclopirox
polyene antifungal drug related to amphotericin B with similar mechanism of action, only used topically, poor absorption, toxic, unpleasant taste, given as a cream, ointments, suppositories, and oral suspections, active against most species of candida, most commonly used to treat local infections like oropharyngeal and vaginal candidiasis
nystatin
two most commonly used topical azoles like clotrimazole and miconazole, used for vulvovaginal candidiases and dermatophyte infections like tinea corporis/pedis/cruris, oral lozenges are available for treatment of oral thrush, alternative to nystatin, absorption is neglible, adverse effects are rare, azole resistance is rare amongst dermatophytes,
topical azoles are available in numerous OTC formulations
