Mkgrady8 Gpmdc Antifungal Agents

just unlucky; world travel; AIDS opportunistic diseases; pts resistant is decreased= antibiotic therapy (broad spectrum), cancer chemotherapy, immunosuppressive therapy, radiation, corticosteroids

cell wall=echinocandins; cell membrane= polyenes, imidazoles, triazoles; nuclear division= griseofulvin; nucleic acid synthesis= flucytosine

nearly insoluble in water and prepared as a colloidal suspension for IV injection; poorly absorbed form GI track never oral for treatment of chronic systemic disease; widely distributed in most tissue but only 2-3% of blood level reached in cerebrospinal fluid; occasionally necessitates intrathecal therapy for certain type of fungal meningitis

binds to ergosterol (fungal cell membrane sterol); alters permeability of cell by forming ampho B associated pores in cell membrane; ions (K+/Mg+) and macromolecules leak out of cell leading to cell death

fever, chills, shock, headache, hypotension are immediate reactions and prevented by slow infusion and premedication with certain corticosteroids; thrombocytopenia (low platelets); cardiac fibrillation/arrest; decreased production of erythroid proteins anemia; thrombophlebitis; renal impairment= increased BUN and serum creatinine decreased creatinine clearance, can be irreversible, must be monitored

liposomal ampho B preparation= toxicity reduced without decreased efficacy, permits use of large doses, less kidney damage (about 50% but still significant); expensive

an antifungal agent with broadest spectrum of action= yeasts (candida albicans, cryptococcus neoformans), pathogenic molds e.g. aspergillus fumigatus, and agents of mucormycosis, fungi causing endemic mycoses including histoplasma capsulatum, blastomyces dermatitidis, and coccidiades immitis/posadasil; remains useful agent for nearly all life threatening mycotic infections although newer, less toxic agents have replaced it for most conditions

ampho B often used as initial induction regimen then replaced by newer azoles for chronic therapy to precent release; for treatment of systemic fungal diseases AmphoB is given by slow IV infusion; intrathecal therapy for fungal meningitis poorly tolerates but remains an option; local or topical use has been successful; mucotic corneal ulcers and herratitis; fungal arthritis has been treated with adjunctive local injection directly into joints; candiduria repsonds well to bladder irrigation with ampho B with no significant systemic toxicity

too toxic for parenteral administration; only used in cream, ointment; not absorbed well from skin, mucous membranes or GI tract; active against candida sp; most commonly used for suppression of local candidal infections; also used for vaginal candidiasis and orpharyngeal thrush

water soluble pyrimidine analog related to 5-fluorouracil (5-FU); spectrum of action much narrower compared to amphoB; available in oral formulation; well absorbed (>90%); toxicity more likely to occur in AIDS pts and those with renal insufficiency; 5-FU taken up by fungal cell via enzyme cytosine premease and converted to 5-FU and then to FdUMP (inhibits DNA synthase) and FUTP (inhibits RNA synthase)

5FC has synergy with amphoB (may be related to enhanced penetration of 5-FU through amphoB damaged cell mem); restricted to C neoformans, some candida sp and some dematiaceous molds that cause chromoblastomycosis; used in combo with amphB to treat crytococcal meningitis or in combo with itraconazole to treat chromoblastomycosis; toxicities= erious bone marrow depression (more toxic in AIDS pts), hepatic dysfunction

imidazoles like ketoconazole, miconazole, or clotrimazole; triazoles like triaconazole, fluconazole, voriconazole, or posaconzaole

used only to treat dermatophytosis and candidiasis; the selective toxicity of azoles (ketazonazole) results from their greater affinity for fungal than for human cytochrome P450 enzymes; ketoconazole has a greater propensity to inhibit mammalian cyto P450 accounting for higher incidence of side effects and drug interactions; MOA= causes reduction in ergosterol synthesis by inhibition of fungal cyto P450 dependent enzymes

available in OTC oral troches (clotrimazole) and cream (miconazole and clotrimazole); used to treat vulvovaginal candidiasis; cream form (of both drugs) used for treatment of dermatophytic infections icluding tinea corporis, tinea pedis and tinea cruris

related to ketozonazole but has less side effects; MOA= causes reduction in ergosterol synthesis; new formulation include an oral liquid and IV formulation; azole of choice for treatment of dimorphic fungi histoplasma, blastomyces, and sporothrix; extensively used to treat dermatophytoses and onychomycosis; has activity against aspergillus (not best choice); poorly penetrates CSF; if taken with rifamycins, itraconazole's bioavailability is reduced; side effects= GI distress, liver damage, hypertension

oral and IV formulations available and hepatically metabolized; well absorbed (bioavail >90%) shows less protein binding than itraconazole; dose reduction of some meds (cyclosporine, tacrolimus, and HMG reductase inhibitors) is required; MOA= reduces ergosterol synthesis; similar to itraconazole, has excellent activity against candida sp (including fluconazole resistant species such as candida krusi) and dimorphic fungi; less toxic than amphoB and DOC for invasive aspergillosis and some environmental molds; toxicities include rash, elevated hepatic enzymes, also visual disturbances (30% pts and resolved within 30mins)

Good water solubility and shows good cerebrospinal fluid penetration and high oral bioavailability; oral and IV formulations; MOA= reduces ergosterol synthesis; drug interactions also less common (than ketoconazoles and itraconzole) because has less effects of all azoles on hepatic microsomal enzymes due to this and better GI tolerance has widest therapeutic index of all azoles so permit aggressive dosing; azole of choice in treatment and secondary prophylaxis of cryptococcal meningitis

IV formulation equivalent to amphoB treatment of candidemia in ICU pts echinocandins may have superior activity for this medication; most commonly used for treatment of mucocutaneous candidiasis; activity against the dimorphic fungi limited to coccidioidal diseases (e.g. meningitis) where high dose of fluconazole often enough to obviate need for amphoB; no activity against aspergillus or other filamentous fungi; prophylactic use to reduce fungal disease in bone marrow transplant and AIDS pts

newest triazole licensed; liquid and oral formulations only; broadest spectrum in azole family; has activity against most species of candida and aspergillus and only azole with significant activity against mucormycosis; licensed for salvage therapy in invasive aspergillosis and prophylaxis of fungal infections during induction chemotherapy (e.g. leukemia and some bone marrow transplant pts); has drug interaction with increased levels of tacrolimus and cyclosporine (i.e. CYP3A4 substrates)

caspofungin, micafungin, and anidulafungin; all available as IV formulation; all act at fungal wall by inhibiting 1-3 beta glucan synthase resulting in disruption of the fungal cell wall and cell death; all well tolerated with minor GI side effects

treats disseminated and mucocutaneous candidal infection; also can be used for empiric anti fungal therapy during febrile neutropenia largely replaced amphoB; licensed to be used for invasive aspergillosis as salvage therapy; dosing adjustment is requested for severe hepatic insufficiency; has drug interaction with cyclosporine causing elevated liver enzymes in some pts

licensed for esophageal candidiasis (150mg/dl) candidemia (100mg/dl) and prophylaxis of candidal infections in bone marrow transplant pts (50mg/dl); shown to increase levels of nifedipine, cyclospoine and sirolimus

licensed for esophageal candidiasis (100 mg/d on 1st day and then 50 mg/d for 14 days) and invasive candidiasis including candidemia; for candidemia use 200 mg dose 2st day and then 100 mg/d for >14 days; dose does not seem to have significant drug interaction but histamine release may occur during IV infusion

very insoluble fungistatic drug absorption improved when taken with fatty foods; used in treatment of systemic dermatophytosis; MOA= not clear but it is deposited in newly forming skin where it binds to keratin protecting skin from new infection, must be administered for 2-6 weeks for skin and hair infection to allow replacement of infected keratin by the resistant structures; adverse effects= allergic syndrome, hepatitis; drug interaction with warfarin and phenobarbital; mostly replaced by intraconazole and terbinafine

synthetic allyamine available in oral formulation; used for treatment of dermatophytosis especially onychomycosis; similar to griseofulvin it is a keratophilic medication but unlike griseofulvin it is fungicidal; MOA= it interferes with ergosterol biosynthesis rather than interaction with the P450 enzyme squalene epoxidase; this leads to accumulation of the sterol squalene (toxic to fungi); one tablet given orally for 12 wks shows cure rate of up to 90% for onychomyycosis; more effective than griseofulvin or itraconazole

GI upset, headache; no significant drug interaction since it does not seem to affect P450 system; topical creams of drug useful for treatment of tinea cruris, tinea corporis

undecylenic acid/tolnaftate; athlete's foot (tinea pedis); ringworm

D. inhibition of thymidylate synthase because itinhibits DNA and RNA synthesis; b. the azoles; c. the polyenes (amphoB andnystatin) e. the echinocandins (cell wall)(candida)

A. increase in the permeability of the fungalmembrane (not sure why you are giving him amphoB seeing as you have these nastyside effects… I would have given an echinocandin); b. giseofulvin (use itraconazoleand terbinafine in its place for dermatophytoses and onychomycosesrespectively); c. azoles; d. flucytosine (combo drug= ampho for cryptococcalmeningitis, itraconazole for chromoblastomycoses); e. echinocandins (candida)