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80 Cards in this Set
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What is the mechanism of action for amphotericin B?
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preferentially binds to ergosterol -> forms pores/channels -> K+ and Mg2+ leaks out of the cell
(toxic b/c it does have some effect on cholesterol) |
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How much is amphotericin B absorbed from the GI tract?
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almost none
administered IV |
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Does amphotericin penetrate into the CNS?
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no
very polar -> reason why it's administered IV |
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Where is amphotericin distributed in the body?
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binds to cholesterol-containing membranes
mainly in liver small amounts in urine (very litte enters CNS, vitreous humor, amniotic fluid) |
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What is the advantage of liposomal amphotericin B?
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less binding to human cell membranes -> less toxicity -> permits higher doses
vesicles serve as an amphotericin B reservoir some fungi contain lipases -> liberate at site of action |
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What are the differences between the older and newer (lipid) formulations of amphotericin B?
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newer forumlations
-extensively cleared from the blood -accumulate in liver, spleen, lymph nodes, lungs (major sites of fungal infections) -much more expensive |
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What are the adverse effects of amphotericin B?
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infusion related - fever, chills, headache, anorexia, nausea, vomiting
(stop by reducing the infusion rate; premedicate w/ antipyretics, antihistamines, corticosteroids) nephrotoxicity (limits amt. of drug given) -> hypokalemia liver failure hypomagnesemia and renal tubular acidosis anemia due to decreased erythopoietin production has affinity for digitalis (can't use in pts. using digitalis) |
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Why is amphotericin given with Na deoxycholate?
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b/c of poor solubility
Na deoxycholate helps improve its solubility |
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At what pH is amphoticin B soluable?
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acidic pH
not soluable at physiological pH |
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What is deoxycholate?
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steroid detergent
forms suspention w/ amphotericin B -> keeps it in solution |
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What is flucytosine active against?
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cryptococcus neoformans
cocciodial meningitis some Candidia sp. (not active against aspergillus) |
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What is flucytosine not active against?
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aspergillis
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How is amphotericin B synergistic with flucytosine?
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makes fungal membrane more leaky -> more 5-FU can get in
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How does flucytosine get into cells?
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via permease (not present in mamallian cells)
fungi lacking permease are resitant (however, if combine w/ AMB, 5-FU does work) |
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What is the mechanism of action for flucytosine?
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deaminated to 5-fluorouracil, an antimetabolite -> inhibits thymidylate synthase, early termination of fungal RNA
(mammalian cells do not do this) toxic effects occur from host cell or bacteria in the gut converting 5-FC -> 5-FU |
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How is flucytosine administered?
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PO
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What is the volume of distribution of flucytosine?
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about equal to total body water
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Does flucytosine penetrate into the CNS?
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yes
present in CNS and aqueous humor |
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Is flucytosine bound to plasma proteins?
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no
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What are the adverse effects of flucytosine?
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bone marrow suppression
rash nausea vomiting diarrhea hepatic dysfunction |
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What is flucytosine predominantly used in combination with?
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amphotericin B
or itraconazole |
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What is caspofungin acetate used for?
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invasive aspergillosis
(but usually only after trying AMB or itraconazole) mainly used as an alternative in pts. who have failed to respond to AMB |
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What is the mechanism of action for caspofungin?
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disrupts fungal cell wall glucan formation via non-competitive inhibition of 1-3-beta-glucan synthase
fungicidal (no 1-3-beta-glucan synthase in humans) |
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What fungi is resistant to caspofungin?
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cryptococcus neoformans
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Is caspofungin bound to plasma proteins
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yes
~97% bound to albumin |
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How is caspofungin excreted?
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broken down into constitutive amino acids and metabolites (N-acetyl-dihydroxyhomotyrosine and dihydroxyhomotyrosine) and excreted in urine and GI tract
reduce dosage in pts. w/ hepatic insufficiency |
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What are the adverse reactions of caspofungins?
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few reported so far
infusion rxns: phlebitis, headache |
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What is the mechanism of action for azols?
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impairs biosynthesis of ergosterol
inhibits sterol 14-alpha-demethylase, a microsomal CYP450 dependent enzyme system -> inhibits conversion of lanosterol -> ergosterol (fungi requires ergosterols in membrane, otherwise gets leaky and cells die) |
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What fungi are susceptable to ketoconazol
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blastomycosis
coccidioidomycosis histoplasmosis paracoccidioidomycosis candidia (not active against aspergillus and mucor) |
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What fungi are resistant to ketoconazol
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aspergillus
mucor |
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What azols are more readily absorbed with a decrease in pH?
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ketoconazole
itraconazole (drink coca-cola to increase absorption) |
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Where is ketoconazole metabolized?
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primarily in the liver -> excretes in feces
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Is ketoconazole bound to plasma proteins?
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yes - 90%
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What are the adverse effects of ketoconazole?
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nausea, anorexia, vomiting
(b/c also inhibits steroid synthesis in pts.) gynecomastia, menstral irregularities, decreased libido - due to depressed testosterone and estradiol (used to suppress testosterone synthesis in prostate cancer) hypertension and fluid retention - assoc. w/ elevated deoxycorticosterone and corticosterone hepatitis contraindicated in pregnancy - enters milk inhibits CYP450 (CYP3A4) -> potentiate toxicities of cyclosporin, phenytoin, H1-histamine antagonists |
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What is fluconazole active against?
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cdandidia
cryptococus |
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What is fluconazol used for?
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oral and esophageal candidiasis and cryptococcal meningitis in AIDS pts
vulvovaginal candidiasis prophylactic for bone marrow transplant pts. |
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Which azol interferes with CYP3A4 the most?
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ketoconizole
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What is the advantage of fluconazole over ketoconzaole?
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completely absorbed from GI tract (water soluable)
bioavailability not altered by food or gastric activity can be given IV well tolerated poorly metabolized no endocrinologic effects |
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What are the triazole drugs?
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fluconazole
itraconazole voriconazole terconazole |
tri = FIVe - Two
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What is itraconazole used for?
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treatment of histoplasmosis and blastomycosis
esophageal or vaginal candidiasis dermatophyte infections of the toenails |
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Which is higher for itraconazole?
tissue concentration or plasma concentration |
tissue concentration
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Does itraconazole penetrate into the CSF?
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no
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How is itraconazole eliminated?
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inactivated in the liver
(drugs that induce hepatic drug-metabolism accelerate metabolism of itraconazole) inactive metabolites excreted in the urine |
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What is itraconazole active against?
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aspergillus
histoplasma blastocyces sporothrix |
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What are the adverse effects of voriconazole?
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rash
elevated hepatic enzymes transient visual disturbances |
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What is vericonazole used for?
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FDA approved use: aspergillis
candidia fluconazole-resistant species: C. krusei, dimorphic fungi |
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What is grisofulvin used for?
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superficial fungal infections
(largely replaced by itraconazole and terbinafine) only effective against dermatophytes microsporum, epidermophyton, trichophyton not active against candidia and aspergillus |
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What is the mechanism of action of griseofulvin?
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inhibits fungal mitosis
disrupts the mitotic spindle by interacting w/ polymerized microtubules |
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How does griseofulvin enter cells?
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via an energy-dependent transport system
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How do you increase the oral absorption of griseofulvin?
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take with a fatty meal
(due to its insolubility) microsized or ultramicrosized powders |
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Where does griseofulvin deposit?
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keratin precursor cells
(tightly bound to keratin) |
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What is the first area to become free of disease after griseofulvin treatment?
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new growth of hair or nails
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What are the adverse effects of griesofulvin?
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headache, lethargy, mental confusion, fatigue, vertigo, blurred vision (augmented w/ alcohol)
GI tract, vomiting, diarrhea, heartburn, flatulence, dry mouth contraindicated in pregnancy (teratogenic in animals) |
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What are the topical applications for the azol drugs?
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tinea corporis
tinia pedis tinea cruris tinea versicolor cutaneous candidiasis |
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What are thea adverse effects of clotrimazole?
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stinging on skin
mild burning in vagina |
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What are the adverse effects of micronazole?
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burning, itching, irritation when applied to vagina
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How is micronazole administered?
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mainly topically
IV for systemic infections (meningitis), however very toxic |
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What is ciclopirox olamine used for?
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dermatophytes
penetrates through epidermis to dermis penetrates hair follicles and sebaceous glands |
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What is haloprogin active against?
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epidermophyton
pityrosporum microsporum trichophyton candidia |
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What are the adverse effects of haloprogin?
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irritation
pruritus burning sensation on foot |
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What is haloprogin primarily used for?
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tinea pedis
tinea cruris |
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What fungus is tolnaftate inactive against?
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candidia
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What is tolnaftate effective against?
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cutaneous mycoses caused by trichophyton sp. and microsporum sp.
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What is the mechanism of action for tolnaftate?
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inhibits squalene 2,3-epoxidase -> inhibition of ergosterol synthesis
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What is the mechanism of action of naftifine?
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inhibits squalene 2,3-epoxidase -> inhibits ergosterol synthesis
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What is the mechanism of action of terbinafine?
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inhibits squalene 2,3-epoxidase -> inhibits ergosterol synthesis
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Which is also available for oral use in the treatment of fungal nail infections?
naftifine, terbinafine, or butenafine |
terbinafine
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What is nystatin only used against?
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candidiasis
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How is nystatin administered?
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oral only
too toxic for IV administration (more toxic than AMB) |
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What is natamycin used for?
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fungal feratitis Fusarium Solani
also active against aspergillus, candidia, and penicillium |
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What is undecyclenic acid composed of?
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calcium and zinc salts
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What might prevent patients from using undecylenic acid?
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rancid odor
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What is undecylenic acid used for?
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retards fungal growth in tinea pedis
approved for use in treatment of diaper rash and tinea cruris |
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What is benzoid acid and salicylic acid used for?
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tinea pedis
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What is potassium iodide used for?
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cutaneous sporotrichosis
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What antifungals are thiocarbamates?
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naftifine
terbinafine butenafine tolnaftate inhibit squalene-2,3-epoxidase -> inhibits mycolic acid synthesis |
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What antifungals are azoles?
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imidazoles: clotrimazole, miconazole, ketoconazole, econazole, butoconazole, oxiconazole, sulconazole
triazole: fluconazole, itraconazole, voriconazole, terconazole inhibits sterol 14-alpha-demethylase -> inhibits the conversion of lanosterol to ergosterol |
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Which antifungals bind ergosterol?
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amphotericin B
nystatin natamycin |
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What is the DOC for aspergillus aspergilliosis?
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amphotericin
alt: itraconazole, caspofungin |
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What is the DOC for blastomyces blastomycosis?
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itraconazole
alt: ketoconazole |
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