Antifungals

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Population at highest risk for systemic fungal infections?

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Immunocompromised

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Amphotericin B - MOA

Back 2

binds to ergosterol and effectively creates pores in the cell membrane

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Amphotericin B - Resistance

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impaired binding to ergosterol - reduced amount of ergosterol in membrane or altered target molecule to reduce affinity for drug

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Amphotericin B - Activity

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Broadest spectrum of action - all but Candida lusitaniae, Thrichosporon spp, Fusarium spp, Aspergillus terreus

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Amphotericin B - Use

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Nearly all life-threatening mycotic infections - second line d/t toxicities; preferred in pregnancy w/ deep fungal infections due to experience

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Amphotericin B - Pharmacokinetics

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Parental - Cannot be used PO; 90% protein bound, wide distribution; no renal or hepatic dose adjustment

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Amphoterincin B - ADR

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Renal toxicity - renal tubular acidosis, hyperkalemia, hypomagnesemia - reversible if d/c within 2wks
Anemia - resolves w/ d/c of drug
Acute infusion related - F/C/N/V/HA/Hypotension/Thrombophlebitis

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Amphoterincin B - Lipid Formulation

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Similar in efficacy to generic
Less renal dysfunction
Significantly more expensive

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Azoles - MOA

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Inhibition of ergosterol synthesis by inhibition of fungal cytochrome P450 enzymes

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Azoles - Activity

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Most Candida species
Cryptococcus mycoses - blasto, coccidio, histoplasm
Dermatophytes
Aspergillus - Itraconazole and Viriconazole

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Ketoconazole (Nizoral)

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More likely to inhibit mammalian CYP 450
PO - used for fungal infections in prostate CA and Cushing's syndrome
Topical - fungal skin infections
Hepatic elimination

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Itraconazole (Sporanax)

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PO
Increased absorption by acidic environment
Poor penetration into CNS
Less effective on mammalian CYP450
ADR: Negative inotropic effect (avoid in CHF), LFT elevated
Hepatic elimination

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Itraconazole (Sporanax) - Tx of choice

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Histoplasma, Blastomyces, Sprothrix

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Fluconazole (Diflucan)

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Good CNS penetration
PO - bioavailability ~90%
Less effective on mammalian CYP450
ADR: N/HA/rash
Renal elimination

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Fluconazole (Diflucan) - Tx and Dose

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100-800 mg/day varies by indication
Cryptococcal meningitis
Candidemia
Mucocutaneous candidiasis

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Voriconazole (Vfend)

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IV or PO
Biovialabilty ~90%
ADR: Rash, Visual disturbances
Primarily Hepatic Metabolism

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Voriconazole (Vfend) - Tx of choice

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Aspergillosis

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Posaconazle (Noxafil)

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PO only
Broadest spectrum
Inhibitor of CYP3A4
Give w/ high fat meal
ADR: N/HA
Hepatic Metabolism

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Topical Azoles

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Clotrimazole and Miconazole
OTC - vulvovaginal candidiasis
Oral troches for oral thrush
Cream - dermatophytic infections

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Echinocandins - MOA

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Glucan synthesis inhibitor - inhibits cell wall synthesis
Newest class of antifungals
IV formulation only

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Echinocandins - Activity

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Candida and Aspergillus
- not zygomycosis and mucomycosis

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Echinocandins - Uses

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Mucocutaneous and invasive Candida infections
Candida infections
Invasive Aspergillosis 2nd line
Febrile neutropenia - empiric tx

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Echinocandins - ADR

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Rash
Headache
GI Disturbances
generally well tolerated

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Caspofungin

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Renal, GI - elimination
Many Drug Interactions - cyclosporine increases capsofungin level

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Micafungin

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Fecal elimination
No significant DI

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Anidulafungin

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Chemical degradation, fecal - elimination
No significant DI

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Flucytosine - MOA

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taken up by fungal cells by enzyme cytosine permease, converted to 5-FU, disrupts DNA/RNA synthesis; human cells cannot convert

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Flucytosine - Resistance

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altered metabolism; occurs rapidly with monotherapy

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Flucytosine - Dose

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Not used as monotherapy
50-150mg/kg/day, q6h, less in renal insufficiency

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Flucytosine - Activity

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Cryptococcus neoformans and some Candida sp.

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Flucytosine - Use

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Cryptocococcal meningitis w/ amphotericin B
Chromoblastomycosis w/ itraconazole

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Flucytosine - Pharmacokinetics

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PO only
Renal - elimination, adjust dose in renal insufficiency

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Flucytosine - ADR

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Narrow therapeutic index - too low : resistances, too high : ADR
Bone Marrow suppression
GI : n/v/d, anorexia

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Terbinafine (Lamisil) - MOA

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Interferes w/ ergosterol biosnythesis by inhibiting fungal enzyme squalene epoxidase

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Terbinafine (Lamisil) - Use

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PO only
Tx dermatophytoses especially onychomycosis

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Terbinafine (Lamisil) - Pharmokinetics

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>70% absorbed; 40% bioavailable (first-pass)
Extensive Liver Metabolism - does not affect P450 system

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Terabinafine (Lamisil) - ADR

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Occasional GI upset and Headache
generally well tolerated
No drug interactions

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Griseofulvin (Fulvicin, Grisactin) - MOA

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unclear; binds to keratin in skin, preventing new infection

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Griseofulvin (Fulvicin, Grisactin) - Use

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Systemic tx of dermatophytosis (tinea unguium)

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Griseofulvin (Fulvicin, Grisactin) - ADR

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Hypersensitivity reaction
Hepatitis

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Nystatin (Mycostatin) - MOA

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pore forming like amphotericin B
toxicity limits use to topical

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Nystatin (Mycostatin) - Use

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Candidal infections, Oropharyngeal thrush, Vaginal candidiasis, Intertriginous candidal infections