Category

Drug Amphotericin B (AMB) Liposomal Amphotericin B (LAMB)

Mechanism of Action Forms pores in membrane creating a transmembrane ion channel

Mechanism of Resistance Decreased level of ergosterol or structural change in ergosterol

Pharmacokinetics ~Not orally absorbed ~Administerd by IV, topical & IT ~Slow clearance via both metabolism and renal elimination ~1/2 life = 15 days ~Poor penetration to CNS

Use Broad spectrum: Aspergillus, Candida, Cryptococcus, Histoplasma, Mucor, Sporothrix Cryptococcal meningitis *DOC: for nearly all life threatening fungal infections Synergistic combination of Amphotericin B + Flucytosine ~Used topically to suppress local Candida infections ~Used orally to treat GI fungal infections in immunocompromised patients

Polyene

Nystatin

Forms pores in membrane creating a transmembrane ion channel Acts by disrupting fungal membrane by binding to ergosterol

Hamycin Natamycin Griseofulvin

Binds to microtubules compromising the spindles and inhibits mitosis

Dermatophytes ONLY!!! Used in skin, hair, nail, feet infections Needs prolonged therapy for results

Antimetabolite

Flucytosine (5-Fluorocytosine)

Inhibits fungal thymidylate Decreased activity of synthase - inhibits fungal cytosine deaminase DNA synthesis

Synergistic combination - use with Amphotericin B for cryptococcal & candidial meningitis

Category Azoles

Drug Clotrimazole Ketoconazole

Mechanism of Action Inhibits 14 -demethylase (which converts lanosterol to ergosterol)

Mechanism of Resistance

Pharmacokinetics Does not enter CNS

Use *DOC: Paracoccidioides *Mucocutaneous candidiasis & dermatophytoses *Used topically for dandruff

Econazole Miconazole Fluconazole

~Well absorbed ~Enters CNS ~Used: orally, IV, eye drop

Itraconazole

*DOC: Esophageal & Oropharyngeal Candidiasis *DOC: infections caused by Coccidioides *For vaginal candidiasis: single dose *Used for prophylaxis & treatment of cryptococcal meningitis ~Absorption increased *DOC: Blastomycosis & by food Sporotrichosis ~Poor penetration to CNS

Voriconazole

Allylamine

Terbinafine

Prevents ergosterol synthesis by inhibiting squalene epoxidase (squalene epoxidase is involved in the synthesis of ergosterol from squalene in the fungal cell wall) Leads to squalene accumulation, membrane disruption and cell death

*1st line of therapy for Tinea: Pedis, Coroporis, Cruris, Capitis & Pityriasis versicolor *Used to treat fungal infections of the nails (Onychomycosis)

Adverse Effects Infusion related: Fever, chills, muscle rigor, hypotension *Nephrotoxicity: dose dependent -Reduced GFR, tubular acidosis, hypokalemia, anemia by decreased EPO ~Can be avoided by using Liposomal Amphotericin B

*Headache *Photosensitivity *Can precipitate acute intermittent porphyria *CYP enzyme inducer *Disulfiram like reaction with alcohol

*Bone marrow suppression anemia, neutropenia

Adverse Effects *Gynecomastia *Loss of hair & libido *Oligospermia *CYP3A4 inhibitor - inhibits metabolism of Warfarin, Sulfonylureas, Cyclosporine, Terfenadine

Lesser adverse reactions & drug interactions when compared to Ketoconazole

*Nausea, vomiting *Liver dysfunction *Hypokalemia *Druf-drug interactions similar to Ketoconazole , but to a lesser degree