ANTIFUNGAL AGENTS

AMPHOTERICIN B (AmB)

AmB is the broadest-spectrum antifungal agent but has significant toxicities, including nephrotoxicity, fever, chills, and nausea.
  • AmB has fungicidal activity and is available only for parenteral administration.
  • Lipid formulations lack nephrotoxicity and infusion reactions; whether there is a clinically significant difference in efficacy between the deoxycholate and lipid formulations remains controversial.

AZOLES

The azoles’ mechanism of action is inhibition of ergosterol synthesis in the fungal cell wall, resulting in fungistatic activity. Azoles cause little or no nephrotoxicity and are available in oral preparations.
  • Fluconazole: Fluconazole is available in both oral and IV formulations, has a long half-life, and penetrates into most body fluids, including ocular fluids and CSF.
    • Toxicity is minimal but includes (usually reversible) hepatotoxicity and—at high doses—alopecia, muscle weakness, dry mouth, and metallic taste.
    • Fluconazole is useful for coccidioidal and cryptococcal meningitis and for candidemia, but it is notably ineffective against aspergillosis or mucormycosis.
    • This drug is effective as fungal prophylaxis in bone-marrow and high-risk liver transplant recipients.
  • Voriconazole: Available in oral and IV formulations, voriconazole is considered the first-line agent against Aspergillus and has a broader spectrum than fluconazole against Candida species (including C. glabrata and C. krusei). It is also active against Scedosporium, Fusarium, and Coccidioides.
    • Disadvantages of voriconazole (compared to fluconazole) include multiple drug interactions, hepatotoxicity, skin rashes (including photosensitivity), visual disturbances, and the need to monitor drug levels.
    • As it is metabolized completely by the liver, dose adjustments are required in pts with liver failure. Dose adjustments for renal insufficiency are not required, but—given the presence of cyclodextrin—the parenteral formulation should be avoided in pts with severe renal insufficiency.
  • Itraconazole: Available in oral and IV formulations, itraconazole is the drug of choice for mild to moderate blastomycosis and histoplasmosis. It is approved by the FDA for use in febrile neutropenic pts, although most centers use other azoles for prophylaxis and treatment in these pts. Disadvantages of itraconazole include its poor penetration into CSF, the use of cyclodextrin in both the oral suspension and the IV preparation, the variable absorption of the drug in capsule form, and the need for monitoring of blood levels in pts taking capsules for disseminated mycoses.
  • Posaconazole: Approved for prophylaxis of aspergillosis and candidiasis in high-risk immunocompromised pts, posaconazole is also effective against fluconazole-resistant Candida isolates and may be useful as salvage therapy for some other fungal infections.
  • Isavuconazole: Approved for aspergillosis and mucormycosis, although clinical experience is still somewhat limited.

ECHINOCANDINS

The echinocandins, including caspofungin, anidulafungin, and micafungin, act by inhibiting the β-1,3-glucan synthase that is necessary for fungal cell wall synthesis. These agents are considered fungicidal for Candida and fungistatic for Aspergillus.
  • Among the safest antifungal agents, echinocandins offer broad-spectrum fungicidal activity against all Candida species, and caspofungin has been efficacious as salvage therapy for aspergillosis.
  • If anidulafungin or micafungin is used in combination with cyclosporine, no dose adjustment is needed for either drug.

FLUCYTOSINE

Flucytosine has excellent CSF penetration, but development of resistance has led to its almost always being used in combination with AmB (e.g., for cryptococcal meningitis). Adverse effects include bone marrow suppression.

GRISEOFULVIN AND TERBINAFINE

Griseofulvin is used primarily for ringworm infection. Terbinafine is used for onychomycosis and ringworm and is as effective as itraconazole.

TOPICAL AGENTS

Many drug classes are used for topical treatment of common fungal skin infections: azoles (e.g., clotrimazole, miconazole), polyene agents (e.g., nystatin), and other classes (e.g., ciclopirox olamine, terbinafine).

Outline

ANTIFUNGAL AGENTSis the Harrison's Manual of Medicine Word of the day!