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INTRODUCTION

GENERAL CONSIDERATIONS

  • Yeasts (e.g., Candida, Cryptococcus) appear microscopically as round, budding forms; molds (e.g., Aspergillus, Rhizopus) appear as filamentous forms called hyphae; and dimorphic fungi (e.g., Histoplasma) are spherical in tissue but appear as molds in the environment.

    • Endemic fungi (e.g., Coccidioides) are not part of the normal human microbial flora and infect hosts preferentially by inhalation.

    • Opportunistic fungi (e.g., Candida and Aspergillus) invade the host from normal sites of colonization (e.g., mucous membranes or the GI tract).

  • Definitive diagnosis of any fungal infection requires histopathologic identification of the fungus invading tissue and evidence of an accompanying inflammatory response.

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 have 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.

    • – It 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 and Fusarium.

    • – 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 the parenteral formulation should be avoided in pts with severe renal insufficiency given the presence of cyclodextrin.

  • 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 U.S. Food and Drug Administration (FDA) for use in febrile neutropenic 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 ...

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