Fungal infections are difficult to treat, particularly in the immunocompromised or neutropenic patient. Most fungi are resistant to conventional antimicrobial agents, and relatively few drugs are available for the treatment of systemic fungal diseases. Amphotericin B, the azoles (fluconazole, itraconazole, ketoconazole, and voriconazole), and the echinocandins are the primary drugs used in systemic infections. They are selectively toxic to fungi because they interact with or inhibit the synthesis of ergosterol, a sterol unique to fungal cell membranes.
DRUGS FOR SYSTEMIC FUNGAL INFECTIONS
Amphotericin B continues to be an important drug for the treatment of systemic fungal infections. However, several azoles and echinocandins are proving to be just as effective in some systemic mycoses with less risk of toxic effects.
1. Classification and pharmacokinetics
Amphotericin B is a polyene antibiotic related to nystatin. Amphotericin is poorly absorbed from the gastrointestinal tract and is usually administered intravenously as a nonlipid colloidal suspension, as a lipid complex, or in a liposomal formulation. The drug is widely distributed to all tissues except the central nervous system (CNS). Elimination is mainly via slow hepatic metabolism; the half-life is approximately 2 weeks. A small fraction of the drug is excreted in the urine; dosage modification is necessary only in extreme renal dysfunction. Amphotericin B is not dialyzable.
The fungicidal action of amphotericin B is due to its effects on the permeability and transport properties of fungal membranes. Polyenes are molecules with both hydrophilic and lipophilic characteristics (ie, they are amphipathic). They bind to ergosterol, a sterol specific to fungal cell membranes, and cause the formation of artificial pores (Figure 48–1). Resistance, though uncommon, can occur via a decreased level of or a structural change in membrane ergosterol.
Targets of antifungal drugs. Except for flucytosine (and possibly griseofulvin, not shown), all available antifungal drugs target the fungal cell membrane or cell wall. (Reproduced, with permission, from Katzung BG, editor: Basic & Clinical Pharmacology, 12th ed. McGraw-Hill, 2012: Fig. 48–1.)
Amphotericin B is one of the most important drugs available for the treatment of systemic mycoses and is often used for initial induction regimens before follow-up treatment with an azole. It has the widest antifungal spectrum of any agent and remains the drug of choice, or codrug of choice, for most systemic infections caused by Aspergillus, Blastomyces, Candida albicans, Cryptococcus, Histoplasma, and Mucor. Amphotericin B is usually given by slow intravenous infusion, but in fungal meningitis intrathecal administration, though dangerous, has been used. Local administration of the drug, with minimal toxicity, has been used in treatment of mycotic corneal ulcers and keratitis.