Antifungal Agents
Antifungal drugs target unique fungal cell biology including ergosterol synthesis, cell membrane integrity, and glucan synthesis to treat systemic and superficial mycoses.
Overview
Fungal infections are increasingly important in immunocompromised populations. Antifungal drugs exploit unique aspects of fungal biology — particularly the fungal cell membrane (ergosterol) and cell wall (beta-glucan) — that differ sufficiently from mammalian cells to allow selective toxicity.
Polyenes: Amphotericin B
Amphotericin B binds ergosterol in the fungal cell membrane, forming pores that cause potassium efflux and cellular damage. Broad spectrum (Candida, Aspergillus, Cryptococcus, Histoplasma, Mucor, Blastomyces, Coccidioides) — the broadest of all antifungals. Fungicidal.
Toxicity: The original deoxycholate formulation causes severe infusion reactions (fever, chills, rigors) and significant nephrotoxicity (reversible and cumulative). Lipid formulations (liposomal amphotericin B — L-AmB; amphotericin B lipid complex — ABLC) have substantially reduced nephrotoxicity and infusion reactions while maintaining efficacy. L-AmB is preferred when azoles fail or are contraindicated.
Azoles
Azoles inhibit CYP51 (lanosterol 14α-demethylase), blocking ergosterol biosynthesis and depleting the fungal membrane of ergosterol. Accumulation of toxic methylated sterols also occurs. Fungistatic against Candida (fungicidal for Candida glabrata and parapsilosis with some agents); activity against molds varies.
- Fluconazole: Excellent bioavailability; limited to Candida (not C. krusei, C. glabrata resistance variable) and Cryptococcus. No mold activity. CNS penetration makes it preferred for cryptococcal meningitis consolidation/maintenance.
- Itraconazole: Broader (Aspergillus, dimorphic fungi, dermatophytes); poor/variable oral bioavailability; significant CYP3A4 inhibitor.
- Voriconazole: Drug of choice for invasive aspergillosis. Broad spectrum including Fusarium. Significant CYP2C19 pharmacogenomics (ultra-rapid metabolizers may have inadequate levels). TDM (target trough 1-5.5 mg/L for Aspergillus) recommended. Visual disturbances, photosensitivity, hepatotoxicity, CNS effects, QTc prolongation.
- Posaconazole: Mucorales coverage (with azoles, only posaconazole is active); Aspergillus; prophylaxis in neutropenic patients and GVHD patients.
- Isavuconazole: Mucorales + Aspergillus; better-tolerated, water-soluble IV formulation.
Echinocandins: Caspofungin, Micafungin, Anidulafungin
Echinocandins inhibit beta-(1,3)-glucan synthase (FKS1 subunit), blocking cell wall glucan synthesis. Fungicidal against Candida; fungistatic against Aspergillus. First-line for invasive candidiasis and empiric treatment of suspected fungemia. Safe in azole-resistant Candida. No CNS penetration. Not active against Cryptococcus or Mucorales.
Key Takeaways
- Polyenes (amphotericin B) target ergosterol directly; broadest spectrum but nephrotoxic (lipid formulations reduce toxicity)
- Azoles inhibit ergosterol synthesis via CYP51; voriconazole is first-line for invasive aspergillosis
- Echinocandins block cell wall glucan synthesis; first-line for invasive candidiasis and candidemia
- Posaconazole and isavuconazole are the only azoles with Mucorales activity