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