Polyene Antifungals — Amphotericin B and Nystatin

Ergosterol is a 28-carbon sterol synthesized by fungi through a pathway that diverges from mammalian cholesterol synthesis at the level of lanosterol. It regulates membrane fluidity, supports membrane-bound enzyme function, and is essential for cell integrity. Because mammalian cells use cholesterol instead of ergosterol, ergosterol is a fungal-specific target.

Amphotericin B is a macrolide polyene produced by the bacterium Streptomyces nodosus. Its molecular structure is amphipathic: one face of the large ring is hydrophobic and polyene-rich, the other hydrophilic. When amphotericin B encounters a membrane containing ergosterol, the hydrophobic face inserts into the lipid bilayer and the drug molecules self-assemble around ergosterol into barrel-shaped transmembrane pore structures.

These pores allow non-selective ion flux across the membrane. Potassium leaks outward down its concentration gradient, the membrane potential collapses, and active transport systems fail. Against susceptible yeasts such as Candida species and Cryptococcus neoformans, amphotericin B is fungicidal. Against molds including Aspergillus species, it is fungistatic. This distinction matters clinically because candidemia and cryptococcal meningitis require rapid fungicidal killing, and amphotericin B provides it reliably in organisms that remain susceptible.

Amphotericin B binds ergosterol with approximately ten-fold higher affinity than it binds cholesterol. That selectivity is real but incomplete. At therapeutic concentrations, amphotericin B interacts with cholesterol in mammalian membranes as well, particularly in the cholesterol-rich apical membranes of renal tubular epithelial cells. This cholesterol interaction is the basis of the nephrotoxicity that defines and limits clinical use of conventional amphotericin B. The higher the free plasma drug concentration, the greater the interaction with renal cholesterol, and this observation drove the development of lipid formulations designed to reduce free drug exposure to the kidney while preserving antifungal delivery to sites of infection.

Liposomal amphotericin B consists of small unilamellar liposomes in which the drug is intercalated into the phospholipid bilayer of the liposome membrane. The liposomal shell shields amphotericin B from contact with mammalian cholesterol during circulation. It is the best-tolerated lipid formulation, with the largest body of clinical trial evidence and the best defined role in current guidelines. It is the preferred formulation when cost is not a limiting factor. Standard dosing is three to five milligrams per kilogram per day intravenously.

Amphotericin B lipid complex consists of ribbon-like lipid bilayer structures rather than closed liposomes. Because of its large particle size, it is rapidly taken up by the mononuclear phagocyte system, producing high drug concentrations in liver, spleen, and lung. Standard dosing is five milligrams per kilogram per day. Nephrotoxicity is reduced compared to amphotericin B deoxycholate but is greater than with liposomal amphotericin B. It is an acceptable and generally less costly alternative when liposomal amphotericin B is not available or budget is a consideration.

Amphotericin B colloidal dispersion consists of disk-shaped cholesteryl sulfate complexes. It is associated with the highest rate of acute infusion reactions among the three lipid formulations and is rarely chosen when the other two are available. It remains approved for aspergillosis refractory to conventional amphotericin B deoxycholate.

Nystatin is a polyene antifungal produced by Streptomyces noursei. It binds ergosterol and forms membrane pores with the same mechanism as amphotericin B. Its antifungal spectrum against Candida species is comparable to amphotericin B. However, nystatin is essentially insoluble in aqueous solution at physiological pH, and early attempts at intravenous formulation produced unacceptable systemic toxicity.

Oral nystatin suspension is used for oropharyngeal candidiasis by swishing and swallowing. It is also used as a swish-and-swallow preparation for esophageal candidiasis, though fluconazole is significantly more effective for documented esophageal disease. Topical nystatin preparations treat cutaneous and mucocutaneous candidiasis. Vaginal nystatin suppositories are an option during pregnancy, when systemic azoles are generally avoided. Because nystatin is not absorbed from the gastrointestinal tract, it produces no systemic toxicity when taken orally; nausea, vomiting, and diarrhea are the only adverse effects at standard doses.

True resistance to amphotericin B is rare, which is one of the defining clinical advantages of the polyene class. The primary resistance mechanism is depletion or structural alteration of ergosterol in the fungal cell membrane. This most commonly results from mutations in ergosterol biosynthesis genes, particularly the gene encoding C-5 sterol desaturase and the gene encoding lanosterol 14-alpha-demethylase. These mutations allow the organism to survive despite the presence of amphotericin B by removing or altering the drug's binding target in the membrane.

Candida lusitaniae is intrinsically resistant through constitutive mutations that reduce membrane ergosterol content. This is clinically actionable: Candida lusitaniae can be misidentified by automated systems as other Candida species, and a patient with Candida lusitaniae fungemia treated empirically with amphotericin B will not respond. Scedosporium species and Trichosporon species have intrinsic polyene resistance. Candida auris shows variable susceptibility with some clades carrying isolates above susceptibility breakpoints. Acquired resistance during therapy is uncommon but has been documented in immunocompromised hosts on prolonged exposure.