Antifungal

Antifungal drugs, also called antimycotics, are used to kill or stop the growth of fungi that cause infections like athlete’s foot, ringworm, thrush, and serious systemic conditions such as cryptococcal meningitis. Most require a prescription, though a few can be bought over the counter. The rise of antifungal resistance is becoming a major global health concern.

These medications can be given in several ways. For eye infections, natamycin is the only dedicated ocular antifungal, though other agents can be compounded. Intrathecal administration, such as with amphotericin B, is used for central nervous system infections when other options can’t reach effective levels. Vaginal treatments, like intravaginal clotrimazole for candida vulvovaginitis, target local fungal infections.

Intravenous

Topical applications, such as terbinafine for tinea pedis, are used for skin infections. Oral antifungals, like ketoconazole for coccidioidomycosis, work when the drug has good absorption. Intravenous delivery, such as IV amphotericin B for coccidioidomycosis, is faster and useful for drugs with poor bioavailability.

Polyenes

Antifungal classes are limited, but new ones are in development and clinical trials as of 2021. Polyenes, like amphotericin B, are macrocyclic compounds with multiple double bonds and a hydroxylated region, making them amphiphilic. They bind to ergosterol in fungal cell membranes, altering the membrane’s fluidity and causing leakage of ions and small molecules, which kills the cell.

Animal cells use cholesterol instead of ergosterol, so they are less affected, though amphotericin B can still bind to cholesterol at therapeutic doses, leading to toxicity like nephrotoxicity. Shorter hydrophobic chains increase sterol binding, raising the risk of binding to cholesterol and harming animals. Examples include amphotericin B, candicidin, filipin (which binds cholesterol and is toxic), hamycin, natamycin (binds ergosterol well), nystatin, and rimocidin.

Azoles

Azoles block the conversion of lanosterol to ergosterol by inhibiting lanosterol 14α-demethylase. They have a five-membered ring with two or three nitrogen atoms.

Imidazoles (two nitrogen atoms) include bifonazole, butoconazole, clotrimazole, econazole, fenticonazole, isoconazole, ketoconazole, luliconazole, miconazole, omoconazole, oxiconazole, sertaconazole, sulconazole, and tioconazole. Triazoles (three nitrogen atoms) include albaconazole, cyproconazole, efinaconazole, epoxiconazole, fluconazole, isavuconazole, itraconazole, posaconazole, propiconazole, ravuconazole, terconazole, and voriconazole. Thiazoles include abafungin.

Allylamines, such as butenafine, naftifine, and terbinafine, inhibit squalene epoxidase, another enzyme needed for ergosterol synthesis. Echinocandins, including anidulafungin, caspofungin, micafungin, and rezafungin, block glucan formation in the fungal cell wall by inhibiting 1,3-beta-glucan synthase. They are given intravenously, especially for resistant Candida species. Triterpenoids include ibrexafungerp.

Other antifungals include acrisorcin; amorolfine (a topical morpholine for dermatophytosis); aurones; benzoic acid (found in Whitfield’s ointment, Friar’s Balsam, and Balsam of Peru); carbol fuchsin (Castellani’s paint); ciclopirox (a hydroxypyridone that disrupts membrane transport and respiration, useful for tinea versicolor); clioquinol; coal tar; copper(II) sulfate; crystal violet (a triarylmethane dye with antibacterial, antifungal, and anthelmintic properties, formerly a topical antiseptic); chlorhexidine (a topical antibacterial and antifungal, much stronger against bacteria than fungi); chlorophetanol; diiodohydroxyquinoline (iodoquinol); flucytosine (a pyrimidine analog antimetabolite); fumagillin; griseofulvin (binds microtubules and inhibits mitosis); haloprogin (discontinued due to side effects); miltefosine (damages fungal cell membranes); nikkomycin (blocks chitin formation in the cell wall); orotomide (F901318, a pyrimidine synthesis inhibitor); piroctone olamine; pentanenitrile; and potassium iodide.