Category:Antifungals

An antifungal is a medicine that kills or inhibits the growth of fungi pathogenic to the human host. The category is narrower than the antibacterial one, both in the number of clinically useful agents and in their mechanistic diversity, because the eukaryotic biochemistry of the fungus offers few molecular targets that a human cell does not share. The few that do exist, principally the sterol ergosterol of the fungal cell membrane, the β-(1,3)-D-glucan of the fungal cell wall, the fungal cytochrome P450 14α-demethylase, and the fungal squalene epoxidase, are the basis of every clinically used antifungal class.

The recognition of human disease caused by fungi predates by some decades the recognition of the antibiotics that treat them. The Polish anatomist Robert Remak cultured Trichophyton schoenleinii in Berlin in 1839 from a patient with favus and showed that the resulting cultures could reproduce the disease on inoculation; the Hungarian physician David Gruby, working in Paris in the 1840s, extended the demonstration to several other dermatophyte genera and is generally credited as the founder of medical mycology.^[1] Effective antifungal medicines, however, did not exist. The dermatologic treatment of tinea and the systemic treatment of the deep mycoses, before 1950, were palliative, surgical, or both; the cutaneous infections were treated with topical keratolytics, the deep ones with iodides, sulphonamides, or with nothing.

The first useful systemic antifungal was an accidental antibiotic. In 1939 a team at the Imperial College of Tropical Agriculture isolated griseofulvin from Penicillium griseofulvum while screening soil microorganisms for plant-pathogenic activity; the compound was found to inhibit dermatophyte fungi by interfering with microtubule function. Its clinical introduction was delayed for nearly twenty years; the Glasgow dermatologist James Gentles reported in 1958 that oral griseofulvin cured chronic dermatophyte infections that had resisted every topical treatment, and the medicine became the standard oral therapy for tinea capitis and onychomycosis until it was superseded by terbinafine and the triazoles forty years later.^[2]

The first effective treatment for an invasive systemic fungal infection came not from London or Glasgow but from the New York State Department of Health in Albany. The mycologist Elizabeth Lee Hazen and the chemist Rachel Brown, working by mail across the state on a project to find a fungal-active antibiotic, isolated in 1950 a polyene compound from Streptomyces noursei, recovered from soil at the Virginia dairy farm of Hazen's friend Walter Nourse. They named the antibiotic nystatin, for the New York State Department of Health that supported the work, and patented it for the Research Corporation foundation, which over the following decades disbursed thirteen million dollars in royalties to scientific research grants.^[3] Nystatin was too toxic to inject systemically but became the standard topical and oral non-absorbed agent for Candida infections. Its more potent and parenterally usable cousin amphotericin B was isolated by Vandeputte and colleagues at the Squibb Institute in 1955 from Streptomyces nodosus recovered from soil along the Orinoco river in Venezuela; for nearly forty years it was the only effective treatment for invasive aspergillosis, cryptococcal meningitis, and the deep endemic mycoses (histoplasmosis, coccidioidomycosis, blastomycosis), although at the cost of an infusion-related toxicity and a nephrotoxicity so reliable that the medicine acquired the clinical nickname of "amphoterrible". The polyene mechanism, the binding of fungal-membrane ergosterol with formation of a transmembrane pore, was established in the 1970s and remains the basis of the class.

The synthetic era of antifungal medicine began at the Janssen Pharmaceutica laboratories in Beerse, Belgium. The first imidazole antifungal, clotrimazole, was developed at Bayer in 1967; miconazole followed at Janssen in 1969. Both were topical agents. The breakthrough was the first orally bioavailable azole, ketoconazole, introduced by Janssen in 1977, which crossed the gut wall in sufficient concentration to treat systemic mycoses without injection.^[4] Ketoconazole's broad inhibition of cytochrome P450 enzymes, including the human steroidogenic enzymes 17,20-lyase and 11β-hydroxylase, produced hepatotoxicity, medicine interactions, gynaecomastia, and adrenal insufficiency, and its systemic use has been progressively restricted. The selectivity problem was solved by the triazoles: fluconazole (Pfizer/Sankyo, approved in 1990), itraconazole (Janssen, 1992), voriconazole (Pfizer, 2002), posaconazole (Schering, 2006), and isavuconazole (Astellas, 2015), each with improved selectivity for the fungal CYP51 and a broader spectrum.

The allylamine class added a separate mechanism: inhibition of the fungal squalene epoxidase, an upstream enzyme in the ergosterol pathway. Terbinafine (Sandoz, 1991) achieved high concentrations in nail and skin, was tolerated by mouth for the months required to treat onychomycosis, and largely replaced griseofulvin in that indication.^[5] The most recent mechanistically novel class, the echinocandins, inhibits the fungal cell-wall synthesis enzyme β-(1,3)-D-glucan synthase, a target absent from the mammalian cell; caspofungin (Merck, 2001), micafungin (Astellas, 2005), and anidulafungin (Pfizer, 2006) are the parenteral agents in the class, used principally for invasive Candida and Aspergillus infection in the immunocompromised host. The newer oral rezafungin (2023) and the wholly novel ibrexafungerp and fosmanogepix, in current trials, may yet extend the class.

The contemporary treatment of fungal infection is, like that of bacterial infection, a discipline that has begun to encounter clinically meaningful resistance. Aspergillus fumigatus strains with pan-azole resistance, attributed to environmental selection by agricultural azole use, have been reported across Europe; Candida auris, a multidrug-resistant species first identified in 2009, has spread between continents and through long-term-care facilities at a rate that has alarmed hospital epidemiologists. The pharmacopoeia of antifungal medicines, smaller than the antibacterial one and slower to expand, is once again under pressure.

By mechanism:

• Polyenes (bind ergosterol, form membrane pore): nystatin, amphotericin B
• Triazoles (inhibit fungal 14α-demethylase, block ergosterol synthesis): fluconazole, itraconazole, voriconazole, posaconazole, isavuconazole
• Imidazoles (older, broader CYP inhibition; principally topical, also systemic ketoconazole): clotrimazole, miconazole, ketoconazole
• Allylamines (inhibit squalene epoxidase): terbinafine, naftifine
• Hydroxypyridones (iron-chelating topical): ciclopirox
• Echinocandins (inhibit cell-wall β-(1,3)-D-glucan synthesis): caspofungin, micafungin, anidulafungin
• Antimetabolites: flucytosine (5-fluorocytosine), used in combination with amphotericin B for cryptococcal and severe candidal infection
• Microtubule disruptors: griseofulvin, still used in paediatric tinea capitis where the triazoles are unavailable
• Topical antifungals (most of the imidazoles, the allylamines, ciclopirox, tolnaftate, undecylenic acid) are also indexed under topical antifungals

The boundary of this category is "medicine that treats infection by a fungus pathogenic to humans." Antifungals used in agriculture and horticulture, although they share several active ingredient classes with the medical agents and have contributed to the emergence of resistance in human pathogens, are not collected here. Antiseptics with antifungal activity (chlorhexidine, povidone-iodine) are listed under antiseptics. The treatment of Pneumocystis jirovecii pneumonia, although the organism is reclassified as a fungus, is conventionally carried out with antibacterial-class agents (trimethoprim-sulfamethoxazole, dapsone, atovaquone) and those medicines are listed under their primary class. The boundary with the antiparasitic agents includes the parasitic-protist species formerly called fungi (the microsporidia, listed under antiparasitics).

This category page is an encyclopedia article about its subject. The actual index of medicines belonging to the category is generated automatically by the wiki engine, from category-membership declarations on the individual medicine pages, and appears at the foot of the page below the references.