There are 200,000 known species of fungi, and estimates of the total size of Kingdom Fungi range to well over a million. Residents of the kingdom are quite diverse and include yeasts, molds, mushrooms, smuts, the pathogens Aspergillus fumigatus and Candida albicans, and the source of penicillin, Penicillium chrysogenum. Fortunately, only ~400 fungi cause disease in animals, and even fewer cause significant human disease. However, fungal infections are becoming more common: Patients with AIDS and patients whose immune systems are compromised by drug therapy are especially susceptible to mycotic infections. Fungi are eukaryotes with unique cell walls containing glucans and chitin, and their eradication requires different strategies than those for treatment of bacterial infections. Available agents have effects on the synthesis of membrane and cell-wall components, on membrane permeability, on the synthesis of nucleic acids, and on microtubule/mitotic spindle function (Figure 57–1).
Sites of action of antifungal drugs. Amphotericin B and other polyenes, such as nystatin, bind to ergosterol in fungal cell membranes and increase membrane permeability. The imidazoles and triazoles, such as itraconazole and fluconazole, inhibit 14-α-sterol demethylase, prevent ergosterol synthesis, and lead to the accumulation of 14-α-methylsterols. The allylamines, such as naftifine and terbinafine, inhibit squalene epoxidase and prevent ergosterol synthesis. The echinocandins, such as caspofungin, inhibit the formation of glucans in the fungal cell wall.
Antifungal agents described in this chapter are discussed under two major headings, systemic and topical, although this distinction is somewhat arbitrary. The imidazole, triazole, and polyene antifungal agents may be used either systemically or topically, and many superficial mycoses can be treated either systemically or topically.
Although Pneumocystis jirovecii, responsible for life-threatening pneumonia in immunocompromised patients, is a fungus and not a protozoan, its treatment is discussed elsewhere because the drugs used are primarily antibacterial or antiprotozoal rather than antifungal.
Major pharmaceutical companies have closed their antifungal development programs, although a few small firms continue to sponsor research in this field. Thus, the near future in this area is likely to be limited to expansion of experience with existing compounds (Table 57–1). The most recent systemic antifungals to reach clinical development, posaconazole (noxafil) and isavuconazole (in phase III trials in the U.S.), are both triazoles.
Table 57-1Pharmacotherapy of Mycoses ||Download (.pdf) Table 57-1 Pharmacotherapy of Mycoses
|DEEP MYCOSES ||DRUGS ||SUPERFICIAL MYCOSES ||DRUGS |
|Invasive aspergillosis || ||Candidiasis || |
| Immunosuppressed ||Voriconazole, amphotericin B ||Vulvovaginal || |
Butoconazole, clotrimazole, miconazole, nystatin, terconazole, tioconazole
| Non-immunosuppressed ||Voriconazole, ampho-tericin B, itraconazole || || |
|Blastomycosis || || ||Oral |
| Rapidly progressive or CNS ||Amphotericin B || || Fluconazole |
| Indolent and non-CNS ||Itraconazole ||Oropharyngeal ||Topical |
|Candidiasis || || || Clotrimazole, nystatin |
| Deeply invasive ||Amphotericin B, fluconazole, voriconazole, caspofungin, micafungin, anidulafungin || ||Oral (systemic) |
| || || || Fluconazole, itraconazole |
| || || || Posaconazole |
|Coccidioidomycosis || ||Cutaneous ||Topical |
| Rapidly progressing ||Amphotericin B || || Amphotericin B, clotrimazole, ciclopirox, econazole, ketoconazole, miconazole, nystatin |