Chapter 42: Drugs for the Treatment of Fungal Infections

Drugs for the Treatment of Fungal Infections begins by categorizing fungal infections, or mycoses, based on their clinical presentation and depth of tissue involvement, distinguishing between superficial mucocutaneous infections affecting keratinized tissues like skin and nails, subcutaneous infections resulting from traumatic inoculation into deeper tissues, and potentially life-threatening systemic infections involving internal organs. A primary focus of the discussion is the distinct biochemical differences between fungal and mammalian cells, particularly the presence of ergosterol in fungal membranes instead of cholesterol, which serves as a vital target for selective toxicity. Polyene antibiotics, such as amphotericin B and nystatin, function by binding directly to this ergosterol, creating pores that lead to lethal cell leakage; however, the systemic use of amphotericin B is notoriously limited by severe renal toxicity, though newer lipid-based formulations have significantly improved its safety profile by altering drug distribution. Azole derivatives, categorized into imidazoles and triazoles, work by inhibiting the fungal cytochrome P450 enzyme 14-alpha-demethylase, thereby halting the biosynthesis of ergosterol. This extensive group includes widely used agents like fluconazole, which is prized for its excellent cerebrospinal fluid penetration for treating fungal meningitis, and second-generation triazoles like voriconazole that offer enhanced activity against resistant molds such as Aspergillus. The chapter also introduces the echinocandin class, featuring drugs like caspofungin, which uniquely target the fungal cell wall by inhibiting the synthesis of beta-1,3-D-glucan, providing a highly effective and well-tolerated option for invasive candidiasis. Furthermore, the text covers allylamines like terbinafine, which are essential for treating stubborn nail infections, the antimetabolite flucytosine which interferes with fungal RNA and protein synthesis when used in combination therapy, and the mitotic inhibitor griseofulvin, which is specifically used for scalp and skin dermatophytes. Understanding these diverse mechanisms, along with their unique pharmacokinetic profiles and potential drug-drug interactions involving human hepatic enzymes, is essential for effectively managing fungal diseases in both healthy and immunocompromised patient populations.