ABCD: amphotericin B colloidal dispersion
ABLC: amphotericin B lipid complex
AIDS: acquired immunodeficiency syndrome
AUC: area under the CP-time curve
C-AMB: conventional amphotericin B
CGD: chronic granulomatous disease
CDC: U.S. Centers for Diseases Control and Prevention
CP: plasma concentration
CSF: cerebrospinal fluid
CYP: cytochrome P450
5FUMP: 5-fluorouracil-ribose monophosphate
HIV: human immundeficiency virus
L-AMB: liposomal amphotericin B
PJP: Pneumocystis jirovecii pneumonia
UPRTase: uracil phosphoribosyl transferase
KINGDOM FUNGI AND ITS IMPACT ON HUMANS
There are 200,000 known species of fungi, and estimates of the total size of the kingdom Fungi range to well over a million. Residents of the kingdom are quite diverse and include yeasts, molds, mushrooms, and smuts. About 400 fungal species cause disease in animals, and even fewer cause human disease. Nonetheless, fungal infections are associated with significant morbidity and mortality. The incidence of life-threatening fungal infections has increased in recent decades owing to an increase in immunocompromised patient populations, such as those receiving hematologic or solid-organ transplantation, cancer chemotherapy, and immunosuppressive medications, as well as those with human immunodeficiency virus–acquired immunodeficiency syndrome (HIV-AIDS). This has made antifungal agents increasingly important in the practice of modern medicine. With the currently available antifungal pharmacopeia, mortality rates for invasive fungal disease remain unacceptably high (Brown et al., 2012; Thornton, 2020).
Fungi are eukaryotes, making the discovery and development of drugs that target the pathogen without posing significant toxicity to the host a challenging undertaking. Differences in the biosynthesis of membrane sterols, the ability of fungi to deaminate cytosine, and the unique fungal cell wall that contains glucans and chitin have all been exploited to produce relatively safe and effective antifungal agents for the treatment of fungal infections (Roemer and Krysan, 2014). Since the advent of amphotericin B-deoxycholate in the late 1950s, research has sought safer and more effective alternatives for the treatment of systemic fungal infections. While amphotericin B remains the gold standard of systemic antifungal pharmacotherapy for a wide range of infections, alternative therapies have emerged for many clinically important fungal pathogens (Wiederhold, 2018).
This chapter provides a comprehensive overview of currently available therapeutic options for the management of invasive, mucosal, and superficial fungal infections. With only a few exceptions, the antifungals in common clinical use act mainly at sites involving the cell wall and cell membrane (Figure 61–1). Table 61–1 summarizes common fungal infections and their pharmacotherapy. Recommended adult dosages are briefly discussed for each agent. Dosing recommendations for antifungal agents in children have been recently reviewed elsewhere (Downes et al., 2020).
Sites of action of antifungal agents. Many antifungal agents act at sites involving cell wall and cell membrane function. Amphotericin B and other polyenes (e.g., nystatin) bind to ergosterol in fungal cell membranes and increase membrane permeability. ...