Current concepts in antifungal pharmacology

Abstract

The introduction of new antifungal agents (eg, echinocandins, second-generation triazoles) in the past decade has transformed the management of invasive mycoses to the point that drug toxicity is no longer the major limiting factor in treatment. Yet, many of these newer antifungal agents have important limitations in their spectrum of activity, pharmacokinetics, and unique predisposition for pharmacokinetic drug-drug interactions and unusual toxicities associated with long-term use. This article reviews key pharmacological aspects of systemic antifungal agents as well as evolving strategies, such as pharmacokinetic-pharmacodynamic optimization and therapeutic drug monitoring, to improve the safety and efficacy of systemic antifungal therapy.

FIGURE 1.

Timeline of systemic antifungal drugs.

FIGURE 2.

Sites of action and mechanisms of systemic antifungal agents. FKS1, FKS2 catalytic subunits of the glucan synthase complex are the putative target binding site of echinocandins. Rho is a cell wall–regulating protein. ^*Isavuconazole is still in phase 3 trials.

FIGURE 3.

Spectrum of action of systemic antifungal agents. Solid blocks represent species in which the antifungal agent has demonstrated microbiological and clinical efficacy. Blocks with dotted lines indicate fungal genera/species in which resistance is common. AMB = amphotericin; ANID = anidulafungin; CAS = caspofungin; 5-FC = flucytosine; FLU = fluconazole; ITRA = itraconazole; MICA = micafungin; POSA = posaconazole; VORI = voriconazole.

FIGURE 4.

Common toxicities of antifungal agents. CNS = central nervous system; 5-FC = flucytosine; GI = gastrointestinal; IV = intravenous; QTc = corrected QT interval.