Novel antifungals and treatment approaches to tackle resistance and improve outcomes of invasive fungal disease

Abstract

SUMMARY Fungal infections are on the rise, driven by a growing population at risk and climate change. Currently available antifungals include only five classes, and their utility and efficacy in antifungal treatment are limited by one or more of innate or acquired resistance in some fungi, poor penetration into “sequestered” sites, and agent-specific side effect which require frequent patient reassessment and monitoring. Agents with novel mechanisms, favorable pharmacokinetic (PK) profiles including good oral bioavailability, and fungicidal mechanism(s) are urgently needed. Here, we provide a comprehensive review of novel antifungal agents, with both improved known mechanisms of actions and new antifungal classes, currently in clinical development for treating invasive yeast, mold (filamentous fungi), Pneumocystis jirovecii infections, and dimorphic fungi (endemic mycoses). We further focus on inhaled antifungals and the role of immunotherapy in tackling fungal infections, and the specific PK/pharmacodynamic profiles, tissue distributions as well as drug-drug interactions of novel antifungals. Finally, we review antifungal resistance mechanisms, the role of use of antifungal pesticides in agriculture as drivers of drug resistance, and detail detection methods for antifungal resistance.

A Mini-Review of In Vitro Data for Candida Species, Including C. auris, Isolated during Clinical Trials of Three New Antifungals: Fosmanogepix, Ibrexafungerp, and Rezafungin

“…Although both oral and IV formulations have been evaluated in preclinical studies, the clinical data are for the oral formulation and in patients refractory to or intolerant of standard antifungal therapy [4]. These have included several studies of patients with vulvovaginal candidiasis (VVC), for which ibrexafungerp is approved for clinical use in the U.S. [44,45], as well as in patients with invasive candidiasis [46][47][48][49][50].…”

“…There are several antifungals with novel mechanisms of action that have recently been approved for clinical use in patients or are in the last stage of clinical development. These include ibrexafungerp and rezafungin, which have been approved by the U.S. Food and Drug Administration (FDA) and are available for clinical use, and fosmanogepix, which has completed phase 2 clinical studies and for which a phase 3 study is soon to begin [3][4][5][6]. The development of new antifungal agents is important because the incidence of fungal infections and rates of drug resistance both continue to increase [7,8].…”