The Role of Novel Antifungals in the Management of Candidiasis: A Clinical Perspective

Abstract

Mucosal and invasive candidiasis can be challenging to treat in the setting of drug intolerance, antifungal resistance, drug-drug interactions, or host immune status. Antifungals with novel mechanisms of action and distinct pharmacokinetic/pharmacodynamic properties have been developed in recent years. Rezafungin is an echinocandin with high-tissue penetration and an extended half-life that allows for once-weekly administration, making it a convenient treatment option for invasive candidiasis while obviating the need for central catheter placement. Ibrexafungerp is an oral glucan synthase inhibitor that is active against most echinocandin-resistant Candida species. At present, it is approved for the treatment of acute vulvovaginal candidiasis and is under investigation as an oral step-down therapy following initial treatment with an echinocandin for cases of invasive candidiasis. Oteseconazole is a long-acting tetrazole that exhibits a higher affinity for the fungal enzyme CYP51, resulting in a potentially lower risk of drug-drug interactions and side effects compared to other azoles. It is currently approved for the treatment of recurrent vulvovaginal candidiasis. Fosmanogepix has a novel mechanism of action and potent activity against several Candida strains resistant to other antifungals. Due to its considerable bioavailability and tissue penetration, it holds promise as a potential treatment option in patients with invasive candidiasis, including those with chorioretinitis or meningitis. Results from clinical trials and observational studies will further delineate the role of these agents in the management of candidiasis. As the usage of these novel antifungals becomes widespread, we expect to acquire a greater understanding of their efficacy and potential benefits.

Keywords: Candidemia; Candidiasis; Fosmanogepix; Ibrexafungerp; Oteseconazole; Rezafungin.

Fig. 1

Mechanism of action of novel antifungals with activity against Candida species. Rezafungin and ibrexafungerp inhibit the cell-wall enzyme complex (1,3)‐β‐d‐glucan synthase at different subunits. FKS genes encode (1,3)‐β‐d‐glucan synthase. Manogepix, the active moiety of fosmanogepix, inhibits the fungal acetyltransferase enzyme (Gwt1) in the endoplasmic reticulum, blocking the acetylation of inositol and preventing the biosynthesis of glycosylphosphatidylinositol, thus, affecting the function of mannoproteins. Oteseconazole inhibits the fungal CYP51 enzyme, blocking the conversion of lanosterol to ergosterol