Abstract
Invasive fungal infections are associated with significant morbidity and mortality, and their management is restricted to a variety of agents from five established classes of antifungal medication. In practice, existing antifungal agents are often constrained by dose-limiting toxicities, drug interactions, and the routes of administration. An increasing prevalence of invasive fungal infections along with rising rates of resistance and the practical limitations of existing agents has created a demand for the development of new antifungals, particularly those with novel mechanisms of action. This article reviews antifungal agents currently in various stages of clinical development. New additions to existing antifungal classes will be discussed, including SUBA-itraconazole, a highly bioavailable azole, and amphotericin B cochleate, an oral amphotericin formulation, as well as rezafungin, a long-acting echinocandin capable of once-weekly administration. Additionally, novel first-in-class agents such as ibrexafungerp, an oral glucan synthase inhibitor with activity against various resistant fungal isolates, and olorofim, a pyrimidine synthesis inhibitor with a broad spectrum of activity and oral formulation, will be reviewed. Various other innovative antifungal agents and classes, including MGCD290, tetrazoles, and fosmanogepix, will also be examined.
Highlights
There are currently five classes of antifungal agents used in the treatment of systemic mycoses: polyenes, azoles, echinocandins, allylamines, and antimetabolites
Maintains activity against echinocandin-resistant Candida spp. and Rezafungin (CD101; Cidara Therapeutics; Table 1) is a next-generation echinocandin in development that shares its mechanism of action, the inhibition of 1,3-β-d-glucan synthesis, with other members of this class [2]
Ongoing clinical studies will continue to define the clinical role of ibrexafungerp, but development appears to be targeted towards resistant fungal infections or oral step-down therapy following treatment with echinocandins
Summary
There are currently five classes of antifungal agents used in the treatment of systemic mycoses: polyenes (amphotericin B), azoles (fluconazole, itraconazole, posaconazole, voriconazole, and isavuconazole), echinocandins (caspofungin, micafungin and anidulafungin), allylamines (terbinafine), and antimetabolites (flucytosine). Use is instead limited by a lack of oral formulations, with all current echinocandins only available as once-daily intravenous infusions Allylamines such as terbinafine interfere with ergosterol synthesis by the inhibition of squalene epoxidase. The final agent of clinical significance, flucytosine, is a pyrimidine analogue that selectively interferes with fungal nucleic acid synthesis to achieve activity [3] It is available as an oral formulation and its major adverse effects are essentially limited to bone marrow suppression. Ibrexafungerp and the tetrazoles act on similar fungal biosynthesis pathways previously targeted by existing classes (1,3-β-d-glucan and ergosterol synthesis), while many other agents in development (olorofim, MGCD290, Fosmanogepix, VL-2397, T-2307) look to establish entirely novel targets of antifungal activity
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