In vitro activity of the novel antifungal olorofim against dermatophytes and opportunistic moulds including Penicillium and Talaromyces species

Abstract

Objectives: Olorofim is a novel antifungal agent with in vitro activity against Aspergillus and other opportunistic moulds. We investigated the in vitro activity of olorofim against a range of filamentous fungi comprising isolates of Aspergillus species, Scedosporium species, Alternaria alternata, dermatophytes, including terbinafine- and multidrug-resistant Trichophyton species, and Penicillium/Talaromyces species originating from patients in North India. Methods: Antifungal susceptibility of olorofim was tested against 241 mould isolates of Penicillium/Talaromyces species, Trichophyton species, A. fumigatus and cryptic Aspergillus species, Scedosporium species, and Alternaria alternata using CLSI broth microdilution. The comparators were five systemic azoles, amphotericin B, terbinafine, and luliconazole. Results: Overall, olorofim showed highly potent in vitro activity against dermatophytes and opportunistic moulds (MIC range of 0.004-0.125 mg/L) except for Alternaria alternata. Penicillium, and Talaromyces species and Trichophyton species exhibited a low geometric mean (GM) MIC (GM 0.027 mg/L and 0.015 mg/L, respectively) of olorofim. Importantly, a 2-12 dilution step decrease in in vitro activity of olorofim as compared with azoles was observed against Penicillium and Talaromyces. Notably, olorofim displayed potent in vitro activity against Trichophyton isolates including terbinafine-resistant and azole-resistant Trichophyton mentagrophytes/interdigitale with a modal MIC value of 0.008 mg/L. Further, azole-resistant A. fumigatus isolates harbouring mutations in azole target Cyp51A genes and several cryptic aspergilli displayed low MICs (range 0.004-0.03 mg/L) of olorofim. However, no in vitro activity of olorofim against Alternaria alternata was observed. Conclusions: The potent in vitro activity of olorofim against drug-resistant dermatophytes and opportunistic moulds is promising, warranting evaluation of the clinical utility of olorofim.