In vitroactivity of the novel antifungal olorofim against dermatophytes and opportunistic moulds includingPenicilliumandTalaromycesspecies

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.

The Antifungal Pipeline: Fosmanogepix, Ibrexafungerp, Olorofim, Opelconazole, and Rezafungin

“…Olorofim is not a broad-spectrum antifungal; however, it does have significant novelty and a spectrum of activity that will be relevant in the future. Olorofim exhibits no activity for yeast, Exophiala dermatitidis [ 151 ], or the Mucorales group [ 152 ] of thermally monomorphic molds, and also no activity against Alternaria alternata [ 153 ], but does have activity against several clinically important groups of fungi, including dimorphic molds (e.g., Histoplasma and Coccidioides spp. ), the hyaline hyphomycetes (e.g., Aspergillus spp.…”

“…Olorofim has shown excellent in vitro activity against both mold and yeast phases of Talaromyces marneffei [ 158 ] , and also against Madurella mycetomatis , the main causative agent of eumycetoma [ 159 ] as well as dermatophytes including Trichophyton spp. [ 153 ]. By virtue of its novel target enzyme and mechanism of action, olorofim has activity against isolates that are resistant to current treatment options, including several species that can be resistant to all commercially available antifungal drugs such as Scedosporium apiospermum , L. prolificans, Rasamsonia spp., Penicillium spp., and Scopulariopsis spp.…”

“…By virtue of its novel target enzyme and mechanism of action, olorofim has activity against isolates that are resistant to current treatment options, including several species that can be resistant to all commercially available antifungal drugs such as Scedosporium apiospermum , L. prolificans, Rasamsonia spp., Penicillium spp., and Scopulariopsis spp. (including Scopulariopsis brumptii ) [ 117 , 151 , 153 , 160 – 164 ]. Olorofim also maintains good activity against azole resistant A. fumigatus isolates [ 151 , 165 ], including CYP51A active mutants and hard-to-treat cryptic species of Aspergillus, such as A. nidulans , A. tubingensis , A. lentulus , and A. calidoustus [ 152 , 154 , 166 , 167 ] .…”

Antifungal Pipeline

“…This includes azole resistant (including A. terreus and cryptic species of Aspergillus), with generally lower MICs than currently approved anti-mold agents (Buil et al, 2017;Lackner et al, 2018;Rivero-Menendez et al, 2019b). This activity extends to Talaromyces, Trichophyton, and Penicillium (Singh et al, 2021;Zhang et al, 2021). Some dematiaceous molds like Alternaria and certain species of Fusarium.…”

Fungal Infection in Lung Transplantation

“…is expected. [71][72][73] A phase IIB clinical trial is underway for invasive mold infections with limited treatment options (ClinicalTrials.gov identifier: NCT03583164).…”