The Dihydroorotate Dehydrogenase Inhibitor Olorofim has Potent In vitro Activity Against Microascus/Scopulariopsis, Rasamsonia, Penicillium, and Talaromyces Species
Mycoses. 2022 Nov 27. doi: 10.1111/myc.13548. Online ahead of print.
BACKGROUND: Treatment options against infections caused by rare but emerging moulds may be limited by their reduced susceptibility or resistance to clinically available antifungals. The investigational antifungal olorofim, which targets the biosynthesis of pyrimidines within fungi, has activity against different species of filamentous fungi, including Aspergillus and Scedosporium/Lomentospora prolificans isolates that are resistant to available antifungals.
OBJECTIVE: We evaluated the in vitro activity of olorofim against 160 isolates within the genera Microascus/Scopulariopsis, Penicillium, Talaromyces, and the Rasamsonia argillacea species complex.
METHODS: One hundred sixty clinical isolates that had previously been identified to the species level by DNA sequence analysis were included. Antifungal susceptibility testing was performed by CLSI M38 broth microdilution for olorofim, amphotericin B, caspofungin, posaconazole, and voriconazole.
RESULTS: Olorofim demonstrated in vitro activity against each of the genera tested. Overall, olorofim MICs ranged from ≤0.008-0.5 mg/L against all isolates tested, with MIC90 and modal MIC values ranging from ≤0.008-0.25 mg/L and ≤0.008-0.03 mg/L, respectively. This activity was also maintained against individual isolates that had reduced susceptibility to or in vitro resistance against amphotericin B, posaconazole, and/or voriconazole.
CONCLUSIONS: The investigational agent olorofim demonstrated good in vitro activity against clinical isolates of emerging mould pathogens, including those with reduced susceptibility or resistance to clinically available antifungals. Further studies are warranted to determine how well this in vitro activity translates into in vivo efficacy against infections caused by these fungi.