In vitro activity of olorofim against clinical isolates of the Fusarium oxysporum and Fusarium solani species complexes

Background: Invasive fusariosis is associated with marked morbidity and mortality in immunocompromised hosts, and clinical outcomes are poor with conventional therapy. Olorofim (F901318) is an investigational antifungal in the orotomide class that selectively targets fungal dihydroorotate dehydrogenase (DHODH) causing inhibition of pyrimidine biosynthesis. Objective: We evaluated the in vitro activity of olorofim against 61 clinical isolates of the Fusarium oxysporum and F solani species complexes (FOSC and FSSC, respectively), the most prevalent causes of invasive fusariosis. Methods: Clinical isolates of FOSC (n = 45) and FSSC (n = 16) were identified using DNA sequence analysis of the translation elongation factor 1-alpha (TEF1α) and RNA polymerase II second largest subunit (RPB2). Antifungal susceptibility testing was performed by CLSI M38 broth microdilution for olorofim, amphotericin B, isavuconazole, posaconazole, voriconazole and micafungin. Results: Olorofim demonstrated good in vitro activity against both FOSC and FSSC. Against the 45 FOSC isolates, olorofim MICs ranged between 0.03-0.5 mg/L and 0.06->4 mg/L at the 50% and 100% inhibition endpoints, respectively. Against FSSC isolates, olorofim MIC ranged between 0.25-1 mg/L and 1->4 mg/L at 50% and 100% inhibition, respectively. While amphotericin B also demonstrated similar in vitro activity (MIC ranges 1-4 and 0.25-4 mg/L against FOSC and FSSC, respectively), neither the triazoles nor micafungin demonstrated consistent in vitro activity against Fusarium isolates at clinically relevant concentrations. Conclusions: The investigational agent olorofim demonstrated good in vitro activity against FOSC and FSSC clinical isolates. Further studies are warranted to determine how well this in vitro activity translates into in vivo efficacy.