The Orotomide Olorofim is Efficacious in an Experimental Model of Central Nervous System Coccidioidomycosis [PublishAheadOfPrint]

Olorofim (formerly F901318) is an advanced analog of the orotomide class that inhibits fungal pyrimidine biosynthesis. We evaluated the in vitro and in vivo activity of olorofim against Coccidioides species. In vitro activity was assessed against 59 clinical Coccidioides isolates. Central nervous system infection was established in mice via intracranial inoculation with C. immitis arthroconidia. Oral therapy began 48 hours post-inoculation and consisted of vehicle control, olorofim daily doses of 20 mg/kg (6.67 mg/kg TID or 10 mg/kg BID), and 40 mg/kg (13.3 mg/kg TID or 20 mg/kg BID), or fluconazole (25 mg/kg BID). Treatment continued for 7 and 14 days in the fungal burden and survival arms, respectively. Fungal burden was assessed by colony-forming unit counts in brains. Olorofim demonstrated potent in vitro activity (MIC range ≤ 0.008 - 0.06 μg/ml). Survival was significantly enhanced in mice treated with olorofim. Reductions in brain tissue fungal burden were also observed on day 9 in the olorofim groups. Improvements in survival and reductions in fungal burden also occurred with fluconazole. More frequent dosing of olorofim was associated with enhanced survival and greater reductions in fungal burden. In the olorofim 13.3 mg/kg TID group, fungal burden remained low on day 30, 15 days after treatment stopped, and was undetectable in 7 of 10 mice. In contrast, elevated fungal burden rebounded in all other groups after therapy stopped. Olorofim was highly active in vitro and in vivo against Coccidioides. These results demonstrate that olorofim may have a role in the treatment of coccidioidomycosis.

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