The Novel Fungal Cyp51 Inhibitor VT-1598 Is Efficacious in Experimental Models of Central Nervous System Coccidioidomycosis Caused by Coccidioides posadasii and Coccidioides immitis

Coccidioidal meningitis can cause significant morbidity, and lifelong antifungal therapy is often required. VT-1598 is a fungus-specific Cyp51 inhibitor that has potentin vitro activity againstCoccidioides species. We evaluated thein vivo efficacy of VT-1598 in murine models of central nervous system coccidioidomycosis caused byC. posadasii andC. immitis . Infection was introduced via intracranial inoculation, and therapy began 48 h postinoculation. Oral treatments consisted of vehicle control, VT-1598, and positive controls of fluconazole in theC. immitis study and VT-1161 in theC. posadasii study. Treatment continued for 7 and 14 days in the fungal-burden and survival studies, respectively. Fungal burden was assessed in brain tissue collected 24 to 48 h posttreatment in the fungal-burden studies, on the days the mice succumbed to infection, or at prespecified endpoints in the survival studies. VT-1598 plasma concentrations were also measured in theC. posadasii study. VT-1598 resulted in significant improvements in survival in mice infected with either species. In addition, the fungal burden was significantly reduced in the fungal-burden studies. Plasma concentrations 48 h after dosing stopped remained above the VT-1598 MIC against theC. posadasii isolate, although levels were undetectable in the survival study after a 4-week washout. Whereas fungal burden remained suppressed after a 2-week washout in theC. immitis model, a higher fungal burden was observed in the survival arm of theC. posadasii model. Thisin vivo efficacy supports human studies to establish the utility of VT-1598 for the treatment of coccidioidomycosis.