Journal
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY
Volume 62, Issue 4, Pages -Publisher
AMER SOC MICROBIOLOGY
DOI: 10.1128/AAC.02258-17
Keywords
VT-1598; Coccidioides posadasii; Coccidioides immitis; murine model; coccidioidal meningitis; fluconazole
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Funding
- National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health, Department of Health and Human Services [HHSN272201100018I, HHSN272201000038I]
- Viamet Pharmaceuticals, Inc., through a NIAID [AI 101497]
- Viamet Pharmaceuticals, Inc. [VT-1598, VT-1161]
- Astellas
- bioMerieux
- Cidara
- F2G
- Merck
- Viamet
- Revolution Medicines
- Viamet Pharmaceuticals, Inc.
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Coccidioidal meningitis can cause significant morbidity, and lifelong antifungal therapy is often required. VT-1598 is a fungus-specific Cyp51 inhibitor that has potent in vitro activity against Coccidioides species. We evaluated the in vivo efficacy of VT-1598 in murine models of central nervous system coccidioidomycosis caused by C. posadasii and C. 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 the C. immitis study and VT-1161 in the C. 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 the C. 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 fungalburden studies. Plasma concentrations 48 h after dosing stopped remained above the VT-1598 MIC against the C. 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 the C. immitis model, a higher fungal burden was observed in the survival arm of the C. posadasii model. This in vivo efficacy supports human studies to establish the utility of VT-1598 for the treatment of coccidioidomycosis.
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