The novel fungal Cyp51 inhibitor VT-1598 is efficacious in experimental models of central nervous system coccidioidomycosis caused by Coccidioides posadasii and Coccidioides immitis

Nathan P. Wiederhold, Lisa F. Shubitz, Laura K. Najvar, Rosie Jaramillo, Marcos Olivo, Gabriel Catano, Hien T. Trinh, Christopher M. Yates, Robert J. Schotzinger, Edward P. Garvey, Thomas F. Patterson

Research output: Contribution to journalArticle

18 Scopus citations

Abstract

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.

Original languageEnglish (US)
Article numbere02258-17
JournalAntimicrobial Agents and Chemotherapy
Volume62
Issue number4
DOIs
StatePublished - Apr 2018

Keywords

  • Coccidioidal meningitis
  • Coccidioides immitis
  • Coccidioides posadasii
  • Fluconazole
  • Murine model
  • VT-1598

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)
  • Infectious Diseases

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    Wiederhold, N. P., Shubitz, L. F., Najvar, L. K., Jaramillo, R., Olivo, M., Catano, G., Trinh, H. T., Yates, C. M., Schotzinger, R. J., Garvey, E. P., & Patterson, T. F. (2018). The novel fungal Cyp51 inhibitor VT-1598 is efficacious in experimental models of central nervous system coccidioidomycosis caused by Coccidioides posadasii and Coccidioides immitis. Antimicrobial Agents and Chemotherapy, 62(4), [e02258-17]. https://doi.org/10.1128/AAC.02258-17