The fungal cyp51 inhibitor vt-1129 is efficacious in an experimental model of cryptococcal meningitis

Nathan P. Wiederhold, Laura K. Najvar, Edward P. Garvey, Stephen R. Brand, Xin Xu, Elizabeth A. Ottinger, Asaf Alimardanov, Jim Cradock, Mark Behnke, William J. Hoekstra, Robert J. Schotzinger, Rosie Jaramillo, Marcos Olivo, William R. Kirkpatrick, Thomas F. Patterson

Research output: Contribution to journalArticle

8 Scopus citations

Abstract

Cryptococcal meningitis is a significant cause of morbidity and mortality in immunocompromised patients. VT-1129 is a novel fungus-specific Cyp51 inhibitor with potent in vitro activity against Cryptococcus species. Our objective was to evaluate the in vivo efficacy of VT-1129 against cryptococcal meningitis. Mice were inoculated intracranially with Cryptococcus neoformans. Oral treatment with VT-1129, fluconazole, or placebo began 1 day later and continued for either 7 or 14 days, and brains and plasma were collected on day 8 or 15, 1 day after therapy ended, and the fungal burden was assessed. In the survival study, treatment continued until day 10 or day 28, after which mice were monitored off therapy until day 30 or day 60, respectively, to assess survival. The fungal burden was also assessed in the survival arm. VT-1129 plasma and brain concentrations were also measured. VT-1129 reached a significant maximal survival benefit (100%) at a dose of 20 mg/kg of body weight once daily. VT-1129 at doses of 0.3 mg/kg/day and each dose of fluconazole significantly reduced the brain tissue fungal burden compared to that in the control after both 7 and 14 days of dosing. The fungal burden was also undetectable in most mice treated with a dose of 3 mg/kg/day, even 20 days after dosing had stopped, in the survival arm. In contrast, rebounds in fungal burden were observed with fluconazole. These results are consistent with the VT-1129 concentrations, which remained elevated long after dosing had stopped. These data demonstrate the potential utility of VT-1129 to have a marked impact in the treatment of cryptococcal meningitis.

Original languageEnglish (US)
Article numbere01071-18
JournalAntimicrobial agents and chemotherapy
Volume62
Issue number9
DOIs
StatePublished - Sep 2018

Keywords

  • Cryptococcal meningitis
  • Cryptococcus neoformans
  • In vivo efficacy
  • VT-1129

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)
  • Infectious Diseases

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    Wiederhold, N. P., Najvar, L. K., Garvey, E. P., Brand, S. R., Xu, X., Ottinger, E. A., Alimardanov, A., Cradock, J., Behnke, M., Hoekstra, W. J., Schotzinger, R. J., Jaramillo, R., Olivo, M., Kirkpatrick, W. R., & Patterson, T. F. (2018). The fungal cyp51 inhibitor vt-1129 is efficacious in an experimental model of cryptococcal meningitis. Antimicrobial agents and chemotherapy, 62(9), [e01071-18]. https://doi.org/10.1128/AAC.01071-1