The novel arylamidine T-2307 demonstrates in vitro and in vivo activity against echinocandin-resistant Candida glabrata

Nathan Wiederhold, Laura K. Najvar, Annette W. Fothergill, Rosie Bocanegra, Marcos Olivo, Dora I. McCarthy, Yoshiko Fukuda, Junichi Mitsuyama, Thomas F Patterson

Research output: Contribution to journalArticle

11 Scopus citations

Abstract

Objectives: Candida species are major causes of invasive mycoses in immunocompetent and immunocompromised hosts. Treatment options are limited in the setting of antifungal resistance and increased rates of echinocandin-resistant Candida glabrata have been reported. The novel arylamidine T-2307 demonstrates potent in vitro antifungal activity against Candida species. Our objective was to evaluate the in vitro and in vivo activity of T-2307 against resistant C. glabrata. Methods: In vitro activity was determined against 42 clinical C. glabrata isolates, including 17 echinocandin-resistant strains. Neutropenic ICR mice were inoculated intravenously with an echinocandin-resistant C. glabrata isolate (T-2307; caspofungin MICs ≤0.008 and 0.5 mg/L, respectively). Therapy with vehicle control, T-2307 (0.75, 1.5, 3 or 6 mg/kg subcutaneously once daily) or caspofungin (1 or 10 mg/kg intraperitoneally once daily) began 1 day post-challenge. Kidneys were collected on day 8 and fungal burden was assessed by counting cfu. Results: T-2307 demonstrated potent in vitro activity against C. glabrata (geometric mean MIC 0.0135 mg/L), which was maintained against echinocandin-resistant isolates (geometric mean MIC 0.0083 mg/L). T-2307 also demonstrated in vivo efficacy in mice infected with echinocandin-resistant C. glabrata. Significant reductions in fungal burden were observed at each dosage level of T-2307 compared with control. Reductions in fungal burden were also observed with high-dose caspofungin. Conclusions: T-2307 demonstrated potent in vitro activity against C. glabrata, including echinocandin-resistant isolates, which translated into in vivo efficacy against invasive candidiasis caused by an echinocandin-resistant C. glabrata strain. These results demonstrate the potential for T-2307 as therapy against echinocandin-resistant Candida.

Original languageEnglish (US)
Article numberdkv398
Pages (from-to)692-695
Number of pages4
JournalJournal of Antimicrobial Chemotherapy
Volume71
Issue number3
DOIs
StatePublished - Mar 1 2016

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)
  • Infectious Diseases

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    Wiederhold, N., Najvar, L. K., Fothergill, A. W., Bocanegra, R., Olivo, M., McCarthy, D. I., Fukuda, Y., Mitsuyama, J., & Patterson, T. F. (2016). The novel arylamidine T-2307 demonstrates in vitro and in vivo activity against echinocandin-resistant Candida glabrata. Journal of Antimicrobial Chemotherapy, 71(3), 692-695. [dkv398]. https://doi.org/10.1093/jac/dkv398