In vitro and in vivo interaction of caspofungin with isavuconazole against Candida auris planktonic cells and biofilms

Fruzsina Nagy, Zoltán Tóth, Fanni Nyikos, Lajos Forgács, Ágnes Jakab, Andrew M. Borman, László Majoros, Renátó Kovács*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

The in vitro and in vivo efficacy of caspofungin was determined in combination with isavuconazole against Candida auris. Drug-drug interactions were assessed utilizing the fractional inhibitory concentration indices (FICIs), the Bliss independence model and an immunocompromised mouse model. Median planktonic minimum inhibitory concentrations (pMICs) of 23 C. auris isolates were between 0.5 and 2 mg/l and between 0.015 and 4 mg/l for caspofungin and isavuconazole, respectively. Median pMICs for caspofungin and isavuconazole in combination showed 2-128-fold and 2-256-fold decreases, respectively. Caspofungin and isavuconazole showed synergism in 14 out of 23 planktonic isolates (FICI range 0.03-0.5; Bliss cumulative synergy volume range 0-4.83). Median sessile MICs (sMIC) of 14 biofilm-forming isolates were between 32 and >32 mg/l and between 0.5 and >2 mg/l for caspofungin and isavuconazole, respectively. Median sMICs for caspofungin and isavuconazole in combination showed 0-128-fold and 0-512-fold decreases, respectively. Caspofungin and isavuconazole showed synergistic interaction in 12 out of 14 sessile isolates (FICI range 0.023-0.5; Bliss cumulative synergy volume range 0.13-234.32). In line with the in vitro findings, synergistic interactions were confirmed by in vivo experiments. The fungal kidney burden decreases were more than three log volumes in mice treated with combination of 1 mg/kg caspofungin and 20 mg/kg isavuconazole daily; this difference was statistically significant compared with control mice (P < 0.001). Despite the favorable effect of isavuconazole in combination with caspofungin, further studies are needed to confirm the therapeutic advantage of this combination when treating an infection caused by C. auris.

Original languageEnglish
Pages (from-to)1015-1023
Number of pages9
JournalMedical Mycology
Volume59
Issue number10
DOIs
Publication statusPublished - 1 Oct 2021
Externally publishedYes

Bibliographical note

Publisher Copyright:
© 2021 The Author(s) 2021. Published by Oxford University Presson behalf of The International Society for Human and Animal Mycology.

Keywords

  • Candida auris
  • biofilms
  • echinocandin
  • isavuconazole
  • mouse
  • synergy

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