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bioRxiv · 10.1101/2022.08.31.506097

Synergistic interaction of caspofungin combined with posaconazole against FKS wild-type and mutant Candida auris planktonic cells and biofilms

Balla, N.·Kovacs, F.·Balazs, B.·Borman, A. M.·Bozo, A.·Jakab, A.·Toth, Z.·Majoros, L.·Kovacs, R.
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Abstract

The in vitro efficacy of caspofungin against FKS wild type and mutant Candida auris isolates was determined in the presence of posaconazole. Drug-drug interactions were assessed utilizing the fractional inhibitory concentration indices (FICIs), the Bliss independence model and a LIVE/DEAD viability assay. Median planktonic minimum inhibitory concentrations (pMICs) of C. auris isolates were between 0.5 and >2 mg/L for caspofungin and between 0.125 and >0.25mg/L for posaconazole. Median pMICs for caspofungin and posaconazole in combination showed a 4- to 256-fold decrease compared to caspofungin and a 2- to 512-fold decrease compared to posaconazole alone. The median sessile minimum inhibitory concentrations (sMICs) of isolates ranged from 32 to >32 mg/L and from 0.06 to >2 mg/L for caspofungin and posaconazole, respectively. Median sMICs for caspofungin and posaconazole in combination showed an 8- to 128-fold decrease compared to caspofungin and a 4- to 512-fold decrease compared to posaconazole alone. Caspofungin and posaconazole showed a synergistic interaction, especially against sessile cells (FICI from 0.033-0.375 and 0.091-0.5, and Bliss cumulative synergy volumes were 6.96 and 32.39 for echinocandin-susceptible and -resistant isolates, respectively). In line with the checkerboard-based findings, synergistic interactions were confirmed by a fluorescent microscopic LIVE/DEAD viability assay. The caspofungin-exposed (4 mg/L) C. auris biofilms exhibited increased cell death in the presence of posaconazole (0.03 mg/L) compared to untreated, caspofungin-exposed and posaconazole-treated sessile cells. The disrupted biofilm structure and increase in cell death was observed for both echinocandin-susceptible and echinocandin-resistant isolates. Despite the favourable effect of caspofungin in the presence of posaconazole, further in vivo studies are needed to confirm the clinical therapeutic potential of this combination when treating C. auris. Contribution to the fieldCandida auris is an emerging fungal pathogen, presumably related to global warming, which is associated with nosocomial infections and is considered a serious health threat worldwide. The treatment of C. auris infections is challenging due to the high level of drug resistance against the traditional antifungal agents. Given the low frequency of resistance to echinocandins, they are recommended as first-line therapy for the management of C. auris infections; however, treatment is complicated by the development of resistance in patients receiving long-term echinocandin treatment. In addition, the biofilm forming ability of this species further complicates the echinocandin-based therapeutic strategies. Combination-based approaches using existing drugs are viable alternatives to overcome the difficult-to-treat C. auris-related infections, including biofilm associated cases. In this study, we examined the in vitro efficacy of caspofungin and posaconazole against FKS wild-type and mutant C. auris planktonic cells and biofilms using classic checkerboard-based investigations and fluorescent imaging. Based on our results, the efficacy of caspofungin and posaconazole is unquestionable, having been confirmed against biofilms, especially in the case of FKS mutants at clinically achievable and safe drug concentrations. This study suggests that the administration of caspofungin with posaconazole may help to expand potential treatment strategies.

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Balla, N., Kovacs, F., Balazs, B., Borman, A. M., Bozo, A., Jakab, A., Toth, Z., Majoros, L., Kovacs, R.. 2022-08-31. Synergistic interaction of caspofungin combined with posaconazole against FKS wild-type and mutant Candida auris planktonic cells and biofilms. https://doi.org/10.1101/2022.08.31.506097

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