Abstract
Candida auris is an emergent fungal pathogen that causes severe infectious outbreaks globally. The public health concern when dealing with this pathogen is mainly due to reduced susceptibility to current antifungal drugs. A valuable alternative to overcome this problem is to investigate the efficacy of combination therapy. The aim of this study was to determine the in vitro interactions of isavuconazole with echinocandins against C. auris. Interactions were determined using a checkerboard method, and absorbance data were analyzed with different approaches: the fractional inhibitory concentration index (FICI), Greco universal response surface approach, and Bliss interaction model. All models were in accordance and showed that combinations of isavuconazole with echinocandins resulted in an overall synergistic interaction. A wide range of concentrations within the therapeutic range were selected to perform time-kill curves. These confirmed that isavuconazole–echinocandin combinations were more effective than monotherapy regimens. Synergism and fungistatic activity were achieved with combinations that included isavuconazole in low concentrations (≥0.125 mg/L) and ≥1 mg/L of echinocandin. Time-kill curves revealed that once synergy was achieved, combinations of higher drug concentrations did not improve the antifungal activity. This work launches promising results regarding the combination of isavuconazole with echinocandins for the treatment of C. auris infections.
Highlights
Candida auris (C. auris) is a multidrug-resistant yeast pathogen responsible for numerous cases of fungemia globally since 2009 [1]
The synergistic interactions obtained from the combination of isavuconazole plus anidulafungin against C. auris by the fractional inhibitory concentration index (FICI) method [14], and from isavuconazole plus micafungin against other non-auris Candida by time-kill studies [15], supports the interest of further studying the isavuconazole–echinocandin combinations against C. auris
Checkerboard experiments showed that none of the antifungal drugs in monotherapy at the concentrations tested were able to stop fungal growth completely, expressed as an absorbance value close to 0%
Summary
Candida auris (C. auris) is a multidrug-resistant yeast pathogen responsible for numerous cases of fungemia globally since 2009 [1]. Combining isavuconazole and echinocadins may be an interesting approach to be further investigated, considering that, on one hand, echinocandins are nowadays the treatment of choice for infections caused by C. auris, and on the other hand, isavuconazole is the newest and safer addition to the triazole group. It is labeled for the treatment of aspergillosis and mucormycosis, its anti-Candida activity together with its biopharmaceutical properties make it an interesting alternative [13]. The synergistic interactions obtained from the combination of isavuconazole plus anidulafungin against C. auris by the fractional inhibitory concentration index (FICI) method [14], and from isavuconazole plus micafungin against other non-auris Candida by time-kill studies [15], supports the interest of further studying the isavuconazole–echinocandin combinations against C. auris
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