In Vitro Characterization of Twenty-One Antifungal Combinations against Echinocandin-Resistant and -Susceptible <i>Candida</i><i>glabrata</i>

• Main Authors: Hazim O. Khalifa, Hidetaka Majima, Akira Watanabe, Katsuhiko Kamei
• Format: Article
• Language: English
• Published: MDPI AG 2021-02-01
• Series: Journal of Fungi
• Subjects: <i>C. glabrata</i>; echinocandins resistance; antifungal synergistic combinations; echinocandins; <i>FKS</i> mutations
• Online Access: https://www.mdpi.com/2309-608X/7/2/108

This study was designed to analyze the interaction of 21 antifungal combinations consisting of seven major antifungal agents against 11 echinocandin- susceptible and six-resistant <i>C. glabrata</i> isolates. The combinations were divided into five major groups and were evaluated by checkerboard, disc diffusion, and time-killing assays. Synergy based on the fractional inhibitory concentration index of ≤ 0.50 was observed in 17.65–29.41% of the cases for caspofungin combinations with azoles or amphotericin B. Amphotericin B combination with azoles induced synergistic interaction in a range of 11.76–29.41%. Azole combinations and 5-flucytosine combinations with azoles or amphotericin B did not show synergistic interactions. None of the 21 combinations showed antagonistic interactions. Interestingly, 90% of the detected synergism was among the echinocandin-resistant isolates. Disk diffusion assays showed that the inhibition zones produced by antifungal combinations were equal to or greater than those produced by single drugs. The time-killing assay showed the synergistic action of caspofungin combination with fluconazole, voriconazole, and posaconazole, and the amphotericin B-5-flucytosine combination. Furthermore, for the first time, this assay confirmed the fungicidal activity of caspofungin-voriconazole and amphotericin B-5-flucytosine combinations. The combination interactions ranged from synergism to indifference and, most importantly, no antagonism was reported and most of the synergistic action was among echinocandin-resistant isolates.