In Vitro Characterization of Twenty-One Antifungal Combinations against Echinocandin-Resistant and -Susceptible Candida glabrata.

Hazim O Khalifa,Akira Watanabe,Hidetaka Majima,Katsuhiko Kamei

doi:10.3390/jof7020108

Abstract

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 C. glabrata 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.

Highlights

Fungal infections are gaining worldwide attention owing to their progressive increase, being responsible for than 1.6 million annual deaths worldwide, especially among immunocompromised patients and patients with severe immunosuppressive diseases [1].Among fungal infections, special attention has been paid to Candida spp. infections, which were identified as the major cause of bloodstream infections in hospitalized patients [2].C. glabrata is one of the most prevalent fungal pathogens worldwide and is considered the second most-common fungal cause of candidemia in the United States [3]
Echinocandin resistance was confirmed in six isolates that were resistant to at least two echinocandins and harbored FKS HS1, but not HS2 confirming its lower role for echinocandin resistance in C. glabrata
Antifungal combinations can be an attractive approach to overcome the emergence and spread of fungal resistance. This approach may have significant value for the treatment of C. glabrata for several reasons: first, this species is intrinsically resistant to fluconazole [6,7]; second, infections with C. glabrata have been confirmed to be associated with long hospitalization periods and high mortality rates as compared with another Candida

Summary

Introduction

Fungal infections are gaining worldwide attention owing to their progressive increase, being responsible for than 1.6 million annual deaths worldwide, especially among immunocompromised patients and patients with severe immunosuppressive diseases [1].Among fungal infections, special attention has been paid to Candida spp. infections, which were identified as the major cause of bloodstream infections in hospitalized patients [2].C. glabrata is one of the most prevalent fungal pathogens worldwide and is considered the second most-common fungal cause of candidemia in the United States [3]. Fungal infections are gaining worldwide attention owing to their progressive increase, being responsible for than 1.6 million annual deaths worldwide, especially among immunocompromised patients and patients with severe immunosuppressive diseases [1]. Special attention has been paid to Candida spp. infections, which were identified as the major cause of bloodstream infections in hospitalized patients [2]. Since the discovery of the first antifungal agent (amphotericin B; 1950s) [8], only three antifungal classes (azoles, polyenes, and echinocandins) are currently indicated for the treatment of invasive candidiasis [2]. Since the introduction of the echinocandin drug caspofungin in 2001, significant progress in the treatment of Candida infections was achieved [3]. Recent reports confirmed the increasing of echinocandin resistance in C. glabrata that has gained special attention [6,9,10]

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Discussion

Conclusion