Impact of New Antifungal Breakpoints on Antifungal Resistance in Candida Species

Abstract

We reviewed our antifungal susceptibility data for micafungin, anidulafungin, fluconazole, and voriconazole against Candida species and compared resistance rates determined by the previous and recently revised CLSI antifungal breakpoints. With the new breakpoints, resistance was significantly increased for micafungin (from 0.8% to 7.6%), anidulafungin (from 0.9% to 7.3%), and voriconazole (from 6.1% to 18.4%) against Candida glabrata. Resistance was also increased for fluconazole against Candida albicans (from 2.1% to 5.7%). The Clinical and Laboratory Standards Institute (CLSI) recently revised the azole and echinocandin clinical breakpoints against Candida species (1). These new breakpoints are now both drug and species specific, whereas the previous breakpoints were not. For most species, with the exception of Candida parapsilosis and Candida guilliermondii against the echinocandins, the breakpoints have been lowered, such that previously susceptible MICs are now classified as resistant. In addition, Candida glabrata isolates are no longer considered susceptible to fluconazole but are rather classified only as either dose-dependent susceptible or resistant. The breakpoint revisions were made based on information from clinical studies, case reports describing clinical failure at MIC values below the previous breakpoints, results from pharmacokinetic/pharmacodynamic studies, and epidemiologic cutoff values (2, 3). Additionally, a goal of harmonizing the antifungal breakpoints with those set by EUCAST was sought. Epidemiologic cutoff values for individual species are used to optimize the detection of non-wild-type strains and, thus, the acquisition of resistance mechanisms and to prevent the breakpoints from dividing wild-type populations (2-4). The impact of the revised clinical breakpoints regarding categorical placement of Candida strains as resistant is unknown. Our objective was to evaluate what effect the new antifungal clinical breakpoints may have on azole and echinocandin resistance patterns in Candida species.(This work was presented in part at the 53rd Interscience Conference on Antimicrobial Agents and Chemotherapy, Denver, CO, 2013.) The antifungal susceptibility database in the Fungus Testing Laboratory at the University of Texas Health Science Center at San Antonio was reviewed. Susceptibility data for fluconazole, voriconazole, anidulafungin, and micafungin against Candida albicans, C. glabrata, Candida tropicalis, Candida krusei, and C. parapsilosis isolates sent to our laboratory for testing between 1 January 2008 and 31 December 2012 were reviewed. During this period, antifungal powders were obtained from the appropriate manufacturers (Pfizer and Astellas) and stock solutions were prepared in water for agents with aqueous solubility or in dimethyl sulfoxide (DMSO) as recommended (1, 5). Susceptibility testing was performed by broth microdilution methodology in RPMI according to the CLSI M27-A3 guidelines (5), and a 50% inhibition of growth compared to the growth control well was used as the ...

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