Definitions and Epidemiology of Candida Species not Susceptible to Echinocandins

Antifungal susceptibility testing of Candida against the echinocandin antifungal agents (anidulafungin [ANF], caspofungin [CSF], micafungin [MCF]) has been standardized by the Clinical and Laboratory Standards Institute (CLSI) Subcommittee on Antifungal Testing. The CLSI proposed a single set of clinical breakpoints (CBPs) for all three echinocandins and all species of Candida: susceptible, minimum inhibitory concentration (MIC)= 2 mu g/mL; nonsusceptible, MIC> 2 mu g/mL. Subsequently, these CBPs have been shown to lack sensitivity in detecting strains of Candida with acquired resistance mechanisms associated with treatment failure. Studies using the CLSI method have defined wild-type (WT) MIC distributions and epidemiologic cutoff values (ECVs) for each echinocandin and the common species of Candida. The ECVs serve as a sensitive means of discriminating WTstrains from those with acquired resistance mechanisms. WT MIC distributions revealed ECV ranges of 0.03 to 0.25 mu g/mL for all major species except C. parapsilosis (1-4 mu g/mL) and C. guilliermondii (4-16 mu g/mL). These ECVs reliably differentiate WT strains of each species from non-WT strains containing fks mutations. These data, coupled with additional biochemical, clinical, pharmacokinetic, and pharmacodynamic considerations, have resulted in new CBPs of <= 0.25 mu g/mL (susceptible), 0.5 mu g/mL (intermediate), and >= 1 mu g/mL (resistant) for ANF, CSF, and MCF for C. albicans, C. tropicalis, and C. krusei. For these agents and C. parapsilosis, the new CBPs are <= 2 mu g/mL (susceptible), 4 mu g/mL (intermediate), and >= 8 mu g/mL (resistant). For C. glabrata, the CBPs for ANF and CSF are <= 0.12 mu g/mL (susceptible), 0.25 mu g/mL (intermediate), and >= 0.5 mu g/mL (resistant), whereas those for MCF are <= 0.06 mu g/mL, 0.12 mu g/mL, and >= 0.25 mu g/mL, respectively. Application of both ECVs and the lower species-specific CBPs for the echinocandins has proven useful in both resistance surveillance and clinical care and will serve as an important step in international harmonization of in vitro susceptibility testing of this important antifungal class.