Clinical breakpoints for the echinocandins and Candida revisited: Integration of molecular, clinical, and microbiological data to arrive at species-specific interpretive criteria

The CLSI established clinical breakpoints (CBPs) for caspofungin (CSF), micafungin (MCF) and anidulafungin (ANF) versus Candida. The same CBP (susceptible (S): MIC <= 2 mcg/ml; non-S: MIC > 2 mcg/ml) was applied to all echinocandins and species. More data now allow reassessment of these CBPs. We examined cases of echinocandin failure where both MICs and fks mutations were assessed; wild type (WT) MICs and epidemiological cutoff values (ECVs) fora large Candida collection; molecular analysis of fks hotspots for Candida with known MICs; and pharmacokinetic and pharmacodynamic (PK/PD) data. We applied these findings to propose new species-specific CBPs for echinocandins and Candida. Of 18 candidiasis cases refractory to echinocandins and with fks mutations, 28% (CSF), 58% (ANF) and 66% (MCF) had MICs in the S category using CBP of <= 2 mcg/ml, while 0-8% would be S using CBP of <= 0.25 mcg/ml. WT MIC distributions revealed ECV ranges of 0.03-0.25 mcg/ml for all major species except C. parapsilosis (1-4 mcg/ml) and C. guilliermondii (4-16 mcg/ml). Among Candida tested for fks mutations, only 15.7-45.1% of 51 mutants were detected using the CBP for NS of > 2 mcg/ml. In contrast, a cutoff of > 0.25 mcg/ml for C. albicans, C. tropicalis, C. krusei, and C. dubliniensis detected 85.6% (MCF) to 95.2% (CSF) of 21 mutant strains. Likewise, a cutoff of > 0.12 mcg/ml for ANF and CSF and of > 0.06 mcg/ml for MCF detected 93% (ANF) to 97% (CSF, MCF) of 30 mutant strains of C. glabrata. These data, combined with PK/PD considerations, support CBPs of <= 0.25 mcg/ml (S), 0.5 mcg/ml (I), >= 1 (R) for CSF/MCF/ANF and C. albicans, C. tropicalis and C krusei and <= 2 mcg/ml (S), 4 mcg/ml (I), and 28 mcg/ml (R) for these agents and C. parapsilosis. The CBPs for ANF and CSF and C glabrata are <= 0.12 mcg/ml (S), 0.25 mcg/ml (I), and >= 0.5 mcg/ml (R), whereas those for MCF are <= 0.06 mcg/ml (S), 0.12 mcg/ml (I), and >= 0.25 mcg/ml (R). New, species-specific CBPs for Candida and the echinocandins are more sensitive to detect emerging resistance associated with fks mutations, and better able to predict risk for clinical failure. (c) 2011 Elsevier Ltd. All rights reserved.