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

Abstract: The CLSI established clinical breakpoints (CBPs) for caspofungin (CSF), micafungin (MCF) and anidulafungin (ANF) versus Candida. The same CBP (susceptible (S): MIC≤2mcg/ml; non-S: MIC>2mcg/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) for a 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 ≤2mcg/ml, while 0–8% would be S using CBP of ≤0.25mcg/ml. WT MIC distributions revealed ECV ranges of 0.03–0.25mcg/ml for all major species except C. parapsilosis (1–4mcg/ml) and C. guilliermondii (4–16mcg/ml). Among Candida tested for fks mutations, only 15.7–45.1% of 51 mutants were detected using the CBP for NS of >2mcg/ml. In contrast, a cutoff of >0.25mcg/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 >0.12mcg/ml for ANF and CSF and of >0.06mcg/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 ≤0.25mcg/ml (S), 0.5mcg/ml (I), ≥1 (R) for CSF/MCF/ANF and C. albicans, C. tropicalis and C. krusei and ≤2mcg/ml (S), 4mcg/ml (I), and ≥8mcg/ml (R) for these agents and C. parapsilosis. The CBPs for ANF and CSF and C. glabrata are ≤0.12mcg/ml (S), 0.25mcg/ml (I), and ≥0.5mcg/ml (R), whereas those for MCF are ≤0.06mcg/ml (S), 0.12mcg/ml (I), and ≥0.25mcg/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. [Copyright &y& Elsevier]