The Presence of anFKSMutation Rather than MIC Is an Independent Risk Factor for Failure of Echinocandin Therapy among Patients with Invasive Candidiasis Due to Candida glabrata

Abstract

ABSTRACTEchinocandins are frontline agents against invasive candidiasis (IC), but predictors for echinocandin therapeutic failure have not been well defined. Mutations inCandida FKSgenes, which encode the enzyme targeted by echinocandins, result in elevated MICs and have been linked to therapeutic failures. In this study, echinocandin MICs by broth microdilution andFKS1andFKS2mutations amongC. glabrataisolates recovered from patients with IC at our center were correlated retrospectively with echinocandin therapeutic responses. Thirty-five patients with candidemia and 4 with intra-abdominal abscesses were included, 92% (36/39) of whom received caspofungin. Twenty-six percent (10) and 74% (29) failed and responded to echinocandin therapy, respectively. Caspofungin, anidulafungin, and micafungin MICs ranged from 0.5 to 8, 0.03 to 1, and 0.015 to 0.5 μg/ml, respectively.FKSmutations were detected in 18% (7/39) ofC. glabrataisolates (FKS1,n= 2;FKS2,n= 5). Median caspofungin and anidulafungin MICs were higher for patients who failed therapy (P= 0.04 and 0.006, respectively). By receiver operating characteristic (ROC) analyses, MIC cutoffs that best predicted failure were >0.5 (caspofungin), >0.06 (anidulafungin), and >0.03 μg/ml (micafungin), for which sensitivity/specificity were 60%/86%, 50%/97%, and 40%/90%, respectively. Sensitivity/specificity of anFKSmutation in predicting failure were 60%/97%. By univariate analysis, recent gastrointestinal surgery, prior echinocandin exposure, anidulafungin MIC of >0.06 μg/ml, caspofungin MIC of >0.5 μg/ml, and anFKSmutation were significantly associated with failure. The presence of anFKSmutation was the only independent risk factor by multivariate analysis (P= 0.002). In conclusion, detection ofC. glabrata FKSmutations was superior to MICs in predicting echinocandin therapeutic responses among patients with IC.