Optimizing Echinocandin Dosing and Susceptibility Breakpoint Determination via In vivo Pharmacodynamic Evaluation Against C. glabrata with and without Fks Mutations

ABSTRACT

Echinocandins are a preferred therapy for invasive candidiasis due to potency and broad spectrum. Resistance, especially in Candida glabrata, is an emerging threat to their use. Pharmacodynamic (PD) studies examining reduced susceptibility secondary to Fks mutations in C. glabrata are lacking. Current study explored PD targets for anidulafungin, caspofungin, and micafungin in an in vivo invasive candidiasis model against 11 C. glabrata with known or putative Fks mutations. PD targets were compared to 9 wild-type (WT) isolates. MIC range in the wild-type group was 0.03 - 0.25 mg/L for anidulafungin, 0.03 - 0.25 mg/L for caspofungin, and 0.01 - 0.06 mg/L micafungin. MIC range for mutants was 0.06 - 4, 0.25 - 16, and 0.13 - 8 mg/L for the same compounds, respectively. The mean free drug 24 h AUC/MIC associated with a stasis endpoint for the WT group was 13.2 for anidulafungin, 2.04 for caspofungin, and 6.78 for micafungin. Comparative values for mutants were 3.43, 2.67, 0.90, respectively. Pharmacokinetic data from patients suggests the C. glabrata PD targets needed for success in this model could be achieved for MIC values of 0.25 mg/L for anidulafungin, 2 mg/L for caspofungin, and 0.5 mg/L for micafungin. These values are higher than recently identified epidemiology cutoff values (ECVs). The results suggest drug specific MIC breakpoints could be increased for caspofungin and micafungin against C. glabrata and could include organisms with mutations in Fks1 and Fks2. While identification of genetic mutants is epidemiologically important, phenotype (MIC) provides a better predictor of therapeutic efficacy.