Caspofungin MICs correlate with treatment outcomes among patients with Candida glabrata invasive candidiasis and prior echinocandin exposure

Abstract

Mutations in Candida glabrata FKS genes, which encode the echinocandin target enzyme, are independent risk factors for treatment failures during invasive candidiasis. We retrospectively compared the ability of caspofungin susceptibility testing methods to identify C. glabrata FKS mutant isolates and predict outcomes among patients at our center. Eight percent (10/120) of sterile-site C. glabrata isolates harbored FKS1 (n = 3) or FKS2 (n = 7) mutations, including 32% (10/32) recovered from patients with prior echinocandin exposure. Median echinocandin exposures for mutant and nonmutant isolates were 55 (range, 7 to 188) and 13 (3 to 84) days, respectively (P = 0.004). Sensitivity and specificity of the CLSI caspofungin resistance breakpoint MIC (>0.12 μg/ml by broth microdilution using RPMI medium [BMD-RPMI]) were 90% (9/10) and 3% (3/110), respectively, for identifying FKS mutants. Sensitivity and specificity of receiver-operator characteristic (ROC) curve-derived breakpoints by BMD-RPMI, BMD-antibiotic medium 3, Etest, and YeastOne ranged from 70 to 100% and 89 to 95%, respectively; susceptibility rates varied from 83 to 90%. The 14-day echinocandin treatment success rate was 67% (44/66); failure was more likely with prior echinocandin exposure (P = 0.002) or infection with an FKS mutant (P = 0.0001) or echinocandin-resistant isolates by BMD-AM3, Etest, and YeastOne (P ≤ 0.03). The failure rate among patients with prior exposure and infection with a resistant isolate was 91% (10/11); it was 22% (12/55) among others (P < 0.0001). In conclusion, ROC-derived caspofungin MIC breakpoints by several methods were sensitive and specific for identifying C. glabrata FKS mutant isolates. Mutations were seen exclusively among patients with prior echinocandin exposure. A paradigm that considers prior echinocandin exposure and caspofungin MICs accurately classified treatment outcomes for C. glabrata invasive candidiasis.

Figures

Fig 1

(A) Correlation of caspofungin MICs when diluted in DMSO or sterile water. This figure demonstrates the correlation between caspofungin MICs determined by broth microdilution when the drug is dissolved in DMSO (y axis) or water (x axis). (B) Correlation of caspofungin MICs when read visually or by optical density (OD). The correlation between caspofungin MICs determined by broth microdilution with 50% inhibition endpoints determined by optical density (y axis) or visual readings (x axis) is shown.

Fig 2

Rates of clinical failure based on prior echinocandin exposure and caspofungin MICs. *, all patients infected with FKS mutant C. glabrata were included in the Yes arm; 90% (9/10) failed echinocandin therapy. A breakdown of rates of clinical failure stratified by prior echinocandin exposure and Etest caspofungin MICs is shown.