Mutant prevention concentration and mutant selection window of micafungin and anidulafungin in clinical Candida glabrata isolates [PublishAheadOfPrint]

Background: We report the mutant prevention concentration (MPC) and mutant selection window (MSW) for micafungin and anidulafungin administered to treat Candida glabrata. We also determine the mutation frequency.

Methods: We studied 20 echinocandin-susceptible, fluconazole-intermediate, and FKS wild-type C. glabrata isolates. Adjusted inocula were stroked directly onto Sabouraud agar plates containing different concentrations of micafungin or anidulafungin and visually inspected daily for up to 5 days of incubation. Individual colonies growing on the plates containing echinocandins at 1 mg/L were selected for antifungal susceptibility testing. The FKS genes of the resulting individual phenotypically resistant colonies were sequenced, and the MPC, the MSW, and the mutation frequency were determined. Biofilm was quantified, and the growth kinetics and virulence (Galleria mellonella model) of the resulting individual FKS mutant colonies were studied.

Results: For micafungin and anidulafungin, we found similar results for the MPC (0.06-2 mg/L and 0.25-2 mg/L, respectively), MSW (0.015-2 mg/L for both echinocandin), and mutation frequency (3.7x10^-8 and 2.8x10^-8, respectively). A total of 12 isolates were able to grow at 1 mg/L on echinocandin-containing plates, yielding a total of 32 phenotypically resistant colonies; however, FKS2 mutations (F658, S663P, W715L, and E655A) were only observed in 21 colonies. We did not find differences in biofilm formation, the kinetic parameters studied, or the median survival of larvae infected by wild-type isolates and the resulting individual FKS2 mutant colonies.

Conclusions: Echinocandin concentrations lower than 2 mg/L can lead to selection of resistance mutations in C. glabrata isolates in vitro.

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