Spontaneous mutational frequency and FKS mutation rates vary by echinocandin agent against Candida glabrata [Mechanisms of Resistance]

Echinocandins are front-line agents for treatment of invasive candidiasis. There are no reported agent-specific differences in Candida mutational frequency of resistance or propensity to develop FKS mutations. The objective of this study was to measure spontaneous and FKS mutation rates among Candida glabrata. Twenty bloodstream isolates from patients with or without prior echinocandin exposure were included. Minimum inhibitory (MIC), minimum fungicidal (MFC) and mutation prevention concentrations were higher for caspofungin than anidulafungin (P<0.0001) and micafungin (P<0.0001). Mutational frequencies of resistance at 3x baseline MIC were highest for caspofungin and lowest for micafungin. Two-hundred and forty-seven isolates were recovered at or above the MFC for caspofungin (n=159), anidulafungin (n=74), or micafungin (n=14). Agent-specific MIC increases were noted for anidulafungin and caspofungin, but not micafungin. Thirty-three percent of isolates harbored hot spot mutations in FKS1 (n=6) or FKS2 (n=76). Mutations at the Ser629 (Fks1) or Ser663 (Fks2) loci were more common following selection with anidulafungin or micafungin than with caspofungin (P = 0.003). Four isolates demonstrated >4-fold increases in MICs without FKS hot spot mutations; 3 of these harbored Fks2 mutations upstream of hot spot 1. The final isolate was FKS1 and FKS2 wild-type, but IC₅₀s of caspofungin and micafungin were increased 2.7-fold and 8-fold, respectively. In conclusion, micafungin may be superior in vitro to the other agents in limiting the emergence of resistance among C. glabrata. On the other hand, caspofungin exposure may be most likely to promote resistance development. These data provide a foundation for future investigations of newly-developed echinocandin agents.

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