Mutations in Candida glabrata FKS Genes Related to Elevated Echinocandin MICs in Isolates from a Population-based Surveillance in the United States

A. J. Zimbeck, N. J. Iqbal, S. R. Lockhart

Author address: 

CDC-APHL EID Fellow, Atlanta, GA, CDC, Atlanta, GA

Abstract: 

Background: Candida glabrata is the second leading cause of bloodstream infections in the United States. Its higher resistance to azole antifungal drugs has led to the increased use of echinocandin drugs for primary therapy of these infections. We used C. glabrata isolates collected in ongoing population-based surveillance to describe the DNA sequences of the FKS genes associated with elevated echinocandin MIC values. Methods: We measured MICs to echinocandins using CLSI M27-A3 guidelines, and categorized 110 isolates into three groups based on MIC distribution: high (MIC ≥ 0.25 ug/ml), moderate (0.125 ug/ml), and low (8804;0.06 ug/ml). We sequenced all or parts of the glucan synthase genes FKS1 and FKS2, with emphasis on the four "œhot spot" (HS) regions described by D.S. Perlin and coworkers. Results: Mutations in FKS genes appeared in isolates with elevated MICs but also in isolates with low MICs; the low MIC isolate mutations were disregarded as not related to echinocandin susceptibility. FKS mutations associated solely with moderate or high MIC categories were found in 31 isolates, 19 of which showed mutations outside the HS regions. Thirteen isolates with high echinocandin MICs showed 5 previously identified mutations (1 in FKS1 HS1 and 12 in FKS2 HS1, 8 of these with a non-conservative amino acid change at S663P). Three additional high MIC isolates lacked HS mutations. Two of these had mutations outside the FKS1 HS regions: one had a conservative mutation at C1231S and a 3 amino acid deletion of A236-K238; the other had a non-conservative mutation at W605R. Of 13 additional isolates with non-conservative mutations of W605R/G in FKS1, 9 showed a moderate MIC (0.125 ug/ml) to caspofungin, but low MIC values to the other two echinocandins. No mutations were detected in HS2 of FKS1 or FKS2. Conclusions: We show that FKS2 HS1 mutations, especially S663P, are the most common mutation in our population of isolates with elevated echinocandin MICs. Mutations outside of the HS regions were found in isolates with high echinocandin MICs. No mutations were found in HS2 of FKS1 or FKS2. Mutations outside of FKS1 HS1, such as W605R, may be good predictors of moderate MICs for caspofungin.
2010

abstract No: 

F-2132

Full conference title: 

110th General Meeting American Society for Microbiology
    • ASM 110th (2010)