title: Rate of FKS Mutations among Consecutive Candida Isolates Causing Bloodstream Infection.
abstract: Precise FKS mutation rates among Candida species are undefined because studies have not systematically screened consecutive, disease-causing isolates. The Sensititre YeastOne (SYO) assay measures echinocandin MICs against Candida with less variability than reference broth microdilution methods. However, clinical breakpoint MICs may overstate caspofungin nonsusceptibility compared to other agents. Our objectives were to determine Candida FKS mutation rates by studying consecutive bloodstream isolates and to determine if discrepant susceptibility results were associated with FKS mutations. FKS hot spots were sequenced in echinocandin-intermediate and -resistant isolates and those from patients with breakthrough candidemia or ≥ 3 days of prior echinocandin exposure. Overall, 453 isolates from 384 patients underwent susceptibility testing; 16% were echinocandin intermediate or resistant. Intermediate susceptibility rates were higher for Candida glabrata than for other species (P < 0.0001) and higher for caspofungin than for other agents (P < 0.0001). Resistance rates were similar between agents. FKS mutations were detected in 5% of sequenced isolates and 2% of isolates overall. Corresponding rates among C. glabrata isolates were 8% and 4%, respectively. Among Candida albicans isolates, rates were 5% and <1%, respectively. Mutations occurred exclusively with prior echinocandin exposure and were not detected in other species. Isolates with discrepant susceptibility results did not harbor FKS mutations. Mutation rates among isolates resistant to ≥ 2, 1, and 0 agents were 75%, 13%, and 0%, respectively. In conclusion, FKS mutations were uncommon among non-C. glabrata species, even with prior echinocandin exposure. Discrepancies in echinocandin susceptibility by SYO testing were not driven by mutations and likely reflect imprecise caspofungin clinical breakpoints.
authors.affiliation: Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA XDR Pathogen Laboratory, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA.
authors.forename: Ryan K
authors.initials: RK
authors.lastname: Shields
authors.affiliation: Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA XDR Pathogen Laboratory, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA mhn5@pitt.edu.
authors.forename: M Hong
authors.initials: MH
authors.lastname: Nguyen
authors.affiliation: Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors.forename: Ellen G
authors.initials: EG
authors.lastname: Press
authors.affiliation: Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Cumbie
authors.affiliation: Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors.forename: Eileen
authors.initials: E
authors.lastname: Driscoll
authors.affiliation: Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors.forename: A William
authors.initials: AW
authors.lastname: Pasculle
authors.affiliation: Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA XDR Pathogen Laboratory, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA VA Pittsburgh Healthcare System, Pittsburgh, Pennsylvania, USA.
authors.forename: Cornelius J
authors.initials: CJ
authors.lastname: Clancy
mesh_terms: D000935:Antifungal Agents / Q000494:pharmacology*; D002175:Candida / Q000187:drug effects / Q000235:genetics* / Q000302:isolation & purification / Q000472:pathogenicity*; D041221:Candida glabrata / Q000187:drug effects / Q000235:genetics / Q000302:isolation & purification; D002177:Candidiasis / Q000097:blood / Q000382:microbiology; D000077336:Caspofungin; D025141:Drug Resistance, Fungal / Q000235:genetics; D054714:Echinocandins / Q000494:pharmacology; D005656:Fungal Proteins / Q000235:genetics*; D006801:Humans; D055666:Lipopeptides / Q000494:pharmacology; D000077551:Micafungin; D008826:Microbial Sensitivity Tests; D059645:Mutation Rate
chemical_list: D000935:Antifungal Agents; D054714:Echinocandins; D005656:Fungal Proteins; D055666:Lipopeptides; D000077336:Caspofungin; D000077551:Micafungin