title: Increasing echinocandin resistance in Candida glabrata: clinical failure correlates with presence of FKS mutations and elevated minimum inhibitory concentrations.
abstract: BACKGROUND
  Fluconazole (FLC) resistance is common in C. glabrata and echinocandins are often used as first-line therapy. Resistance to echinocandin therapy has been associated with FKS1 and FKS2 gene alterations.
  
  
  METHODS
  We reviewed records of all patients with C. glabrata bloodstream infection at Duke Hospital over the past decade (2001-2010) and correlated treatment outcome with minimum inhibitory concentration (MIC) results and the presence of FKS gene mutations. For each isolate, MICs to FLC and echinocandins (anidulafungin, caspofungin, and micafungin) and FKS1 and FKS2 gene sequences were determined.
  
  
  RESULTS
  Two hundred ninety-three episodes (313 isolates) of C. glabrata bloodstream infection were analyzed. Resistance to echinocandins increased from 4.9% to 12.3% and to FLC from 18% to 30% between 2001 and 2010, respectively. Among the 78 FLC resistant isolates, 14.1% were resistant to 1 or more echinocandin. Twenty-five (7.9%) isolates harbored a FKS mutation. The predictor of a FKS mutant strain was prior echinocandin therapy (stepwise multivariable analysis, odds ratio, 19.647 [95% confidence interval, 7.19-58.1]). Eighty percent (8/10) of patients infected with FKS mutants demonstrating intermediate or resistant MICs to an echinocandin and treated with an echinocandin failed to respond or responded initially but experienced a recurrence.
  
  
  CONCLUSIONS
  Echinocandin resistance is increasing, including among FLC-resistant isolates. The new Clinical and Laboratory Standards Institute clinical breakpoints differentiate wild-type from C. glabrata strains bearing clinically significant FKS1/FKS2 mutations. These observations underscore the importance of knowing the local epidemiology and resistance patterns for Candida within institutions and susceptibility testing of echinocandins for C. glabrata to guide therapeutic decision making.
authors.affiliation: Duke University, Durham, NC 27710, USA. barbara.alexander@dm.duke.edu
authors.forename: Barbara D
authors.initials: BD
authors.lastname: Alexander
authors.forename: Melissa D
authors.initials: MD
authors.lastname: Johnson
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Pfeiffer
authors.forename: Cristina
authors.initials: C
authors.lastname: Jiménez-Ortigosa
authors.forename: Jelena
authors.initials: J
authors.lastname: Catania
authors.forename: Rachel
authors.initials: R
authors.lastname: Booker
authors.forename: Mariana
authors.initials: M
authors.lastname: Castanheira
authors.forename: Shawn A
authors.initials: SA
authors.lastname: Messer
authors.forename: David S
authors.initials: DS
authors.lastname: Perlin
authors.forename: Michael A
authors.initials: MA
authors.lastname: Pfaller
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000935:Antifungal Agents / Q000494:pharmacology* / Q000627:therapeutic use; D041221:Candida glabrata / Q000187:drug effects* / Q000235:genetics; D002177:Candidiasis / Q000188:drug therapy* / Q000382:microbiology*; D002648:Child; D002675:Child, Preschool; D025141:Drug Resistance, Fungal; D054714:Echinocandins / Q000494:pharmacology* / Q000627:therapeutic use; D005260:Female; D005656:Fungal Proteins / Q000235:genetics*; D005964:Glucosyltransferases / Q000235:genetics; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D008826:Microbial Sensitivity Tests; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D012189:Retrospective Studies; D016896:Treatment Outcome
chemical_list: D000935:Antifungal Agents; D054714:Echinocandins; D005656:Fungal Proteins; D008565:Membrane Proteins; D005964:Glucosyltransferases
keywords: Candida glabrata; echinocandin; micafungin; resistance; susceptibility