title: In vitro Synergistic Activity of Caspofungin Plus Polymyxin B Against Fluconazole-Resistant Candida glabrata.
abstract: BACKGROUND
  Candida species account for most invasive fungal infections, and the emergence of fluconazole and caspofungin resistance is problematic. Overcoming resistance with synergism between 2 drugs may be useful. In a 2013 in vitro study, caspofungin plus colistin (polymyxin E) was found to act synergistically against fluconazole-resistant and susceptible Candida albicans isolates. The purpose of our study was to extend this finding by evaluating caspofungin plus polymyxin B for in vitro synergy against fluconazole-resistant Candida glabrata isolates.
  
  
  METHODS
  A total of 7 fluconazole-resistant C. glabrata bloodstream infection isolates were obtained from 2010-2011. Of these, 2 isolates were also resistant to caspofungin. Minimum inhibitory concentrations (MICs) for caspofungin and polymyxin B were determined by Etest and broth microdilution. Clinical and Laboratory Standards Institute breakpoints were used for fluconazole and caspofungin MIC interpretations. No interpretive guidelines exist for testing polymyxin B against C. glabrata. Synergy testing with caspofungin (1 × MIC) and polymyxin B (½MIC) was performed using a modified bacterial Etest synergy method and time-kill assay.
  
  
  RESULTS
  With the Etest synergy method, 4 out of 7 isolates showed in vitro synergy and 1 out of 7 showed additivity. The remaining isolates (both caspofungin resistant) showed indifference. Using the time-kill assay, 1 out of 7 isolates showed synergy, 1 showed additivity and the remaining 5 (including both caspofungin-resistant isolates) showed indifference.
  
  
  CONCLUSIONS
  Caspofungin susceptibility may be required for synergism between caspofungin and polymyxin B. Further synergy testing with caspofungin plus polymyxin B and additional fluconazole-resistant C. glabrata isolates should be performed. In vitro synergy/additivity may or may not correlate with in vivo benefit.
authors.affiliation: Department of Infectious Disease Translational Research, Ochsner Clinic Foundation, New Orleans, Louisiana.
authors.forename: Emily K
authors.initials: EK
authors.lastname: Adams
authors.affiliation: Department of Infectious Disease Translational Research, Ochsner Clinic Foundation, New Orleans, Louisiana.
authors.forename: Deborah S
authors.initials: DS
authors.lastname: Ashcraft
authors.affiliation: Department of Infectious Disease Translational Research, Ochsner Clinic Foundation, New Orleans, Louisiana. Electronic address: gpankey@ochsner.org.
authors.forename: George A
authors.initials: GA
authors.lastname: Pankey
mesh_terms: D000935:Antifungal Agents / Q000008:administration & dosage*; D041221:Candida glabrata / Q000187:drug effects* / Q000302:isolation & purification; D000077336:Caspofungin; D025141:Drug Resistance, Fungal / Q000187:drug effects* / Q000502:physiology; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D054714:Echinocandins / Q000008:administration & dosage*; D015725:Fluconazole / Q000008:administration & dosage*; D006801:Humans; D055666:Lipopeptides; D008826:Microbial Sensitivity Tests / Q000379:methods; D011112:Polymyxin B / Q000008:administration & dosage*
chemical_list: D000935:Antifungal Agents; D054714:Echinocandins; D055666:Lipopeptides; D015725:Fluconazole; D000077336:Caspofungin; D011112:Polymyxin B
keywords: Candida glabrata; Caspofungin; Fluconazole resistance; Polymyxin B; Synergy