In vitro Synergistic Activity of Caspofungin Plus Polymyxin B Against Fluconazole-Resistant Candida glabrata

Am J Med Sci. 2016 Mar;351(3):265-70. doi: 10.1016/j.amjms.2015.12.014.


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.

Materials and 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.

Keywords: Candida glabrata; Caspofungin; Fluconazole resistance; Polymyxin B; Synergy.

MeSH terms

  • Antifungal Agents / administration & dosage*
  • Candida glabrata / drug effects*
  • Candida glabrata / isolation & purification
  • Caspofungin
  • Drug Resistance, Fungal / drug effects*
  • Drug Resistance, Fungal / physiology
  • Drug Synergism
  • Drug Therapy, Combination
  • Echinocandins / administration & dosage*
  • Fluconazole / administration & dosage*
  • Humans
  • Lipopeptides
  • Microbial Sensitivity Tests / methods
  • Polymyxin B / administration & dosage*


  • Antifungal Agents
  • Echinocandins
  • Lipopeptides
  • Fluconazole
  • Caspofungin
  • Polymyxin B