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.
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.
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References
- Global trends in the distribution of Candida species causing candidemia.Clin Microbiol Infect. 2014; 20: 5-10
Centers for Disease Control and Prevention. Antibiotic resistance threats in the United States, 2013. Atlanta (GA): US Department of Health and Human Services, CDC; 2013. Available at: http://www.cdc.gov/drugresistance/threat-report-2013/index.html. Accessed 28.07.15.
- Candida infections, causes, targets, and resistance mechanisms: traditional and alternative antifungal agents.Biomed Res Int. 2013; 2013 (Article ID 204237)
- Candida glabrata fungemia: experience in a tertiary care center.Clin Infect Dis. 2005; 41: 975-981
- Current epidemiology of Candida infection.Clin Microbiol Newsletter. 2014; 36: 131-136
- Species identification and antifungal susceptibility testing of Candida bloodstream isolates from population-based surveillance studies in two U.S. cities from 2008 to 2011.J Clin Microbiol. 2012; 50: 3435-3442
- Variation in susceptibility of bloodstream isolates of Candida glabrata to fluconazole according to patient age and geographic location.J Clin Microbiol. 2003; 41: 2176-2179
- Variation in susceptibility of bloodstream isolates of Candida glabrata to fluconazole according to patient age and geographic location in the United States in 2001 to 2007.J Clin Microbiol. 2009; 47: 3185-3190
- The changing epidemiology of healthcare-associated candidemia over three decades.Diagn Microbiol Infect Dis. 2012; 73: 45-48
- Frequency of decreased susceptibility and resistance to echinocandins among fluconazole-resistant bloodstream isolates of Candida glabrata.J Clin Microbiol. 2012; 50: 1199-1203
- Increasing echinocandin resistance in Candida glabrata: clinical failure correlates with presence of FKS mutations and elevated minimum inhibitory concentrations.Clin Infect Dis. 2013; 56: 1724-1732
- Time-kill assay and Etest evaluation for synergy with polymyxin B and fluconazole against Candida glabrata.Antimicrob Agents Chemother. 2014; 58: 5795-5800
- Synergy of the antibiotic colistin with echinocandin antifungals in Candida species.J Antimicrob Chemother. 2013; 68: 1285-1296
- Polymyxin B, in combination with fluconazole, exerts a potent fungicidal effect.J Antimicrob Chemother. 2010; 65: 931-938
- Synergistic fungicidal activities of polymyxin B and ionophores, and their dependence on direct disruptive action of polymyxin B on fungal vacuole.J Antibiot. 2009; 62: 81-87
- In-vitro activity of commonly used antifungal agents in the presence of rifampin, polymyxin B and norfloxacin against Candida albicans.J Chemother. 1995; 7: 525-529
- Reference Method for Broth Dilution Antifungal Susceptibility Testing of Yeasts: 4Th Informational Supplement.([CLSI document M27-S4]) CLSI, Wayne (PA)2012
- Performance Standards for Antimicrobial Susceptibility Testing: 25Th Informational Supplement.([CLSI document M100-S25]) CLSI, Wayne (PA)2015
- Reference Method for Broth Dilution Antifungal Susceptibility Testing of Yeasts: Approved Standard.3rd ed. CLSI, [CLSI document M27-A3]. Wayne (PA)2008
- Antimicrobial combinations.in: Lorian V. Antibiotics in Laboratory Medicine. 5th ed. Lippincott Williams and Wilkins, Philadelphia2005: 365-405
- Influence of test conditions on antifungal time-kill curve results: proposal for standardized methods.Antimicrob Agents Chemother. 1998; 42: 1207-1212
- Antimicrobial resistance: resistance to antifungal agents: mechanisms and clinical impact.Clin Infect Dis. 2008; 46: 120-128
- In vitro simulation of in vivo conditions: physical state of the culture medium.J Clin Microbiol. 1989; 27: 2403-2406
Article info
Publication history
Accepted:
November 2,
2015
Received:
August 4,
2015
Footnotes
☆Part of this work was presented at the Southern Regional Meeting of the American Federation for Medical Research, New Orleans, LA, abstract 511, February 2015 and at Ochsner’s 12th Annual Research Day, New Orleans, LA, abstract 6, May 2015.
☆☆The authors have no financial or other conflicts of interest to disclose.
Identification
Copyright
© 2016 Southern Society for Clinical Investigation. Published by Elsevier Inc. All rights reserved.
