Evaluating polymyxin B-based combinations against carbapenemresistant Escherichia coli in time-kill studies and in a hollow-fiber infection model

Yiying Cai, Tze Peng Lim, Jocelyn Qi Min Teo, Suranthran Sasikala, Eric Chun Yong Chan, Yanjun HONG, Winnie Lee, Thean Yen Tan, Thuan Tong Tan, Tse Hsien Koh, Li Yang Hsu, Andrea L. Kwa*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

6 Citations (Scopus)

Abstract

Polymyxin B-based combinations have emerged as a mainstay treatment against carbapenem-resistant Escherichia coli (CREC). We investigated the activity of polymyxin B-based two-antibiotic combinations against CREC using time-kill studies (TKS) and validated the findings in a hollow-fiber infection model (HFIM). TKS were conducted using 5 clinical CREC strains at 5 log10 CFU/ml against 10 polymyxin B-based two-antibiotic combinations at maximum clinically achievable concentrations. HFIMs simulating dosing regimens with polymyxin B (30,000U/kg/day) and tigecycline (100 mg every 12 h) alone and in combination were conducted against two CREC strains at 5 log10 CFU/ml over 120 h. Emergence of resistance was quantified using antibiotic-containing media. Phenotypic characterization (growth rate and stability of resistant phenotypes) of the resistant isolates was performed. All five CREC strains harbored carbapenemases. Polymyxin B and tigecycline MICs ranged from 0.5 mg/liter to 2 mg/liter and from 0.25 mg/liter to 8 mg/liter, respectively. All antibiotics alone did not have bactericidal activity at 24 h in the TKS, except for polymyxin B against two strains. In combination TKS, only polymyxin B plus tigecycline demonstrated both bactericidal activity and synergy in two out of five strains. In the HFIM, polymyxin B alone was bactericidal against both CREC strains before regrowth was observed at 8 h. Phenotypically stable polymyxin B-resistant mutants were observed for both strains, with a reduced growth rate observed in one strain. Tigecycline alone resulted in a slow reduction in bacterial counts. Polymyxin B plus tigecycline resulted in rapid and sustained bactericidal killing up to 120 h. Polymyxin B plus tigecycline is a promising combination against CREC. The clinical relevance of our results warrants further investigations.

Original languageEnglish
Article numbere01509
JournalAntimicrobial Agents and Chemotherapy
Volume61
Issue number1
DOIs
Publication statusPublished - Jan 2017

Scopus Subject Areas

  • Pharmacology
  • Pharmacology (medical)
  • Infectious Diseases

User-Defined Keywords

  • Antibiotic combination testing
  • Carbapenem-resistant Enterobacteriaceae
  • Hollow-fiber infection model
  • Polymyxin B

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