Evaluating polymyxin B-based combinations against carbapenem-resistant Escherichia coli in time-kill studies and in a hollow-fiber infection model [PublishAheadOfPrint]

Objectives: 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).

Methods: TKS was conducted using 5 clinical CREC strains at 5 log₁₀ CFU/mL against 10 polymyxin B-based two-antibiotic combinations at maximum clinically achievable concentrations. A HFIM simulating polymyxin B (30,000U/kg/day) and tigecycline (100mg every 12h) dosing regimens alone and in combination was conducted against two CREC strains at 5 log₁₀ CFU/mL over 120h. Emergence of resistance was quantified using antibiotic-containing media. Phenotypic characterization (growth rate, stability of resistant phenotypes) of the resistant isolates were performed.

Results: All five CRECs strains harbored carbapenemases. Polymyxin B and tigecycline MICs ranged from 0.5mg/L–2mg/L and 0.25mg/L–8mg/L respectively. All antibiotics alone did not have bactericidal activity at 24h in the TKS, except for polymyxin B against two strains. In combination TKS, only polymyxin B+ 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 8h. Phenotypically stable polymyxin B-resistant mutants were observed for both strains, with reduced growth rate observed in one strain. Tigecycline alone resulted in slow reduction in bacterial counts. Polymyxin B+ tigecycline resulted in rapid and sustained bactericidal killing up to 120h.

Conclusions: Polymyxin B+ tigecycline is a promising combination against CREC. The clinical relevance of our results warrants further investigations.

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