Combination therapy retards the emergence of resistant E. coli

Double and / or triple combinations of ampicillin, fosfomycin and ciprofloxacin showed a stronger effect in delaying the emergence of resistant subpopulations of Escherichia coli compared to a single dose of each drug, according to data presented in ASM Microbe. These findings suggest that this system may potentially delay the onset of resistance in other antibacterial drugs.

Because inappropriate use of antibiotics is a major contributor to the problem of drug resistance, researchers led by Tesfalem Rezene Zere of the FDA’s Center for Drug Evaluation and Research sought to compare the effectiveness of the therapy with antibiotics. Using a well-controlled in vitro bioreactor system, known as a hollow fiber infection model, evaluated three antibacterial drugs (ampicillin, fosfomycin and ciprofloxacin) and combinations thereof against a clinical isolate, uropathogenic strain E. coli CFT073.

The researchers exposed single and double or triple simultaneous combinations of bacteria to the humanized pharmacokinetic concentrations of the three drugs, produced by computer control of the flow rates and the diluent flowing through the internal lumens of the hollow fibers for 5 to 10 days . For ampicillin, the dosing regimen was established to model the dosage every 8 hours with a Cmax of 14 μg / mL, whereas ciprofloxacin and fosfomycin were used with a PK profile of a single daily dose with Cmax values ​​of 2, 5 μg / ml and 210 μg / ml. Bacterial samples were collected at different time points and plated to quantify the total population and resistant mutant subpopulations.

The results showed that double and / or triple combinations of ampicillin, fosfomycin and ciprofloxacin appeared to have a stronger effect on the suspension of the emergence of resistant E. coli subpopulations compared to the single use of each drug. The data from this research support the selection of antibacterial drug dosing regimens for non-clinical in vivo studies and eventual clinical studies. These preliminary results show that this system could potentially be used to identify clinically relevant combination dosage regimens that may significantly delay the occurrence of resistance to antibacterial drugs. – by Savannah Demko

Reference: Zere T, et al. Abstract 3485. Presented at: ASM Microbe 2017; 1 to 5 June 2017; New Orleans.