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Combination therapy slows emergence of resistant E. coli

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

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

Researchers exposed single and double or triple simultaneous combinations of bacteria to humanized pharmacokinetic concentrations of the three drugs, produced by computer control of the flow rates and diluent flowing through the inner lumens of the hollow fibers, for 5 to 10 days. For ampicillin, the dosing regimen was set up to model dosing every 8 hours with an intended Cmax of 14 µg/mL whereas ciprofloxacin and fosfomycin were used with a PK profile of a single daily dose with target Cmax values of 2.5 µg/mL and 210 µg/mL. They collected bacterial samples at different time points and plated them to quantify the total population and the resistant mutant subpopulations.

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

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

Disclosure: Zere reports no relevant financial disclosures.

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

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

Researchers exposed single and double or triple simultaneous combinations of bacteria to humanized pharmacokinetic concentrations of the three drugs, produced by computer control of the flow rates and diluent flowing through the inner lumens of the hollow fibers, for 5 to 10 days. For ampicillin, the dosing regimen was set up to model dosing every 8 hours with an intended Cmax of 14 µg/mL whereas ciprofloxacin and fosfomycin were used with a PK profile of a single daily dose with target Cmax values of 2.5 µg/mL and 210 µg/mL. They collected bacterial samples at different time points and plated them to quantify the total population and the resistant mutant subpopulations.

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

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

Disclosure: Zere reports no relevant financial disclosures.

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