Effect of drug combinations on the kinetics of antibiotic resistance emergence in Escherichia coli CFT073 using an in vitro hollow-fibre infection model.

• Escherichia coli CFT073 develops resistance to ampicillin (AMP), ciprofloxacin (CIP) and fosfomycin (FOF) monotherapies. • AMP, CIP and FOF combinations delayed antibiotic resistance emergence in E. coli. • The HFIM system could potentially be used to identify clinically relevant antibiotic combinations. Antibiotic resistance is one of the major threats to public health today. To address this problem requires an urgent comprehensive approach. Strategic and multitargeted combination therapy has been increasingly used clinically to treat bacterial infections. The hollow-fibre infection model (HFIM) is a well-controlled in vitro bioreactor system that is increasingly being used in the assessment of resistance emergence with monotherapies and combination antibiotic therapies. In this study, the HFIM was evaluated as a reliable in vitro method to quantitatively and reproducibly analyse the emergence of antibiotic resistance using ampicillin, fosfomycin and ciprofloxacin and their simultaneous combinations against Escherichia coli CFT073, a clinical uropathogenic strain. Bacteria were exposed to clinically relevant pharmacokinetic (PK) concentrations of the drugs for 10 days. Drug and bacterial samples were collected at different time points for PK analysis and to enumerate total and resistant bacterial populations, respectively. The results demonstrated that double or triple combinations significantly delayed the emergence of resistant E. coli CFT073 subpopulations. These findings suggest that strategic combinations of antimicrobials may play a role in controlling the emergence of resistance during treatment. Further animal and human trials will be needed to confirm this and to ensure that there is no adverse impact on the host microbiome or unexpected toxicity. The HFIM system could potentially be used to identify clinically relevant combination dosing regimens for use in a clinical trial evaluating the appearance of resistance to antibacterial drugs. Image, graphical abstract [ABSTRACT FROM AUTHOR]