The Effect of Drug Combinations on the Kinetics of the Emergence of Antibiotic Resistance in E. coli CFT073 Using the In Vitro Hollow Fiber Infection Model

Abstract: Antibiotic resistance is one of the major threats to public health today. To address this problem requires an urgent comprehensive approach. Strategic and multi-targeted combination therapy has been increasingly used clinically to fight bacterial infections. The Hollow-Fiber Infection Model (HFIM) is a well-controlled bioreactor system that is increasingly being used in the assessment of emergence of resistance with mono- and combination antibiotic therapies. In this study, we have evaluated the HFIM as a reliable in vitro method to quantitatively and reproducibly analyze 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 concentrations (PK) of the drugs for ten days. Samples were collected at different time points for PK analysis and for total and resistant bacterial counts. Our results demonstrate 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.