Cefotaxime and Amoxicillin-Clavulanate Synergism against Extended-Spectrum-β-Lactamase-Producing Escherichia coli in a Murine Model of Urinary Tract Infection

We investigated the efficacies of cefotaxime (CTX) and amoxicillin (AMX)-clavulanate (CLA) (AMC) against extended-spectrum-β-lactamase (ESBL)-producingEscherichia coli in vitro and in a murine model of urinary tract infection (UTI). MICs, the checkerboard dilution method, and time-kill curves were used to explore thein vitro synergism between cefotaxime and amoxicillin-clavulanate against two isogenicE. coli strains—CFT073-RR and its transconjugant, CFT073-RR Tcbla CTX-M-15 —harboring abla CTX-M-15 plasmid and abla OXA-1 plasmid. Forin vivo experiments, mice were separately infected with each strain and treated with cefotaxime, amoxicillin, and clavulanate, alone or in combination, or imipenem, using therapeutic regimens reproducing time of free-drug concentrations above the MIC (fT ≥MIC) values close to that obtained in humans. MICs of amoxicillin, cefotaxime, and imipenem were 4/>1,024, 0.125/1,024, and 0.5/0.5 mg/liter, for CFT073-RR and CFT073-RR Tcbla CTX-M-15 , respectively. The addition of 2 mg/liter of clavulanate (CLA) restored the susceptibility of CFT073-RR Tcbla CTX-M-15 to CTX (MICs of the CTX-CLA combination, 0.125 mg/liter). The checkerboard dilution method and time-kill curves confirmed anin vitro synergy between amoxicillin-clavulanate and cefotaxime against CFT073-RR Tcbla CTX-M-15 .In vivo , this antibiotic combination was similarly active against both strains and as effective as imipenem. In conclusion, the cefotaxime and amoxicillin-clavulanate combination appear to be an effective, easy, and already available alternative to carbapenems for the treatment of UTI due to CTX-M-producingE. coli strains.