In vitro pharmacodynamics of a novel ceftibuten-clavulanate combination antibiotic against Enterobacteriaceae

Abstract

A novel antibiotic combination of the oral cephalosporin ceftibuten (CTB) and the -lactamase inhibitor clavulanate (CLA) is currently in development for urinary tract infections, including those caused by extended-spectrum-lactamase (ESBL)-producing organisms. This study aimed to identify the pharmacodynamic index and magnitude of this index for CLA, when combined with a fixed CTB exposure (59% free time above the CTB-CLA MIC) against ESBL-producing Escherichia coli and Klebsiella pneumoniae (CTB-CLA MICs of 0.25/0.125 to 1/0.5 g/ml) using the in vitro chemostat model. Dose fractionation studies identified the time that free CLA concentrations remained above a threshold concentration (fTthreshold) to be the best pharmacodynamic index (R2 0.85) compared with the free area under the curve (AUC)/threshold ratio (R2 0.62) and free maximum concentration/threshold ratio (R2 0.37). For E. coli isolates, stasis and 1-log10 CFU reductions were achieved at 30.9 and 47.9% fTCTB concentrations of the 2:1 CTB-CLA MIC (fTMIC here), respectively. For K. pneumoniae isolates, stasis and 1-log10 CFU reductions were achieved at 51.9 and 92.0% fTMIC, respectively. These data inform exposure requirements for CLA combined with CTB for optimizing pharmacodynamics against Enterobacteriaceae and should be useful in designing dosage regimens for this combination antibiotic.