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 ß-lactamase inhibitor clavulanate (CLA) is currently in development for urinary tract infections, including those caused by extended-spectrum-ß-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 µg/ml) using the in vitro chemostat model. Dose fractionation studies identified the time that free CLA concentrations remained above a threshold concentration (fT>threshold) 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% fT>CTB concentrations of the 21 CTB-CLA MIC (fT>MIC here), respectively. For K. pneumoniae isolates, stasis and 1-log10 CFU reductions were achieved at 51.9 and 92.0% fT>MIC, 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.