Assessment of urinary pharmacodynamic profiles of faropenem against extended-spectrum β-lactamase-producing Escherichia coli with canine ex vivo modeling

Abstract

Extended-spectrum {beta}-lactamase (ESBL)-producing bacteria are of great concern in companion animals with urinary tract infections (UTIs). Because of its high safety and stability in the presence of ESBLs, faropenem is assumed to be a candidate antimicrobial agent for canine UTIs with ESBL-producing bacteria. This study was performed to investigate the urinary pharmacokinetics and pharmacodynamics of faropenem administered at 5 mg/kg body weight in six healthy dogs using an ex vivo model. Six UTI pathogenic strains of ESBL-producing Escherichia coli (ESBL-EC) with the following faropenem minimum inhibitory concentrations (MICs) were used: 1 {micro}g/mL (n = 2), 2 {micro}g/mL (n = 2), 4 {micro}g/mL (n = 1), and 16 {micro}g/mL (n = 1). Urine samples were obtained every 4 h for the first 12 h after faropenem administration for measurement of the urine drug concentration and urinary bactericidal titers (UBTs). The urine concentration of faropenem peaked at 0 to 4 h after administration, with a mean maximum concentration of 584 g/mL, and markedly decreased at 8 to 12 h (23 g/mL). The median UBTs for all tested ESBL-EC strains were highest at 0 to 4 h and then significantly decreased at 8 to 12 h. These findings indicate that administration of faropenem more than once daily is recommended for the treatment of ESBL-EC-related UTIs in dogs. In addition, the median areas under the UBT-time curves (AUBTs) were significantly inversely correlated with the corresponding MICs for faropenem in the tested strains (P < 0.05). Notably, the median AUBTs were significantly higher in ESBL-EC strains with an MIC of 1 {micro}g/mL than in those with an MIC of [&ge;]4 {micro}g/mL (P < 0.05). The present study serves as the basis of clinical application of faropenem for ESBL-producing bacteria-related UTIs in dogs.