Assessment of urinary pharmacokinetic and pharmacodynamic profiles of faropenem against extended-spectrum β-lactamase-producing Escherichia coli with canine ex vivo modelling: a pilot study

Abstract

This study was carried out to investigate the urinary pharmacokinetics and pharmacodynamics of faropenem administered orally at 5 mg kg−1 in six healthy dogs to assess the efficacy of the drug for canine urinary tract infections (UTIs) with extended-spectrum β-lactamase (ESBL)-producing bacteria. Six strains of ESBL-producing Escherichia coli (ESBL-EC) with the following faropenem minimum inhibitory concentrations (MICs) were used: 1 µg ml−1 (n=2), 2 µg ml−1 (n=2), 4 µg ml−1 (n=1) and 16 µg ml−1 (n=1). Urine samples were obtained every 4 h for the first 12 h after administration to measure urinary drug concentration and urinary bactericidal titres (UBTs). Both the urine concentration of faropenem and the UBTs for all tested strains peaked at 0–4 h after administration, and decreased markedly at 8–12 h. The mean urinary concentration of faropenem at 8–12 h (23±5.2 µg ml−1) exceeded the MIC of 1 µg ml−1 by fourfold, which is required to inhibit the growth of 90 % of ESBL-EC. These findings indicate that faropenem administered twice daily at a dose of 5 mg kg−1 is acceptable for the treatment of most dogs with ESBL-EC-related UTIs.

Urinary Pharmacokinetic and Pharmacodynamic Profiles of Fosfomycin against Extended-Spectrum β-Lactamase-Producing Escherichia coli with Canine Ex Vivo Modeling: A Pilot Study

“…T 1/2 in urine was calculated by linear regression of the semi-logarithmic plot of urinary concentration versus the midpoint of the urine collection time [24]. The area under the UBT-versus-time curve within 12 h after administration (AUBT 0-12 ) was calculated as the sum of the products of the reciprocal UBT values and the respective time intervals (h) for each test organism, to easily compare UBT data among the tested strains [22,24,25]. The urinary AUC 0-12 was calculated with the trapezoidal rule by assuming that a drug concentration remains constant in the urinary bladder during each time interval [24].…”

“…The UBTs correspond to the maximal dilution titer of urine allowing bactericidal activity for each examined strain and were determined using each dog's urine as previously described [22,24,25]. Each well of the microplates contained 100 µL of the logarithmic serial twofold dilution, ranging from 1:2 to 1:1024, acquired by mixing an equal volume of the urine sample obtained every 4 h after drug administration with the respective individual dog's antimicrobial-free urine obtained prior to drug administration.…”

“…A UBT of 0 was defined as no bactericidal activity, and a UBT of 1 was assigned when only undiluted urine displayed bactericidal activity. UBTs were transformed into ordinal data and described with reciprocal numbers [22,24,25]. Simultaneously with the UBT determination, the absence of growth of the tested organisms was confirmed in all urine samples which had not been inoculated.…”