Rational dosage regimens for cephalothin and cefazolin using pharmacokinetics and pharmacodynamics analysis in healthy horses

Kuroda, T; Minamijima, Y; Niwa, H; Tamura, N; Mita, H; Fukuda, K; Kaimachi, M; Suzuki, Y; Enoki, Y; Taguchi, K; Matsumoto, K; Toutain, PL; Bousquet-Melou, A; Kasashima, Y

Abstract

Background: First-generation cephalosporins have good activity against gram-positive bacteria and are extensively used in horses. There are few reports of pharmacokinetics and pharmacodynamics (PK/PD) analysis of cephalosporins in horses. Objective: To optimise the dosages of the two first-generation cephalosporins cephalothin (CET) and cefazolin (CEZ) in horses using PK/PD concepts. Study design: Experimental study with single administration. Methods: Drug plasma concentrations following a single intravenous (i.v.) administration of 22 mg/kg bodyweight (bwt) CET in 12 horses and of 10 mg/kg bwt CEZ in six horses were measured using LC-MS/MS. Data were modelled using a nonlinear mixed effect modelling followed by Monte Carlo simulations. Minimum inhibitory concentrations (MICs) against Streptococcus zooepidemicus and Staphylococcus aureus isolated from horses were determined by the microbroth dilution method. Results: The percentages of CET and CEZ binding to serum proteins were 19.9% +/- 8.4% and 15.2% +/- 8.5% respectively. For both CET and CEZ, the MIC90 against S. zooepidemicus was 0.12 mg/L and against S. aureus was 0.5 mg/L. For CET, to achieve a probability of target attainment (PTA) of 90% for a PK/PD target of a free serum plasma concentration exceeding the MIC90 for 40% of the dosing interval, an empirical CET dosage regimen of 22 mg/kg bwt q8h and 22 mg/kg bwt q4h i.v. administration were required for S. zooepidemicus and S. aureus respectively. For CEZ, the corresponding dosage regimens were 10 mg/kg bwt q12h and 10 mg/kg bwt q8h. Main limitations: Small sample size only in healthy horses. Conclusions: For CET, more frequent administration than that currently recommended (22 mg/kg bwt q6-12h) is required to empirically control S. aureus infection in horses. For CEZ, less frequent administration compared to the dosage regimen currently proposed (10-22 mg/kg bwt q6h) could control S. zooepidemicus and S. aureus infections in horses.

Citation

Kuroda, T., Minamijima, Y., Niwa, H., Tamura, N., Mita, H., Fukuda, K., …Kasashima, Y. (2021). Rational dosage regimens for cephalothin and cefazolin using pharmacokinetics and pharmacodynamics analysis in healthy horses. Equine Veterinary Journal, 53(6), 1239-1249. https://doi.org/10.1111/evj.13406

• Journal Article Type: Article
• Acceptance Date: Sep 19, 2020
• Publication Date: 2021
• Deposit Date: Jan 5, 2022
• Publicly Available Date: Jan 5, 2022
• Print ISSN: 0425-1644
• Publisher: Wiley
• Peer Reviewed: Peer Reviewed
• Volume: 53
• Issue: 6
• Pages: 1239-1249
• DOI: https://doi.org/10.1111/evj.13406
• Keywords: horse; cefazolin; cephalothin; gram positive infection
• Public URL: https://rvc-repository.worktribe.com/output/1554028