Rational dosage regimens for cephalothin and cefazolin in horses

The following study suggests that dosage regimens need to be reconsidered for both cephalothin and cefazolin.
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Rational dosage regimens for cephalothin and cefazolin using pharmacokinetics and pharmacodynamics analysis in healthy horses

Equine Vet J. 2020 Dec 20.
Authors
Taisuke Kuroda 1 , Yohei Minamijima 2 , Hidekazu Niwa 3 , Norihisa Tamura 1 , Hiroshi Mita 1 , Kentaro Fukuda 1 , Masahiro Kaimachi 4 , Yuto Suzuki 4 , Yuki Enoki 4 , Kazuaki Taguchi 4 , Kazuaki Matsumoto 4 , Pierre-Louis Toutain 5 , Alain Bousquet-Melou 6 , Yoshinori Kasashima 1
Affiliations

1 Clinical Veterinary Medicine Division Equine Research Institute, Shimotsuke, Japan.
2 Drug Analysis Department, Laboratory of Racing Chemistry, Utsunomiya, Japan.
3 Microbiology Division Equine Research Institute, Shimotsuke, Japan.
4 Division of Pharmacodynamics, Keio University, Faculty of Pharmacy Tokyo, Japan.
5 Comparative Biomedical Sciences, The Royal Veterinary College, London, UK.
6 INTHERES, Université de Toulouse, INRA, ENVT, Toulouse, France.

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 modeled using a nonlinear mixed effect modeling 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.