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

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 MIC 90 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 MIC 90 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

Concentration of cephalothin in body fluids and tissue samples of Thoroughbred horses

“…Thus, CET administration twice or three times a day could control gram-positive bacteria that were frequently isolated from horses with cellulitis [6]. Administration of CET every 6-12 hr resulted in a high cure rate (94.7%) in 3,292 horses with limb infections [9]; our results for the CET concentrations in subcutaneous and hoof tissues are in line with the effectiveness of CET for treating limb infections.…”

“…This study considered the treatment of infectious diseases at different sites in horses by evaluating CET concentrations in body fluids and tissue samples in adult Thoroughbred horses and the MIC 90 values of bacteria isolated from Thoroughbred racehorses with infectious diseases, including pneumonia and cellulitis, at two training facilities (Ritto and Miho training centers) in a previous report [9]. CET concentrations or MICs of bacteria may be different between this In this study, CET showed good penetration into body fluids, and a dose of 22 mg/kg twice a day was effective for septic arthritis, pleuritis, and peritonitis caused by grampositive bacteria but ineffective for osteomyelitis due to an insufficient bone concentration.…”

“…The first-generation cephalosporin cephalothin (CET) is effective against gram-positive bacteria and is used to treat equine infectious diseases [ 3 , 5 ]. CET is metabolized to deacetylcephalothin, but deacetylcephalothin does not have a significant antibacterial effect compared with CET [ 9 ]. Plasma concentrations of CET have been reported in horses [ 9 , 10 , 16 ], but the penetration of CET into each part of the body has not been sufficiently evaluated.…”

“…CET is metabolized to deacetylcephalothin, but deacetylcephalothin does not have a significant antibacterial effect compared with CET [ 9 ]. Plasma concentrations of CET have been reported in horses [ 9 , 10 , 16 ], but the penetration of CET into each part of the body has not been sufficiently evaluated. In this study, we investigated the concentrations of CET in body fluids and tissue samples to consider the treatment of infectious diseases at each site in horses.…”

“…In all 12 horses, 22 mg/kg bwt of CET (Coaxin injection 1 g, Chemix Inc., Yokohama, Japan) was dissolved in 50 m l of sterile physiological saline and administered into the right jugular vein by bolus infusion. The dosage of 22 mg/kg was determined according to a previous pharmacokinetic study [ 9 ]. Body fluids (plasma, synovial fluid of radiocarpal joint, pleural fluid, peritoneal fluid, and aqueous humor) and tissue samples (bone marrow of the proximal phalanx, lung, jejunum, subcutaneous tissue, and hoof, including the digital cushion, laminar layer, and sole dermis of the forelimb) were collected from four different horses at 1, 3, and 5 hr after administration.…”