title: Altered plasma pharmacokinetics of ceftiofur hydrochloride in cows affected with severe clinical mastitis.
abstract: Mastitis is a frequent problem among dairy cows, reducing milk yield and increasing cull rates. Systemic therapy with the cephalosporin antimicrobial ceftiofur hydrochloride (CEF) may improve therapeutic outcomes, but the incidence of CEF violative residues has increased annually since 2011. One potential explanation is that disease status may alter the pharmacokinetics (PK) of CEF. To test this hypothesis, we compared the plasma PK of CEF in healthy cows with those with severe endotoxic mastitis. Eight cows with naturally occurring mastitis and 8 clinically healthy cows were treated with 2.2 mg of CEF per kilogram of body weight once daily for 5d via the intramuscular route. Blood was collected at 0, 0.33, 0.67, 1, 1.5, 2, 3, 4, 8, 16, and 24h after the first CEF administration and every 8h thereafter until 120 h after the final dose. Plasma samples were analyzed for CEF concentrations using liquid chromatography coupled with mass spectrometry. With the exception of time 0, CEF was detected at all time points. The disease group had a significantly higher plasma CEF concentration at t=3h after the first injection and a significantly lower plasma concentration from 40 to 152 h following the first injection, with the exception of the t=64 h time point. Data following the first injection (time 0-24 h) were fit to a single-dose, noncompartmental PK model. This model indicated that the disease group had a shorter plasma half-life. A multidose, noncompartmental model was used to determine steady-state PK. Compared with control cows, the disease group had an initially higher peak concentration and a higher volume of distribution and drug clearance rates. The disease group also had a lower area under the curve per dosing interval, steady-state concentration maximum, and dose-adjusted peak steady-state concentration. All other PK parameters were not different between the 2 groups. Altered PK, as suggested by this trial, may contribute to an increased risk for the development of a violative residue in meat. Further research is needed to more completely characterize drug distribution in diseased cattle and to study the effect of coadministration of other drugs on drug distribution.
authors.affiliation: Veterinary Diagnostic and Production Animal Medicine, College of Veterinary Medicine, Iowa State University, Ames 50011. Electronic address: pgorden@iastate.edu.
authors.forename: P J
authors.initials: PJ
authors.lastname: Gorden
authors.affiliation: Veterinary Diagnostic and Production Animal Medicine, College of Veterinary Medicine, Iowa State University, Ames 50011.
authors.forename: M D
authors.initials: MD
authors.lastname: Kleinhenz
authors.affiliation: Veterinary Diagnostic and Production Animal Medicine, College of Veterinary Medicine, Iowa State University, Ames 50011; Pharmacology Analytical Support Team (PhAST), Veterinary Diagnostic Laboratory, College of Veterinary Medicine, Iowa State University, Ames 50011.
authors.forename: L W
authors.initials: LW
authors.lastname: Wulf
authors.affiliation: Department of Anatomy and Physiology, College of Veterinary Medicine, Kansas State University, Manhattan 66502.
authors.forename: B
authors.initials: B
authors.lastname: KuKanich
authors.affiliation: Veterinary Diagnostic and Production Animal Medicine, College of Veterinary Medicine, Iowa State University, Ames 50011; Pharmacology Analytical Support Team (PhAST), Veterinary Diagnostic Laboratory, College of Veterinary Medicine, Iowa State University, Ames 50011.
authors.forename: C J
authors.initials: CJ
authors.lastname: Lee
authors.affiliation: Veterinary Diagnostic and Production Animal Medicine, College of Veterinary Medicine, Iowa State University, Ames 50011.
authors.forename: C
authors.initials: C
authors.lastname: Wang
authors.affiliation: Veterinary Diagnostic and Production Animal Medicine, College of Veterinary Medicine, Iowa State University, Ames 50011; Pharmacology Analytical Support Team (PhAST), Veterinary Diagnostic Laboratory, College of Veterinary Medicine, Iowa State University, Ames 50011. Electronic address: hcoetzee@iastate.edu.
authors.forename: J F
authors.initials: JF
authors.lastname: Coetzee
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D002417:Cattle; D002511:Cephalosporins / Q000008:administration & dosage / Q000493:pharmacokinetics*; D005260:Female; D007273:Injections, Intramuscular / Q000662:veterinary; D008414:Mastitis, Bovine / Q000188:drug therapy* / Q000378:metabolism; D008892:Milk / Q000378:metabolism*
chemical_list: D000900:Anti-Bacterial Agents; D002511:Cephalosporins; C053503:ceftiofur
keywords: bovine mastitis; ceftiofur; drug residue; pharmacokinetics