Pharmacokinetics of cefoxitin after intravenous and intramuscular administration to cats

Abstract

Cefoxitin is a semi-synthetic cephamycin belonging to the second generation cephalosporins. It is active against many Gram-negative (including Enterobacter spp., Serratia spp.) and some Gram-positive bacteria; also it is very active against anaerobes including beta-lactamase producing strains of Bacteroides fragilis (Prescott, 2006). Cefoxitin is used in the treatment of severe mixed infections with anaerobes (aspiration pneumonia, severe bite infections, gangrene, peritonitis, pleuritis) and prophylaxis for colonic surgery or ruptured intestine (Prescott, 2006). Cefoxitin minimum inhibitory concentrations (MIC) for susceptible bacteria ranged between 1 and 8 lg ⁄ mL (CLSI, 2008). As other betalactam antibiotics, its antibacterial activity relates with the proportion of time that plasma concentration is above the MIC of susceptible micro-organism on which the drug produces a time-dependent bactericidal effect. The T > MIC is considered the most accurate pharmacokinetic-pharmacodynamic index of efficacy (Toutain et al., 2002; McKellar et al., 2004). Pharmacokinetic profile of cefoxitin has been characterized in same domestic animals like dogs (Petersen & Rosin, 1993), calves (Soback, 1988) and mares (Brown et al., 1986). To the authors knowledge there are no studies on cats. Therefore, the objective of this study was to characterize the pharmacokinetic profiles of cefoxitin after intravenous (i.v.) and intramuscular (i.m.) administration to cats. Experimental animals were five adult mixed breed cats, weighing 5.13 ± 0.52 kg. All cats were healthy as determined by clinical examination, complete blood and serum biochemical analysis and urinalysis. Animals were housed in the UBA School of Veterinary Medicine facilities. Access to high quality commercial dry food (Fit 32 ; Royal Canin, Buenos Aires, Argentina) and water was ad libitum. All animal procedures were approved by the Institutional Animal Care and Use Committee, School of Veterinary Science, University of Buenos Aires, Argentina. Cefoxitin was dosed at 30 mg ⁄ kg bodyweight. An aqueous 10% solution of sodium cefoxitin (Cefoxitina Richet , Richet, Buenos Aires, Argentina) was prepared for the i.v. (cephalic vein) and i.m. (dorsal lumbar muscles) administration. A crossover experimental design with a 2 weeks washout period was applied. All animals were fasted overnight before antibiotic administration. For sample collection, a jugular vein was catheterized 24 h before each study according to a technique previously described (Albarellos et al., 2003). Blood samples (0.7 mL) were withdrawn at 0, 5, 10, 20, 30 and 45 min and at 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10 and 12 h, allowed to clot at room temperature and centrifuged at 1500 g, for 15 min. The supernatant serum was frozen at )20 C until analysis. Serum samples were assayed during the week following collection. Cefoxitin serum concentrations were determined by microbiological assay (Bennet et al., 1966) using Micrococcus luteus ATCC 9341 as test micro-organism. Standard curves, in the range 1.56–200 lg ⁄ mL, were prepared in normal cat serum. Each sample was seeded in triplicate and each standard dilution in quintuplicate. The method was linear between 1.56 and 200 lg ⁄ mL (r = 0.9924). Inter and intra-assay coefficients of variation were <10%. The limits of detection and quantification of the method were 1.56 and 3.12 lg ⁄ mL, respectively. The limit of quantification was the lower limit of concentration used in the pharmacokinetics analysis. Individual cefoxitin serum concentration–time curves were analyzed by noncompartmental techniques using the PCNONLIN 4.0 software (SCI Software, Lexington, KY, USA). Major pharmacokinetic parameters were calculated according classical equations (Gibaldi & Perrier, 1982). For peak serum concentration (Cmax) and time to peak concentration (tmax) observed values were taken. The apparent terminal rate constant, kz, was determined by linear regression of the last 5–6 points on the terminal phase of the logarithmic serum concentration vs. time curve. Terminal half-life (t1⁄2) was calculated as ln2 ⁄ kz. J. vet. Pharmacol. Therap. 33, 619–621. doi: 10.1111/j.1365-2885.2010.01179.x. SHORT COMMUNICATION