Vaccination mitigates the impact of PRRSv infection on the pharmacokinetics of ceftiofur crystalline‐free acid in pigs

The pharmacokinetics of intramuscularly administered ceftiofur crystalline‐free acid (CCFA) were determined in pigs that were clinically healthy (n = 8), vaccinated with a Porcine reproductive and respiratory syndrome modified live virus (PRRS MLV) (n = 10), challenged with wild‐type porcine reproductive and respiratory syndrome virus (PRRSv) VR‐2385 (n = 10), or vaccinated with PRRS MLV and later challenged with wild‐type PRRSv VR‐2385 (n = 10). Animals were given a single dose of CCFA intramuscularly at 5 mg/kg body weight. Blood was collected at 0 (pretreatment), 0.25, 0.5, 1, 6, 12, 24, 48, 96, 144, 192, and 240 h postinjection. Plasma was analyzed using liquid chromatography‐mass spectrometry. Plasma concentration–time curves for each group were evaluated with noncompartmental modeling. When compared to control animals, those receiving the PRRSv wild‐type challenge only had a lower AUC_0‐last, higher Cl/F, and higher Vz/F. The PRRSv wild‐type challenge only group had the longest T_1/2λ. The C_max did not differ among all four treatments. Control animals had no statistically significant differences from animals vaccinated with PRRS MLV alone or animals vaccinated with PRRS MLV and later challenged with wild‐type PRRSv. Our results suggest that PRRSv wild‐type infection has the potential to alter CCFA pharmacokinetics and PRRS MLV vaccination may attenuate those changes.     

Pharmacokinetics of ceftiofur sodium and ceftiofur crystalline free acid in neonatal foals

Ceftiofur, a third generation cephalosporin, demonstrates in vitro efficacy against microorganisms isolated from septicemic neonatal foals. This pharmacokinetic study evaluated the intravenous and subcutaneous administration of ceftiofur sodium (5 mg/kg body weight; n = 6 per group) and subcutaneous administration of ceftiofur crystalline free acid (6.6 mg/kg body weight; n = 6) in healthy foals. Plasma ceftiofur- and desfuroylceftiofur-related metabolite concentrations were measured using high performance liquid chromatography following drug administration. Mean (±SD) noncompartmental pharmacokinetic parameters for i.v. and s.c. ceftiofur sodium were: AUC(0→∝) (86.4 ± 8.5 and 91 ± 22 h·μg/mL for i.v. and s.c., respectively), terminal elimination half-life (5.82 ± 1.00 and 5.55 ± 0.81 h for i.v. and s.c., respectively), C(max(obs)) (13 ± 1.9 μg/mL s.c.), T(max(obs)) (0.75 ± 0.4 h for s.c.). Mean (± SD) noncompartmental pharmacokinetic parameters for s.c. ceftiofur crystalline free acid were: AUC(0→∝) (139.53 ± 22.63 h·μg/mL), terminal elimination half-life (39.7 ± 14.7), C(max(obs)) (2.52 ± 0.35 μg/mL) and t(max(obs)) (11.33 ± 1.63 h). No adverse effects attributed to drug administration were observed in any foal. Ceftiofur- and desfuroylceftiofur-related metabolites reached sufficient plasma concentrations to effectively treat common bacterial pathogens isolated from septicemic foals.     

Pharmacokinetic and pharmacodynamic characterization of ceftiofur crystalline‐free acid following subcutaneous administration in domestic goats

Pharmacokinetic (PK)–pharmacodynamic (PD) integration of crystalline ceftiofur‐free acid (CCFA) was established in six healthy female goats administered subcutaneously (s.c.) on the left side of the neck at a dosage of 6.6 mg/kg body weight. Serum concentrations of ceftiofur and desfuroylceftiofur (DFC) were determined using high‐performance liquid chromatography. Mutant prevention concentration (MPC), minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) of ceftiofur were determined for Pasteurella (P.) multocida. Mean terminal half‐life and mean residence time of ceftiofur + DFC were 48.6 h and 104 h, respectively. In vitro plasma protein binding of ceftiofur was 46.6% in goats. The MIC and MBC values of ceftiofur were similar in serum and MHB and a very small difference between these values confirmed bactericidal activity of drug against P. multocida. In vitro and ex vivo time–kill curves for P. multocida demonstrated a time‐dependent killing action of drug. Considering target serum concentration of 0.20 μg/mL, PK‐PD values for AUC_24 h/MIC₉₀ and T > MIC₉₀, respectively, were 302 h and 192 h against P. multocida. A MPC/MIC ratio of 10–14 indicated that selective pressure for proliferation of resistant mutants of P. multocida is minimal after CCFA single‐dose administration. Based on MPC = 1.40 μg/mL for P. multocida, the PK‐PD indices, viz. T > MPC and AUC₂₄/MPC, were 48 h and 43 h, respectively. The data suggested the use of single dose (6.6 mg/kg, s.c.) of CCFA in goats to obtain clinical and bacteriological cure of pneumonia due to P. multocida.     

Pharmacokinetic parameters for single‐ and multi‐dose regimens for subcutaneous administration of a high‐dose ceftiofur crystalline‐free acid to neonatal foals

The objective of this study was to determine the pharmacokinetics of single‐ and multi‐dose ceftiofur crystalline‐free acid (CCFA) administered subcutaneously at a dose of 13.2 mg/kg to 12 neonatal foals 1–3 days of age. Six foals received a single subcutaneous dose, while 6 additional foals received 4 doses of CCFA at 48‐h intervals. Blood samples were collected at pre‐determined times following drug administration, and plasma concentrations of ceftiofur free acid equivalents (CFAE) were measured using high‐performance liquid chromatography. Following single‐dose administration of CCFA, the mean ± standard deviation maximum observed plasma concentration was 3.1 ± 0.6 μg/mL and observed time to maximal plasma concentration was 14.0 ± 4.9 h. Following multi‐dose administration of CCFA, the mean ±standard deviation times above CFAE concentrations of ≥0.5 μg/mL and ≥2.0 μg/mL were 192.95 ± 15.86 h and 78.80 ± 15.31 h, respectively. The mean ± standard deviation area under the concentration vs time curve (AUC_0→∝) was 246.2 ± 30.7 h × μg/mL and 172.7 ± 27.14 h × μg/mL following single‐ and multi‐dose CCFA administrations, respectively. Subcutaneous administration of CCFA at 13.2 mg/kg in neonatal foals was clinically well‐ tolerated and resulted in plasma concentrations sufficient for the treatment of most bacterial pathogens associated with neonatal foal septicemia. Multi‐dose administration of four doses at dosing interval of 48 h between treatments maintains appropriate therapeutic concentrations in neonatal foals.     

Evaluation of an extended‐release formulation of ceftiofur crystalline‐free acid in koi (Cyprinus carpio)

The use of an extended release ceftiofur crystalline‐free acid formulation (CCFA, Excede For Swine^®, Pfizer Animal Health) in koi was evaluated after administration of single intramuscular (i.m.) or intracoelomic (i.c.) doses. Twenty koi were divided randomly into a control group and four treatment groups (20 mg/kg i.m., 60 mg/kg i.m., 30 mg/kg i.c., and 60 mg/kg i.c.). Serum ceftiofur‐free acid equivalents (CFAE) concentrations were quantified. The pharmacokinetic data were analyzed using a nonlinear mixed‐effects approach. Following a CCFA injection of 60 mg/kg i.m., time durations that serum CFAE concentrations were above the target concentration of 4 μg/mL ranged from 0.4 to 2.5 weeks in 3 of 4 fish, while serum CFAE concentrations remained below 4 μg/mL for lower doses evaluated. Substantial inter‐individual variations and intra‐individual fluctuations of CFAE concentrations were observed for all treatment groups. Histological findings following euthanasia included aseptic granulomatous reactions, but no systemic adverse effects were detected. Given the unpredictable time vs. CFAE concentration profiles for treated koi, the authors would not recommend this product for therapeutic use in koi at this time. Further research would be necessary to correlate serum and tissue concentrations and to better establish MIC data for Aeromonas spp. isolated from naturally infected koi.     

Comparison of plasma pharmacokinetics and bioavailability of ceftiofur sodium and ceftiofur hydrochloride in pigs after a single intramuscular injection

Ceftiofur sodium, a broad-spectrum cephalosporin, is active against gram-positive and gram-negative pathogens of veterinary importance. Two studies were designed to compare the intramuscular bioavailability of the current sodium salt and the new hydrochloride salt in pigs at doses of either 3 mg or 5 mg ceftiofur equivalents (CE)/kg body weight. Twenty-six healthy young pigs were selected for these two-period, two-treatment crossover studies, 12 for the 3 mg/kg study and 14 for the 5 mg/kg study. Each animal received one intramuscular (i.m.) injection of ceftiofur sodium and one i.m. injection of ceftiofur hydrochloride with a 14-day washout period between the two treatments. Blood samples were collected serially for up to 96 h postinjection. Plasma samples were then analysed using a validated assay that measures ceftiofur and all desfuroylceftiofur-related metabolites by high-performance liquid chromatography. In the 3 mg/kg dosage study, average maximum plasma concentration (C(max)) after administration of ceftiofur sodium was 15.8+/-3.40 microg/mL at 0.4-4 h after injection. After administration of ceftiofur hydrochloride, the C(max) was 11.8+/-1.67 microg/mL at 1-4 h after injection. Concentrations of ceftiofur and metabolites 72 h after the injection were 0.392+/-0.162 microg/mL for ceftiofur hydrochloride and 0.270+/-0.118 microg/mL for ceftiofur sodium. The mean area under the curve (AUC), from time 0 to the limit of quantitation (AUC(O-LOQ)) after ceftiofur hydrochloride administration, was 216+/-28.0 microg x h/mL, compared to 169+/-45.4 microg x h/mL after ceftiofur sodium administration. The calculated time during which plasma concentrations remained above 0.02 microg/mL (t(>0.2)) was 85.3+/-10.6 h for ceftiofur sodium and 77.2+/-10.7 h for ceftiofur hydrochloride. In the 5 mg/kg dosage study, C(max) after administration of ceftiofur sodium was 28.3+/-4.45 microg/mL at 0.33-2 h after injection. After administration of ceftiofur hydrochloride, the C(max) was 29.7+/-6.72 microg/mL at 0.66-2 h after injection. Concentrations of ceftiofur and metabolites 96 h after the injection were 0.274+/-0.0550 microg/mL for ceftiofur hydrochloride and 0.224+/-0.0350 microg/mL for ceftiofur sodium. The mean AUC(O-LOQ) after ceftiofur hydrochloride administration was 382+/-89.8 microg x h/mL compared to 302+/-54.4 microg x h/mL after ceftiofur sodium administration. The t(>0.2) was 78.9+/-9.65 h for ceftiofur sodium and 94.2+/-8.64 h for ceftiofur hydrochloride. Based on the similarity of the pharmacokinetic parameters of the sodium and hydrochloride formulations of ceftiofur, similar therapeutic efficacy can be inferred for the two products.     

Preparation and pharmacokinetics of ceftiofur sodium liposomes in cows

Liu, S., Guo, D., Guo, Y., Zhou, W. Preparation and pharmacokinetics of ceftiofur sodium liposomes in cows. J. vet. Pharmacol. Therap. 34 , 35–41. The objective of this study was to prepare ceftiofur sodium liposomes and assess their physical properties, stability, antibacterial effects, and pharmacokinetics. These liposomes appeared as a milky, light yellow suspension with encapsulation efficiency at 57.2 ± 1.17%, and there were no significant changes in all estimated indexes at 4 °C for 90 days. The minimum inhibitory concentrations of liposomes were all 1/4th that of ceftiofur sodium against Streptococcus suis, Staphylococcus aureus, Escherichia coli, and Salmonella enteritidis. Six healthy, adult cows in two treatment groups were dosed intravenously with ceftiofur sodium liposomes and ceftiofur sodium, serial blood samples collected, and plasma concentrations determined by high performance liquid chromatography. Intravenous plasma concentration profiles of liposomes best fit a two‐compartment model and the elimination half‐life was 2.11 times that of ceftiofur sodium. Thus, this liposome preparation provided therapeutically effective plasma concentrations for a longer duration than with the drug alone, making it more effective and convenient for use in treating bovine mastitis that requires long duration maintenance of therapeutic plasma concentrations.     

头孢噻呋钠在猪体内的药代动力学和生物利用度研究

用微生物杯蝶法测定血清药物浓度,6头实验猪按5 mg/kg单剂量静注、肌注头孢噻呋钠(Ceftiofur Sodium),对其药代动力学和生物利用度进行了研究.试验菌为蜡样芽孢杆菌1.1687,结果平均回收率为96.52%,血清最低检测浓度为0.15 μg/ml,日内日间变异系数为2.5%～4.9%,血清浓度在0.3～0.8 μg/ml范围内呈良好线性关系(r=0.9884).药时数据经Mcpkp药代动力学计算机程序处理,猪静注、肌注头孢噻呋钠体内药物运转都符合二室开放模型,其中静注的药代动力学参数为T1/2α=2.22 h,T1/2β=14.64 h, K12=0.09/h, K21=0.078/h, Kel=0.20/h, V1=0.34 l/kg, VB =1.38 l/kg, CLB=0.07 l/kg/h,AUC=76.56 mg/l*h; 肌注药代动力学参数为Tmax=0.69 h,Cmax=12.09 μg/ml,T1/2ka=0.19 h,T1/2β=15.18 h,Kel=0.23/h,K12=0.14/h,K21=0.08/h;生物利用度为AUCi.m/AUCi.v=87.97%.     

Efficacy of ceftiofur for treatment of experimental salmonellosis in neonatal calves

OBJECTIVE: To evaluate therapeutic efficacy of a high extralabel dose of ceftiofur for treatment of experimental salmonellosis in neonatal calves. ANIMALS: Forty-two 1- to 4-day-old Holstein bull calves. PROCEDURE: 36 calves were orally challenged with Salmonella enteritica serovar Typhimurium (6.5 x 10(8) colony-forming units). Six additional calves were retained as nonmedicated nonchallenged control calves. Four days following Salmonella challenge, surviving calves were randomly allocated to ceftiofur-treated (5 mg/kg, IM, q 24 h) or nonmedicated control groups. Calves assigned to the treated group were medicated daily for 5 days starting on day 4 after challenge. Calves were monitored for 18 days following Salmonella challenge. Outcome assessments included clinical parameters (attitude, appetite, fecal characteristics, and rectal temperature), mortality rate, and quantitative Salmonella culture of fecal samples, mesenteric lymph nodes, and cecal contents. RESULTS: Ceftiofur treatment was associated with a significant decrease in rectal temperature and diarrhea. Three of 15 medicated calves and 4 of 14 non-medicated calves died or were euthanatized between days 4 and 18. A significant decrease in fecal shedding of Salmonella organisms was observed in treated calves, compared with nonmedicated calves. Salmonella organisms were isolated from all 10 non-medicated calves at necropsy, whereas no Salmonella organisms were isolated from 5 of 12 medicated calves. CONCLUSIONS AND CLINICAL RELEVANCE: Treatment of salmonellosis in neonatal calves with a high extralabel dose of ceftiofur (5 mg/kg, IM, q 24 h) promotes animal welfare, reduces fecal shedding of Salmonella organisms, and may promote clearance of Salmonella infections when plasma ceftiofur concentrations are maintained above minimal inhibitory concentrations.     

Comparison of plasma pharmacokinetics and bioequivalence of ceftiofur sodium in cattle after a single intramuscular or subcutaneous injection

Ceftiofur sodium, a broad-spectrum cephalosporin, is active against gram-positive and gram-negative pathogens of veterinary importance. This study was designed to compare the bioequivalence of the sodium salt in cattle after a single intramuscular (i.m.) or subcutaneous dose (s.c.) of 2.2 mg ceftiofur equivalents/kg body weight. The criteria used to evaluate bioequivalence were (1) the area under the curve from time of injection to the limit of quantitation (LOQ) of the assay (AUC0-LOQ), and (2) time concentrations remained above 0.2 microg/mL (t>0.2). Twelve crossbred beef cattle were enrolled in a three-period, two-treatment crossover trial, with a minimum 2-week washout period between doses of 2.2 mg ceftiofur equivalents/kg. Blood samples were collected serially for up to 72 h post-injection. Plasma samples were then analyzed using a validated assay that measures ceftiofur, and all desfuroylceftiofur-related metabolites, by high-performance liquid chromatography (HPLC) as the stable derivative, desfuroylceftiofur acetamide. A maximum plasma concentration (Cmax) of 13.9+/-3.55 microg/mL was observed from 0. 67-2.0 h after i.m. administration, whereas a Cmax of 13.6+/-3.85 microg/mL was observed from 0.67-3.0 h after s.c. administration. The AUC0-LOQ was 108+/-35.0 microg. h/mL after i.m. dosing, compared with 105+/-29.8 microg. h/mL after s.c. dosing. The pre-established criterion for equivalence of the AUC0-LOQ for the i.m. and s.c. routes of administration was satisfied. The t>0.2 was 49.2+/-8.55 h after i.m. administration, compared with 47.0+/-9.40 h after s.c. administration. The pre-established criterion for equivalence of the t>0.2 for i.m. and s.c. administration was satisfied. The equivalence of AUC0-LOQ and t>0.2 for i.m. and s.c. administration of 2.2 mg ceftiofur equivalents (CE)/kg doses of ceftiofur sodium suggest similar therapeutic efficacy and systemic safety for the two routes of administration.     

Distribution of ceftiofur into Mannheimia haemolytica‐infected tissue chambers and lung after subcutaneous administration of ceftiofur crystalline free acid sterile suspension

Washburn, K., Johnson, R., Clarke, C, Anderson, K. Distribution of ceftiofur into Mannheimia haemolytica‐infected tissue chambers and lung after subcutaneous administration of ceftiofur crystalline free acid sterile suspension. J. vet. Pharmacol. Therap. 33 , 141–146. The objective of this study was to evaluate the penetration of ceftiofur‐ and desfuroylceftiofur‐related metabolites (DCA) into sterile and infected tissue chambers, lung tissue and disposition of DCA in plasma across four different sacrifice days postdosing. Twelve healthy calves were utilized following implantation with tissue chambers in the paralumbar fossa. Tissue chambers in each calf were randomly inoculated with either Mannheimia haemolytica or sterile PBS. All calves were dosed with ceftiofur crystalline free acid sterile suspension (CCFA‐SS) subcutaneously in the ear pinna. Calves were randomly assigned to 4 groups of 3 to be sacrificed on days 3, 5, 7 and 9 postdosing. Prior to euthanasia, plasma and tissue chamber fluid were collected, and immediately following euthanasia, lung tissue samples were obtained from four different anatomical sites DCA concentration analysis. Results of our study found that, in general, DCA concentrations followed a rank order of plasma > infected tissue chamber fluid > noninfected tissue chamber fluid > lung tissue. Data also indicated DCA concentrations remained above the therapeutic threshold of 0.2 μg/mL for plasma and chamber fluid and 0.2 μg/g for lung tissue for at least 7 days post‐treatment.     

Comparative pharmacokinetics of acetylsalicylic acid and sodium salicylate in chickens and turkeys

1. Pharmacokinetics of acetylsalicylic acid (ASA) and sodium salicylate (SS) were assessed following single intravenous (i.v.) and oral administration at doses of 50 mg/kg body weight to chickens and turkeys. Plasma drug concentrations were determined using high-performance liquid chromatography with ultraviolet detection and pharmacokinetic variables were calculated using a non-compartmental model.

2. The mean residence time (MRT) of salicylate (SA) after i.v. administration of SS was 6.08 ± 0.59 and 3.32 ± 0.27 h and after oral administration was 6.95 ± 0.72 and 4.55 ± 0.71 h in chickens and turkeys, respectively. The elimination half-life (T _{1/2 e}) was shorter in turkeys compared with chickens. The value of body clearance (Cl_B) was higher in turkeys than in chickens, but the apparent volume of distribution (V _ss) was similarly low in both species. The bioavailability of SS was complete and the maximal plasma concentration of SA (C _max) after oral administration was 96.93 ± 8.06 and 91.76 ± 9.64 µg/ml, respectively, in chickens and turkeys.

3. The MRT of ASA after iv administration was 0.24 ± 0.08 and 0.24 ± 0.02 h and after oral administration was 0.78 ± 0.25 and 0.59 ± 0.13 h, respectively, in chickens and turkeys. In both species, T _{1/2 e} was very short, Cl_B and V _ss were similar and markedly higher than those of salicylate. The bioavailability of unchanged ASA was low and C _max after oral administration was 6.9 ± 3.6 µg/ml in chickens and 8.6 ± 1.3 µg/ml in turkeys.     

Comparative pharmacokinetics of amikacin sulphate in calves and sheep

The pharmacokinetics of amikacin sulphate were investigated in calves and sheep. Five animals of each species were given 7.5 mg kg-1 intravenously and intramuscularly. After intravenous administration the pharmacokinetic parameters significantly different (P less than 0.01) between calves (first value) and sheep (second value), were: the initial concentration (87.05, 146.6 micrograms ml-1), the apparent distribution volume (350, 200 ml kg-1), the area under curve (5512, 11,018 min micrograms ml-1) and the clearance (1.5, 0.7 ml min-1 kg-1). After dosing intramuscularly the peak concentration (23.5, 34.36 micrograms ml-1), the peak time (45, 75 min) and the area under curve (5458, 9191 min micrograms ml-1) were significantly different (P less than 0.01). No significant differences were observed in the terminal halflife values, suggesting that elimination rate was independent of both route of administration and animal species. The drug in aqueous solution showed a good bioavailability in both animal species (about 0.87 in sheep and greater than 0.99 in calves) despite the greater serum concentrations always attained in sheep.