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.     

Antimicrobial susceptibility of Riemerella anatipestifer isolated from ducks and the efficacy of ceftiofur treatment.

The in vitro susceptibilities of 50 field isolates of Riemerella anatipestifer from ducks to ceftiofur and 16 other commonly used antimicrobials were determined. The MIC90 values (MIC refers to minimum inhibitory concentrations) for the antimicrobials used in this study are as follows: penicillin was 16 microg/ml; ceftiofur was 32 microg/ml; cephalothin, chloramphenicol, flumequine, and kanamycin were 64 microg/ml; nalidixic acid, nitrofurantoin, and sulfamethoxazole were 128 microg/ml; amikacin, ampicillin, gentamicin, lincomycin, spectinomycin, streptomycin, tetracycline, and trimethoprim were > or = 256 microg/ml. The therapeutic efficacy of ceftiofur against a highly lethal experimental R. anatipestifer infection in ducks was also evaluated. All experimental ducks were infected through the infraorbital sinus with 1 ml of 9 x 10(9) CFU of R. anatipestifer. Ceftiofur (0, 0.25, 0.5, 1, and 2 mg/kg) was injected subcutaneously 5 hours after infection. A single dose of 2 mg/kg resulted in 73% survival as compared with 10% survival in the infected, but untreated controls.     

Pharmacokinetics of ceftiofur crystalline-free acid sterile suspension in the equine

Collard, W. T., Cox, S. R., Lesman, S. P., Grover, G. S., Boucher, J. F., Hallberg, J. W., Robinson, J. A., Brown, S. A. Pharmacokinetics of ceftiofur crystalline‐free acid sterile suspension in the equine. J. vet. Pharmacol. Therap. 34 , 476–481. Absolute bioavailability and dose proportionality studies were performed with ceftiofur in horses. In the absolute bioavailability study, thirty animals received either an intravenous dose of ceftiofur sodium at 1.0 mg/kg or an intramuscular (i.m.) dose of ceftiofur crystalline‐free acid (CCFA) at 6.6 mg/kg. In the dose proportionality study, 48 animals received daily i.m. ceftiofur sodium injections at 1.0 mg/kg for ten doses or two doses of CCFA separated by 96 h, with CCFA doses of 3.3, 6.6, or 13.2 mg/kg. Noncompartmental and mixed‐effect modeling procedures were used to assess pharmacokinetics (PK). CCFA was well absorbed with a bioavailability of 100%. AUC_0–∞ and C_max increased in a dose‐related manner following administration of the two doses of CCFA at 3.3, 6.6, and 13.2 mg/kg. The least‐squares mean terminal half‐life (t_½) following the tenth daily i.m. injection of ceftiofur sodium at 2.2 mg/kg was 40.8 h, but the least‐squares mean t_½ following the second i.m. injection of CCFA at 6.6 mg/kg was 100 h. The time that plasma ceftiofur equivalent concentrations remain above a threshold concentration of 0.2 μg/mL has been associated with efficacy, and following administration of two 6.6 mg/kg doses of CCFA, the mean time above 0.2 μg/mL was 262 h. Simulations with the nonlinear mixed‐effect PK model predicted that more than 97.5% of horses will have plasma ceftiofur equivalent concentrations >0.2 μg/mL for 96 h after the second 6.6 mg/kg dose of CCFA.     

Pharmacokinetics of ceftiofur sodium after intramuscular or subcutaneous administration in green iguanas (Iguana iguana)

OBJECTIVE: To determine the pharmacokinetics of ceftiofur sodium after IM and SC administration in green iguanas. ANIMALS: 6 male and 4 female adult green iguanas. PROCEDURE: In a crossover design, 5 iguanas received a single dose of ceftiofur sodium (5 mg/kg) IM, and 5 iguanas received the same dose SC. Blood samples were taken at 0, 20, and 40 minutes and 1, 2, 4, 8, 24, 48, and 72 hours after administration. After a 10-week washout period, each iguana was given the same dose via the reciprocal administration route, and blood was collected in the same fashion. Ceftiofur free-acid equivalents were measured via high-performance liquid chromatography. RESULTS: The first phase intercepts were significantly different between the 2 administration routes. Mean maximum plasma concentration was significantly higher with the IM (28.6 +/- 8.0 microg/mL) than the SC (18.6 +/- 8.3 microg/mL) administration route. There were no significant differences between terminal half-lives (harmonic mean via IM route, 15.7 +/- 4.7 hours; harmonic mean via SC route, 19.7 +/- 6.7 hours) and mean areas under the curve measured to the last time point (IM route, 11,722 +/- 7,907 microg x h/mL; SC route, 12,143 +/- 9,633 microg x h/mL). Ceftiofur free-acid equivalent concentrations were maintained > or = 2 microg/mL for > 24 hours via both routes. CONCLUSIONS AND CLINICAL RELEVANCE: A suggested dosing schedule for ceftiofur sodium in green iguanas for microbes susceptible at > 2 microg/mL would be 5 mg/kg, IM or SC, every 24 hours.     

Comparative plasma pharmacokinetics of ceftiofur sodium and ceftiofur crystalline‐free acid in neonatal calves

The objective of this study was to compare the plasma pharmacokinetic profile of ceftiofur crystalline‐free acid (CCFA) and ceftiofur sodium in neonatal calves between 4 and 6 days of age. In one group (n = 7), a single dose of CCFA was administered subcutaneously (SQ) at the base of the ear at a dose of 6.6 mg/kg of body weight. In a second group (n = 7), a single dose of ceftiofur sodium was administered SQ in the neck at a dose of 2.2 mg/kg of body weight. Concentrations of desfuroylceftiofur acetamide (DCA) in plasma were determined by HPLC. Median time to maximum DCA concentration was 12 h (range 12–48 h) for CCFA and 1 h (range 1–2 h) for ceftiofur sodium. Median maximum plasma DCA concentration was significantly higher for calves given ceftiofur sodium (5.62 μg/mL; range 4.10–6.91 μg/mL) than for calves given CCFA (3.23 μg/mL; range 2.15–4.13 μg/mL). AUC_0‐∞ and Vd/F were significantly greater for calves given CCFA than for calves given ceftiofur sodium. The median terminal half‐life of DCA in plasma was significantly longer for calves given CCFA (60.6 h; range 43.5–83.4 h) than for calves given ceftiofur sodium (18.1 h; range 16.7–39.7 h). Cl/F was not significantly different between groups. The duration of time median plasma DCA concentrations remained above 2.0 μg/mL was significantly longer in calves that received CCFA (84.6 h; range 48–103 h) as compared to calves that received ceftiofur sodium (21.7 h; range 12.6–33.6 h). Based on the results of this study, CCFA administered SQ at a dose of 6.6 mg/kg in neonatal calves provided plasma concentrations above the therapeutic target of 2 μg/mL for at least 3 days following a single dose. It is important to note that the use of ceftiofur‐containing products is restricted by the FDA and the use of CCFA in veal calves is strictly prohibited.     

Pharmacokinetics of ceftiofur in plasma and uterine secretions and tissues after subcutaneous postpartum administration in lactating dairy cows

A study was conducted to measure concentrations of potentially active ceftiofur derivatives, in plasma, in uterine tissues (endometrium and caruncles) and in uterine secretions at different time points after a single subcutaneous administration of ceftiofur hydrochloride (Excenel RTU Sterile Suspension) at the dose of 1 mg/kg body weight in Holstein-Friesian dairy cows. The animals (n=4) were injected within 24 h of calving, after expulsion of the foetal membranes. Plasma, lochial fluid, caruncles and endometrium were collected before ceftiofur hydrochloride administration and at 1, 2, 4, 8, 12 and 24 h after treatment. For each cow the concentrations of ceftiofur in the biological matrices were quantified using an high-performance liquid chromatography (HPLC) assay. The limit of quantification of the method was 0.1 microg/mL for plasma and 0.1 microg/g for lochial fluid, caruncles and endometrium. The concentrations of potentially active ceftiofur derivatives detected in plasma reached a maximum of 2.85 +/- 1.11 microg/mL at 2 h and decreased to 0.64 +/- 0.14 microg/mL at 24 h after administration. In lochial fluid, these concentrations reached a maximum of 0.97 +/- 0.25 microg/g at 4 h and decreased to 0.22 +/- 0.21 microg/g at 24 h after administration. In endometrium, these concentrations reached a maximum of 2.23 +/- 0.82 microg/g at 4 h and decreased to 0.56 +/- 0.14 microg/g at 24 h following the injection, whereas these levels in caruncles were 0.96 +/- 0.45 and 0.60 +/- 0.39 microg/g obtained at 8 and 24 h, respectively. At the dose of 1 mg/kg body weight in healthy dairy cows, subcutaneous administration of ceftiofur (as ceftiofur hydrochloride) after parturition results in concentrations of ceftiofur derivatives in uterine tissues and in lochial fluid that exceed the reported minimal inhibitory concentrations (MICs) for the common pathogens (Escherichia coli, Fusobacterium necrophorum, Bacteroides spp., and Arcanobacterium pyogenes) associated with acute puerperal metritis.     

Pharmacokinetics of enrofloxacin after single-dose oral and intravenous administration in the American alligator (Alligator mississippiensis).

The pharmacokinetics of enrofloxacin administered orally and i.v. to American alligators (Alligator mississippiensis) at 5 mg/kg was determined. Plasma levels of enrofloxacin and its metabolite ciprofloxacin were measured using high-performance liquid chromatography and the resulting concentration versus time curve analyzed using compartmental modeling techniques for the i.v. data and noncompartmental modeling techniques for the oral data. A two-compartment model best represented the i.v. data. Intravenous administration of enrofloxacin resulted in an extrapolated mean plasma concentration of 4.19 +/- 4.23 microg/ml at time zero, with average plasma drug levels remaining above 1.0 microg/ml for an average of 36 hr. Plasma volume of distribution for i.v. enrofloxacin was 1.88 +/- 0.96 L/kg, with a harmonic mean elimination half-life of 21.05 hr and mean total body clearance rate of 0.047 +/- 0.021 L/hr/kg. Plasma levels of p.o. enrofloxacin remained below 1.0 microg/ml in all test animals, and average concentrations ranged from 0.08 to 0.50 microg/ml throughout the sampling period. Oral administration of enrofloxacin achieved a mean maximum plasma concentration of 0.50 +/- 0.27 microg/ml at 55 +/- 29 hr after administration, with a harmonic mean terminal elimination half-life of 77.73 hr. Minimal levels of ciprofloxacin were detected after both oral and i.v. enrofloxacin administration, with concentrations below minimum inhibitory concentrations for most susceptible organisms. On the basis of the results of this study, enrofloxacin administered to American alligators at 5 mg/kg i.v. q 36 hr is expected to maintain plasma concentrations that approximate the minimum inhibitory concentration for susceptible organisms (0.5 microg/ml). Enrofloxacin administered to American alligators at 5 mg/kg p.o. is not expected to achieve minimum inhibitory values for susceptible organisms.     

Pharmacokinetics of orally administered phenylbutazone in African and Asian elephants (Loxodonta africana and Elephas maximus)

The pharmacokinetic parameters of phenylbutazone were determined in 18 elephants (Loxodonta africana and Elephas maximus) after single-dose oral administration of 2, 3, and 4 mg/kg phenylbutazone, as well as multiple-dose administrations with a 4-wk washout period between trials. After administration of 2 mg/kg phenylbutazone, mean serum concentrations peaked in approximately 7.5 hr at 4.3 +/- 2.02 microg/ml and 9.7 hr at 7.1 +/- 2.36 microg/ml for African and Asian elephants, respectively, while 3 mg/kg dosages resulted in peak serum concentrations of 7.2 +/- 4.06 microg/ml in 8.4 hr and 12.1 +/- 3.13 microg/ml in 14 hr. The harmonic mean half-life was long, ranging between 13 and 15 hr and 39 and 45 hr for African and Asian elephants, respectively. There was evidence of enterohepatic cycling of phenylbutazone in Asian elephants. Significant differences (P < 0.0001) in pharmacokinetic values occurred between African and Asian elephants for clearance (27.9 and 7.6 ml/hr/kg, respectively), terminal half-life (15.0 and 38.7 hr, respectively), and mean residence time (22.5 and 55.5 hr, respectively) using 2-mg/kg dosages as an example. This suggests that different treatment regimens for Asian and African elephants should be used. There were no apparent gender differences in these parameters for either elephant species.     

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.     

Pharmacokinetics of orally administered ibuprofen in African and Asian elephants (Loxodonta africana and Elephas maximus).

The pharmacokinetic parameters of S(+) and R(-) ibuprofen were determined in 20 elephants after oral administration of preliminary 4-, 5-, and 6-mg/kg doses of racemic ibuprofen. Following administration of 4 mg/kg ibuprofen, serum concentrations of ibuprofen peaked at 5 hr at 3.9 +/- 2.07 microg/ml R(-) and 10.65 +/- 5.64 microg/ml S(+) (mean +/- SD) in African elephants (Loxodonta africana) and at 3 hr at 5.14 +/- 1.39 microg/ml R(-) and 13.77 +/- 3.75 microg/ml S(+) in Asian elephants (Elephas maximus), respectively. Six-milligram/kilogram dosages resulted in peak serum concentrations of 5.91 +/- 2.17 microg/ml R(-) and 14.82 +/- 9.71 microg/ml S(+) in African elephants, and 5.72 +/- 1.60 microg/ml R(-) and 18.32 +/- 10.35 microg/ml S(+) in Asian elephants. Ibuprofen was eliminated with first-order kinetics characteristic of a single-compartment model with a half-life of 2.2-2.4 hr R(-) and 4.5-5.1 hr S(+) in African elephants and 2.4-2.9 hr R(-) and 5.9-7.7 hr S(+) in Asian elephants. Serum concentrations of R(-) ibuprofen were undetectable at 24 hr, whereas S(+) ibuprofen decreased to below 5 microg/ml 24 hr postadministration in all elephants. The volume of distribution was estimated to be between 322 and 356 ml/kg R(-) and 133 and 173 ml/kg S(+) in Asian elephants and 360-431 ml/kg R(-) and 179-207 ml/kg S(+) in African elephants. Steady-state serum concentrations of ibuprofen ranged from 2.2 to 10.5 microg/ml R(-) and 5.5 to 32.0 microg/ml S(+) (mean: 5.17 +/- 0.7 R(-) and 13.95 +/- 0.9 S(+) microg/ml in African elephants and 5.0 +/- 1.09 microg/ml R(-) and 14.1 +/- 2.8 microg/ml S(+) in Asian elephants). Racemic ibuprofen administered at 6 mg/kg/12 hr for Asian elephants and at 7 mg/kg/12 hr for African elephants results in therapeutic serum concentrations of this antiinflammatory agent.     

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.     

Plasma and pulmonary disposition of ceftiofur and its metabolites after intramuscular administration of ceftiofur crystalline free acid in weanling foals

The objectives of this study were to determine the plasma and pulmonary disposition of ceftiofur crystalline free acid (CCFA) in weanling foals and to compare the plasma pharmacokinetic profile of weanling foals to that of adult horses. A single dose of CCFA was administered intramuscularly to six weanling foals and six adult horses at a dose of 6.6 mg/kg of body weight. Concentrations of desfuroylceftiofur acetamide (DCA) were determined in the plasma of all animals, and in pulmonary epithelial lining fluid (PELF) and bronchoalveolar lavage (BAL) cells of foals. After intramuscular (IM) administration to foals, median time to maximum plasma and PELF concentrations was 24 h (12-48 h). Mean (± SD) peak DCA concentration in plasma (1.44 ± 0.46 μg/mL) was significantly higher than that in PELF (0.46 ± 0.03 μg/mL) and BAL cells (0.024 ± 0.011 μg/mL). Time above the therapeutic target of 0.2 μg/mL was significantly longer in plasma (185 ± 20 h) than in PELF (107 ± 31 h). The concentration of DCA in BAL cells did not reach the therapeutic level. Adult horses had significantly lower peak plasma concentrations and area under the curve compared to foals. Based on the results of this study, CCFA administered IM at 6.6 mg/kg in weanling foals provided plasma and PELF concentrations above the therapeutic target of 0.2 μg/mL for at least 4 days and would be expected to be an effective treatment for pneumonia caused by Streptococcus equi subsp. zooepidemicus at doses similar to the adult label.     

Pharmacokinetics of ceftiofur crystalline free acid after single and multiple subcutaneous administrations in healthy alpacas (Vicugna pacos)

Dechant, J. E., Rowe, J. D., Byrne, B. A., Wetzlich, S. E., Kieu, H. T., Tell, L. A. Pharmacokinetics of ceftiofur crystalline free acid after single and multiple subcutaneous administrations in healthy alpacas (Vicugna pacos). J. vet. Pharmacol. Therap.  36 , 122–129. Six adult male alpacas received one subcutaneous administration of ceftiofur crystalline free acid (CCFA) at a dosage of 6.6 mg/kg. After a washout period, the same alpacas received three subcutaneous doses of 6.6 mg/kg CCFA at 5‐day intervals. Blood samples collected from the jugular vein before and at multiple time points after each CCFA administration were assayed for ceftiofur‐ and desfuroylceftiofur‐related metabolite concentrations using high‐performance liquid chromatography. Pharmacokinetic disposition of CCFA was analyzed by a noncompartmental approach. Mean pharmacokinetic parameters (±SD) following single‐dose administration of CCFA were C_max (2.7 ± 0.9 μg/mL); T_max (36 ± 0 h); area under the curve AUC_0→∞ (199.2 ± 42.1 μg·h/mL); terminal phase rate constant λz (0.02 ± 0.003/h); and terminal phase rate constant half‐life t_1/2λz (44.7 h; harmonic). Mean terminal pharmacokinetic parameters (±SD) following three administrations of CCFA were C_max (2.0 ± 0.4 μg/mL); T_max (17.3 ± 16.3 h); AUC_0→∞ (216.8 ± 84.5 μg·h/mL); λz (0.01 ± 0.003/h); and t_1/2λz (65.9 h; harmonic). The terminal phase rate constant and the T_max were significantly different between single and multiple administrations. Local reactions were noted in two alpacas following multiple CCFA administrations.     

Pharmacokinetics of ceftiofur sodium in equine pregnancy

Eleven pregnant pony mares (D270‐326) were administered ceftiofur sodium intramuscularly at 2.2 mg/kg (n = 6) or 4.4 mg/kg (n = 5), once daily. Plasma was obtained prior to ceftiofur administration and at 0.5, 1, 2, 4, 8, 12, and 24 hr after administration. Eight pony mares were re‐enrolled in the study at least 3 days from expected foaling to ensure steady‐state concentrations of drug at the time of foaling. Mares were administered ceftiofur sodium (4.4 mg/kg, IM) daily until foaling. Parturition was induced using oxytocin 1 hr after ceftiofur sodium administration. Allantoic and amniotic fluid, plasma, and colostrum samples were collected at time of foaling. Serial foal plasma samples were obtained. Placental tissues were collected. Desfuroylceftiofur acetamide (DCA) concentrations were measured in samples by high‐performance liquid chromatography (HPLC). Mean (±SD) peak serum concentrations of DCA were 3.97 ± 0.50 μg/ml (low dose) and 7.45 ± 1.05 μg/ml (high dose). Terminal half‐life was significantly (p = .014) shorter after administration of the low dose (2.91 ± 0.59 hr) than after administration of the high dose (4.10 ± 0.72 hr). The mean serum concentration of DCA from mares at time of foaling was 7.96 ± 1.39 μg/ml. The mean DCA concentration in colostrum was 1.39 ± 0.70 μg/ml. DCA concentrations in allantoic fluid, amniotic fluid, placental tissues, and foal plasma were below the limit of quantification (<0.1 μg/ml) and below the minimum inhibitory concentration of ceftiofur against relevant pathogens. These results infer incomplete passage of DCA across fetal membranes after administration of ceftiofur sodium to normal pony mares.     

Changes in antimicrobial susceptibility in a population of Escherichia coli isolated from feedlot cattle administered ceftiofur crystalline-free acid

OBJECTIVE: To determine effects of administration of ceftiofur crystalline-free acid (CCFA) on antimicrobial susceptibility of Escherichia coli in feedlot cattle. ANIMALS: 61 feedlot steers. PROCEDURES: A cohort study was conducted. Steers were housed in pens (5 pens with 10 steers and 1 pen with 11 steers). Five steers in each pen were administered CCFA, and 5 served as control steers (1 pen had 6 control steers). The CCFA administration included a single-dose regimen (6.6 mg/kg, SC, on day 0), two-thirds-dose regimen (4.4 mg/kg, SC, on day 0), and 3-dose regimen (6.6 mg/kg, SC, on days 0, 6, and 13). Fecal samples were collected on days 0, 2, 6, 9, 13, 16, 20, and 28. Fecal samples were collected immediately before CCFA administration. Minimum inhibitory concentrations of 15 antimicrobials were determined for 3 E coli isolates/fecal sample. Escherichia coli were enumerated by use of direct-plating techniques. RESULTS: Resistance to 1 or more antimicrobials was detected in 986 of 1,441 (68.4%) isolates recovered. Administration of CCFA was associated with a transient increase in the population of ceftiofur-resistant isolates. Susceptibility returned to day 0 values (ie, samples collected immediately before CCFA administration) approximately 2 weeks after completion of CCFA administration. Agreement between ceftiofur resistance and co-resistance to ampicillin, chloramphenicol, streptomycin, sulfisoxazole, and tetracycline was almost perfect (kappa 0.97). We did not detect variation in susceptibility of E coli recovered from commingled control steers. CONCLUSIONS AND CLINICAL RELEVANCE: Administration of CCFA provided selection pressure that favored transient expansion of multiple-resistant variants.     

Plasma and urine disposition and dose proportionality of ceftiofur and metabolites in dogs after subcutaneous administration of ceftiofur sodium

Nine male dogs (10.3–13.5 kg body weight) were randomly assigned to three groups of three dogs each and administered ceftiofur sodium subcutaneously as a single dose of 0.22, 2.2, or 4.4 mg ceftiofur free acid equivalents/kg body weight. Plasma and urine samples were collected serially for 72 h and assayed for ceftiofur and metabolites (derivatized to desfuroylceftiofur acetamide) using high-performance liquid chromatography. Urine concentrations remained above the MIC ₉₀ for Escherichia coll (4.0 μg/mL) and Proteus mirabilis (1.0 μg/mL) for over 24 h after doses of 2.2 mg/kg (8.1 μg/mL) and 4.4 mg/kg (29.6 μg/mL), the interval between treatments for ceftiofur sodium in dogs, whereas urine concentrations 24 h after dosing at 0.22 mg/kg (0.1 mg/Ib) were below the MIC ₉₀ for E.coli and P. mirabills (0.6 μg/mL). Plasma concentrations were dose-proportional, with peak concentrations of 1.66 ± 0.0990 μg/mL, 8.91 ± 6.42 μg/mL, and 26.7 ± 1.07 μg/mL after doses of 0.22, 2.2, and 4.4 mg/kg, respectively. The area under the plasma concentration versus time curve, when normalized to dose, was similar across all dosage groups.     

Pharmacokinetics of piperacillan after intramuscular injection in red-tailed hawks (Buteo jamaicensis) and great horned owls (Bubo virginianus).

This study characterized and compared the pharmacokinetics of piperacillin after single 100 mg/kg i.m. injections in nine red-tailed hawks (Buteo jamaicensis) and five great horned owls (Bubo virginianus) over 48 hr by a modified agar well diffusion microbial inhibition assay. The mean maximum plasma piperacillin concentrations were 204 microg/ml and 221 microg/ml for the hawks and owls, respectively, and times of maximum concentrations were 15 min and 30 min, respectively. The calculated mean terminal elimination half-lives were 77 min in the hawks and 118 min in the owls. Area-under-the-curve values were 218 +/- 52 microg x hr/ml in the hawks and 444 +/- 104 microg x hr/ml in the owls. On the basis of the most common minimal inhibitory concentration (90%) for various bacterial isolates from clinical samples of 8 microg/ml, analysis of the data suggests that the maximum dosing interval for piperacillin at 100 mg/kg in medium sized raptors should be 4-6 hr.     

Synovial fluid and plasma concentrations of ceftiofur after regional intravenous perfusion in the horse

OBJECTIVE: To determine radiocarpal (RC) joint synovial fluid and plasma ceftiofur concentrations after regional intravenous perfusion (RIP) and systemic intravenous (IV) administration. STUDY DESIGN: Experimental cross-over study. ANIMALS: Five normal adult horses. METHODS: One RC joint was randomly selected for RIP and the contralateral RC joint was sampled to determine intrasynovial ceftiofur concentrations after IV administration. Wash-out between IV and RIP was > or = 14 days. After surgical introduction of an intraarticular catheter, ceftiofur (2 g) was administered under general anesthesia either IV or by RIP after tourniquet application. Plasma and synovial fluid were collected over 24 hours. Samples were analyzed using high-performance liquid chromatography with ultraviolet detection and the results were statistically analyzed using a linear mixed effect model. RESULTS: Mean synovial fluid ceftiofur concentrations were consistently higher after RIP than after IV administration and were > 1 mug/mL (minimal inhibitory concentration [MIC] for common pathogens) for >24 hours. Mean synovial fluid peak concentration of ceftiofur after RIP and IV administration was 392.7+/-103.29 microg/mL at 0.5 hours postinjection (HPI) and 2.72+/-0.31 mug/mL at 1 HPI, respectively. Large variations in synovial fluid and plasma ceftiofur concentrations were observed between horses regardless of administration technique. RIP did not cause adverse effects. CONCLUSIONS: Under the present experimental conditions RIP with ceftiofur (2 g) induced significantly higher intraarticular antibiotic concentrations in the RC joint in comparison with IV administration. Moreover, after RIP, synovial fluid ceftiofur concentrations remain above the MIC for common pathogens (1 microg/mL) for > 24 hours. No adverse effects from the technique or the antibiotic were observed. CLINICAL RELEVANCE: RIP with high doses of ceftiofur may be a beneficial adjunctive therapy when treating equine synovial infections which are caused by cephalosporin susceptible microorganisms.     

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.     

Pharmacokinetics of ceftiofur sodium in Peekapoo dogs following a single intravenous and subcutaneous injection

The present study aimed to determine the pharmacokinetic profiles of ceftiofur (as measured by ceftiofur and its active metabolites concentrations) in a small-size dog breed, Peekapoo, following a single intravenous or subcutaneous injection of ceftiofur sodium. The study population comprised of five clinically healthy Peekapoo dogs with an average body weight (BW) of 3.4 kg. Each dog received either intravenous or subcutaneous injection, both at 5 mg/kg BW (calculated as pure ceftiofur). Plasma samples were collected at different time points after the administration. Ceftiofur and its active metabolites were extracted from plasma samples, derivatized, and further quantified by high-performance liquid chromatography. The concentrations versus time data were subjected to noncompartmental analysis to obtain the pharmacokinetic parameters. The terminal half-life (t_1/2λz) was calculated as 7.40 ± 0.79 and 7.91 ± 1.53 hr following intravenous and subcutaneous injections, respectively. After intravenous treatment, the total body clearance (Cl) and volume of distribution at steady-state (V_SS) were determined as 39.91 ± 4.04 ml hr⁻¹ kg⁻¹ and 345.71 ± 28.66 ml/kg, respectively. After subcutaneous injection, the peak concentration (C_max; 10.50 ± 0.22 μg/ml) was observed at 3.2 ± 1.1 hr, and the absorption half-life (t_1/2ka) and absolute bioavailability (F) were calculated as 0.74 ± 0.23 hr and 91.70%±7.34%, respectively. The pharmacokinetic profiles of ceftiofur and its related metabolites demonstrated their quick and excellent absorption after subcutaneous administration, in addition to poor distribution and slow elimination in Peekapoo dogs. Based on the time of concentration above minimum inhibitory concentration (T > MIC) values calculated here, an intravenous or subcutaneous dose at 5 mg/kg of ceftiofur sodium once every 12 hr is predicted to be effective for treating canine bacteria with a MIC value of ≤4.0 μg/ml.