Ceftiofur Free Acid Equivalents Research Articles

Pharmacokinetics of a Single Intramuscular Injection of Ceftiofur Crystalline Free Acid in Bald Eagles (Haliaeetus leucocephalus).

The objective of this study was to evaluate the pharmacokinetic properties of ceftiofur crystalline free acid (CCFA) administered intramuscularly at dosages of 10 and 20 mg/kg in bald eagles (BAEAs) (Haliaeetus leucocephalus). Ceftiofur crystalline free acid is a long-acting, injectable, third-generation cephalosporin antibiotic drug. A prospective, randomized, complete crossover design was used for this pharmacokinetic investigation. CCFA (10 or 20 mg/kg) was administered intramuscularly, and blood samples were obtained from 6 adult, nonreleasable, healthy BAEAs at predetermined sampling times. After a 4-week washout period, the protocol was repeated with each bird receiving the dose not given during the initial sample collection according to the randomized crossover design. Plasma ceftiofur free acid equivalents were quantified and data were analyzed by a noncompartmental pharmacokinetic approach. The mean observed peak plasma concentrations were 9.23 µg/mL and 15.08 µg/mL for 10 and 20 mg/kg CCFA IM administration, respectively. The mean observed time to maximum plasma concentration was 18 and 17.6 hours, and the mean terminal elimination half-life was 32.38 and 38.08 hours for intramuscular administration of 10 and 20 mg/kg CCFA, respectively, in the BAEAs. Reported minimum inhibitory concentrations of raptor bacterial isolates from a prior study was used to determine the target minimum inhibitory concentration of 1 µg/mL selected for this investigation. From the previously published information, a target plasma concentration of 4 µg/mL was determined for the CCFA in the BAEAs. From the results of this study, CCFA may be dosed every 60 and 110 hours at 10 mg/kg IM, and every 80 and 160 hours at 20 mg/kg IM in BAEAs.

Evaluation of Heat and pH Treatments on Degradation of Ceftiofur in Whole Milk.

Waste milk feeding practices have been implicated as a potential source for disseminating antimicrobial resistant bacteria among animals and the environment. Two interventions that have shown potential for degrading antimicrobial drugs in milk are heat and pH treatment. The aim of this study was to evaluate the effect of heat and pH treatments on the degradation of ceftiofur and ceftiofur free acid equivalents in milk at concentrations previously found in waste milk on dairy farms by spiking saleable pasteurized whole milk with ceftiofur sodium. Three heat treatments of ceftiofur sodium spiked milk were evaluated for their ability to degrade ceftiofur: 63°C for 30 min (LTLT), 72°C for 15 s (HTST) and 92°C for 20 min (HTLT). Two pH treatments of ceftiofur sodium spiked milk were evaluated: pH 4.0 (LpH) and pH 10 (HpH). Control samples spiked with ceftiofur sodium were kept at room temperature and samples collected at corresponding times for heat and pH treatments. Four treatment replicates were performed for each treatment group. Ceftiofur was quantified in milk samples using liquid chromatography mass spectrometry (LC-MS/MS) and ceftiofur free acid equivalents (CFAE) were measured using high-performance liquid chromatography (HPLC). HTLT resulted in a degradation of 35.24% of the initial concentration of ceftiofur. Ceftiofur degradation did not differ between control and the remaining two heat treatment groups (LTLT and HTST). HpH resulted in degradation of the 95.72 and 96.28% of the initial concentration of ceftiofur and CFAE, respectively. No significant changes in degradation of ceftiofur or CFAE were observed for control or LpH treatments. In conclusion, our study results were that alkalinizing milk to pH 10 and heating milk to 92°C for 20 min degraded ceftiofur and CFAE in spiked simulated waste milk demonstrated promising potential as treatment options for degrading ceftiofur and CFAE in waste milk, and further research is needed to evaluate the viability for implementation of these treatments in dairy farms.

Evaluation of heat and pH treatments on degradation of ceftiofur in whole milk

Waste milk feeding practices have been implicated as a potential source for disseminating antimicrobial resistant bacteria among animals and the environment. Feeding dairy heifers raw milk with low concentrations of antimicrobials increases the proportion of antimicrobial resistance. Two potential interventions to degrade antimicrobial drugs in milk are heat and pH treatment. The aim of this study was to evaluate the effect of heat and pH treatments on the degradation of ceftiofur and ceftiofur free acid equivalents (CFAE) in milk at concentrations previously found in waste milk on dairy farms

Pharmacokinetics of a Single Intramuscular Injection of Long-Acting Ceftiofur Crystalline-Free Acid in Cattle Egrets (Bubulcus ibis)

We determined the pharmacokinetic properties of ceftiofur crystalline-free acid (CCFA), a long-acting antibiotic, after a single intramuscular injection in cattle egrets ( Bubulcus ibis). A dose of 20 mg/kg was administered intramuscularly to 18 birds and blood samples were collected via jugular venipuncture at 1, 2, 4, 8, 12, 24, 48, 72, 96, 120, 144, 168, 192, 216, and 240 hours after CCFA administration. Plasma concentrations of ceftiofur free acid equivalents (CFAEs) were measured via high-performance liquid chromatography. The minimum inhibitory concentration (MIC) of 1 μg/mL was reached by 1 hour after administration and remained higher than the MIC for at least 72 hours in all birds. This target concentration is effective for many bacterial infections in avian species. The area under the plasma concentration versus time curve was 451.3 h*μg/mL, maximum plasma concentration was 16.22 μg/mL, time to maximum plasma concentration was 3.2 hours, mean harmonic half-life was 37.92 hours, and time that the concentrations of CFAEs were higher than the target MIC was a minimum of 72 hours.

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 13.2mg/kg to 12 neonatal foals 1-3days 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±0.6μg/mL and observed time to maximal plasma concentration was 14.0±4.9h. Following multi-dose administration of CCFA, the mean±standard deviation times above CFAE concentrations of ≥0.5μg/mL and ≥2.0μg/mL were 192.95±15.86h and 78.80±15.31h, respectively. The mean±standard deviation area under the concentration vs time curve (AUC0→∝ ) was 246.2±30.7h×μg/mL and 172.7±27.14h×μg/mL following single- and multi-dose CCFA administrations, respectively. Subcutaneous administration of CCFA at 13.2mg/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 48h 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 (20mg/kg i.m., 60mg/kg i.m., 30mg/kg i.c., and 60mg/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 60mg/kg i.m., time durations that serum CFAE concentrations were above the target concentration of 4μg/mL ranged from 0.4 to 2.5weeks in 3 of 4 fish, while serum CFAE concentrations remained below 4μg/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 ceftiofur crystalline-free acid following subcutaneous administration of a single dose to sheep

To determine the pharmacokinetics of ceftiofur crystalline-free acid (CCFA) following SC administration of a single dose to sheep. 9 healthy adult female Suffolk-crossbred sheep. Each sheep was administered 6.6 mg of CCFA/kg, SC, in the cervical region once. Serial blood samples were collected at predetermined intervals for 14 days. Serum concentration of ceftiofur free-acid equivalents (CFAE) was determined by high-performance liquid chromatography. Pharmacokinetic parameters were determined by compartmental and noncompartmental methods. Pharmacokinetics for CCFA following SC administration in sheep was best described with a 1-compartment model. Mean ± SD area under the concentration-time curve from time 0 to infinity, peak serum concentration, and time to peak serum concentration were 206.6 ± 24.8 μ•h/mL, 2.4 ± 0.5 μg/mL, and 23.1 ± 10.1 h, respectively. Serum CFAE concentrations ≥ 1 μg/mL (the target serum CFAE concentration for treatment of disease caused by Mannheimia haemolytica and Pasteurella multocida) were maintained for 2.6 to 4.9 days. No significant adverse reactions to CCFA administration were observed. Results indicated that adequate therapeutic serum concentrations of CFAE for treatment of disease caused by M haemolytica and P multocida were achieved in sheep following SC administration of a single dose (6.6 mg/kg) of CCFA. Thus, CCFA might be useful for the treatment of common respiratory tract pathogens in sheep.

Pharmacokinetics of a single intramuscular injection of ceftiofur crystalline-free acid in American black ducks (Anas rubripes)

To determine the pharmacokinetic properties of 1 IM injection of ceftiofur crystalline-free acid (CCFA) in American black ducks (Anas rubripes). 20 adult American black ducks (6 in a preliminary experiment and 14 in a primary experiment). Dose and route of administration of CCFA for the primary experiment were determined in a preliminary experiment. In the primary experiment, CCFA (10 mg/kg, IM) was administered to ducks. Ducks were allocated into 2 groups, and blood samples were obtained 0.25, 0.5, 1, 2, 4, 8, 12, 48, 96, 144, 192, and 240 hours or 0.25, 0.5, 1, 2, 4, 8, 24, 72, 120, 168, and 216 hours after administration of CCFA. Plasma concentrations of ceftiofur free acid equivalents (CFAEs) were determined by use of high-performance liquid chromatography. Data were evaluated by use of a naive pooled-data approach. The area under the plasma concentration versus time curve from 0 hours to infinity was 783 h•μg/mL, maximum plasma concentration observed was 13.1 μg/mL, time to maximum plasma concentration observed was 24 hours, terminal phase half-life was 32.0 hours, time that concentrations of CFAEs were higher than the minimum inhibitory concentration (1.0 μg/mL) for many pathogens of birds was 123 hours, and time that concentrations of CFAEs were higher than the target plasma concentration (4.0 μg/mL) was 73.3 hours. On the basis of the time that CFAE concentrations were higher than the target plasma concentration, a dosing interval of 3 days can be recommended for future multidose CCFA studies.

Determination of ceftiofur in bovine plasma by HPLC-DAD

Ceftiofur sodium is a third generation broad-spectrum cephalosporin, formulated as an intramuscular injection, which is used to treat respiratory diseases in swine, ruminants and horses. The thioester bond on ceftiofur is rapidly cleaved to give desfuroylceftiofur which is further metabolized to a disulfide dimer and various desfuroylceftiofur-protein and amino acid conjugates. Methods of analysis of ceftiofur rely on cleavage by dithioerythritol to produce desfuroylceftiofur, which is further stabilized by derivatization to desfuroylceftiofur acetamide using iodoacetamide. Previous analytical methods have extracted derivatized analyte from plasma and tissue using solid-phase extraction clean-up steps followed by HPLC analysis with results reported as ceftiofur-free acid equivalents (CFAE). The simplified method presented here involves direct HPLC injection of a cleaved and derivatized sample following a protein precipitation step with calibration by external standardization and selectivity achieved based on chromatography and diode-array detection (DAD). The assay was linear over the calibration range 0.4–40 μg/ml in plasma. Intra-batch reproducibility R.S.D. was 10.3% and intra-batch sample repeatability R.S.D. was 2.1% at the 5 μg/ml level. The mean accuracy over the range of the calibration curve was −4.2% and the detection limit was 0.15 μg/ml. The assay was successfully applied to bovine plasma following intramuscular injection of ceftiofur sodium. This simplified method is suitable for pharmacokinetic applications involving ceftiofur at normal therapeutic levels.

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

To determine the pharmacokinetics of ceftiofur sodium after IM and SC administration in green iguanas. 6 male and 4 female adult green iguanas. 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. 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. 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.

Pharmacokinetics of ceftiofur and metabolites after single intravenous and intramuscular administration and multiple intramuscular administrations of ceftiofur sodium to dairy goats.

Twelve (12) lactating dairy goats (46-71 kg body wt at study initiation) were divided into four treatment groups and dosed with ceftiofur sodium at 1.1 mg ceftiofur free acid equivalents (CFAE)/kg or 2.2 CFAE/kg using a complete two route (intravenous, i.v.; intramuscular, i.m.), two-period crossover design, with a 2-week washout between injections. After another 2-week washout period, the goats were dosed with ceftiofur sodium i.m. for 5 consecutive days at either 1.1 or 2.2 mg CFAE/kg. The goats from the 2.2 mg/kg multiple dose group were dried off and the i.v. kinetic study repeated. After all injections, blood samples were obtained serially for determination of combined serum concentrations of ceftiofur and metabolites. After intravenous doses of 1.1 and 2.2 mg/kg, the harmonic means of the terminal phase half-lives were 171.8 and 233 min, respectively, for lactating does. The harmonic mean of the terminal phase half-life after an i.v. dose of 2.2 mg/kg in non-lactating does was 254 min. The AUC0-infinity was significantly less and the clearance significantly greater during lactation. After i.m. doses of 1.1 and 2.2 mg/kg, the harmonic mean terminal phase half-lives were 163 and 156 min, respectively. The i.m. bioavailability of ceftiofur sodium in goats was 100%, and the AUC0-infinity was dose-proportional from 1.1-2.2 mg CFAE/kg body weight. After five daily i.m. doses of ceftiofur sodium at either 1.1 or 2.2 mg CFAE, there was minimal accumulation of drug in serum as assessed by Cmax, and serum concentrations were dose-proportional after the multiple dosing regimen.

Metabolism of [14C]Ceftiofur Hydrochloride in Swine after Intramuscular Injections

Twelve mix-breed swine (26.5−42.5 kg) received three intramuscular doses of [14C]ceftiofur hydrochloride at 24 h intervals. Three males and three females received 6.76 ± 0.83 mg of [14C]ceftiofur free acid equivalents (CE)/kg body weight (bw)/day, while three males and three females received 4.41 ± 0.97 mg of CE/kg bw/day. All swine were euthanatized 12 h after the last dose. Most of the 14C-residues (>80%) in tissues were associated with macromolecules. The rest of the 14C-activity corresponded to desfuroylceftiofur (DFC)−cysteine. The type and percentages of metabolites present in the urine of swine were similar to those previously observed for ceftiofur sodium (Gilbertson et al., J. Agric. Food Chem. 1995, 43, 229−234), with DFC−cysteine and DFC-dimer being the major ones. In plasma, the major portion of the 14C-activity (>85%) was associated with macromolecules. DFC−cysteine was the only detectable 14C-component of the macromolecule-free plasma fraction. This study indicated that ceftiofur hydrochloride was absorbed in the same ionic form as ceftiofur sodium, acceding to the same primary metabolite DFC. The type of metabolites present in swine after intramuscular injection were the same, regardless of the salt administered. Keywords: Metabolism; ceftiofur hydrochloride; swine; EXCENEL sterile suspension

Pharmacokinetics of ceftiofur and metabolites after single intravenous and intramuscular administration and multiple intramuscular administrations of ceftiofur sodium to sheep.

Twenty-four sheep (38.0-54.1 kg body wt) were allocated into four treatment groups and dosed with ceftiofur sodium at 1.1 mg ceftiofur free acid equivalents (CFAE)/kg or 2.2 CFAE/kg using a complete two-route (intravenous, i.v.: intramuscular, i.m.), two-period crossover design, with a two-week washout between injections. After another two-week washout period, 12 sheep were selected and dosed with ceftiofur sodium i.m. for five consecutive days at either 1.1 or 2.2 mg CFAE/kg. After all injections, blood samples were obtained serially for determination of serum concentrations of ceftiofur and metabolites. The terminal phase half-lives derived from the last 3-5 concentration-time points were 350 and 292 min (harmonic means) after i.v. doses of 1.1 and 2.2 mg/kg, respectively, and 389 and 459 min after i.m. doses of 1.1 and 2.2 mg/kg, respectively. The i.m. bioavailability of ceftiofur sodium in sheep was 100%, and the area under the curve from time 0 to the limit of quantitation (AUC0 LOQ) was dose-proportional from 1.1-2.2 mg CFAE/kg body wt in sheep. After 5 daily i.m. doses of ceftiofur sodium at either 1.1 or 2.2 mg CFAE/kg there was minimal accumulation of drug in serum as assessed by the observed maximum serum concentration (Cmax), and serum concentrations were dose-proportional after the multiple dosing regimen.