Penetration of parenterally administered ceftiofur into sterile vs. Pasteurella haemolytica-infected tissue chambers in cattle

The effect of bacterial infection on antibiotic activity and penetration of parenterally administered ceftiofur into implanted tissue chambers was studied in cattle. Tissue chambers were implanted subcutaneously in the paralumbar fossae of eight calves (256-290 kg body weight). Approximately 80 days after implantation, the two chambers on one side of each animal were inoculated with Pasteurella haemolytica (10⁶ CFU/chamber). Eighteen hours after inoculation, ceftiofur sodium was administered intravenously (5 mg/kg) to each of the calves. Non-infected chamber fluid, infected chamber fluid and heparinized blood samples were collected immediately before and at 1, 3, 6, 12 and 24 h after drug administration. Concentrations of ceftiofur and desfuroylceftiofur metabolites and ceftiofur-equivalent microbiological activity were measured by high-pressure liquid chromatography and microbiological assay respectively. Concentrations of ceftiofur and desfuroylceftiofur metabolites and antimicrobial activity in P. haemolytica -infected tissue chambers were significantly higher than those in non-infected tissue chambers at all sampling times, indicating that ceftiofur, regardless of the method used for analysis, localizes at higher concentrations at tissue sites infected with P. haemolytica . Antibiotic activity-concentration ratios were lower in plasma and infected chamber fluid compared with non-infected chamber fluid, suggesting that antibiotic was bound to proteins. However, higher antimicrobial activity in the infected chamber fluid compared with the non-infected chamber fluid suggests that active drug is reversibly bound to proteins. Protein-bound desfuroylceftiofur may represent a reservoir for release of active drug at the site of infection in the animal.     

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.     

Dose determination and confirmation of a long-acting formulation of ceftiofur (ceftiofur crystalline free acid) administered subcutaneously for the treatment of bovine respiratory disease

The objective of this work was to determine and confirm an effective dose of ceftiofur crystalline free acid sterile oil suspension (CCFA-SS, 100 mg ceftiofur equivalents (CE)/mL], a long-acting single-administration ceftiofur formulation, for the treatment of the bacterial component of bovine respiratory disease (BRD). Study 1 was a dose determination study that used an intratracheal Mannheimia haemolytica (Pasteurella haemolytica) challenge model to evaluate single-administration doses of CCFA-SS at 0.0, 1.1, 2.2, 3.3, 4.4 or 5.5 mg CE/kg body weight (BW) for the treatment of BRD. Data from this study were used to select doses for field testing in three multi-location clinical studies. In Study 2, the efficacy of a single administration dose of CCFA-SS at 4.4 mg CE/kg BW was compared with a negative control for the treatment of naturally occurring BRD in feedlot cattle. Treatments were administered when uniform clinical signs of BRD were present. Study 3 used a design similar to Study 2, and compared single-administration doses of CCFA-SS at 3.0 or 4.4 mg CE/kg BW with the positive-control tilmicosin (Micotil(R) 300 Injection, Elanco Animal Health) at 10 mg/kg BW. Study 4 compared the efficacy of single doses of CCFA-SS of 1.1-8.8 mg CE/kg BW with tilmicosin at 10 mg/kg BW. A total of 1176 cattle were included in these clinical studies. In Study 1, a dose of 4.55 mg CE/kg BW was determined to be effective. This was rounded to 4.4 mg CE/kg for field testing. In Study 2, a single dose of CCFA-SS at 4.4 mg CE/kg BW had a higher treatment success rate on day 14 (61%) than negative controls (26%, P < 0.01). However, in Study 3 this dose was judged to be at the beginning of an efficacious dose range for the treatment of BRD when compared with tilmicosin. In Study 4, day 28 treatment success rates were higher for CCFA-SS at 4.4-8.8 CE/kg BW than for tilmicosin (P=0.002) or the noneffective CCFA-SS dose of 1.1 mg CE/kg BW (P < 0.001). Based on decision criteria for Study 4, the effective dose was determined to be 4.4-5.5 mg CE/kg BW. These clinical studies demonstrated that a single dose of CCFA-SS (100 mg CE/mL) administered subcutaneously (s.c.) in the neck at 4.4-5.5 mg CE/kg BW is an effective treatment for BRD in feedlot cattle. However, this route of administration is no longer being considered for this formulation because of the ceftiofur residues that are present at the injection site for extended periods of time.     

Dose determination and confirmation for ceftiofur crystalline-free acid administered in the posterior aspect of the ear for control and treatment of bovine respiratory disease

Three studies were conducted to determine and confirm the effective dosage rate of ceftiofur crystalline-free acid sterile suspension (CCFA-SS, 200 mg ceftiofur equivalents [CE]/ml), a long-acting ceftiofur formulation, for control and treatment of bovine respiratory disease (BRD). In each study, CCFA-SS was administered once by subcutaneous (SC) injection in the middle third of the posterior aspect of the ear. Study 1 was conducted using an intratracheal challenge with Mannheimia (formerly Pasteurella) haemolytica and dosages ranging from 0 to 8.8 mg CE/kg to select a dosage for further field testing. In Study 2, a single dose of CCFA-SS at 0.0, 4.4, or 6.6 mg CE/kg was administered when uniform clinical signs of BRD were present in feedlot cattle. Study 3 was conducted in several feedlots to evaluate the efficacy, practicality, and safety of CCFA-SS at 4.4 or 6.6 mg CE/kg compared with a placebo control or tilmicosin for preemptive control of BRD. In Study 1, the effective dose was determined to be 5.35 mg CE/kg; therefore, 4.4 and 6.6 mg CE/kg were selected as the dosages for further field testing. Administration of CCFA-SS at 4.4 or 6.6 mg CE/kg improved treatment success compared with negative controls (P < or =.05 for both doses) in Study 2. In Study 3, a single administration of 4.4 or 6.6 mg CE/kg was comparable to tilmicosin (P <.001) and was significantly better than placebo (P <.001) for the control of BRD. Using the ear as an administration site was acceptable under field conditions and was well tolerated by all animals. These studies demonstrated that a single administration of CCFA-SS by SC injection in the middle third of the posterior aspect of the ear at 4.4 or 6.6 mg CE/kg is effective, safe, and practical for preemptive control and treatment of the bacterial component of BRD in feedlot cattle. Administration in an inedible tissue results in a short withdrawal time and no injection-site trimming at slaughter.     

Concentration of ceftiofur metabolites in the plasma and lungs of horses following intramuscular treatment

Jaglan, P.S., Roof, R.D., Yein, F.S., Arnold, T.S., Brown, S.A., Gilbertson. T.J. Concentration of ceftiofur metabolites in the plasma and lungs of horses following intramuscular treatment. J. vet. Pharmacol Therap. 17, 24–30. Ceftiofur sodium, a broad spectrum cephalosporin antibiotic approved for veterinary use, is metabolized to desfuroylceftiofur which is conjugated to micro as well as macromolecules. Twelve horses, weighing 442–618 kg, were injected intramuscularly with a single dose of 2.2 mg ceftiofur/kg (1.0 mg/lb) body weight. Blood was collected at various intervals over 24 h after treatment. Three groups of four horses each were euthanized and lungs were collected at 1,12, and 24 h after treatment. The concentration of desfuroylceftiofur and desfuroylceftiofur conjugates in the plasma and lungs was determined by converting them to desfuroylceftiofur acetamide (DCA) and measured DCA by high performance liquid chromatography with UV detection. The average maximum concentration (C_max) of desfuroylceftiofur and related metabolites in plasma expressed as ceftiofur equivalents was 4.46 ± 0.93 m̈g/ml occurred at 1.25 ± 0.46 h after treatment. These concentrations declined to 0.99 ± 0.16, 0.47 ± 0.15 and 0.17 ± 0.02 m̈g/ml at 8, 12, and 24 h, respectively. The mean residence time of ceftiofur metabolites was 6.10 ± 1.27 h. Concentration of desfuroylceftiofur and desfuroylceftiofur conjugates in the lungs of horses expressed as ceftiofur equivalents were 1.40 ± 0.36, 0.27 ± 0.07, and 0.15 ± 0.08 m̈g/ml at 1, 12, and 24 h, respectively. These concentrations of the drug at 12 and 24 h in lung homogenate were similar but slightly lower than plasma concentrations in the same horses, and the plasma pharmacokinetic values including half-life were similar to those observed at the approved dose of 1.1–2.2 mg ceftiofur/kg body weight administered intramuscularly once daily for 3–5 days in cattle.     

Effect of Pasteurella haemolytica infection on the distribution of sulfadiazine and trimethoprim into tissue chambers implanted subcutaneously in cattle

A study was designed to determine the effect of Pasteurella haemolytica infection on the rate and extent of penetration of sulfadiazine and trimethoprim into tissue chambers implanted SC in cattle. Thermoplastic tissue chambers were implanted SC in 6 calves. At 35 days after implantation, sulfadiazine (25 mg/kg of body weight) and trimethoprim (5 mg/kg) were administered IV to 5 of the calves. Chamber fluid and blood samples were collected from each animal at various time intervals for 24 hours after administration. Ten days later, all chambers were inoculated with P haemolytica serotype 1. At 36 hours after inoculation, a second pharmacokinetic study was conducted, using sulfadiazine and trimethoprim. Drug doses and sampling schedules were identical to those used prior to inoculation. A histologic study of infected chamber tissue was conducted, using the calf not included in the pharmacokinetic studies. Disposition curves of antimicrobials in serum and chamber fluid were well described by 2-compartment and 1-compartment pharmacokinetic models, respectively. Inoculation of P haemolytica into tissue chambers was accompanied by marked changes in the composition of chamber fluid. Increased total protein and albumin concentrations, decreased pH, and disruption of chamber tissue vasculature were associated with a significant increase in the penetration of sulfadiazine and trimethoprim into infected tissue chambers, compared with that in noninfected chambers. This increased penetration was accompanied by increases in the apparent volume of distribution for sulfadiazine and trimethoprim.     

Feedlot performance of steers treated concurrently with ceftiofur crystalline-free acid subcutaneously in the posterior aspect of the ear and a growth-promoting implant

Ceftiofur crystalline-free acid sterile suspension (CCFA-SS), a long-acting formulation of ceftiofur formulated for subcutaneous injection in the middle third of the posterior aspect of the ear, is being developed for the control and treatment of bovine respiratory disease. A study was designed to evaluate average daily gain (ADG) and feed efficiency (FE) for cattle through 140 days in the feedlot after CCFA-SS was administered concurrently in the same ear with a growth-promoting implant. On Day 0, steers (n = 207) averaging 189 kg in weight were randomly assigned to the following treatments: Revalor -S implant (120 mg trenbolone acetate and 24 mg estradiol per implant; Hoechst-Roussel Agri-Vet Company) (n = 64); CCFA-SS at 6.6 mg ceftiofur equivalents/kg and a Revalor -S implant (n = 64); untreated control (no CCFA-SS or implant) (n = 63); or CCFA-SS only (n = 16). On Day 56, an Implus-S implant (200 mg progesterone USP plus 20 mg estradiol benzoate; Pharmacia and Upjohn Animal Health) was administered to all cattle. Tolerance of administration of all materials was observed visually and by palpation of the treated ears. Average daily gain and FE from Day 0 through Day 56 were significantly (P <.001) better for steers of both groups with an implanted growth-promotant than for untreated controls. From Day 0 through Day 140, ADG was significantly (P <.05) better for cattle given an implant or an implant plus CCFA-SS than for untreated controls and FE was significantly (P <.05) better for cattle given an implant plus CCFA-SS than for controls. Mild or moderate, transient swelling of the treated ear was observed in two cattle (CCFA-SS plus implant) on Day 52. On Day 56, 88 % of cattle treated with CCFA-SS, 84 % of the cattle treated with an implant plus CCFA-SS, and 100 % of cattle in other groups were normal. Administration of CCFA-SS in the middle third of the posterior aspect of the ear at the same time as growth-promoting implants did not affect performance of cattle in the feedlot and was well tolerated by the animals.     

Response of Pasteurella haemolytica to erythromycin and dexamethasone in calves with established infection.

A subcutaneous soft tissue infection model in calves was used to study the in vivo response of Pasteurella haemolytica to erythromycin and dexamethasone. Two tissue chambers were implanted SC in each of 12 calves. At 45 days after implantation, all tissue chambers were inoculated with an erythromycin-sensitive strain of P haemolytica. Starting 24 hours after inoculation, calves were allotted to 4 groups of equal size and a 2 x 2-factorial arrangement of treatments was applied: 3 calves were given erythromycin (30 mg/kg of body weight, IM, for 5 days), 3 calves were given dexamethasone (0.05 mg/kg, IM, for 2 days), 3 calves were given erythromycin and dexamethasone, and the remaining calves served as nontreated controls. Chamber fluids were tested daily, and the response to treatment was measured. Neither erythromycin nor dexamethasone affected viability or growth of bacteria within tissue chambers. Dexamethasone had no effect on the influx of neutrophils into infected chambers. Despite repeated administration of a high dose of erythromycin and attainment of adequate concentration in serum, erythromycin concentration in chamber fluids did not exceed the minimal inhibitory concentration established in vitro. These results indicate that the clinical efficacy of erythromycin against P haemolytica sequestered in consolidated pneumonic lesions may not be well correlated with predictions based on serum pharmacokinetic and in vitro susceptibility data.     

Distribution of intramuscularly administered erythromycin into subcutaneous tissue chambers before and after inoculation with Pasteurella haemolytica

Distribution of erythromycin into subcutaneous tissue chambers was characterised pharmacokinetically and the effect of Pasteurella haemolytica infection on the extent of penetration was studied. Thermoplastic tissue chambers were implanted subcutaneously in the paralumbar fossae of six calves. Thirty-five days after implantation, the tissue chamber distribution of intramuscularly administered erythromycin (30 mg kg⁻¹) was studied. Chambers were then inoculated with P haemolytica and the tissue chamber pharmacokinetics of erythromycin were again studied. Diffusion of erythromycin into tissue chambers was best described using a two-compartment model with tissue chambers representing a relatively inaccessible compartment. Despite changes in chamber fluid pH, the extent of erythromycin penetration into chambers was not affected by P haemolytica inoculation. Comparison of computer simulated concentration-time curves resulting from different routes of administration revealed that penetration of erythromycin into less accessible sites was more likely to be higher after intravenous administration than after intramuscular administration.     

Efficacy of sustained release needle-less ceftiofur sodium implants in treating calves with bovine respiratory disease

Three experiments were conducted to determine preliminary efficacy of sustained release needle-less implants in effecting cure in calves with bovine respiratory disease. One hundred and twenty beef calves with a rectal temperature > or = 40 degrees C and shallow or labored respiration and coughing were used in these experiments. Four groups (1-ceftiofur sodium injections [days 1, 2, and 3], 2-ceftiofur sodium needle-less implants [days 1, 2, and 3], 3-ceftiofur sodium needle-less implants [days 1 and 3], and 4-ceftiofur sodium needle-less implants [day 1] were included. All treatments contained 250 mg of ceftiofur sodium and were administered intramuscularly in the neck after diagnosis of bovine respiratory disease. Experiment 1 included 20 calves (group 1-10 calves and group 3-10 calves; 213 to 255 kg) and calves were monitored for clinical efficacy. Experiment 2 included five calves per group (all four groups; 164 to 192 kg) and calves were bled frequently after treatment for desfuroylceftiofur (the primary ceftiofur metabolite) concentrations. Experiment 3 included 20 calves per group (all four groups; 160 to 205 kg) and calves were monitored for clinical efficacy. Blood desfuroylceftiofur concentrations remained above the minimum inhibitory concentration for Pasteurella haemolytica, Pasteurella multocida, and Haemophilus somnus for 24 hours after injection and 72 hours after implantation (P < 0.05). Mortalities and the number of calves with a positive response and relapse response were similar (P < 0.25) among the four groups. In summary, the administration of one-250 mg ceftiofur sodium needle-less sustained release implant was as efficacious in treating bovine respiratory disease as three daily 250 mg injections of ceftiofur sodium.     

Effects of age on the pharmacokinetics of single dose ceftiofur sodium administered intramuscularly or intravenously to cattle

The effects of maturation on the intravenous (IV) and intramuscular (IM) pharmacokinetics of ceftiofur sodium following a dose of 2.2 mg ceftiofur equivalents/kg body weight were evaluated in 16 one-day-old Holstein bull calves (33-53 kg body weight initially; Group 1) and 14 six-month-old Holstein steers (217-276 kg body weight initially; Group 2). Group 1 calves were fed unmedicated milk replacer until 30 days of age and were then converted to the same roughage/concentrate diet as Group 2. Groups 1-IV and 2-IV received ceftiofur sodium IV, and Groups 1-IM and 2-IM received ceftiofur sodium IM. Group 1 calves were dosed at 7 days of age and at 1 and 3 months of age; group 2 calves were dosed at 6 and 9 months of age. Blood samples were obtained serially from each calf, and plasma samples were analysed using an HPLC assay that converts ceftiofur and all desfuroylceftiofur metabolites to desfuroylceftiofur acetamide. C_max values were similar in all calves, and were no higher in younger calves than in older calves. Plasma concentrations remained above 0.150 μg ceftiofur free acid equivalents/mL for 72 h in 7-day-old calves, but were less than 0.150 μg/mL within 48 h following IV or IM injection for 6- and 9-month-old calves. Intramuscular bioavailability, assessed by comparing the model-derived area under the curve (AUC_mod) from IM and IV injection at each age, appeared to be complete. After IV administration, the AUC_mod in 7-day-old and 1-month-old calves (126.92±21.1 μg-h/mL and 135.0±21.6 μg.h/mL, respectively) was significantly larger than in 3-, 6- and 9-month-old calves (74.0±10.7 μg.h/mL, 61.0±17.7 μg.h/mL and 68.5±12.8 μg.h/mL, respectively; P< 0.0001). The V_d(ss) decreased linearly within the first 3 months of life in cattle (0.345±0.0616 L/kg, 0.335±0.919 L/kg and 0.284±0.0490 L/kg, respectively; P= 0.031), indicative of the decreasing extracellular fluid volume in maturing cattle. The Cl_b was significantly smaller in 7-day-old and 1-month-old calves (0.0178±0.00325 L/h.kg and 0.0167±0.00310 L/h.kg, respectively) than in 3-, 6- and 9-month-old calves (0.0303±0.0046 L/h.kg, 0.0398±0.0149 L/h.kg and 0.0330±0.00552 L/h.kg, respectively; P≦0.001). This observation may be indicative of maturation of the metabolism and/or excretion processes for ceftiofur and desfuroylceftiofur metabolites. The approved dosage regimens for ceftiofur sodium of 1.1-2.2 mg/kg administered once daily for up to 5 consecutive days will provide plasma concentrations above the MIC for bovine respiratory disease pathogens for a longer period of time in neonatal calves than in older calves. Peak plasma concentrations of ceftiofur and desfuroylceftiofur metabolites were no higher in neonatal calves than in more mature cattle, highly suggestive that peak tissue concentrations would be no higher in neonatal calves than in more mature cattle.     

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.     

Clinical efficacy of a single injection of ceftiofur crystalline free acid sterile injectable suspension versus three daily injections of ceftiofur sodium sterile powder for the treatment of footrot in feedlot cattle

A study was conducted in a feedlot in Alberta, Canada, to compare the clinical efficacy of a single injection of ceftiofur crystalline free acid sterile injectable suspension with three daily treatments of ceftiofur sodium sterile powder for the treatment of footrot. Use of a long-acting antimicrobial to treat footrot would reduce labor costs and hospital pen space requirements during high-risk periods. Four hundred cattle clinically diagnosed with footrot were systematically randomized to one of two treatment groups. The treatment success rate at 14 days after treatment (99.5% for ceftiofur crystalline free acid sterile injectable suspension and 99.0% for ceftiofur sodium sterile powder for injection) was not statistically different (P>.05) between the two drugs.     

Determination of synovial fluid and serum concentrations, and morphologic effects of intraarticular ceftiofur sodium in horses

OBJECTIVES: To determine the serum and synovial fluid concentrations of ceftiofur sodium after intraarticular (IA) and intravenous (IV) administration and to evaluate the morphologic changes after intraarticular ceftiofur sodium administration. STUDY DESIGN: Strip plot design for the ceftiofur sodium serum and synovial fluid concentrations and a split plot design for the cytologic and histopathologic evaluation. ANIMALS: Six healthy adult horses without lameness. METHODS: Stage 1: Ceftiofur sodium (2.2 mg/kg) was administered IV. Stage 2: 150 mg (3 mL) of ceftiofur sodium (pHavg 6.57) was administered IA into 1 antebrachiocarpal joint. The ceftiofur sodium was reconstituted with sterile sodium chloride solution (pH 6.35). The contralateral joint was injected with 3 mL of 0.9% sterile sodium chloride solution (pH 6.35). Serum and synovial fluid samples were obtained from each horse during each stage. For a given stage, each type of sample (serum or synovial fluid) was collected once before injection and 12 times after injection over a 24-hour period. All horses were killed at 24 hours, and microscopic evaluation of the cartilage and synovium was performed. Serum and synovial fluid concentrations of ceftiofur sodium were measured by using a microbiologic assay, and pharmacokinetic variables were calculated. Synovial fluid was collected from the active joints treated during stage 2 at preinjection and postinjection hours (PIH) 0 (taken immediately after injection of either the ceftiofur sodium or sodium chloride), 12, and 24, and evaluated for differential cellular counts, pH, total protein concentration, and mucin precipitate quality. RESULTS: Concentrations of ceftiofur in synovial fluid after IA administration were significantly higher (P = .0001) than synovial fluid concentrations obtained after IV administration. Mean peak synovial fluid concentrations of ceftiofur after IA and IV administration were 5825.08 microg/mL at PIH .25 and 7.31 microg/mL at PIH 4, respectively. Mean synovial fluid ceftiofur concentrations at PIH 24 after IA and IV administration were 4.94 microg/mL and .12 microg/mL, respectively. Cytologic characteristics of synovial fluid after IA administration did not differ from cytologic characteristics after IA saline solution administration. White blood cell counts after IA ceftiofur administration were < or =3,400 cells/ML. The mean synovial pH of ceftiofur treated and control joints was 7.32 (range, 7.08-7.5) and 7.37 (range, 7.31-7.42), respectively. Grossly, there were minimal changes in synovium or cartilage, and no microscopic differences were detected (P = .5147) between ceftiofur-treated joints and saline-treated joints. The synovial half-life of ceftiofur sodium after IA administration joint was 5.1 hours. CONCLUSIONS: Synovial concentrations after intraarticular administration of 150 mg of ceftiofur sodium remained elevated above minimal inhibitory concentration (MIC90) over 24 hours. After 2.2 mg/kg IV, the synovial fluid ceftiofur concentration remained above MIC no longer than 8 hours. CLINICAL RELEVANCE: Ceftiofur sodium may be an acceptable broad spectrum antimicrobial to administer IA in septic arthritic equine joints.     

Interaction between Pasteurella haemolytica, sulfadiazine/trimethoprim, and bovine viral diarrhea virus

A study was designed to develop and define a sc tissue chamber as a suitable device for establishing a soft-tissue infection model in cattle and to use this model to study the interaction between Pasteurella haemolytica, sulfadiazine/trimethoprim, and bovine viral diarrhea virus (BVDV). Thermoplastic tissue chambers were implanted in the paralumbar fossae of 20 calves. At 35 days after implantation, calves were allotted to 4 groups of equal size and the calves in 2 groups were inoculated intratracheally with a New York-1 strain of BVDV. At 45 days after implantation, all chambers were inoculated with a 6-hour culture of P haemolytica serotype 1. Starting 36 hours after bacterial inoculation, sulfadiazine/trimethoprim was administered IV once a day to half of the virus-inoculated calves and to half of those calves that had not been exposed to virus. Inoculation of P haemolytica into tissue chambers resulted in the establishment of a localized soft-tissue infection, characteristic of pneumonic pasteurellosis. Despite the maintenance of chamber antimicrobial concentrations that exceeded minimal bactericidal concentrations established in vitro, the infections were not sterilized. This lack of efficacy was associated with decreased pH and increased protein concentrations in chamber fluids after inoculation. Infection with BVDV, which is thought to depress host defenses, had no effect on the response of P haemolytica to sulfadiazine/trimethoprim administration. Observation of responsive antibody titers, bacterial phagocytosis, and high leukocyte viability within P haemolytica-infected chambers documented functional host defenses within tissue chambers.     

Pharmacokinetics of ceftiofur crystalline free acid after single subcutaneous administration in lactating and nonlactating domestic goats (Capra aegagrus hircus)

Doré, E., Angelos, J. A., Rowe, J. D., Carlson, J. L., Wetzlich, S. E., Kieu, H. T., Tell, L. A. Pharmacokinetics of ceftiofur crystalline free acid after single subcutaneous administration in lactating and nonlactating domestic goats (Capra aegagrus hircus). J. vet. Pharmacol. Therap. 34 , 25–30. Six nonlactating and six lactating adult female goats received a single subcutaneous injection of ceftiofur crystalline free acid (CCFA) at a dosage of 6.6 mg/kg. Blood samples were collected from the jugular vein before and at multiple time points after CCFA administration. Milk samples were collected twice daily. Concentrations of ceftiofur and desfuroylceftiofur‐related metabolites were measured using high‐performance liquid chromatography. Data were analyzed using compartmental and noncompartmental approaches. The pharmacokinetics of CCFA in the domestic goat was best described by a one compartment model. Mean (±SD) pharmacokinetic parameters were as follows for the nonlactating goats: area under the concentration time curve_0–∞ (159 h·μg/mL ± 19), maximum observed serum concentration (2.3 μg/mL ± 1.1), time of maximal observed serum concentration (26.7 h ± 16.5) and terminal elimination half life (36.9 h; harmonic). For the lactating goats, the pharmacokinetic parameters were as follows: area under the concentration time curve_0–∞ (156 h·μg/mL ± 14), maximum observed serum concentration (1.5 μg/mL ± 0.4), time of maximal observed serum concentration (46 h ± 15.9) and terminal elimination half life (37.3 h; harmonic). Ceftiofur and desfuroylceftiofur‐related metabolites were only detectable in one milk sample at 36 h following treatment. There were no significant differences in the pharmacokinetic parameter between the nonlactating and lactating goats.     

Pharmacokinetics of intravenous ceftiofur sodium and concentration in body fluids of foals

The objectives of this study were to determine pharmacokinetics of intravenous (i.v.) ceftiofur in foals, to compare ultra-high performance liquid chromatography tandem mass spectometry (UPLC-MS/MS) and microbiologic assay for the measurement of ceftiofur concentrations, and to determine the minimum inhibitory concentration ( MIC ) of ceftiofur against common equine bacterial pathogens. In a cross-over design, ceftiofur sodium was administered i.v. to six foals (1–2 days-of-age and 4–5 weeks-of-age) at dosages of 5 and 10 mg/kg. Subsequently, five doses of ceftiofur were administered i.v. to six additional foals between 1 and 5 days of age at a dose of 5 mg/kg q 12 h. Concentrations of desfuroylceftiofur acetamide (DCA), the acetamide derivative of ceftiofur and desfuroylceftiofur-related metabolites were measured in plasma, synovial fluid, urine, and CSF by use of UPLC-MS/MS. A microbiologic assay was used to measure ceftiofur activity for a subset of plasma samples. Following i.v. administration of ceftiofur at a dose of 5 mg/kg to 1–2 day-old foals, DCA had a t _½ of 7.8 ± 0.1 h, a body clearance of 74.4 ± 8.4 mL/h/kg, and an apparent volume of distribution of 0.83 ± 0.09 L/kg. After multiple i.v. doses at 5 mg/kg, DCA concentrations in CSF were significantly lower than concurrent plasma concentrations. Ceftiofur activity using a microbiologic assay significantly underestimated plasma concentrations of DCA. The MIC of ceftiofur required to inhibit growth of 90% of isolates of Escherichia coli , Pasteurella spp, Klebsiella spp, and β-hemolytic streptococci was <0.5 μg/mL. Intravenous administration of ceftiofur sodium at the rate of 5 mg/kg every 12 h would provide sufficient coverage for the treatment of susceptible bacterial isolates.     

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

Ceftiofur, a third‐generation cephalosporin antibiotic, is being extensively used by pet doctors in China. In the current study, the detection method was developed for ceftiofur and its metabolites, desfuroylceftiofur (DCE) and desfuroylceftiofur conjugates (DCEC), in feline plasma. Then, the pharmacokinetics studies were performed following one single intravenous and subcutaneous injection of ceftiofur sodium in cats both at 5 mg/kg body weight (BW) (calculated as pure ceftiofur). Ceftiofur, DCE, and DCEC were extracted from plasma samples, then derivatized and further quantified by high‐performance liquid chromatography. The concentrations versus time data were subjected to noncompartmental analysis to obtain the pharmacokinetics parameters. The terminal half‐life (t_1/2λz) was calculated as 11.29 ± 1.09 and 10.69 ± 1.31 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 14.14 ± 1.09 ml hr^‐1 kg^‐1 and 241.71 ± 22.40 ml/kg, respectively. After subcutaneous injection, the peak concentration (C_max; 14.99 ± 2.29 μg/ml) was observed at 4.17 ± 0.41 hr, and the absorption half‐life (t_1/2ka) and absolute bioavailability (F) were calculated as 2.83 ± 0.46 hr and 82.95%±9.59%, respectively. The pharmacokinetic profiles of ceftiofur sodium and its related metabolites demonstrated their relatively slow, however, good absorption after subcutaneous administration, poor distribution, and slow elimination in cats. Based on the time of drug concentration above the minimum inhibitory concentration (MIC) (T>MIC) calculated in the current study, an intravenous or subcutaneous dose at 5 mg/kg BW of ceftiofur sodium once daily is predicted to be effective for treating feline bacteria with a MIC value of ≤4.0 μg/ml.     

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 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.