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

Abstract

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.

Pharmacokinetics of ceftiofur crystalline-free acid following subcutaneous administration of a single dose to sheep

“…Subcutaneous administration of CCFA (6.6 mg/kg) to the sheep of the present study resulted in a Cmax of 2.45 µg/mL and Tmax of 23.11 hours. 25 Additionally, the λ z and t 1/2λz were much higher for the sheep administered CCFA in the present study, compared with those for the sheep administered ceftiofur sodium in that other study. Ceftiofur sodium is a water-based sodium salt that is formulated for rapid absorption, whereas CCFA contains ceftiofur in a caprylic and capric triglyceride and cottonseed oil-based suspension that is formulated for slow release.…”

“…15 In cattle, a single dose of CCFA administered SC in the cervical region causes violative residues of CFAE in tissues at and adjacent to the injection site for an extensive period, 29 whereas SC administration of a single dose of CCFA in the base of an ear results in a relatively short (13 days) withdrawal time because the ears of cattle are considered inedible by the USDA and are removed from the carcass at slaughter. Although the cervical region is the preferred site for injecting medications in sheep because it minimizes the risk for injection site lesions in the prime cuts of meat, it differs from the FDAapproved site for injection of CCFA in cattle, which is the caudal aspect of the middle third of the pinna or base of an ear.…”

Accidental Intra-Auricular Artery Injection of Ceftiofur in Two Beef Steers

“…Ear injection of this antibiotic preparation has been shown to be as effective as other routes of administration and has the added benefits of no injection site trimmings at slaughter and, because the ear is an inedible tissue, a short withdrawal time. 5 The 2 presented animals became recumbent 2 to 3 minutes after injection and were dead 5 minutes later as perceived by the owner. At necropsy, both animals were in good body condition with moderate postmortem autolysis (death occurred the day before necropsy).…”

Ceftiofur Distribution in Plasma and Tissues Following Subcutaneously Administration in Ducks

“…Ceftiofur has been world-widely used for cattle to treat bovine respiratory disease associated with Pasteurella hemolytica, Pasteurella multocida, and Haemophilus somnus, for swine to treat pleuropneumonia caused by Actinobacillus pleuropneumonia, and for chickens to treat fowl typhus and diarrhea associated with Salmonella Garinarium and Escherichia coli [10,18].…”