Cephalosporins are an important class of antibacterial agents in use today for both humans and animals. Four generations of cephalosporins have evolved, all of which contain the beta-lactam sub-structure first found in penicillin. The range of cephalosporins available for use in food-producing animals, which is the subject of this review, is limited compared to humans. A few first- and second-generation cephalosporins are approved worldwide strictly for treatment of mastitis infections in dairy cattle. A third-generation cephalosporin, ceftiofur, and a fourth-generation cephalosporin, cefquinome, have been developed strictly for veterinary use. Cefquinome has been approved in several countries for the treatment of respiratory disease in cattle and swine, foot rot in cattle and for mastitis in dairy cattle. Ceftiofur has worldwide approvals for respiratory disease in swine, ruminants (cattle, sheep and goats) and horses and has also been approved for foot rot and metritis infections in cattle. Ceftiofur has also been approved in various countries for early mortality infections in day-old chicks and turkey poults. This review summarizes cephalosporin use in general terms, and provides an overview of ceftiofur, in terms of its spectrum of activity, indications, metabolism, and degradation in the environment. The safety of ceftiofur is also reviewed, with respect to food-animal residues, rapid metabolism and degradation, and non-persistence of ceftiofur in the environment. The environmental fragility of cephalosporins have not been explored generally, but may be an important characteristic of this antibiotic class with respect to safety of use in animals.

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Ceftiofur sodium, a new broad-spectrum cephalosporin, has been approved in the US, Canada, and several other countries throughout the world to treat bovine respiratory disease in cattle and dairy cows. In Experiment 1, 6 lactating cows were intramuscularly treated with 2.29 mg of [14C]ceftiofur/kg of BW daily for 5 d. In Experiment 2, 30 additional cows at three locations were similarly treated with 2.2 mg of ceftiofur (unlabeled)/kg of BW. Milk was collected every 12 and 24 h after each dose and every 12 h up to 5 d after the last dose. The majority of milk samples, both during treatment (12 and 24 h after each dose) and after the last dose (up to 5 d following ceftiofur treatment), were negative by screening procedures based on microbial inhibition (Delvotest-P, Bacillus stearothermophilus disk assay, and cylinder plate assays). The receptor-binding Charm Test II assay, which has a limit of detection of .005 ppm of ceftiofur, gave positive tests for milk samples up to 48 h following treatment. When the Charm Test II assay is used with .008 IU/ml of penicillin as a positive control, 44% of the samples from individual cows were negative at 12 h posttreatment. Ninety percent of the samples from individual cows were negative at 24 h after the last treatment. The use of ceftiofur in dairy cattle in accordance with the label directions does not result in total residues in milk higher than the FDA-calculated safe concentration of 1-ppm ceftiofur equivalents. The milk from individual cows did not test positive by the commercial screening assays examined in this study, except for the Charm Test II. The Charm Test II was 90% negative using the Charm Sciences criteria at 24 h after the last treatment.

Twelve mixed-breed swine (26.5-42.5 kg) received three daily intramuscular (i.m.) doses of 14C-ceftiofur hydrochloride. Three males and three females, received 6.76 +/- 0.83 mg of 14C-ceftiofur free acid equivalents (CFAE)/kg body weight (b.w.)/day, while the other group received 4.41 +/- 0.97 mg.CFAE/kg b.w./day. The swine were slaughtered 12 h following the last dose. Total dose accountability for the 6.76 mg dose was 91.44 +/- 16.11% (72.51% in urine; 12.63% in faeces). For the 4.41 mg dose, accountability was 100.35 +/- 20.45% (82.48% in urine; 12.85% in faeces). Within the tissues used for residue monitoring, the highest concentrations were observed in the kidneys (10.68 and 6.33 micrograms.CFAE/g for the 6.76 and 4.41 mg doses, respectively), followed by the injection sites, lungs, liver and muscle. In a separate study, twelve mix-breed swine (23.1-39.7 kg) received 14C-ceftiofur hydrochloride at 3.08 mg.CFAE/kg b.w. once daily for 3 days. Two males and two females were slaughtered at either 12, 72 or 120 h after the last dose. Total dose accountability for the 3.08 mg dose was > 83% (> 68% in urine; > 13% in faeces). In swine slaughtered 12 h after last dose, residue concentrations closest to the safe concentrations were observed in the kidneys (3.62 micrograms.CFAE/g), followed by the injection sites, lungs, liver and muscle.

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15 min at 85°. Distillation gave dimethylphenyldifiuorophos-phorane25•26 (10) in 91% yield. This substance had bp 30°( 0.02 mm). The nmr spectrum of a fresh solution in CDC13 at 25°h ad six protons at 8.20 ppm, /m> = 17.7 cps, /hf = 12.5 cps (doublet of triplets), and five aromatic protons. For (C6H5)-(CH3)2P: t 8.75 ppm, /up = 2.7 cps. See 31P nmr data in the Results section.The residue from the above distillation solidified and was characterized as (C6FFP)S ( 12), mp 150-155=, 31 = +4.3 ppm; the material was isolated in 85 % yield.(b) An equimolar mixture of dimethylphenylphosphine and difluorophenylphosphine was kept 5 min at 20°. The mixture was dissolved in CH2C12 and the solution was analyzed by 31P nmr spectrometry. It contained unreacted tertiary phosphine and fluorophosphine and relatively small amounts of the phosphorane, 10, and (C6HaP)3,12, but no other intermediates or by-products.Reaction with Methyldiphenylphosphine. Equimolar amounts of the reagents were kept 15 min at 20°. No reaction was detected. Reaction was complete after 7 days at 20c. The products were methyldiphenyldifluorophosphorane25'26 (11) and (CeFEP).-, (12).