The fluoroquinolone antimicrobial drug danofloxacin was administered to sheep intravenously (i.v.) and intramuscularly (i.m.) at a dose of 1.25 mg/kg of body weight in a two-period crossover study. The pharmacokinetic properties of danofloxacin in serum, inflamed tissue cage fluid (exudate), and noninflamed tissue cage fluid (transudate) were established by using a tissue cage model. The in vitro and ex vivo activities of danofloxacin in serum, exudate, and transudate against a pathogenic strain of Mannheimia haemolytica were established. Integration of in vivo pharmacokinetic data with the in vitro MIC provided mean values for the area under the curve (AUC)/MIC for serum, exudate, and transudate of 60.5, 85.6, and 45.7 h, respectively, after i.v. dosing and 55.9, 77.9, and 49.1 h, respectively, after i.m. dosing. After i.m. dosing, the maximum concentration/MIC ratios for serum, exudate, and transudate were 10.8, 3.0, and 1.6, respectively. The ex vivo growth inhibition data after i.m. dosing were fitted to the inhibitory sigmoid E max equation to provide the values of AUC/MIC required to produce bacteriostasis, bactericidal activity, and elimination of bacteria. The respective values for serum were 17.8, 20.2, and 28.7 h, and slightly higher values were obtained for transudate and exudate. It is proposed that use of these data might provide a novel approach to the rational design of dosage schedules.Danofloxacin is an antibacterial drug of the fluoroquinolone group developed for use in veterinary medicine. It achieves high concentrations in several tissues, including the lung (11,22,23,33). Moreover, studies in our laboratory have demonstrated that the volume of distribution exceeds 3 liters/kg in four ruminant species after intravenous (i.v.) dosing (28). However, only one previous publication has described the pharmacokinetics (PK) of danofloxacin in sheep (22).The spectrum of antimicrobial activity of danofloxacin is wide and includes most gram-negative bacteria and some gram-positive bacteria, mycoplasmas, and intracellular pathogens, such as Brucella and Chlamydia species; but it has poor activity against anaerobes (1,13,25,32). Detailed studies of its spectrum of activity against sheep pathogens have not been described, but MICs at which 90% of strains are inhibited (MIC 90 s) of Յ0.25 g/ml for the cattle pathogens Mannheimia haemolytica, Pasteurella multocida, Haemophilus somnus, Mycoplasma bovis, and Mycoplasma dispar have been reported (3,10,12,21).Bacterial diseases in sheep cause morbidity, mortality, suffering, and significant economic losses. Antibacterial drugs are therefore used in both treatment and prevention programs. However, there are only limited data on the pharmacology of antibacterial drugs in sheep. Such data are required for the design of rational dosage schedules for clinical use. In addition, the sheep is a suitable species for use in models of disease and inflammation because of its size, temperament, and the ease of repeated samplings of blood and other body fluids.The design of e...