Pharmacokinetic and Pharmacodynamic Profiles of Danofloxacin Administered by Two Dosing Regimens in Calves Infected withMannheimia(Pasteurella)haemolytica

Abstract

The pharmacokinetics and pharmacodynamics of danofloxacin in calves with induced Mannheimia (Pasteurella) haemolytica pneumonia were evaluated. Calves received either saline as an intravenous (IV) bolus or danofloxacin (0.738 mg/kg of body weight) administered as either a single IV bolus or a 36-h continuous IV infusion. Blood samples and bronchial secretions were collected before and at predetermined times over 48 h following the start of treatment. Calves were assessed clinically throughout, and lung consolidation was assessed at necropsy. Bronchial secretions and lung tissue were cultured for M. haemolytica. Bolus administration of danofloxacin produced a high maximum drug concentration-to-MIC ratio (C max :MIC) of 14.5 and a time period of 9.1 h when plasma danofloxacin concentrations exceeded the MIC (T>MIC). Danofloxacin is a fluoroquinolone antimicrobial drug with rapid bactericidal activity against a broad range of pathogens responsible for a number of disease syndromes of economic importance in the commercial rearing of livestock (8,15). Since their introduction in the late 1980s, fluoroquinolones have been shown by a number of studies to exhibit concentration-dependent bactericidal activity, whereby the optimal effect is attained by the administration of high doses over a short period (4,6,14). This is a property shared by the aminoglycosides but is in contrast to the predominantly time-dependent bactericidal action shown by the ␤-lactam antibiotics (3), where the time that bacteria are exposed to antimicrobial concentrations exceeding the MIC (TϾMIC) is the major determinant of efficacy. These different types of action have been confirmed for danofloxacin and amoxicillin in an in vitro pharmacodynamic model against Actinobacillus pleuropneumoniae (9).The purpose of this study was to establish the pharmacokinetic and pharmacodynamic properties of danofloxacin in vivo by using an experimental model of calf pneumonia and to determine whether the concentration-dependent activity of danofloxacin in cattle operates under simulated clinical conditions. A fixed equal total dose of danofloxacin was administered either as a single intravenous (IV) bolus or by continuous infusion over a 36-h period, and the clinical and bacteriological outcomes in calves with induced infections of Mannheimia (Pasteurella) haemolytica were compared. The study was conducted in compliance with Good Clinical Practice guidelines (5), the analysis of samples was conducted in accordance with Good Laboratory Practice guidelines (16), and the husbandry of all animals was in compliance with the requirements of national legislation and local animal welfare guidelines. The study was conducted under veterinary supervision, with veterinary attention available at all times. MATERIALS AND METHODSAnimals. Thirty-three male Friesian calves (approximately 11 to 13 weeks of age, with initial body weights of 66.5 to 106 kg) were enrolled in the study and inoculated with M. haemolytica. Prior to enrollment, the calves were free from preexisting medic...

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