Altered pharmacokinetic disposition of ciprofloxacin and vancomycin after single and multiple doses in rabbits

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Abstract
The pharmacokinetic disposition of vancomycin and ciprofloxacin was assessed in rabbits before the efficacy of these compounds in experimental staphylococcal endocarditis was compared. Ciprofloxacin was given in single intravenous bolus doses of 25 and 35 mg/kg and also in a multiple-dose regimen of 35 mg/kg every 6 h. Vancomycin was given in a similar manner in single doses of 17.5 and 25 mg/kg and in a multiple-dose regimen of 17.5 mg/kg every 6 h. Serum was sampled frequently after injections and analyzed by microbiologic assay for drug concentration. The pharmacokinetic parameters of clearance and steady-state volume of distribution were calculated by compartment-independent methods. These studies revealed that clearance of ciprofloxacin was reduced significantly after multiple doses (7.42 .+-. 0.85 [standard deviation] versus 6.09 .+-. 0.71 liters/h, P < 0.01). Although the half-life and volume of distribution increased after multiple dosing, the differences were not statistically significant. The disposition of vancomycin following single doses was significantly altered after the 25-mg/kg dose compared with the 17.5-mg/kg dose. Half-life, clearance, and volume of distribution changed from 1.27 .+-. 0.2 to 1.60 .+-. 0.21 h (P < 0.05), 0.54 .+-. 0.05 to 0.39 .+-. 0.04 liters/h (P < 0.01), and 0.37 .+-. 0.04 to 0.31 .+-. 0.03 liters/kg (P < 0.05), respectively. The disposition of ciprofloxacin was not altered with increases in dose size, and the disposition of vancomycin was not altered after multiple doses. If such alterations in the pharmacokinetic disposition of antimicrobial agents are unanticipated, the higher and more prolonged than expected serum concentrations may have an effect on the outcome of experimental infections.

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