Dose-Finding Investigations of Intravenous Ciprofloxacin in a Pharmacodynamic Model

Abstract

Major predictive parameters for the therapeutic efficacy of antibiotics are its minimal inhibitory concentrations (MICs) against a broad spectrum of pathogens and the concentrations of the compound achievable in humans (e.g., plasma, tissues, and other sites of infections) at various dosing regimens. The relationship between these two parameters is conventionally used to define an MIC breakpoint below which pathogens are classified as susceptible to therapy by this drug. Thus predictions on efficacy of therapy by an antibacterial agent rely mainly on the relationship of bacteriological and pharmacokinetic parameters. The approach suffers from various dissimilarities between in vitro and in vivo conditions; for example, the MIC is determined by exposing a bacterial culture for 16 h to a constant concentration of antibiotic. In vivo, however, the pathogen is exposed to a gradient of antibiotic which follows its pharmacokinetics at the site of infection. Therefore it appears desirable to have both parameters integrated into a single system which could evaluate the effect of an antibiotic against a pathogen of known MIC during exposure to concentrations of the compound which follow its pharmacokinetics in vivo, for example, in human serum. Pharmacodynamic models for this type of investigation have been used for many years [12, 16]. These have been extensively reviewed and compared by Bergan [7]. We used a system of this type for an experimental approach to the question of dosing of ciprofloxacin and to elaborate suggestions for optimal dosing.