Pharmacodynamics of levofloxacin: A new paradigm for early clinical trials

Abstract

Context.-One purpose of early clinical trials is to establish the appropriate dose of an antibiotic for phase 3 trials. Development of a relationship between the ratio of drug exposure to organism minimum inhibitory concentration (MIC) and therapeutic response early in the development process would allow an optimal choice of dose to maximize response. Objective.-To prospectively quantitate the relationship between plasma levels of levofloxacin and successful clinical and/or microbiological outcomes and occurrence of adverse events in infected patients. Design.- Multicenter open-label trial. Setting.-Twenty-two enrolling university- affiliated medical centers. Patients.-A total of 313 patients with clinical signs and symptoms of bacterial infections of the respiratory tract, skin, or urinary tract. Main Outcome Measures.-Clinical response and microbiological eradication of pathogenic organisms. Results.-Of 313 patients, 272 had plasma concentration-time data obtained. Of these, 134 patients had a pathogen recovered from the primary infection site and had an MIC of the pathogen to levofloxacin determined. These patients constituted the primary analysis group for clinical outcome. Groups of 116 and 272 patients, respectively, were analyzed for microbiological outcome and incidence of adverse events. In a logistic regression analysis, the clinical outcome was predicted by the ratio of peak plasma concentration to MIC (Peak/MIC) and site of infection (P