Pharmacodynamic analysis of the microbiological efficacy of telithromycin in patients with community-acquired pneumonia

Background and objective: Telithromycin, a ketolide antibacterial, demonstrates concentration-dependent bactericidal activity against the major pathogens causing community-acquired respiratory tract infections. The objective of this study was to explore the relationships between pharmacokinetic/pharmacodynamic predictor variables, such as area under the plasma concentration-time curve (AUC) over minimum inhibitory concentration (MIC) [AUC/MIC], maximum plasma concentration (C-max) over MIC (C-max/MIC) and microbiological outcome from telithromycin therapy for community-acquired pneumonia (CAP). Patients and methods: Data were pooled from five phase III studies of oral telithromycin (800mg once daily for 7-10 days) for the outpatient treatment of adults with CAP. Only subjects with a single pathogen isolated at baseline, a telithromycin MIC determination and at least one plasma pharmacokinetic sample were included. Bacteriologically modified intent-to-treat (bmITT) and bacteriologically evaluable per protocol (PPb) populations were analysed. Individual AUC and Cmax Bayesian estimates were obtained with a population pharmacokinetic model. Logistic regression, nonparametric smoothing, and classification analysis and regression tree (CART) were used to assess the relationship between AUC/MlC and C-max/MIC and microbiological outcome by pathogen. Results: The bmITT population included 224 patients (Streptococcus pneumoniae in 113, Haemophilus influenzae in 89 and Staphylococcus aureus in 22). Median telithromycin MIC was 0.015 mu g/mL for S. pneumoniae, 2.0 mu g/mL for H. influenzae and 0.12 mu g/mL for S. aureus, with median AUC/MIC of 907.1, 6.9 and 98.4, and median C-max/MIC of 172.0, 1.3 and 20.4 for the three pathogens, respectively. Both logistic regression and nonparametric smoothing showed the probability of microbiological cure to be consistently greater than 90% over the observed range of predictor variables. No reliable AUC/MIC or C-max/MIC breakpoints were identified by CART. Conclusion: Telithromycin exhibits near-maximal efficacy against three major pathogens causing CAP at a dose of 800mg once daily.