Pharmacodynamic rationale for short-duration antibacterial therapy

With the global spread of antibacterial resistance, selecting appropriate therapy for respiratory tract infections (RTIs) presents a major challenge. Current opinion favours short-duration chemotherapy, which can improve patient compliance, thereby reducing potential resistance, minimize toxicodynamic profiles and decrease treatment costs. Neither microbiological nor pharmacokinetic (PK) data alone can determine whether a drug is suitable for short-duration therapy. Pharmacodynamics (PD) seeks to integrate PK and microbiological data into models that can then be used to predict clinical outcomes and to guide rational dosing strategies. Telithromycin is the first ketolide antibacterial to undergo clinical development. Its novel structure provides enhanced microbiological activity, even against beta-lactam and macrolide-resistant pathogens, and the potential to minimize the selection of resistance. PK profiling of telithromycin reveals that once-daily oral administration of 800 mg achieves plasma concentrations that exceed the MICs of key respiratory pathogens throughout most of the dosing period. PK-PD modelling indicates that the AUC:MIC ratio is predictive of outcome for this antibacterial. Telithromycin achieves high AUC:MIC ratios, has a prolonged postantibiotic effect, shows excellent penetration into respiratory and inflammatory tissues and has a long elimination half-life from these tissues. These variables strongly suggest that telithromycin is suitable for short-duration therapy and a once-daily dosing regimen.