Levofloxacin exhibits concentration-dependent bactericidal activity with clinical outcomes most closely related to Cmax/MIC and AUC/MIC ratios. Using a higher dose of levofloxacin (750 mg vs. 500 mg) will increase the peak concentration and AUC achieved in plasma and target tissues. While the increase from the 500 mg to the 750 mg dose represents an increase in dose of 50%, the AUC increases by more than 50%. The usual serum Cmax increases from 5.7 to 8.6 and the AUC from 47.5 to approx 91 (1, 2). Thus, there is almost a doubling of the AUC which represents a significant increase in the pharmacodynamic parameters. This is particularly important since it has been demonstrated that the pharmacodynamic parameter which best predicts bacterial eradication and clinical outcomes associated with fluoroquinolones is the AUC/MIC (3).

In addition to plasma, the levels of levofloxacin achieved in epithelial lining fluid increase significantly when the dose is increased to 750 mg. Since there appears to be a correlation between antimicrobial penetration into this fluid compartment and clinical outcomes for pneumonia, this is of great consequence. Gotfried and co-workers compared the epithelial lining fluid and alveolar macrophage levels in patients receiving levofloxacin 750 mg or 500 mg daily for 5 days (4). The mean maximum steady-state levofloxacin concentration four hours after administration in epithelial lining fluid was 9.9 μg/mL for the 500 mg dose compared to 22.1 μg/mL for the 750 mg dose. An increase in the concentration of the drug in alveolar macrophages was also observed. The higher concentrations obtained with the 750 mg dose, especially in epithelial lining fluid, maximizes the AUC/MIC and Cmax/MIC at key sites of microbial killing of both extracellular (for example, S. pneumoniae, H. influenzae) and intracellular (Legionella, Chlamydophila pneumoniae) pathogens associated with CAP.