A Randomized, Crossover Design Study of the Pharmacology of Extended-Spectrum Fluoroquinolones for Pneumococcal Infections

The objectives of this study were to characterize the single-dose and steady-state plasma pharmacokinetics of IV levofloxacin and IV alatrofloxacin, and to compare the results to pneumococcal isolate sensitivities in order to estimate the clinical efficacy of current community-acquired pneumonia treatment regimens against pneumococcal infections. Two-way, open-label, randomized, crossover study. Each of 12 healthy volunteer subjects received IV levofloxacin, 500 mg qd for 7 days, and IV alatrofloxacin, 200 mg qd for 7 days. The two regimens were separated by a 2-week washout period. Plasma concentration profiles were collected around the first and final doses of both regimens and were assayed for their respective quinolone concentrations. When the peak concentrations for both agents were compared to standard twofold dilution minimum inhibitory concentration (MIC) values for pneumococcal isolates, it was discovered that the breakpoint MIC value at which each compound would no longer achieve a peak plasma concentration/MIC ratio of at least 12:1 was 0.5 mg/L for levofloxacin and 0.25 mg/L for alatrofloxacin. Based on the MIC that inhibits 90% of isolates of Streptococcus pneumoniae for both of these agents (1.0 to 2.0 mg/L for levofloxacin and 0.125 to 0.25 mg/L for trovafloxacin), our results indicate that although the once-daily regimen of alatrofloxacin appears to be appropriate for this pathogen, a more aggressive regimen may need to be investigated to optimize the clinical and microbiological effects of levofloxacin.