Question 7

Could you discuss the role of this high-dose, short-course therapeutic strategy in the treatment of CAP?

The PK/PD features of levofloxacin appeared to make the high-dose, short-course regimen tailor-made for improving the management of CAP. To investigate whether this would translate into clinical results we performed a randomized double-blinded study comparing 750 mg levofloxacin IV or PO administered for 5 days versus standard therapy of 500 mg IV or PO for 10 days in CAP patients. The characteristics of participants in both groups of the study were comparable. Our rationale for performing this study was based upon the high peak concentrations achieved by the 750 mg dose, which exploits the concentration dependent killing of this agent, allowing it to achieve double C_max and AUC values in serum and ELF. In addition, it was known that dosing flexibility was possible due to earlier studies demonstrating a favorable safety profile (48-50). The shorter duration of therapy allows less total drug exposure which potentially reduces the risk of adaptive resistance.

We enrolled 256 patients into the 750 mg group, 198 of whom were clinically evaluable and 103 microbiologically evaluable. In the 500 mg group, 272 were enrolled, with 192 clinically evaluable and 92 microbiologically evaluable (50). Results confirmed that the shorter duration of therapy using the high-dose levofloxacin regimen was as effective as the previously approved 10-day course (Figure 3). Overall clinical success (cured plus improved) as measured at the post-therapy visit (7-14 days after the last dose) was 92.4% for the 750 mg group and 91.1% for the 500 mg group. Microbiological eradication for the microbiologically evaluable patients was also comparable between the two treatment regimens (93.2% for the 750 mg group and 92.4% for the 500 mg group). There were no significant differences in adverse events between the two groups of this study. Results of this study led to the approval of the high-dose regimen for CAP.

Figure 3. 750 mg, short-course levofloxacin for CAP: clinical and microbiologic results ^a

^a Patients evaluable at the 7- to 14-day post-therapy visit.
^b Clinical success includes cured and improved.
Abbreviation: CAP = community-acquired pneumonia.
Adapted from reference (50).