Question 2

You mention the benefit of an oral, once-daily dosing schedule. Could you comment on the pharmacologic features of fluoroquinolones that make this possible?

Pharmacokinetic (PK) and pharmacodynamic (PD) features associated with specific fluoroquinolones, exemplified by levofloxacin, support their administration once-daily (1, 2). Their antibacterial activity is concentration-dependent, meaning that the higher the dose, the higher peak concentration achieved, and the faster and more effective the bacterial killing. In addition, they exhibit excellent oral absorption, with levofloxacin, in particular, achieving almost 100% bioavailability following oral administration (1). Levofloxacin is also extensively distributed throughout respiratory tract tissues, including epithelial lining fluid and alveolar macrophages, making it an effective treatment of intracellular pathogens. The long half-life of levofloxacin also allows antibacterial concentrations to be maintained over a 24-hour period, resulting in effective once-daily dosing. These features have been further confirmed in a recent population PK study of oral levofloxacin 500 mg in China (3). This study investigated 1,052 patients with community- acquired lower RTI and found that the area under the concentration-time curve (AUC)_0-24/minimum inhibitory concentration (MIC) ratio exceeded the target for all major pathogens. In addition, levofloxacin achieved a maximum serum drug concentration (C_max) / MIC ratio of 5 for Streptococcus pneumoniae indicating that the emergence of levofloxacin-resistant S. pneumoniae could be prevented with this dose.
The high systemic concentrations achieved by levofloxacin following oral administration also provide physicians with the opportunity of replacing intravenous (IV) therapy with oral therapy or switching from IV to oral at an earlier stage of therapy. This enables patients to be discharged from hospital earlier or even to reduce the need for initial hospitalization. This advantage is not possessed by many other antimicrobials, as they do not exhibit such high oral bioavailability. Once-daily therapy with levofloxacin has become the standard administration schedule and this is associated with much greater compliance, allowing effective treatment for all those patients who struggle with three times or even twice-daily schedules. While the once-daily schedule was initially regarded with skepticism, especially in the Asia-Pacific region where there was a tradition of prescribing lower doses more often, this has now been overcome. It is now well recognized that the once-daily levofloxacin schedule is an effective and advantageous regimen.