The Way Forward: High-Dose, Short-Course Levofloxacin Leads the Field

29 March, 2018

Question 3

How does the 750 mg levofloxacin dose compare to other fluoroquinolone regimens in terms of achieving these targets?

As noted, the shape of the serum concentration curve versus time is an important factor for predicting clinical and microbiological efficacy. Clinicians have been able to exploit this feature by increasing the dosage regimen of levofloxacin, thereby achieving much higher Cmax and AUC values. This increase in dosage has been made possible by the excellent safety profile of levofloxacin and is not a characteristic associated with most of the other fluoroquinolones.

In addition, the plasma protein binding of levofloxacin is lower than that of many other fluoroquinolones, resulting in a larger percentage of administered drug being free and available for action. This helps in clarifying the relative potencies of the different fluoroquinolones. For example, while both the 500 mg and 750 mg doses of levofloxacin have an MIC of 1 against S. pneumoniae, the AUC of free drug for the 500 mg dose is 33.6 giving an AUC/MIC ratio of 34 (Table 1). In contrast, the AUC/MIC ratio for the 750 mg dose is more than double that of the 500 mg dose, reaching 71. Furthermore, while the MICs of moxifloxacin and gatifloxacin are lower than those of levofloxacin, due to their higher rates of protein binding they have lower free drug AUCs. This results in the AUC/MIC for gatifloxacin being much lower than that of 750 mg levofloxacin (54 vs. 71). Even more noticeable is the fact that ciprofloxacin, with an MIC of 2 and an AUC of 14.1, only achieves an AUC/MIC ratio of 7, reflecting a much lower potency and confirming that levofloxacin is an excellent respiratory fluoroquinolone, and certainly a better respiratory agent than ciprofloxacin.

Table 1. Pharmacodynamic activity of fluoroquinolones against Streptococcus pneumoniae

Antimicrobial S. pneumoniae AUC (24hr) AUC (24hr)/MIC90
MIC90 Total/free
Levofloxacin 500 mg q.d. 1 48.0/33.6 34
Levofloxacin 750 mg q.d. 1 101.0/70.7 71
Moxifloxacin 400 mg q.d. 0.25 33.8/17.6 70
Gatifloxacin 400 mg q.d. 0.5 33.8/27.0 54
Ciprofloxacin 500 mg b.i.d. 2 20.2/14.1 7
Abbreviations: S. pneumoniae = Streptococcus pneumoniae, MIC90 = minimum inhibitory concentration at which 90% of isolates are inhibited, AUC = area under the plasma concentration-time curve, q.d. = once daily, b.i.d. = twice a day.

Adapted from reference (2, 8-11).