Comparative pharmacodynamics of moxifloxacin and levofloxacin in an in vitro dynamic model: Prediction of the equivalent AUC/MIC breakpoints and equiefficient doses

Abstract

To demonstrate the impact of the different pharmacokinetics of moxifloxacin and levofloxacin on their antimicrobial effects (AMEs), killing and regrowth kinetics of two clinical isolates of Staphylococcus aureus and one each of Escherichia coli and Klebsiella pneumoniae were studied. With each organism, a series of monoexponential pharmacokinetic profiles of single doses of moxifloxacin (T 1/2 = 12.1 h) and levofloxacin (T 1/2 = 6.8 h) were simulated. The respective eight-fold ranges of the ratios of area under the concentration-time curve (AUC) to the MIC were 58-475 and 114-934. Species- and strain-independent linear relationships observed between the intensity of AME (I(E)) and log AUC/MIC were not superimposed for moxifloxacin and levofloxacin (I2 = 0.99 in both cases). The predicted AUC/MIC ratios for moxifloxacin and levofloxacin that might be equivalent to Schentag's AUC/MIC breakpoint for ciprofloxacin (125) were estimated at 80 and 130, respectively. The respective equivalent MIC breakpoints were 0.41 mg/L (for a 400 mg dose of moxifloxacin) and 0.35 mg/L (for a 500 mg dose of levofloxacin). Based on the I(E)-log AUC/MIC relationships, equiefficient 24 h doses (D24s) of moxifloxacin and levofloxacin were calculated for hypothetical strains of S. aureus, E. coli and K. pneumoniae with MICs equal to the respective MIC50s (weighted geometric means of reported values). To provide an 'acceptable' I(E) = 200 (log cfu/mL)·h, the D24s of moxifloxacin for all three organisms were much lower (150, 30 and 60 mg, respectively) than the clinically proposed 400 mg dose. Although the usual dose of levofloxacin (500 mg) would be in excess for E. coli and K. pneumoniae (D24 =36 and 220 mg, respectively), it might be insufficient for S. aureus (the estimated D24 = 850 mg). Moreover, to provide the same effect as a 400 mg D24 of moxifloxacin against staphylococci, levofloxacin would have to be given in a 5000 mg D24, which is 10-fold higher than its clinically accepted dose. The described method of generalization of data obtained with specific organisms to other representatives of the same species might be useful to predict the AMEs of new quinolones.