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

To demonstrate the impact of the different pharmacokinetics of moxifloxacin and levofloxacin on their antimicrobial effects (AMEs), killing and regrow th kinetics of two clinical isolates of Staphylococcus aureus and one each of Escherichia coli and Klebsiella pneumoniae were studied. With each organ ism, a series of monoexponential pharmacokinetic profiles of single doses o f moxifloxacin (T-1/2 = 12.1 h) and levofloxacin (T-1/2 = 6.8 h) were simul ated. The respective eight-fold ranges of the ratios of area under the conc entration-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 levofl oxacin (r(2) = 0.99 in both cases). The predicted AUC/MIC ratios for moxifl oxacin and levofloxacin that might be equivalent to Schentag's AUC/MIC brea kpoint 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 o n the I-E-log AUC/MIC relationships, equiefficient 24 h doses (D(24)s) of m oxifloxacin and levofloxacin were calculated for hypothetical strains of S. aureus, E. coli and K. pneumoniae with MICs equal to the respective MIC(50 )s (weighted geometric means of reported values). To provide an 'acceptable ' I-E = 200 (log cfu/mL).h, the D(24)s of moxifloxacin for all three organi sms were much lower (150, 30 and 60 mg, respectively) than the clinically p roposed 400 mg dose. Although the usual dose of levofloxacin (500 mg) would be in excess for E. coli and K. pneumoniae (D-24 = 36 and 220 mg, respecti vely), it might be insufficient for S. aureus (the estimated D-24 = 850 mg) . Moreover, to provide the same effect as a 400 mg D-24 of moxifloxacin aga inst staphylococci, levofloxacin would have to be given in a 5000 mg D-24, which is 10-fold higher than its clinically accepted dose. The described me thod of generalization of data obtained with specific organisms to other re presentatives of the same species might be useful to predict the AMEs of ne w quinolones.