AUC/MIC relationships to different endpoints of the antimicrobial effect: multiple-dose in vitro simulations with moxifloxacin and levofloxacin.

Most integral endpoints of antimicrobial effect, including area between the control growth and time-kill curves (ABBC), area above the curve (AAC) and area under the time-kill curve (AUBC) are determined over a dosing interval (tau), regardless of the actual effect duration. Unlike these tau-related endpoints, the intensity of antimicrobial effect (I(E)) considers the area between the control growth and time-kill curves from time zero to the time when bacterial counts on the regrowth curve achieve the same maximal numbers as in the absence of antibiotic, even if this time is greater than tau. Recently, important differences between ABBC-, AAC-, AUBC- and I(E)-AUC/MIC relationships were reported in single-dose simulations. The present study was designed to examine these relationships in multiple-dose simulations. A clinical isolate of Staphylococcus aureus was exposed to simulated pharmacokinetics of moxifloxacin (MIC = 0.37 mg/L) and levofloxacin (MIC = 0.6 mg/L), simulating three consecutive 24 h doses, which varied over a 32-fold range in the 24 h AUC/MIC ratio (AUC(tau)/MIC: 14-444 h and 15-484 h, respectively). The cumulative effect of each treatment was expressed by I(E), determined from time zero to the time after the third dose when the effect could no longer be detected, and by ABBC, AAC and AUBC calculated over a 72 h period (i.e. over three dosing intervals). With all four endpoints, systematic AUCtau/MIC increase-induced changes in effect-an increase in I(E), ABBC and AAC, or a decrease in AUBC-were observed and the log AUC(tau)/MIC-response curves were fitted by an E(max) model. Using I(E), the effects of moxifloxacin and levofloxacin could be distinguished over a wider range of AUC(tau)/MIC ratios than with ABBC and AUBC, whereas no differences between the fluoroquinolones could be seen based on the AAC-AUC(tau)/MIC curves. Although ABBC and AUBC were more descriptive than AAC, these two endpoints distinguished the fluoroquinolone effects only over a relatively narrow AUC(tau)/MIC range ( approximately 40-100 h), which includes therapeutically achievable values for levofloxacin but not for moxifloxacin. Similar limitations of the tau-related endpoints might be critical in comparative studies with other new fluoroquinolones where therapeutic AUCtau/MIC ratios are >100 h.