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In Vitro Dynamic Models as Prediction Tools 57(C max )-to-MIC ratio is 16, whereas C min /MIC for Drug II is 2 and C max /MIC 8(Fig. 10, upper panel). Assuming bacterial regrowth begins when fluoroquinoloneconcentration falls below the MIC, later regrowth should be expected after a singledose of Drug II compared to Drug I if no further dosing is to occur (Fig. 10,bottom panel). This difference is reflected by the greater I E that reflects the effectof Drug II relative to Drug I despite similar time-kill curves observed with bothdrugs within the dosing interval.At first glance, the different I E s determined after single administration ofDrug I and Drug II make no sense: the second and subsequent doses may whittleaway the distinction between the drugs. For example, antibiotic-specific AUC/MIC relationships of I E that reflect killing of daptomycin- and vancomycinexposedS. aureus were seen better in single-dose simulations (68) than in multiple-dosesimulations (69). However, with pharmacokinetically different fluoroquinolones,antibiotic-specific relationships between I E and AUC/MIC were reportedboth in single- and multiple-dose studies. Moreover, the ratio of equiefficientAUC/MICs of moxifloxacin and levofloxacin against S. aureus reported in singledosesimulations (38) was similar to the respective ratio of AUC t /MICs (t ¼ 24hours) in multiple-dose simulations with the same antibiotics (64).Why then do differences in pharmacodynamics observed after single administrationof the fluoroquinolones not disappear after subsequent dosing, and whyare they predictive of multiple-dose fluoroquinolone pharmacodynamics? Toanswer these questions, let us return to the above example with two hypotheticalantibiotics. As seen in Figure 10, the antimicrobial potential of Drug I at the end ofthe first dosing interval is completely exhausted (C min /MIC ¼ 1) whereas therespective potential of Drug II is not (C min /MIC ¼ 2). Therefore, multiple dosingof Drug II but not Drug I will be accompanied by accumulation of the50Concentration/MIC510.5Drug IDrug IIτ = 24 hTimeLogrithm of viable countsDrug Iτ = 24 hDrug IITimeFIGURE 10 Pharmacokinetics and pharmacodynamicsof hypothetical antibiotics. Source: Adaptedfrom Ref. 36.