MIC-BASED INTERSPECIES PREDICTION OF THE ANTIMICROBIAL EFFECTS OF CIPROFLOXACIN ON BACTERIA OF DIFFERENT SUSCEPTIBILITIES IN AN IN-VITRO DYNAMIC-MODEL

Multiple predictors of fluoroquinolone antimicrobial effects (AMEs) ar e not usually examined simultaneously in most studies. To compare the predictive potentials of the area under the concentration-time curve ( AUC)-to-MIC ratio (AUC/MIC), the AUC above MIC (AUC(eff)), and the tim e above MIC (T-eff), the kinetics of killing and regrowth of four bact erial strains exposed to monoexponentially decreasing concentrations o f ciprofloxacin were studied in an in vitro dynamic model. The MICs of ciprofloxacin for clinical isolates of Staphylococcus aureus, Escheri chia coli 11775 (I) and 204 (II), and Pseudomonas aeruginosa were 0.6, 0.013, 0.08, and 0.15 mu g/ml, respectively. The simulated values of AUC were designed to provide similar 1,000-fold (S. aureus, E. coli I, and P. aeruginosa) or 2,000-fold (E. coli II) ranges of the AUC/MIC. In each case except for the highest AUC/MIC ratio, the observation per iods included complete regrowth in the time-kill curve studies. The AM E was expressed by its intensity, I-E (the area between the control gr owth and time-kill and regrowth curves up to the point where the viabl e counts of regrowing bacteria are close to the maximum values observe d without drug). For most AUC ranges the I-E-AUC curves were fitted by an E-max (maximal effect) model, whereas the effects observed at very high AUCs were greater than those predicted by the model. The AUCs th at produced 50% of maximal AME were proportional to the MICs for the s trains studied, but maximal AMEs (I-Emax) and the extent of sigmoidici ty (s) were not related to the MIC. Both T-eff and log AUC/MIC correla ted well with I-E (r(2) = 0.98 in both cases) in a species-independent fashion. Unlike T-eff or log AUC/MIC, a specific relationship between I-E and log AUC(eff) was inherent in each strain. Although each I-E a nd log AUC(eff) plot was fitted by linear regression (r(2) = 0.97 to 0 .99), these plots were not superimposed and therefore are bacterial sp ecies dependent. Thus, AUC/MIC and T-eff were better predictors of cip rofloxacin's AME than AUC(eff). This study suggests that optimal predi ctors of the AME produced by a given quinolone (intraquinolone predict ors) may be established by examining its AMEs against bacteria of diff erent susceptibilities. T-eff was shown previously also to be the best interquinolone predictor, but unlike AUC/MIC, it cannot be used to co mpare different quinolones. AUC/MIC might be the best predictor of the AME in comparisons of different quinolones.