A NEW APPROACH TO IN-VITRO COMPARISONS OF ANTIBIOTICS IN DYNAMIC-MODELS - EQUIVALENT AREA UNDER THE CURVE MIC BREAKPOINTS AND EQUIEFFICIENTDOSES OF TROVAFLOXACIN AND CIPROFLOXACIN AGAINST BACTERIA OF SIMILAR SUSCEPTIBILITIES/

Time-kill studies, even those performed,vith in vitro dynamic models, often do not provide definitive comparisons of different antimicrobial agents. Also, they do not allow determinations of equiefficient doses or predictions of area under the concentration-time curve (AUC)/MIC b reakpoints that might be related to antimicrobial effects (AMEs), In t he present study, a wide range of single doses of trovafloxacin (TR) a nd twice-daily doses of ciprofloxacin (CI) were mimicked in an in vitr o dynamic model. The AMEs of TR and CI against gram-negative bacteria with similar susceptibilities to both drugs were related to AUC/MICs t hat varied over similar eight-fold ranges [from 54 to 432 and from 59 to 473 (mu g.h/ml)/(mu g/ml), respectively]. The observation periods w ere designed to include complete bacterial regrowth, and the AME was e xpressed by its intensity (the area between the control growth in the absence of antibiotics and the antibiotic-induced time-kill and regrow th curves up to the point where viable counts of regrowing bacteria eq ual those achieved in the absence of drug [I-E]). In each experiment m onoexponential pharmacokinetic profiles of TR and CI were simulated wi th half-lives of 9.2 and 4.0 h, respectively, Linear relationships bet ween I-E and log AUC/MIC were established for TR and CI against three bacteria: Escherichia coli (MIC of TR [MICTR] = 0.25 mu g/ml; MIC of C I [MICCI] = 0.12 mu g/ml), Pseudomonas aeruginosa (MICTR = 0.3 mu g/ml ; MICCI = 0.15 mu g/ml), and Klebsiella pneumoniae (MICTR = 0.25 mu g/ ml; MICCI = 0.12 mu g/ml). The slopes and intercepts of these relation ships differed for TR and CI, and the I-E-log AUC/MIC plots were not s uperimposed, although they were similar for all bacteria with a given antibiotic. By using the relationships between I-E and log AUC/MIC, TR was more efficient than CI. The predicted value of the AUC/MIC breakp oint for TR [mean for all three bacteria, 63 (mu g.h/ml)/(mu g/ml)] wa s approximately twofold lower than that for CI, Based on the I,-log AU C/MIC relationships, the respective dose (D)-response relationships we re reconstructed. Like the I-E-log AUC/MIC relationships, the I-E-log D plots showed TR to be more efficient than CI. Single doses of TR tha t are as efficient as two 500-mg doses of CI (500 mg given every 12 h) were similar for the three strains (199, 226, and 203 mg). This study suggests that in vitro evaluation of the relationships between I-E an d AUC/MIC or D might be a reliable basis for comparing different fluor oquinolones and that the results of such comparative studies may be hi ghly dependent on their experimental design and datum quantitation.