A New Approach to In Vitro Comparisons of Antibiotics in Dynamic Models: Equivalent Area under the Curve/MIC Breakpoints and Equiefficient Doses of Trovafloxacin and Ciprofloxacin against Bacteria of Similar Susceptibilities

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Abstract
Time-kill studies, even those performed with 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 breakpoints that might be related to antimicrobial effects (AMEs). In the present study, a wide range of single doses of trovafloxacin (TR) and twice-daily doses of ciprofloxacin (CI) were mimicked in an in vitro dynamic model. The AMEs of TR and CI against gram-negative bacteria with similar susceptibilities to both drugs were related to AUC/MICs that varied over similar eight-fold ranges [from 54 to 432 and from 59 to 473 (μg · h/ml)/(μg/ml), respectively]. The observation periods were designed to include complete bacterial regrowth, and the AME was expressed by its intensity (the area between the control growth in the absence of antibiotics and the antibiotic-induced time-kill and regrowth curves up to the point where viable counts of regrowing bacteria equal those achieved in the absence of drug [ I E ]). In each experiment monoexponential pharmacokinetic profiles of TR and CI were simulated with half-lives of 9.2 and 4.0 h, respectively. Linear relationships between I E and log AUC/MIC were established for TR and CI against three bacteria: Escherichia coli (MIC of TR [MIC TR ] = 0.25 μg/ml; MIC of CI [MIC CI ] = 0.12 μg/ml), Pseudomonas aeruginosa (MIC TR = 0.3 μg/ml; MIC CI = 0.15 μg/ml), and Klebsiella pneumoniae (MIC TR = 0.25 μg/ml; MIC CI = 0.12 μg/ml). The slopes and intercepts of these relationships differed for TR and CI, and the I E -log AUC/MIC plots were not superimposed, 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 breakpoint for TR [mean for all three bacteria, 63 (μg · h/ml)/(μg/ml)] was approximately twofold lower than that for CI. Based on the I E -log AUC/MIC relationships, the respective dose ( D )-response relationships were 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 that 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 and AUC/MIC or D might be a reliable basis for comparing different fluoroquinolones and that the results of such comparative studies may be highly dependent on their experimental design and datum quantitation.