Comparative Pharmacodynamics of Gatifloxacin and Ciprofloxacin in an In Vitro Dynamic Model: Prediction of Equiefficient Doses and the Breakpoints of the Area under the Curve/MIC Ratio

Abstract

ABSTRACT To demonstrate the impact of the pharmacokinetics of gatifloxacin (GA) relative to those of ciprofloxacin (CI) on the antimicrobial effect (AME), the killing and regrowth kinetics of two differentially susceptible clinical isolates each of Staphylococcus aureus , Escherichia coli , and Klebsiella pneumoniae were studied. With each organism, a series of monoexponential pharmacokinetic profiles of GA (half-life [ t 1/2 ], 7 h) and CI ( t 1/2 = 4 h) were simulated to mimic different single doses of GA and two 12-h doses of CI. The respective eightfold ranges of the ratios of the area under the concentration-time curve (AUC) to the MIC were 58 to 466 and 116 to 932 (μg · h/ml)/(μg/ml). The species- and strain-independent linear relationships observed between the intensity of AME ( I E ) and log AUC/MIC were not superimposed for GA and CI ( r 2 = 0.99 in both cases). The predicted AUC/MIC ratio for GA that might be equivalent to a clinically relevant AUC/MIC breakpoint for CI was estimated to be 102 rather than 125 (μg · h/ml)/(μg/ml). The respective MIC breakpoints were 0.32 μg/ml (for a 400-mg dose of GA) and 0.18 μg/ml (for two 500-mg doses of CI). On the basis of the I E -log AUC/MIC relationships, equiefficient 24-h doses ( D 24h s) of GA and CI were calculated for hypothetical strains of S. aureus , E. coli , and K. pneumoniae for which the MICs were equal to the MICs at which 50% of isolates are inhibited. To provide an “acceptable” I E equal to 200 (log CFU/ml) · h, i.e., the I E provided by AUC/MIC of 125 (μg · h/ml)/(μg/ml) for ciprofloxacin, the D 24h s of GA for all three organisms were much lower (115, 30, and 60 mg) than the clinically proposed 400-mg dose. Although the usual dose of CI (two doses of 500 mg) would be in excess for E. coli and K. pneumoniae ( D 24h = two doses of 40 mg and two doses of 115 mg, respectively), even the highest clinical dose of CI (two doses of 750 mg) might be insufficient for S. aureus ( D 24h , > two doses of 1,000 mg). The method of generalization of data obtained with specific organisms to other representatives of the same species described in the present report might be useful for prediction of the AMEs of new quinolones.