In vitro dynamic model for determining the comparative pharmacology of fluoroquinolones

An in vitro model for determining the comparative pharmacology of fluoroquinolones is presented. The true therapeutic potential of fluoroquinolones against bacterial pathogens may be best understood before clinical testing with the use of in vitro dynamic models. These models simulate pharmacokinetics in humans and can be used to compare different drugs in the same class over a wide range of dosages with respect to the antimicrobial effect (AME). Two models for evaluating AME are described. In one (a two-compartment model), a simple bacterial killing curve is generated after exposure to simulated clinical doses of antimicrobial. In the other (a one-compartment model), AME is defined as the area between the control bacterial growth curve in the absence of drug and the curve that represents bacterial killing and regrowth. This area can be readily measured and is referred to as the intensity of the effect (I(e)). In general, AME is correlated with drug exposure, as simulated in the model at different ratios of the area under the concentration-time curve (AUC) to the minimum inhibitory concentration (MIC) for the organism under study. With this in vitro dynamic model, several fluoroquinolones were tested over a range of AUC/MIC ratios for their AMEs against Staphylococcus aureus, Escherichia coli, and Klebsiella pneumoniae. The data generated illustrate the usefulness of in vitro dynamic models for comparing AMEs of different fluoroquinolones. Because the model incorporates pharmacokinetic variables, it provides a method for comparing various dosage regimens or schedules of administration and is useful in preclinical drug development.