Inter- and intraquinolone predictors of antimicrobial effect in an in vitro dynamic model: New insight into a widely used concept

Abstract

Earlier efforts to search for pharmacokinetic and bacteriological predictors of fluoroquinolone antimicrobial effects (AMEs) have resulted in conflicting findings. To elucidate whether these conflicts are real or apparent, several predictors of the AMEs of two pharmacokinetically different antibiotics, trovafloxacin (TRO) and ciprofloxacin (CIP), as well as different dosing regimens of CIP were examined. The AMEs of TRO given once daily (q.d.) and CIP given q.d. and twice daily (b.i.d.) against Escherichia coli, Pseudomonas aeruginosa, and Klebsiella pneumoniae were studied in an in vitro dynamic model. Different monoexponential pharmacokinetic profiles were simulated with a TRO half-life of 9.2 h and a CIP half-life of 4.0 h to provide similar eightfold ranges of the area under the concentration-time curve (AUC)-to-MIC ratios, from 54 to 432 and from 59 to 473 (μg · h/ml)/(μg/ml), respectively. In each case the observation periods were designed to incorPorate full-term regrowth phases in the time-kill curves, and the AME was expressed by its intensity (I(E); the area between the control growth and time-kill and regrowth curves up to the point at which the viable counts of regrowing bacteria are close to the maximum values observed without drug). Species-independent linear relationships were established between I(E) and log AUC/MIC, log AUC above MIC (log AUC(eff)), and time above the MIC (T(eff)). Specific and nonsuperimposed I(E) versus log AUC/MIC or log AUC(eff) relationships were inherent in each of the treatments: TRO given q.d. (r2 = 0.97 and 0.96), CIP given q.d. (r2 = 0.98 and 0.96), and CIP given b.i.d. (r2 = 0.95 and 0.93). This suggests that in order to combine data sets obtained with individual quinolones to examine potential predictors, one must be sure that these sets may be combined. Unlike AUC/MIC and AUC(eff), the I(E)-T(eff) relationships plotted for the different quinolones and dosing regimens were nonspecific and virtually super-imposed (r2 = 0.95). Hence, AUC/MIC, AUC(eff), and T(eff) were equally good predictors of the AME of each of the quinolones and each dosing regimen taken separately, whereas T(eff) was also a good predictor of the AMEs of the quinolones and their regimens taken together. However, neither the quinolones nor the dosing regimens could be distinguished solely on the basis of T(eff), whereas they could be distinguished on the basis of AUC/MIC or AUC(eff). Thus, two types of predictors of the quinolone AME may be identified: intraquinolone and/or intraregimen predictors (AUC/MIC, AUC(eff) and T(eff)) and an interquinolone and interregimen predictor (T(eff)). T(eff) may be able to accurately predict the AME of one quinolone on the basis of the data obtained for another quinolone.