INTERQUINOLONE AND INTRAQUINOLONE PREDICTORS OF ANTIMICROBIAL EFFECT IN AN IN-VITRO DYNAMIC-MODEL - NEW INSIGHT INTO A WIDELY USED CONCEPT

Earlier efforts to search for pharmacokinetic and bacteriological pred ictors of fluoroquinolone antimicrobial effects (AMEs) have resulted i n 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), a s 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 pne umoniae were studied in an in vitro dynamic model. Different monoexpon ential 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 range s of the area under the concentration-time curve (AUC)-to-MIC ratios, from 54 to 432 and from 59 to 473 (mu g.h/ml)/ (mu g/ml), respectively . In each case the observation periods were designed to incorporate fu ll-term regrowth phases in the time-kill curves, and the AME was expre ssed by its intensity (I-E; the area between the control growth and ti me-kill and regrowth curves up to the point at which the viable counts of regrowing bacteria are close to the maximum values observed withou t drug), Species-independent linear relationships were established bet ween I-E and log AUC/MIC, log AUC above MIC (log AUC(eff)) and time ab ove the MIC (T-eff). Specific and nonsuperimposed I-E versus log AUC/M IC or log AUC(eff) relationships were inherent in each of the treatmen ts: TRO given q.d. (r(2) = 0.97 and 0.96), CIP given q.d. (r(2) = 0.98 and 0.96), and CIP given b.i.d. (r(2) = 0.95 and 0.93), This suggests that in order to combine data sets obtained with individual quinolone s to examine potential predictors, one must be sure that these sets ma y be combined. Unlike AUC/MIC and AUC(eff), the I-E-T-eff relationship s plotted for the different quinolones and dosing regimens were nonspe cific and virtually superimposed (r(2) = 0.95). Hence, AUC/MIC, AUC(ef f), and T-eff were equally good predictors of the AME of each of the q uinolones 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 regime ns could be distinguished solely on the basis of T-eff, whereas they c ould be distinguished on the basis of AUC/MIC or AUC(eff). Thus, two t ypes of predictors of the quinolone AME may be identified: intraquinol one and/or intra-regimen predictors (AUC/MIC, AUC(eff) and T-eff) and an interquinolone and interregimen predictor (T-eff). T-eff may be abl e to accurately predict the AME of one quinolone on the basis of the d ata obtained for another quinolone.