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 (IE ; 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 IE and log AUC/MIC, log AUC above MIC (log AUCeff), and time above the MIC (T eff). Specific and nonsuperimposedIE versus log AUC/MIC or log AUCeffrelationships were inherent in each of the treatments: 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 quinolones to examine potential predictors, one must be sure that these sets may be combined. Unlike AUC/MIC and AUCeff, the IE -T effrelationships plotted for the different quinolones and dosing regimens were nonspecific and virtually superimposed (r 2 = 0.95). Hence, AUC/MIC, AUCeff, 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 AUCeff. Thus, two types of predictors of the quinolone AME may be identified: intraquinolone and/or intraregimen predictors (AUC/MIC, AUCeff and Teff) 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.

Enrichment of resistant Staphylococcus aureus at ciprofloxacin concentrations simulated within the mutant selection window: bolus versus continuous infusion

“…The reliability of ciprofloxacin pharmacokinetic simulations and the high reproducibility of time-kill curves provided by the model have been reported elsewhere [15].…”

Linezolid pharmacodynamics with Staphylococcus aureus in an in vitro dynamic model

“…Peristaltic pumps circulated fresh nutrient medium to and from the central unit (volume 100 mL) at a flow rate of 11.6 mL/h for linezolid. The reliability of antibiotic pharmacokinetic simulations and the high reproducibility of the time-kill curves provided by the model have been reported elsewhere [12].…”

“…A previously described dynamic model was used in this study [12]. Briefly, the model consisted of two connected flasks, one containing fresh MHB and the other with a magnetic stirrer, the central unit, with the same broth containing either a bacterial culture alone (control growth experiment) or a bacterial culture plus antibiotic (killing/re-growth experiments).…”

Fluoroquinolones in the treatment of meningitis

“…This feature is probably due to the short sub-MIC effect (postantibiotic effect) of quinolones against pneumococci [49,50]. In an in vitro pharmacodynamic model, the importance of T > MBC has also been demonstrated for quinolone therapy against gram-negative pathogens [51].…”