Predictive Potential of Pharmacokinetic-Pharmacodynamic Parameters in Evaluation of Doripenem and Levofloxacin Effects: A Study in an in vitro Dynamic Model with Pseudomonas aeruginosa

Background. Antibiotics are classified into «time-dependent», «concentration-dependent», and «concentration-and-timedependent» based on the relationship of their effectiveness and pharmacokinetic-pharmacodynamic (PK/PD) parameters: T _>МIC (time of the dosing interval during which the concentration of the antibiotic exceeds MIC), C_MAX/MIC (ratio of maximal concentration to MIC), or AUC/MIC (the ratio of the area under the pharmacokinetic curve to MIC), is currently undergoing significant revision.

The aim of the study. Analysis of the relationships between the values of AUC/MIC and T _>МIC and the effects of doripenem and levofloxacin against Pseudomonas aeruginosa in an in vitro dynamic model.

Materials and methods. Clinical isolates of P. aeruginosa 180 and P. aeruginosa 52 were exposed to doripenem or levofloxacin at different dosing regimens, including the therapeutic ones, in an in vitro dynamic model for 5 consecutive days. The antimicrobial effect was evaluated using the integral parameter AUBC; the relationship between the effect of each antibiotic and AUC/MIC or T_>МIC was studied. The presence of a statistically significant dependence proves the ability of the parameter to predict the effect.

Results. The maximum antimicrobial effect of doripenem was observed in the setting that simulated the therapeutic dose of the antibiotic, while a comparable effect of levofloxacin was achievable under conditions simulating double therapeutic dose and only for one P. aeruginosa strain. The relationships «effect — AUC/MIC or T_>МIC» were described by the Hill equation, in the case of doripenem with equally high r², and in the case of levofloxacin, a reliable relationship was established only with the AUC/MIC parameter.

Conclusion. According to our results, the PK/PD parameter associated with the effect of levofloxacin is AUC/MIC, and in the case of doripenem, the parameters AUC/MIC and T_>МIC correlated with its effect equally well. Therefore, AUC/MIC can be considered a universal PK/PD parameter applicable for predicting the effect of both concentration-and-time- and time-dependent antibiotics, since it takes into account both exposure indicators: time and concentration.

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