Cefotaxime dosage optimization in intensive care patients by population pharmacokinetic analysis

Background: Cefotaxime is a beta-lactam antibiotics commonly used in intensive care unit (ICU). In this population, pathophysiological modifications induce a high inter-individual and intra-individual pharmacokinetic variability. This variability can result in supra or sub-therapeutic concentrations of cefotaxime and adapted drug regimen are required. The aim of this study was to propose optimized cefotaxime treatment in ICU patients by a population pharmacokinetic approach. Methods: In this prospective, multicenter, observational study (October 2015 – May 2017), patients hospitalized in ICU received continuous administration of cefotaxime. The cefotaxime dosing regimen was a loading dose (2g-4g/0.5h) then a continuous infusion (1-24g/24h). Therapeutic drug monitoring allowed the measurement of cefotaxime concentration at day 1, 4 and 7 after drug initiation. Concentrations were assayed by a validated HPLC-UV method, and nonlinear mixed-effects modeling was performed (NONMEM version 7.4). After determination of the base model that best described the data set, the influence of several covariates was tested on the model. Simulations were realized to propose adapted dosing regimens allowing to achieve the PK/PD target, namely 100% of time during a dosing interval with the free drug concentration exceeding 4 times the Minimum Inhibitory Concentration (MIC).Results: From 77 ICU hospitalized patients (31 females, 45 males, age = 55.84 ± 18.1 years), 255 cefotaxime plasma concentrations were available for analysis. The data were best described by a one-compartment model with proportional residual error. The model was qualified based on goodness-of-fit plots and precision of the parameter estimates. Typical population clearance (11.4 L/min) and volume of distribution (27 L) were in line with previously published results in different adult and pediatric population. Model-based simulations were performed under various cefotaxime regimen to assess target attainment and identify optimal protocols. Conclusions: To our knowledge, we developed the first pharmacokinetic model of cefotaxime in critically ill adult population. After external evaluation, this model will allow to adapt empirical cefotaxime treatment dose to improve antibiotic exposure and PK/PD target attainment in ICU patients.