Optimization of Cefotaxime Treatment in Intensive Care Patients: Impact of Inter- and Intra-patient Variability on Pharmacokinetics and Target Attainment.

BACKGROUND

Cefotaxime is a beta-lactam antibiotic commonly used in critically ill patients. In this population, pathophysiological features induce high inter- and intra-individual pharmacokinetic variability that can result in supra or sub-therapeutic concentrations of cefotaxime. However, factors leading to variability during the treatment course remain poorly described.

OBJECTIVE

The objective of the present study was to characterize the pharmacokinetics of cefotaxime and associated inter- and intra-individual variability in order to optimize individual dosing regimens for adult intensive care patients. Simulations based on the population pharmacokinetic model characterized the impact of these covariates on pharmacokinetic/pharmacodynamic target attainment.

METHODS

Adult intensive care patients were included in a prospective observational study. Cefotaxime concentrations were measured 30 min after the loading dose, during the continuous infusion at days 1, 4, and 7 after drug initiation, and 4 h after the end of infusion. Pharmacokinetic analyses were performed using a parametric population approach. The impact of covariates was determined by combining a baseline covariate model with a time-varying covariate model. Monte Carlo simulations were performed to evaluate the probability of target attainment for different dosing regimens, with a pharmacokinetic/pharmacodynamic target of 100% of the time with cefotaxime free concentration over the minimal inhibitory concentration.

RESULTS

The study included 76 intensive care patients (251 cefotaxime plasma concentrations). A one-compartment model with linear elimination and proportional residual error best described the data. Serum albumin concentration, age, sex, and time-varying serum creatinine concentration were identified as significant covariates. Simulations based on the final model showed that the recommended dosing regimen (2-g loading dose followed by 6 g per day) only achieves pharmacokinetic/pharmacodynamic targets for a minimal inhibitory concentration ≤1 mg/L. As a consequence of serum creatinine concentration intra-individual variability, observed probability of target attainment decreased with time: 59.3, 56.4, and 50.7%, respectively at days 1, 4, and 7, for patients with a baseline serum creatinine concentration between 100 and 150 µmol/L. For minimum inhibitory concentration values above 1 mg/L, an initial dosing regimen of a 2-g loading dose followed by 10 g per day could be appropriate.

CONCLUSIONS

A population pharmacokinetic model of cefotaxime was developed to determine both inter- and intra-individual variability in intensive care patients and was applied to evaluate the impact of various dosing regimens on pharmacokinetic/pharmacodynamic target attainment. Serum creatinine concentration explained a significant part of the observed inter- and intra-individual pharmacokinetic variability and a biomarker model would be helpful to anticipate serum creatinine concentration evolution and improve the prediction.