Population pharmacokinetics of ceftriaxone in critically ill septic patients: a reappraisal

Abstract

Aims: To investigate the population pharmacokinetics of ceftriaxone in critically ill patients suffering from sepsis, severe sepsis or septic shock.

Methods: Blood samples were collected at preselected times in 54 adult patients suffering from sepsis, severe sepsis or septic shock in order to determine ceftriaxone concentrations using high-performance liquid chromatography-ultraviolet detection. The pharmacokinetics of ceftriaxone were assessed on two separate occasions for each patient: on the second day of ceftriaxone therapy and 48 h after catecholamine withdrawal in patients with septic shock, or on the fifth day in patients with sepsis. The population pharmacokinetics of ceftriaxone were studied using nonlinear mixed effects modelling.

Results: The population estimates (interindividual variability; coefficient of variation) for ceftriaxone pharmacokinetics were: a clearance of 0.88 l h(-1) (49%), a mean half-life of 9.6 h (range 0.83-28.6 h) and a total volume of distribution of 19.5 l (range 6.48-35.2 l). The total volume of distribution was higher than that generally found in healthy individuals and increased with the severity of sepsis. However, the only covariate influencing the ceftriaxone pharmacokinetics was creatinine clearance. Dosage simulations showed that the risk of ceftriaxone concentrations dropping below the minimum inhibitory concentration threshold was low.

Conclusions: Despite the wide interpatient variability of ceftriaxone pharmacokinetic parameters, our results revealed that increasing the ceftriaxone dosage when treating critically ill patients is unnecessary. The risk of ceftriaxone concentrations dropping below the minimum inhibitory concentration threshold is limited to patients with high glomerular filtration rates or infections with high minimum inhibitory concentration pathogens (>1 mg l(-1)).

Trial registration: ClinicalTrials.gov NCT00449800.

© 2011 The Authors. British Journal of Clinical Pharmacology © 2011 The British Pharmacological Society.

Figures

Figure 1

Correlation between ceftriaxone clearance and creatinine clearance (CLcr)

Figure 2

Plot of observed vs. individual predicted concentrations of ceftriaxone for the final model

Figure 3

Plots of visual predictive checks obtained for the simulations with ceftriaxone 2 g i.v. once per day using the final model (median and 95% confidence interval)

Figure 4

Simulation of ceftriaxone pharmacokinetics (total [top] and free [bottom] concentrations) following a 1 g (A) or 2 g (B) injection in a patient with a creatinine clearance of 120 ml min−1 (median, 25 and 75 centiles). The dotted line represents the desired threshold concentrations (1 and 8 mg l−1, respectively)