Population pharmacokinetics of ceftriaxone in critically ill septic patients: a reappraisal
Authors: Garot Denis , Respaud Renaud , Lanotte Philippe , Simon Nicolas , Mercier Emmanuelle , Ehrmann Stephan , Perrotin Dominique , Dequin Pierre‐François , Le Guellec Chantal 
Published: May 2011

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• Intensive care unit patients exhibit altered pharmacokinetics for many drugs and suboptimal exposure may be detrimental.

• Despite frequent use of ceftriaxone in critically ill patients, its pharmacokinetics have not been studied in large cohorts of critically ill patients.

• Population pharmacokinetic analysis provides pharmacokinetic parameter estimates, estimates of inter‐ individual and intra‐individual variability in these parameters and allows patient characteristics explaining inter‐individual variability to be quantified.

• Coupled with pharmacodynamic analysis, this approach can help in simulating an optimal dosing regimen based on individual characteristics.

WHAT THIS STUDY ADDS

• Our population model characterized the pharmacokinetic profile of ceftriaxone in patients with highly variable characteristics

• Creatinine clearance was identified as the main covariate influencing ceftriaxone pharmacokinetics, particularly for high values. Haemofiltration had no effect.

• Model‐based simulations showed that the risk of being under threshold concentrations is low for infections due to common pathogens, but exists in patients with high glomerular filtration rates.

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).