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Multicenter Study
. 2022 Jun 21;66(6):e0218921.
doi: 10.1128/aac.02189-21. Epub 2022 May 16.

Multicenter Population Pharmacokinetic Study of Unbound Ceftriaxone in Critically Ill Patients

Aaron J Heffernan  1   2 , Fekade B Sime  1 , Nilesh Kumta  1 , Steven C Wallis  1 , Brett McWhinney  3 , Jacobus Ungerer  3   4 , Gloria Wong  1 , Gavin M Joynt  5 , Jeffrey Lipman  1   6   7 , Jason A Roberts  1   7   8
Affiliations
Multicenter Study

Multicenter Population Pharmacokinetic Study of Unbound Ceftriaxone in Critically Ill Patients

Aaron J Heffernan et al. Antimicrob Agents Chemother. .

Abstract

The objective of this study was to describe the total and unbound population pharmacokinetics of ceftriaxone in critically ill adult patients and to define optimized dosing regimens. Total and unbound ceftriaxone concentrations were obtained from two pharmacokinetic studies and from a therapeutic drug monitoring (TDM) program at a tertiary hospital intensive care unit. Population pharmacokinetic analysis and Monte Carlo simulations were used to assess the probability of achieving a free trough concentration/MIC ratio of ≥1 using Pmetrics for R. A total of 474 samples (267 total and 207 unbound) were available from 36 patients. A two-compartment model describing ceftriaxone-albumin binding with both nonrenal and renal elimination incorporating creatinine clearance to explain the between-patient variability best described the data. An albumin concentration of ≤20 g/L decreased the probability of target attainment (PTA) by up to 20% across different dosing regimens and simulated creatinine clearances. A ceftriaxone dose of 1 g twice daily is likely therapeutic in patients with creatinine clearance of <100 mL/min infected with susceptible isolates (PTA, ~90%). Higher doses administered as a continuous infusion (4 g/day) are needed in patients with augmented renal clearance (creatinine clearance, >130 mL/min) who are infected by pathogens with a MIC of ≥0.5 mg/L. The ceftriaxone dose should be based on the patient's renal function and albumin concentration, as well as the isolate MIC. Hypoalbuminemia decreases the PTA in patients receiving intermittent dosing by up to 20%.

Keywords: ceftriaxone; dose; intensive care; intensive care unit; pharmacodynamics; pharmacokinetics; population pharmacokinetics.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

FIG 1
FIG 1
Observed unbound ceftriaxone concentration-time data and visual predictive check of the final model. Dots represent observed patient unbound ceftriaxone concentrations.
FIG 2
FIG 2
Observed total concentration ceftriaxone concentration-time data and visual predictive check of the final model. Dots represent observed patient total ceftriaxone concentrations.
FIG 3
FIG 3
Observed versus predicted goodness-of-fit plots for unbound and total ceftriaxone concentrations (open circles). (A) Population predicted unbound ceftriaxone concentration; (B) individual predicted unbound ceftriaxone concentration; (C) population predicted total ceftriaxone concentration; (D) individual predicted total ceftriaxone concentration. The ceftriaxone concentrations shown are milligrams per liter.
FIG 4
FIG 4
Residual diagnostic plots. (A) Weighted residual error versus predicted concentration; (B) weighted residual error versus time; (C) weighted residual error frequency histogram.
See this image and copyright information in PMC

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