Population pharmacokinetics and dosing simulations of cefuroxime in critically ill patients: non-standard dosing approaches are required to achieve therapeutic exposures

Carlier, Mieke, Noe, Michael, Roberts, Jason A., Stove, Veronique, Verstraete, Alain G., Lipman, Jeffrey and De Waele, Jan J. (2014) Population pharmacokinetics and dosing simulations of cefuroxime in critically ill patients: non-standard dosing approaches are required to achieve therapeutic exposures. Journal of Antimicrobial Chemotherapy, 69 10: 2797-2803. doi:10.1093/jac/dku195


Author Carlier, Mieke
Noe, Michael
Roberts, Jason A.
Stove, Veronique
Verstraete, Alain G.
Lipman, Jeffrey
De Waele, Jan J.
Title Population pharmacokinetics and dosing simulations of cefuroxime in critically ill patients: non-standard dosing approaches are required to achieve therapeutic exposures
Journal name Journal of Antimicrobial Chemotherapy   Check publisher's open access policy
ISSN 0305-7453
1460-2091
Publication date 2014-10-01
Year available 2014
Sub-type Article (original research)
DOI 10.1093/jac/dku195
Open Access Status DOI
Volume 69
Issue 10
Start page 2797
End page 2803
Total pages 7
Place of publication Oxford, United Kingdom
Publisher Oxford University Press
Language eng
Subject 3004 Pharmacology
2736 Pharmacology (medical)
2725 Infectious Diseases
Abstract Objectives: To investigate the population pharmacokinetics of cefuroxime in critically ill patients.
Formatted abstract
Objectives: To investigate the population pharmacokinetics of cefuroxime in critically ill patients.

Methods: In this observational pharmacokinetic study, multiple blood samples were taken over one dosing interval of intravenous cefuroxime. Blood samples were analysed using a validated ultra HPLC tandem mass spectrometry technique. Population pharmacokinetic analysis and dosing simulations were performed using non-linear mixed-effects modelling.

Results: One hundred and sixty blood samples were collected from 20 patients. CLCR ranged between 10 and 304 mL/min. A two-compartment model with between-subject variability on CL, V of the central compartment and V of the peripheral compartment described the data adequately. Twenty-four hour urinary CLCR was supported as a descriptor of drug CL. The population model for CL was CL = θ1 × CLCR/100, where θ1 is the typical cefuroxime CL in the population, which is 9.0 L/h. The mean V was 22.5 L. Dosing simulations showed failure to achieve the pharmacokinetic/pharmacodynamic target of 65% fT>MIC for an MIC of 8 mg/L with standard dosing regimens for patients with CLCR ≥50 mL/min.

Conclusions: Administration of standard doses by intermittent bolus is likely to result in underdosing for many critically ill patients. Continuous infusion of higher than normal doses after a loading dose is more likely to achieve pharmacokinetic/pharmacodynamic targets. However, even continuous infusion of high doses (up to 9 g per day) does not guarantee adequate levels for all patients with a CLCR of ≥300 mL/min if the MIC is 8 mg/L.
Keyword Beta-lactams
Cephalosporins
Antibiotics
PK/PD
Critical care medicine
ICUs
Q-Index Code C1
Q-Index Status Confirmed Code
Grant ID APP1048652
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2015 Collection
School of Medicine Publications
 
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