Population pharmacokinetics and dosing simulations of amoxicillin/clavulanic acid in critically ill patients

Carlier, Mieke, Noe, Michael, De Waele, Jan J., Stove, Veronique, Verstraete, Alain G., Lipman, Jeffrey and Roberts, Jason A. (2013) Population pharmacokinetics and dosing simulations of amoxicillin/clavulanic acid in critically ill patients. Journal of Antimicrobial Chemotherapy, 68 11: 2600-2608. doi:10.1093/jac/dkt240

Author Carlier, Mieke
Noe, Michael
De Waele, Jan J.
Stove, Veronique
Verstraete, Alain G.
Lipman, Jeffrey
Roberts, Jason A.
Title Population pharmacokinetics and dosing simulations of amoxicillin/clavulanic acid in critically ill patients
Journal name Journal of Antimicrobial Chemotherapy   Check publisher's open access policy
ISSN 0305-7453
Publication date 2013-01-01
Year available 2013
Sub-type Article (original research)
DOI 10.1093/jac/dkt240
Open Access Status DOI
Volume 68
Issue 11
Start page 2600
End page 2608
Total pages 9
Place of publication Oxford, United Kingdom
Publisher Oxford University Press
Language eng
Subject 3004 Pharmacology
2736 Pharmacology (medical)
2725 Infectious Diseases
Abstract Objectives: The objective of this studywas to investigate the population pharmacokinetics and pharmacodynamics of amoxicillin and clavulanic acid in critically ill patients. Methods: In this observational pharmacokinetic study, multiple blood sampleswere taken overone dosing interval of intravenous amoxicillin/clavulanic acid (1000/200 mg). 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-four blood samples were collected from 13 patients. For both amoxicillin and clavulanic acid, a two-compartment model with between-subject variability for both the clearance and the volume of distribution of the central compartment described the data adequately. For both compounds, 24 h urinary creatinine clearancewas supported as a descriptor of drug clearance. Themeanclearance ofamoxicillinwas10.0 L/h and the meanvolume of distributionwas 27.4 L. For clavulanic acid, themeanclearancewas 6.8 L/h and themeanvolume of distribution was 19.2 L. Dosing simulations for amoxicillin supported the use of standard dosing regimens (30 min infusion of 1 g four-times daily or 2 g three-times daily) for most patients when using a target MIC of 8 mg/L and a pharmacodynamic target of 50% fT>MIC, except for those with a creatinine clearance >190 mL/ min. Dosing simulations for clavulanic acid showed little accumulation when high doses were administered to patients with high creatinine clearance. Conclusions: Although vast pharmacokinetic variability exists for both amoxicillin and clavulanic acid in intensive care unit patients, current dosing regiments are appropriate for most patients, except those with very high creatinine clearance.
Keyword β-lactams
Clavulanic acid
Critical care medicine
Q-Index Code C1
Q-Index Status Confirmed Code
Grant ID 11E8512N
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2014 Collection
School of Medicine Publications
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