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Open Access Highly Accessed Study protocol

Antibiotic dosing in the 'at risk' critically ill patient: Linking pathophysiology with pharmacokinetics/pharmacodynamics in sepsis and trauma patients

Jason A Roberts123*, Michael S Roberts45, Andrew Semark2, Andrew A Udy12, Carl MJ Kirkpatrick6, David L Paterson78, Matthew J Roberts1, Peter Kruger49 and Jeffrey Lipman12

Author Affiliations

1 Burns, Trauma and Critical Care Research Centre, The University of Queensland, Royal Brisbane and Women's Hospital, Brisbane, Queensland, Australia

2 Department of Intensive Care Medicine, Royal Brisbane and Women's Hospital, Brisbane, Queensland, Australia

3 Pharmacy Department, Royal Brisbane and Women's Hospital, Brisbane, Queensland, Australia

4 School of Medicine, The University of Queensland, Brisbane, Queensland, Australia

5 School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, Australia

6 School of Pharmacy, The University of Queensland, Brisbane, Queensland, Australia

7 Departments of Infectious Diseases and Microbiology, Royal Brisbane and Women's Hospital, Herston, Brisbane, Australia

8 University of Queensland Centre for Clinical Research, Brisbane, Australia

9 Department of Intensive Care Medicine, Princess Alexandra Hospital

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BMC Anesthesiology 2011, 11:3  doi:10.1186/1471-2253-11-3

Published: 20 February 2011

Abstract

Background

Critical illness, mediated by trauma or sepsis, can lead to physiological changes that alter the pharmacokinetics of antibiotics and may result in sub-therapeutic concentrations at the sites of infection. The first aim of this project is to identify the clinical characteristics of critically ill patients with significant trauma that have been recently admitted to ICU that may predict the dosing requirements for the antibiotic, cefazolin. The second aim of this is to identify the clinical characteristics of critically ill patients with sepsis that may predict the dosing requirements for the combination antibiotic, piperacillin-tazobactam.

Methods/Design

This is an observational pharmacokinetic study of patients with trauma (cefazolin) or with sepsis (piperacillin-tazobactam). Participants will have samples from blood and urine, collected at different intervals. Patients will also have a microdialysis catheter inserted into subcutaneous tissue to measure interstitial fluid penetration of the antibiotic. Participants will be administered sinistrin, indocyanine green and sodium bromide as well as have cardiac output monitoring performed and tetrapolar bioimpedance to determine physiological changes resulting from pathology. Analysis of samples will be performed using validated liquid chromatography tandem mass-spectrometry. Pharmacokinetic analysis will be performed using non-linear mixed effects modeling to determine individual and population pharmacokinetic parameters of antibiotics.

Discussion

The study will describe cefazolin and piperacillin-tazobactam concentrations in plasma and the interstitial fluid of tissues in trauma and sepsis patients respectively. The results of this study will guide clinicians to effectively dose these antibiotics in order to maximize the concentration of antibiotics in the interstitial fluid of tissues.