Antibacterial dosing in intensive care: Pharmacokinetics, degree of disease and pharmacodynamics of sepsis

Roberts, J. A. and Lipman, J. (2006) Antibacterial dosing in intensive care: Pharmacokinetics, degree of disease and pharmacodynamics of sepsis. Clinical Pharmacokinetics, 45 8: 755-773. doi:10.2165/00003088-200645080-00001

Author Roberts, J. A.
Lipman, J.
Title Antibacterial dosing in intensive care: Pharmacokinetics, degree of disease and pharmacodynamics of sepsis
Journal name Clinical Pharmacokinetics   Check publisher's open access policy
ISSN 0312-5963
Publication date 2006
Sub-type Article (original research)
DOI 10.2165/00003088-200645080-00001
Open Access Status
Volume 45
Issue 8
Start page 755
End page 773
Total pages 19
Editor Amitabh Prakash
Place of publication Auckland, New Zealand
Publisher Adis International
Collection year 2006
Language eng
Subject C1
321009 Intensive Care
730100 Clinical (Organs, Diseases and Abnormal Conditions)
1103 Clinical Sciences
Abstract Treatment of sepsis remains a significant challenge with persisting high mortality and morbidity. Early and appropriate antibacterial therapy remains an important intervention for such patients. To optimise antibacterial therapy, the clinician must possess knowledge of the pharmacokinetic and pharmacodynamic properties of commonly used antibacterials and how these parameters may be affected by the constellation of pathophysiological changes occurring during sepsis. Sepsis, and the treatment thereof, increases renal preload and, via capillary permeability, leads to 'third-spacing', both resulting in higher antibacterial clearances. Alternatively, sepsis can induce multiple organ dysfunction, including renal and/or hepatic dysfunction, causing a decrease in antibacterial clearance. Aminoglycosides are concentration-dependent antibacterials and they display an increased volume of distribution (V-d) in sepsis, resulting in decreased peak serum concentrations. Reduced clearance from renal dysfunction would increase the likelihood of toxicity. Individualised dosing using extended interval dosing, which maximises the peak serum drug concentration (C-max)/minimum inhibitory concentration ratio is recommended. beta-Lactams and carbapenems are time-dependent antibacterials. An increase in Vd and renal clearance will require increased dosing or administration by continuous infusion. If renal impairment occurs a corresponding dose reduction may be required. Vancomycin displays predominantly time-dependent pharmacodynamic properties and probably requires higher than conventionally recommended doses because of an increased V-d and clearance during sepsis without organ dysfunction. However, optimal dosing regimens remain unresolved. The poor penetration of vancomycin into solid organs may require alternative therapies when sepsis involves solid organs (e.g. lung). Ciprofloxacin displays largely concentration-dependent kill characteristics, but also exerts some time-dependent effects. The V-d of ciprofloxacin is not altered with fluid shifts or over time, and thus no alterations of standard doses are required unless renal dysfunction occurs. In order to optimise antibacterial regimens in patients with sepsis, the pathophysiological effects of systemic inflammatory response syndrome need consideration, in conjunction with knowledge of the different kill characteristics of the various antibacterial classes. In conclusion, certain antibacterials can have a very high V-d, therefore leading to a low C-max and if a high peak is needed, then this would lead to underdosing. The Vd of certain antibacterials, namely aminoglycosides and vancomycin, changes over time, which means dosing may need to be altered over time. Some patients with serum creatinine values within the normal range can have very high drug clearances, thereby producing low serum drug levels and again leading to underdosing. Copyright © 2010 Elsevier Inc. All rights reserved.
Keyword Sepsis
Antibacterial therapy
Renal replacement therapy
Ventilator-associated pneumonia
Beta-lactam antibiotics
Renal dysfunction
Altered aminoglycoside pharmacokinetics
Continuous venovenous hemofiltration
Resistant staphylococcus-aureus
Q-Index Code C1

Document type: Journal Article
Sub-type: Article (original research)
Collections: Excellence in Research Australia (ERA) - Collection
2007 Higher Education Research Data Collection
School of Medicine Publications
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Citation counts: TR Web of Science Citation Count  Cited 137 times in Thomson Reuters Web of Science Article | Citations
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Created: Wed, 15 Aug 2007, 09:53:21 EST