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Adv Drug Deliv Rev. 2014 Nov 20;77:3-11. doi: 10.1016/j.addr.2014.07.006. Epub 2014 Jul 15.

The effect of pathophysiology on pharmacokinetics in the critically ill patient--concepts appraised by the example of antimicrobial agents.

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Dept. of Internal Medicine, Faculty of Medicine & Health Science, Ghent University, De Pintelaan 185, 9000 Ghent, Belgium; The Burns Trauma and Critical Care Research Centre, The University of Queensland, Brisbane, Australia. Electronic address:
Institute of Clinical Pharmacology, Azienda Ospedaliero-Universitaria Santa Maria della Misericordia, Italy; Department of Experimental and Clinical Medical Sciences, University of Udine, Udine, Italy. Electronic address:
The Burns Trauma and Critical Care Research Centre, The University of Queensland, Brisbane, Australia; Dept. of Intensive Care Medicine, Royal Brisbane and Women's Hospital, Butterfield St, Herston QLD 4006, Australia. Electronic address:


Critically ill patients are at high risk for development of life-threatening infection leading to sepsis and multiple organ failure. Adequate antimicrobial therapy is pivotal for optimizing the chances of survival. However, efficient dosing is problematic because pathophysiological changes associated with critical illness impact on pharmacokinetics of mainly hydrophilic antimicrobials. Concentrations of hydrophilic antimicrobials may be increased because of decreased renal clearance due to acute kidney injury. Alternatively, antimicrobial concentrations may be decreased because of increased volume of distribution and augmented renal clearance provoked by systemic inflammatory response syndrome, capillary leak, decreased protein binding and administration of intravenous fluids and inotropes. Often multiple conditions that may influence pharmacokinetics are present at the same time thereby excessively complicating the prediction of adequate concentrations. In general, conditions leading to underdosing are predominant. Yet, since prediction of serum concentrations remains difficult, therapeutic drug monitoring for individual fine-tuning of antimicrobial therapy seems the way forward.


Acute kidney injury; Antimicrobial agents; Hepatic failure; Intensive care unit; Organ failure; Pharmacodynamics; Pharmacokinetics; Sepsis

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