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Antimicrobial Agents and Chemotherapy, July 2006, p. 2455-2463, Vol. 50, No. 7
0066-4804/06/$08.00+0     doi:10.1128/AAC.01468-05
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Pharmacokinetics of Unbound Linezolid in Plasma and Tissue Interstitium of Critically Ill Patients after Multiple Dosing Using Microdialysis

Cornelia Buerger,1 Nele Plock,1 Pejman Dehghanyar,2 Christian Joukhadar,2 and Charlotte Kloft1,3*

Department of Clinical Pharmacy, Institute of Pharmacy, Freie Universitaet Berlin, D-12169 Berlin, Germany,1 Department of Clinical Pharmacology, Medical University Vienna, A-1090 Vienna, Austria,2 Department of Clinical Pharmacy, Martin-Luther-Universitaet Halle-Wittenberg, D-06120 Halle, Germany3

Received 13 November 2005/ Returned for modification 20 February 2006/ Accepted 28 April 2006

The antimicrobial agent linezolid is approved for the treatment of severe infections caused by, e.g., methicillin-resistant Staphylococcus strains. In order to evaluate the penetration of linezolid into the interstitial space fluid (ISF) of subcutaneous adipose tissue and skeletal muscle of the target population, a microdialysis study was performed with 12 patients with sepsis or septic shock after multiple intravenous infusions. Unbound linezolid concentrations were determined for plasma and microdialysates by use of a validated high-performance liquid chromatography method. Individual compartmental pharmacokinetic (PK) analysis was performed using WinNonlin. In vivo microdialysis was found to be feasible for the determination of unbound linezolid concentrations at steady state in the ISF of critically ill patients. On average, linezolid showed good distribution into ISF but with high interindividual variability. A two-compartment model was fitted to unbound concentrations in plasma with a geometric mean distribution volume of 62.9 liters and a mean clearance of 9.18 liters/h at steady state. However, disposition characteristics changed intraindividually within the time course. In addition, an integrated model for simultaneous prediction of concentrations in all matrices was developed and revealed similar results. Based on the model-predicted unbound concentrations in ISF, a scheme of more-frequent daily dosing of linezolid for some critically ill patients might be taken into consideration to avoid subinhibitory unbound concentrations in the infected tissue. The developed integrated model will be a valuable basis for further PK data analysis to explore refined dosing guidelines that achieve effective antimicrobial therapy in all patients by use of the population PK approach.

* Corresponding author. Mailing address: Martin-Luther-Universitaet Halle-Wittenberg, Faculty of Pharmacy, Dept. Clinical Pharmacy, Wolfgang-Langenbeck-Str. 4, D-06120 Halle, Germany. Phone: 49 345 5525190. Fax: 49 345 5527257. E-mail: charlotte.kloft{at}pharmazie.uni-halle.de.

Antimicrobial Agents and Chemotherapy, July 2006, p. 2455-2463, Vol. 50, No. 7
0066-4804/06/$08.00+0     doi:10.1128/AAC.01468-05
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

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  • Plock, N., Buerger, C., Joukhadar, C., Kljucar, S., Kloft, C. (2007). Does Linezolid Inhibit Its Own Metabolism? Population Pharmacokinetics As a Tool to Explain the Observed Nonlinearity in Both Healthy Volunteers and Septic Patients. Drug Metab. Dispos. 35: 1816-1823 [Abstract] [Full Text]  
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