Linezolid Concentrations in Plasma and Subcutaneous Tissue are Reduced in Obese Patients, Resulting in a Higher Risk of Underdosing in Critically Ill Patients: A Controlled Clinical Pharmacokinetic Study

URN to cite this document:

urn:nbn:de:bvb:355-epub-430633 Copy

DOI to cite this document:

10.5283/epub.43063 Copy

Simon, Philipp ; Busse, David ; Petroff, David ; Dorn, Christoph ; Ehmann, Lisa ; Hochstädt, Sophie ; Girrbach, Felix ; Dietrich, Arne ; Zeitlinger, Markus ; Kees, Frieder ; Kloft, Charlotte ; Wrigge, Hermann

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Date of publication of this fulltext: 15 Apr 2020 08:54

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Item type:	Article
Journal or Publication Title:	Journal of Clinical Medicine
Publisher:	MDPI
Place of Publication:	BASEL
Volume:	9
Number of Issue or Book Chapter:	4
Page Range:	p. 1067
Date:	2020
Institutions:	Chemistry and Pharmacy > Institute of Pharmacy > Group Clinical Pharmacy (Dr. Dorn) Chemistry and Pharmacy > Institute of Pharmacy > Alumni or Retired Professors > Prof. Wiegrebe
Identification Number:	Value Type 10.3390/jcm9041067 DOI
Keywords:	INTENSIVE-CARE-UNIT; POPULATION PHARMACOKINETICS; MORBIDLY OBESE; INFECTIONS; PENETRATION; MANAGEMENT; SINGLE; SKIN; PHARMACODYNAMICS; DIAGNOSIS; antibiotic dosing; concentrations; linezolid; microdialysis; obesity; pharmacokinetics; soft tissue
Dewey Decimal Classification:	600 Technology > 615 Pharmacy
Status:	Published
Refereed:	Yes, this version has been refereed
Created at the University of Regensburg:	Yes
Item ID:	43063

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Abstract

Background: Linezolid is used for the treatment of soft tissue infections in critically ill patients. However, data for characterizing the pharmacokinetics (PK) and assessing whether effective concentrations are reached at the target site are lacking. We hypothesized that current dosing regimens do not lead to effective concentrations in the plasma and interstitial fluid (ISF) of subcutaneous ...

Abstract

Background: Linezolid is used for the treatment of soft tissue infections in critically ill patients. However, data for characterizing the pharmacokinetics (PK) and assessing whether effective concentrations are reached at the target site are lacking. We hypothesized that current dosing regimens do not lead to effective concentrations in the plasma and interstitial fluid (ISF) of subcutaneous tissue in obese patients. Methods: As a controlled clinical model, critically ill obese and non-obese patients undergoing intra-abdominal surgery received 600 mg linezolid as a single infusion. Concentrations in the plasma and microdialysate from the ISF of subcutaneous tissue were determined up to 8 h after dosing. Pharmacokinetic analysis was performed by non-compartmental methods. As a therapeutic target, we used fAUC/MIC > 80. Results: Fifteen obese (BMI: 48.7 +/- 11.2 kg/m(2)) and 15 non-obese (23.9 +/- 2.1 kg/m(2)) patients were analyzed. AUC(0-8) in ISF decreased by -1.69 mg*h/L (95% CI: -2.59 to -0.79, p < 0.001) for every 10 kg increase in weight. PK in obese patients were characterized by lower maximal plasma concentrations (median 3.8 vs. 8.3 mg/L, p < 0.001) and a higher volume of distribution (41.0 vs. 30.8 L, p < 0.001), and the therapeutic target was not reached for MIC >= 1 mg/L in ISF and >= 2 mg/L in plasma. Conclusions: Increasing the weight led to a decrease of linezolid concentrations in the plasma and subcutaneous tissue. The current dosing regimen does not seem to produce sufficient concentrations to kill bacteria with MIC >= 2 mg/L, especially as empirical antimicrobial therapy in critically ill obese patients.

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