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Article

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

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Department of Anaesthesiology and Intensive Care, University of Leipzig Medical Centre, 04103 Leipzig, Germany
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Integrated Research and Treatment Centre (IFB) Adiposity Diseases, University of Leipzig, 04103 Leipzig, Germany
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Department of Clinical Pharmacy and Biochemistry, Institute of Pharmacy, Freie Universitaet Berlin, 12169 Berlin, Germany
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Graduate Research Training program PharMetrX, 12169 Berlin, Germany
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Clinical Trial Centre Leipzig, University of Leipzig, 04107 Leipzig, Germany
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Institute of Pharmacy, University of Regensburg, 93053 Regensburg, Germany
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Department of Visceral, Transplant, Thoracic and Vascular Surgery, Division of Bariatric and Metabolic Surgery, University of Leipzig Medical Centre, 04103 Leipzig, Germany
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Department of Clinical Pharmacology, Medical University of Vienna, 1090 Vienna, Austria
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Department of Pharmacology, University of Regensburg, 93053 Regensburg, Germany
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Department of Anaesthesiology, Intensive Care and Emergency Medicine, Pain Therapy, Bergmannstrost Hospital Halle, 06112 Halle, Germany
*
Author to whom correspondence should be addressed.
These authors contributed equally to the work.
J. Clin. Med. 2020, 9(4), 1067; https://doi.org/10.3390/jcm9041067
Received: 1 March 2020 / Revised: 27 March 2020 / Accepted: 7 April 2020 / Published: 9 April 2020
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/m2) and 15 non-obese (23.9 ± 2.1 kg/m2) patients were analyzed. AUC0–8 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. View Full-Text
Keywords: antibiotic dosing; concentrations; linezolid; microdialysis; obesity; pharmacokinetics; soft tissue antibiotic dosing; concentrations; linezolid; microdialysis; obesity; pharmacokinetics; soft tissue
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MDPI and ACS Style

Simon, P.; Busse, D.; Petroff, D.; Dorn, C.; Ehmann, L.; Hochstädt, S.; Girrbach, F.; Dietrich, A.; Zeitlinger, M.; Kees, F.; Kloft, C.; Wrigge, H. 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. J. Clin. Med. 2020, 9, 1067. https://doi.org/10.3390/jcm9041067

AMA Style

Simon P, Busse D, Petroff D, Dorn C, Ehmann L, Hochstädt S, Girrbach F, Dietrich A, Zeitlinger M, Kees F, Kloft C, Wrigge H. 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. Journal of Clinical Medicine. 2020; 9(4):1067. https://doi.org/10.3390/jcm9041067

Chicago/Turabian Style

Simon, Philipp, David Busse, David Petroff, Christoph Dorn, Lisa Ehmann, Sophie Hochstädt, Felix Girrbach, Arne Dietrich, Markus Zeitlinger, Frieder Kees, Charlotte Kloft, and Hermann Wrigge. 2020. "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" Journal of Clinical Medicine 9, no. 4: 1067. https://doi.org/10.3390/jcm9041067

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