Ehmann, L. and Simon, P. and Busse, D. and Petroff, D. and Dorn, C. and Huisinga, W. and Dietrich, A. and Zeitlinger, M. and Wrigge, H. and Kloft, C. (2020) Risk of target non-attainment in obese compared to non-obese patients in calculated linezolid therapy. CLINICAL MICROBIOLOGY AND INFECTION, 26 (9). pp. 1222-1228. ISSN 1198-743X, 1469-0691
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Objectives: The aim was to characterize linezolid population pharmacokinetics in plasma and interstitial space fluid of subcutaneous adipose tissue (target site) of obese compared with non-obese patients and to determine dosing regimens enabling adequate therapy using Monte Carlo simulations. Methods: In this prospective, parallel group, open-label, controlled, single-centre trial, 30 surgery patients (15 obese, 15 non-obese) received 600 mg of intravenous linezolid. A population pharmacokinetic analysis characterizing plasma and microdialysis-derived target site pharmacokinetics was followed by Monte Carlo simulations using twice/thrice daily 600-1200 mg short-term and extended infusions of linezolid. Adequacy of therapy was assessed by the probability of pharmacokinetic/pharmacodynamic target attainment for time and exposure-related indices. Results: In the model, lean body weight and obesity status largely explained between-patient variability in linezolid PK parameters (12.0-44.9%). Both factors caused lower area under the concentration-time curve in typical obese patients in plasma (-20.4%, 95% CI -22.0% to -15.9%) and at target-site (-37.7%, 95% CI -47.1% to -24.2%) compared with non-obese patients. Probability of target attainment showed improvement with increasing linezolid doses. Depending on lean body weight, adequate therapy was partially attained for 900- and 1200-mg linezolid doses and minimum inhibitory concentrations (MICs) <= 2 mg/L (probability of target attainment 62.5-100%) but could not be reached for MIC = 4 mg/L (probability of target attainment <= 82.3%). Additionally, lower linezolid distribution into the target site in obese patients as described above might compromise the plasma-based probability of target attainment analysis. Discussion: This analysis revealed risks of linezolid underdosing in empirical antibiotic therapy of most resistant bacteria for obese and non-obese patients. Doubling the standard dose is associated with adequate probability of target attainment throughout most body masses for MIC <= 2 mg/L. Further clinical studies with adjusted dosing regimens in for example intensive care patients are needed. L. Ehmann, Clin Microbiol Infect 2020;26:1222 (C) 2020 Published by Elsevier Ltd on behalf of European Society of Clinical Microbiology and Infectious Diseases.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | MONTE-CARLO-SIMULATION; POPULATION PHARMACOKINETICS; PHARMACODYNAMICS; MICRODIALYSIS; PLASMA; Adipose tissue; Anti-infectives; Interstitial space fluid; Linezolid; Microdialysis; Obesity; Pharmacodynamics; Population pharmacokinetics; Probability of target attainment; Target-site |
| Subjects: | 600 Technology > 615 Pharmacy |
| Divisions: | Chemistry and Pharmacy > Institute of Pharmacy Chemistry and Pharmacy > Institute of Pharmacy > Group Clinical Pharmacy (Dr. Dorn) |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 15 Mar 2021 10:17 |
| Last Modified: | 15 Mar 2021 10:17 |
| URI: | https://pred.uni-regensburg.de/id/eprint/43950 |
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