Variable Linezolid Exposure in Intensive Care Unit Patients—Possible Role of Drug–Drug Interactions

Töpper, Christoph; Steinbach, Cathérine Louise; Dorn, Christoph; Kratzer, Alexander; Wicha, Sebastian G.; Schleibinger, Michael; Liebchen, Uwe; Kees, Frieder; Salzberger, Bernd; Kees, Martin G.

doi:10.1097/ftd.0000000000000324

Cited by 24 publications

(20 citation statements)

References 33 publications

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“…In the last year, several authors further supported the hypothesis that TDM might represent the way forward for optimizing linezolid therapy in specific subpopulations of patients .…”

Section: Discussionmentioning

confidence: 92%

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A 10‐Year Experience of Therapeutic Drug Monitoring (TDM) of Linezolid in a Hospital‐wide Population of Patients Receiving Conventional Dosing: Is there Enough Evidence for Suggesting TDM in the Majority of Patients?

Pea

Cojutti

Baraldo

2017

Basic Clin Pharma Tox

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A retrospective study was conducted to assess our 10-year experience of therapeutic drug monitoring (TDM) of linezolid in a large patient population to establish whether conventional dosing may result in adequate drug exposure in the majority of patients. Patients included in this study underwent TDM of linezolid trough concentration (C ) during treatment with conventional doses of 600 mg every 12 hr in the period between January 2007 and June 2016. The desired range of C was set between 2 and 7 mg/L (underexposure, C < 2 mg/L; overexposure, C > 7 mg/L). Multivariate logistic regression analysis investigated variables potentially correlated with linezolid C . One thousand and forty-nine patients had 2484 linezolid C assessed during treatment with conventional doses. Median (IQR) linezolid C was 5.08 mg/L (2.78-8.52 mg/L). Linezolid C was within the desired range in 50.8% of cases (1262/2484). Overexposure (n = 821; 33%) occurred much more frequently than underexposure (n = 401; 16.2%) and was severe (>20 mg/L) in 3.9% of cases (98/2484). Linezolid overexposure was significantly associated with CrCL estimates ≤40 mL/min. (OR 1.463; 95% CI 1.124-1.904, p = 0.005). Linezolid underexposure was significantly associated with CrCL estimates >100 mL/min. (OR 3.046; 95% CI 2.234-4.152, p < 0.001). Linezolid C was not correlated linearly with CrCL (R = 0.061). Variability in renal function explained only partially the very wide interindividual linezolid C variability. Our study suggests that TDM could represent a valuable approach in optimizing linezolid exposure in the majority of patients.

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“…In the last year, several authors further supported the hypothesis that TDM might represent the way forward for optimizing linezolid therapy in specific subpopulations of patients .…”

Section: Discussionmentioning

confidence: 92%

“…We supposed that the interindividual variability of linezolid C min may be related mainly to drug–drug interactions . Other authors suggested that linezolid C min may be influenced also by the degree of renal function , by the severity of critical illness or even by some other factors .…”

mentioning

confidence: 92%

A 10‐Year Experience of Therapeutic Drug Monitoring (TDM) of Linezolid in a Hospital‐wide Population of Patients Receiving Conventional Dosing: Is there Enough Evidence for Suggesting TDM in the Majority of Patients?

Pea

Cojutti

Baraldo

2017

Basic Clin Pharma Tox

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“…Based on a population kinetic approach, a dosing schedule of 450 mg linezolid thrice daily has been suggested, in order to avoid high peak plasma concentrations during multiple dosing [10]. Based on the result of the present study, an alternative and practicable twice daily dosing schedule could include a loading dose of 600 mg or even 900 mg, accounting for the higher volume of distribution in obese patients and the slower diffusion into the tissue, followed by standard dosing of 600 mg linezolid twice daily, accounting for the similar clearance in both groups, and preferably administered as prolonged infusion, starting, e.g., after 8 h instead of 12 h. Regarding further dose adjustments during multiple dosing in critically ill patients, therapeutic drug monitoring is advised due to the high variability of linezolid plasma concentrations in these patients [27,50,51].…”

Section: Discussionmentioning

confidence: 99%

“…Linezolid was determined by a validated HPLC-UV method, as described previously [26,27]. Sample treatment for the determination of total linezolid included the deproteinization of plasma with perchloric acid, and microdialysate was directly injected into the column.…”

Section: Drug Analysismentioning

confidence: 99%

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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

Simon

Busse

Petroff

et al. 2020

JCM

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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 f AUC/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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Therapeutisches Drugmonitoring und pharmakokinetische Modelle als Strategie zur rationalen Antibiotikatherapie bei IntensivpatientInnen

et al. 2022

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Variable Linezolid Exposure in Intensive Care Unit Patients—Possible Role of Drug–Drug Interactions

Cited by 24 publications

References 33 publications

A 10‐Year Experience of Therapeutic Drug Monitoring (TDM) of Linezolid in a Hospital‐wide Population of Patients Receiving Conventional Dosing: Is there Enough Evidence for Suggesting TDM in the Majority of Patients?

A 10‐Year Experience of Therapeutic Drug Monitoring (TDM) of Linezolid in a Hospital‐wide Population of Patients Receiving Conventional Dosing: Is there Enough Evidence for Suggesting TDM in the Majority of Patients?

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

Therapeutisches Drugmonitoring und pharmakokinetische Modelle als Strategie zur rationalen Antibiotikatherapie bei IntensivpatientInnen

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