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17.10.2016 | Original Research Article | Ausgabe 6/2017

Clinical Pharmacokinetics 6/2017

Clinical Determinants of Target Non-Attainment of Linezolid in Plasma and Interstitial Space Fluid: A Pooled Population Pharmacokinetic Analysis with Focus on Critically Ill Patients

Zeitschrift:
Clinical Pharmacokinetics > Ausgabe 6/2017
Autoren:
Iris K. Minichmayr, André Schaeftlein, Joseph L. Kuti, Markus Zeitlinger, Charlotte Kloft
Wichtige Hinweise

Electronic supplementary material

The online version of this article (doi:10.​1007/​s40262-016-0463-7) contains supplementary material, which is available to authorized users.
I. K. Minichmayr and A. Schaeftlein contributed equally to this work.

Abstract

Objectives

We aimed to assess linezolid pharmacokinetics in the plasma and interstitial space fluid (ISF) of patients with sepsis, diabetic foot infections or cystic fibrosis and healthy volunteers. The impacts of joint characteristics and disease on plasma and target-site exposure were to be identified together with the benefit of dose intensification in critically ill patients.

Methods

Rich plasma (n = 1598) and ISF concentrations in subcutaneous adipose (n = 1430) and muscle tissue (n = 1089) measured by microdialysis were pooled from three clinical trials with 51 individuals receiving 600 mg of intravenous and oral linezolid. All data were analysed simultaneously by a population approach also considering methodological aspects of microdialysis. The impact of covariates on the attainment of the pharmacokinetic/pharmacodynamic targets, AUC/MIC = 100 (area under the concentration-time curve/minimum inhibitory concentration) and fT>MIC = 99 % (time that unbound concentrations exceed the MIC), was assessed by deterministic and Monte Carlo simulations.

Results

A two-compartment pharmacokinetic model with nonlinear elimination and tissue distribution factors accounting for differences between plasma and ISF concentrations adequately predicted all measurements. Clearance (CL) was highest in septic patients (11.2 L/h vs. CLHealthy/CLCystic fibrosis/CLDiabetic = 7.67/6.87/6.35 L/h). Penetration into subcutaneous adipose ISF was lowest in diabetic patients (−34.9 % compared with healthy volunteers). Creatinine clearance and total body weight further impacted linezolid exposure. To achieve timely efficacious therapy, front-loaded dosing and continuous infusion seemed beneficial in septic patients.

Conclusions

Our analysis suggests that after standard linezolid doses, particularly patients with sepsis and conserved renal function are at risk of not attaining pharmacokinetic/pharmacodynamic targets and would benefit from initial dose intensification.

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Zusatzmaterial
Supplementary material 1 (PDF 232 kb)
40262_2016_463_MOESM1_ESM.pdf
Supplementary material 2 (PDF 77 kb)
40262_2016_463_MOESM2_ESM.pdf
Literatur
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