title: 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.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: Department of Clinical Pharmacy and Biochemistry, Institute of Pharmacy, Freie Universitaet Berlin, Kelchstr. 31, 12169, Berlin, Germany.|Graduate Research Training Program PharMetrX, Berlin, Germany.
authors.forename: Iris K
authors.initials: IK
authors.lastname: Minichmayr
authors.affiliation: Department of Clinical Pharmacy and Biochemistry, Institute of Pharmacy, Freie Universitaet Berlin, Kelchstr. 31, 12169, Berlin, Germany.|Graduate Research Training Program PharMetrX, Berlin, Germany.
authors.forename: André
authors.initials: A
authors.lastname: Schaeftlein
authors.affiliation: Center for Anti-Infective Research and Development, Hartford Hospital, Hartford, CT, USA.
authors.forename: Joseph L
authors.initials: JL
authors.lastname: Kuti
authors.affiliation: Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria.
authors.forename: Markus
authors.initials: M
authors.lastname: Zeitlinger
authors.affiliation: Department of Clinical Pharmacy and Biochemistry, Institute of Pharmacy, Freie Universitaet Berlin, Kelchstr. 31, 12169, Berlin, Germany. charlotte.kloft@fu-berlin.de.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Kloft
mesh_terms: D000273:Adipose Tissue / Q000378:metabolism; D000328:Adult; D000368:Aged; D000900:Anti-Bacterial Agents / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000627:therapeutic use; D001424:Bacterial Infections / Q000097:blood / Q000188:drug therapy / Q000378:metabolism; D016638:Critical Illness; D003550:Cystic Fibrosis / Q000097:blood / Q000188:drug therapy / Q000378:metabolism; D017719:Diabetic Foot / Q000097:blood / Q000188:drug therapy / Q000378:metabolism; D045604:Extracellular Fluid / Q000378:metabolism*; D005260:Female; D064368:Healthy Volunteers; D006801:Humans; D000069349:Linezolid / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000627:therapeutic use; D008297:Male; D008826:Microbial Sensitivity Tests; D008875:Middle Aged; D008954:Models, Biological; D018805:Sepsis / Q000097:blood / Q000188:drug therapy / Q000378:metabolism; D055815:Young Adult
chemical_list: D000900:Anti-Bacterial Agents; D000069349:Linezolid