Iris K Minichmayr1,2, André Schaeftlein1,2, Joseph L Kuti3, Markus Zeitlinger4, Charlotte Kloft5. 1. Department of Clinical Pharmacy and Biochemistry, Institute of Pharmacy, Freie Universitaet Berlin, Kelchstr. 31, 12169, Berlin, Germany. 2. Graduate Research Training Program PharMetrX, Berlin, Germany. 3. Center for Anti-Infective Research and Development, Hartford Hospital, Hartford, CT, USA. 4. Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria. 5. Department of Clinical Pharmacy and Biochemistry, Institute of Pharmacy, Freie Universitaet Berlin, Kelchstr. 31, 12169, Berlin, Germany. charlotte.kloft@fu-berlin.de.
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.
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 illpatients. 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 diabeticpatients (-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.
Authors: M A Zeitlinger; P Dehghanyar; B X Mayer; B S Schenk; U Neckel; G Heinz; A Georgopoulos; M Müller; C Joukhadar Journal: Antimicrob Agents Chemother Date: 2003-11 Impact factor: 5.191
Authors: S Luque; S Grau; F Alvarez-Lerma; O Ferrández; N Campillo; J P Horcajada; M Basas; J Lipman; J A Roberts Journal: Int J Antimicrob Agents Date: 2014-08-20 Impact factor: 5.283
Authors: David F Gaieski; Mark E Mikkelsen; Roger A Band; Jesse M Pines; Richard Massone; Frances F Furia; Frances S Shofer; Munish Goyal Journal: Crit Care Med Date: 2010-04 Impact factor: 7.598
Authors: R Schwameis; S Syré; D Marhofer; A Appelt; D Burau; K Sarahrudi; C Kloft; M Zeitlinger Journal: Antimicrob Agents Chemother Date: 2017-09-22 Impact factor: 5.191
Authors: D Busse; P Simon; D Petroff; N El-Najjar; L Schmitt; D Bindellini; A Dietrich; M Zeitlinger; W Huisinga; R Michelet; H Wrigge; C Kloft Journal: Antimicrob Agents Chemother Date: 2022-05-23 Impact factor: 5.938
Authors: Ferdinand Anton Weinelt; Miriam Songa Stegemann; Anja Theloe; Frieder Pfäfflin; Stephan Achterberg; Franz Weber; Lucas Dübel; Agata Mikolajewska; Alexander Uhrig; Peggy Kiessling; Wilhelm Huisinga; Robin Michelet; Stefanie Hennig; Charlotte Kloft Journal: Antibiotics (Basel) Date: 2022-06-02
Authors: Laurynas Mockeliunas; Lina Keutzer; Marieke G G Sturkenboom; Mathieu S Bolhuis; Lotte M G Hulskotte; Onno W Akkerman; Ulrika S H Simonsson Journal: Pharmaceutics Date: 2022-03-30 Impact factor: 6.525