Plasma and cerebrospinal fluid population pharmacokinetics of vancomycin in patients with external ventricular drain
Zhendong Chen (1), Max Taubert (1), Chunli Chen (1,2), Charalambos Dokos (1), Uwe Fuhr (1), Thomas Weig (3), Michael Zoller (3), Suzette Heck (4), Konstantinos Dimitriadis (4,5), Nicole Terpolilli (5,6), Christina Kinast (3), Christina Scharf (3), Constantin Lier (7), Christoph Dorn (7), Uwe Liebchen (3)
(1) Department I of Pharmacology, Center for Pharmacology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany, (2) College of Veterinary Medicine, Northeast Agricultural University, Harbin, PR China, (3) Department of Anesthesiology, University Hospital, LMU Munich, Munich, Germany, (4) Department of Neurology, University Hospital, LMU Munich, Munich, Germany. (5) Institute for Stroke and Dementia Research (ISD), University Hospital, LMU Munich, Munich, Germany, (6) Department of Neurosurgery, University Hospital, LMU Munich, Munich, Germany, (7) Institute of Pharmacy, Faculty of Chemistry and Pharmacy, University of Regensburg, Regensburg, Germany.
Introduction: Vancomycin is a standard therapy for central nervous system (CNS) infections, specifically nosocomial infections, caused by Gram-positive penicillin-resistant pathogens [1]. However, vancomycin cannot easily penetrate through the blood-brain barrier (BBB) into the cerebrospinal fluid (CSF) due to its pronounced hydrophilicity and large molecular weight [2]. Vancomycin CSF concentrations are highly variable also because the extent of vancomycin penetration depends much on the integrity of the BBB [3-5]. So far, only a few studies investigated CSF pharmacokinetics of vancomycin in neurological/neurosurgical, while available data in individual studies is sparse and validation of developed exposure predictors is limited [6-8].
Objectives: (i) To investigate predictors for vancomycin penetration into CSF using a population pharmacokinetic (PopPK) approach based on vancomycin plasma and CSF data from patients who had external ventricular drainage (EVD); (ii) to assess the feasibility of collecting CSF samples at the distal port of the EVD system for therapeutic drug monitoring (TDM); (iii) to examine the benefits of different infusion modes and dosages through model-based simulations.
Methods: This study was conducted among patients who had an EVD and were treated with vancomycin. Blood and CSF samples from the proximal and/or distal ports of the EVD system were collected to measure vancomycin concentrations and clinical parameters [9]. Patients were classified according to whether or not the primary infection was a CNS infection.
The PopPK model was developed and diagnosed based on vancomycin plasma and CSF concentrations using the nonlinear mixed-effects model software NONMEM and Perl-speaks-NONMEM (PsN) [10,11]. The model was developed using first-order conditional estimation with interaction, where a decrease of >3.84 in the objective function value (OFV) between 2 nested models (P < 0.05) upon the inclusion of a parameter was used as a statistical criterion. Covariates were assessed by stepwise forward inclusion (P = 0.05) using the PsN tool.
Different dosing regimens were tested separately in virtual patients with primary CNS infection by model-based simulations. Three infusion modes, including intermittent infusion, continuous infusion with loading dose, and continuous infusion without loading dose, were compared in terms of the daily area under the curve in plasma and the trough concentration in CSF which are common PK/PD targets for vancomycin therapy. [12,13]
Results: A three-compartment model with first-order elimination best-described vancomycin data. Estimated parameters included clearance (CL, 4.53 L/h), central compartment volume (Vc, 24.0 L), inter-compartmental clearance between central and peripheral compartments (Qp, 5.69 L/h), peripheral compartment volume (Vp, 38.7 L), apparent CSF compartment volume (VCSF, 0.445 L), and clearance between central and CSF compartments (QCSF, 0.00322 L/h and 0.00135 L/h for patients with and without primary CNS infection, respectively). Creatinine clearance was a significant covariate on vancomycin CL. Three CSF-related covariates including CSF protein, glucose, and lactate concentrations in CSF were found to have significant effects on QCSF when tested separately, the ΔOFVs were -29.755, -9.394, and -6.587, respectively. There was no detectable difference between sampling from the proximal and the distal port. Intermittent and continuous infusion with a loading dose reached the CSF target concentration faster compared to continuous infusion only. All infusion schedules reached similar CSF trough concentrations. Beyond adjusting doses according to renal function, starting treatment with a loading dose in patients with primary CSF infection is recommended.
Conclusion: In this study, a PopPK model for vancomycin was successfully established using the data from patients with EVD. Three substances quantified in CSF were identified as predictors associated with vancomycin CSF concentrations, while the relationship was closest with CSF protein. The model fully supported the feasibility of collecting CSF samples at the distal port of the EVD system for TDM. Beyond adjusting doses according to renal function, starting treatment with a loading dose in patients with primary CSF infection is recommended.
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