Plasma and Cerebrospinal Fluid Population Pharmacokinetics of Vancomycin in Patients with External Ventricular Drain

Abstract

Vancomycin is a commonly used antibacterial agent in patients with primary central nervous system (CNS) infection. This study aims to examine predictors of vancomycin penetration into cerebrospinal fluid (CSF) in patients with external ventricular drainage and the feasibility of CSF sampling from the distal drainage port for therapeutic drug monitoring. Fourteen adult patients (9 with primary CNS infection) were treated with vancomycin intravenously. The vancomycin concentrations in blood and CSF (from proximal [CSF_P] and distal [CSF_D] drainage ports) were evaluated by population pharmacokinetics. Model-based simulations were conducted to compare various infusion modes. A three-compartment model with first-order elimination best described the vancomycin data. Estimated parameters included clearance (CL, 4.53 L/h), central compartment volume (V_c, 24.0 L), apparent CSF compartment volume (V_CSF, 0.445 L), and clearance between central and CSF compartments (Q_CSF, 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. CSF protein was the primary covariate to explain the variability of Q_CSF. There was no detectable difference between the data for sampling from the proximal and the distal port. Intermittent infusion and continuous infusion with a loading dose reached the CSF target concentration faster than 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. Occasionally, very high and possibly toxic doses would be required to achieve adequate CSF concentrations, which calls for more investigation of direct intraventricular administration of vancomycin. (This study has been registered at ClinicalTrials.gov under registration no. NCT04426383).

Keywords: CSF protein; central nervous system infection; distal port; population pharmacokinetics model; vancomycin; ventriculitis.

FIG 1

Combined goodness-of-fit plots of the final model for vancomycin plasma (A to D) and CSF (E to H) concentrations. DV, observed concentrations; IPRED, individual predicted concentrations; PRED, population predicted concentrations; CWRES, conditional weighted residuals; TIME, time after the first dose. Red lines show the local polynomial regression fit.

FIG 2

Confidence interval prediction-corrected visual predictive check (n = 1,000) for the final model for plasma and CSF. Dots represent observed concentrations. Black solid lines represent the median values, while dashed lines show the 5th and 95th percentiles of observed concentrations. Shaded areas are the model-predicted 95% confidence intervals for the 5th (red), 50th (blue), and 95th (red) percentiles from 1,000 simulated data sets.

FIG 3

Median concentration-versus-time curves simulated in plasma and CSF after different dosing regimens of vancomycin over 5 days in patients with CNS infection. II, intermittent infusion; q12h, every 12 h; CI_L, continuous infusion with a loading dose same as the first dose of q12h; CI, continuous infusion without a loading dose.

FIG 4

Scheme of the transit compartment model (left) and the bulk flow model (right; preferred and used for further evaluations) for the CSF compartment. In both models, vancomycin directly entered the central compartment with zero-order absorption. In the transit compartment model, vancomycin entered the CSF compartment from the central compartment (compartment volume, V_c) with an intercompartment clearance (Q_CSF), while the CSF compartment volume (V_CSF) was fixed at 0.002 L/kg × weight. Then, vancomycin returned to the central compartment through a separate transit compartment with an independent parameter transit rate (KTR). In the bulk flow model, vancomycin entered the CSF compartment from the central compartment with Q_CSF, but with an additional bulk flow (Q_BULK, 0.025 L/h) when vancomycin returned to the central compartment. Both models contain a peripheral compartment with the parameters intercompartment clearance (Q_p) and peripheral compartment volume (V_P). Vancomycin was ultimately eliminated by first order from the central compartment.