Kris Oliver Jalusic (1), Silke Gastine (2), Michael Heßler (3), Georg Hempel (1)
(1) Institute of Pharmaceutical and Medical Chemitry – Department of Clinical Pharmacy, Westfälische Wilhelms-Universität Münster, Münster, Germany, (2) University College London - Great Ormond Street Institute of Child Health, London United Kingdom, (3) Department of Anesthesiology, Intensive Care and Pain Medicine, University Hospital of Münster, Münster Germany
Introduction: Although the penetration into the central nervous system is believed to be poor, vancomycin is the recommended therapy in patients suffering from ventriculitis [1][2]. To determine the distribution of vancomycin into the cerebrospinal fluid (CSF), the pharmacokinetics of vancomycin in patients with ventriculitis were evaluated and covaraiate relationships explored.
Objectives:
- Investigating dosage adjustments for vancomycin in critically ill patients with regard to adequate drug concentrations in the CSF
- Screening of covariates that influence the pharmacokinetics of vancomycin in critically ill patients
Methods: For the population pharmacokinetic model, 29 patients were recruited in an intermediate care unit at the university hospital of Münster in the period between January 2014 and June 2015. A total of 184 Blood and 133 CSF samples were collected. All patients had a clinical evidence of EVD (External ventricular drainage) -associated ventriculitis [3]. Vancomycin was either applied as bolus 6h (n=23) or continous infusion (n=6) with daily plasma and CSF trough concentrations measured. In the interval dosing scheme, the doses were adjusted to reach serum trough levels of 15-20 mg/L. For continuous dosing, adjustments targeted serum concentrations of 20-25 mg/L. This dosing regimen was designed to achieve vancomycin CSF trough concentrations above 1 mg/L [4]. For all patients demographic covariates, as well as leucocytes count, creatine, creatine clearance, C-reactive protein, urea in serum and total protein, glucose, lactate, granulocytes, cell count, erythrocytes in the CSF
The enzyme-multiplied immunoassay technique was used to analyse plasma concentrations [5]. The therapy with vancomycin was continued for 7 to 14 days, unless the antibiotic therapy was deescalated or adverse events led to a discontinuation. The population pharmacokinetic analysis was conducted by using nonlinear mixed effects modelling (NONMEM®).
Results: The median and range for the concentration in plasma were as follows 17.7( 2.4-49.1) [mg/L] and the median concentration in the CSF 2.9 ( 1.1-11.0) [mg/L], respectively. For the final population pharmacokinetic model a three-compartment model with linear elimination was developed. Two compartments describe vancomycin pharmacokinetics in plasma with a third discribing the disribution into the CSF. Creatinine clearance (ClCr) and lactate were detected as significant covariates. The model shows that the total vancomycin plasma clearance (Cl) depends on ClCr. Furthermore, the clearance (Cldif) between the central and CSF compartment correlates with blood lactate concentration. Based on the final model, the following values were estimated by NONMEM®: Cl = 5.15 L/h, Q = 3.31 L/h, Cldif = 0.0031 L/h, Vcentral = 42.1 L, VCSF = 0.32 L and the value of Vperipheral was fixed to 86.2 L. Monte-Carlo simulations for diffent dosing regiments indicate that a dose of 4 g per day, administered every 8 hours, adequately results in the CSF target concentrations of 1 mg/L.
Conclusion: In the daily clinical routine, the final PK model can be useful in dosing of vancomycin in critically ill patients. The lactate concentration is a determinant of CSF vancomycin concentrations.
References:
[1] Moon HJ, Kim SD, Lee JB et al. (2007) Clinical Analysis of External Ventricular Drainage Related Ventriculitis. J Korean Neurosurg Soc 41(4): 236.
[2] Rybak MJ (2006) The pharmacokinetic and pharmacodynamic properties of vancomycin. Clin Infect Dis 42 Suppl 1: S35-9.
[3] Horan TC, Andrus M, Dudeck MA (2008) CDC/NHSN surveillance definition of health care-associated infection and criteria for specific types of infections in the acute care setting. Am J Infect Control 36(5): 309–332.
[4] Lutsar I, McCracken GH, Friedland IR (1998) Antibiotic pharmacodynamics in cerebrospinal fluid. Clin Infect Dis 27(5): 1117-27, quiz 1128-9
[5] Milone MC (2012) Therapeutic drug monitoring: Newer drugs and biomarkers. Analytical Techniques used in Therapeutic Drug Monitoring. AcademicElsevier Science, London
Reference: PAGE 28 (2019) Abstr 9071 [www.page-meeting.org/?abstract=9071]
Poster: Drug/Disease Modelling - Infection