Population Pharmacokinetics and Dosing Regimen Optimization of Meropenem in Cerebrospinal Fluid and Plasma in Patients with Meningitis after Neurosurgery

Antimicrob Agents Chemother. 2016 Oct 21;60(11):6619-6625. doi: 10.1128/AAC.00997-16. Print 2016 Nov.


Meropenem is used to manage postneurosurgical meningitis, but its population pharmacokinetics (PPK) in plasma and cerebrospinal fluid (CSF) in this patient group are not well-known. Our aims were to (i) characterize meropenem PPK in plasma and CSF and (ii) recommend favorable dosing regimens in postneurosurgical meningitis patients. Eighty-two patients were enrolled to receive meropenem infusions of 2 g every 8 h (q8h), 1 g q8h, or 1 g q6h for at least 3 days. Serial blood and CSF samples were collected, and concentrations were determined and analyzed via population modeling. Probabilities of target attainment (PTA) were predicted via Monte Carlo simulations, using the target of unbound meropenem concentrations above the MICs for at least 40% of dosing intervals in plasma and at least of 50% or 100% of dosing intervals in CSF. A two-compartment model plus another CSF compartment best described the data. The central, intercentral/peripheral, and intercentral/CSF compartment clearances were 22.2 liters/h, 1.79 liters/h, and 0.01 liter/h, respectively. Distribution volumes of the central and peripheral compartments were 17.9 liters and 3.84 liters, respectively. The CSF compartment volume was fixed at 0.13 liter, with its clearance calculated by the observed drainage amount. The multiplier for the transfer from the central to the CSF compartment was 0.172. Simulation results show that the PTAs increase as infusion is prolonged and as the daily CSF drainage volume decreases. A 4-hour infusion of 2 g q8h with CSF drainage of less than 150 ml/day, which provides a PTA of >90% for MICs of ≤8 mg/liter in blood and of ≤0.5 mg/liter or 0.25 mg/liter in CSF, is recommended. (This study has been registered at ClinicalTrials.gov under identifier NCT02506686.).

Publication types

  • Clinical Trial

MeSH terms

  • Adult
  • Aged
  • Anti-Bacterial Agents / cerebrospinal fluid
  • Anti-Bacterial Agents / pharmacokinetics*
  • Brain Injuries, Traumatic / pathology
  • Brain Injuries, Traumatic / surgery
  • Brain Neoplasms / pathology
  • Brain Neoplasms / surgery
  • Drug Administration Schedule
  • Female
  • Gram-Negative Bacteria / drug effects*
  • Gram-Negative Bacteria / growth & development
  • Humans
  • Infusions, Intravenous
  • Male
  • Meningitis, Bacterial / cerebrospinal fluid
  • Meningitis, Bacterial / drug therapy*
  • Meningitis, Bacterial / etiology
  • Meningitis, Bacterial / microbiology
  • Meropenem
  • Microbial Sensitivity Tests
  • Middle Aged
  • Monte Carlo Method
  • Neurosurgery*
  • Postoperative Complications
  • Prospective Studies
  • Thienamycins / cerebrospinal fluid
  • Thienamycins / pharmacokinetics*


  • Anti-Bacterial Agents
  • Thienamycins
  • Meropenem

Associated data

  • ClinicalTrials.gov/NCT02506686

Grant support

This work was supported by New Drug Creation and Manufacturing Program of the Ministry of Science and Technology of China (2012ZX09303004-001).