Population Pharmacokinetics and Dosing Regimen Optimization of Meropenem in Cerebrospinal Fluid and Plasma in Patients with Meningitis after Neurosurgery
Antimicrob. Agents Chemother. November 2016 V.60 N.11 P.6619-6625
Cheng Lu, Yuyi Zhang, Mingyu Chen, Ping Zhong, Yuancheng Chen, Jicheng Yu, Xiaojie Wu, Jufang Wu, and Jing Zhang
aInstitute of Antibiotics, Huashan Hospital Affiliated to Fudan University, Shanghai, China
bKey Laboratory of Clinical Pharmacology of Antibiotics, Ministry of Health, Shanghai, China
cDepartment of Neurosurgery, Huashan Hospital Affiliated to Fudan University, Shanghai, China
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.)
Entry filed under: Antimicrobianos, Bacterias, Bacteriemias, Epidemiología, FIEBRE en el POSTOPERATORIO, Health Care-Associated Infections, Infecciones del SNC, Infecciones nosocomiales, Infecciones sitio quirurgico, Metodos diagnosticos, Profilaxis Antibiótica en Cirugía - PAC, REPORTS, Resistencia bacteriana, Sepsis.