Cerebrospinal Pharmacokinetic and Pharmacodynamic Evaluation of Sulbactam: Dosing Considerations for Acinetobacter baumannii Meningitis in Pediatric Patients.

Abstract

Background: Effective sulbactam dosing regimens for treating Acinetobacter baumannii meningitis in pediatric patients, considering the degree of cerebrospinal fluid (CSF) inflammation and its consequent effect on drug penetration, have not been thoroughly studied. This study aimed to describe a cerebrospinal pharmacokinetic (PK) model of sulbactam and propose a dosing strategy in pediatric patients based on pharmacodynamic (PD) evaluation with stochastic simulation.

Methods: Publications were systematically extracted from MEDLINE for sulbactam CSF PK data collection. A cerebrospinal PK model was described using CSF samples and applied to estimate the probability of attaining the PK/PD target (60% time above the minimum inhibitory concentration [T > MIC] in CSF). The cerebrospinal PK/PD breakpoint was defined as the highest MIC at which the target attainment probability in CSF was ≥90% for each age group (infants [4 weeks to 11 months], children [1-6 years], and pediatrics [7-16 years]).

Results and discussion: The study population included 21 pediatric patients aged 0.083-13.5 years. The CSF/serum concentration ratio at the various sampling points ranged 0.002-0.695. Based on the result of covariate analysis, CSF protein and CSF glucose levels were incorporated into the CSF-to-serum partition coefficient. The visual predictive check of CSF concentrations indicated no major bias. Regarding the cerebrospinal PK/PD evaluation, in infants and children groups with meningeal inflammation (eg, CSF protein > 100 mg/dL and CSF glucose < 40 mg/dL) a sulbactam dose of 200 mg/kg/day (as sulbactam component) with 0.5-h infusion was required to achieve 90% probability of CSF target attainment (60% T > MIC) up to an MIC of 4 μg/mL for A. baumanii.

Conclusions: This study identified effective dosing regimens for A. baumannii meningitis in pediatric patients in consideration of the degree of inflammation in CSF. High-dose sulbactam regimens can be considered to optimize CSF target attainment for A. baumannii meningitis in pediatric patients.