Pharmacokinetics of Intrapartum Benzylpenicillin: Insights Into Candidate Regimens to Prevent Early Onset Neonatal Group B Streptococcus Disease.

Abstract

Early onset neonatal Group B Streptococcus (GBS) infection accounts for significant global morbidity and mortality. Intrapartum prophylaxis with benzylpenicillin is advised for women at high risk of having a baby affected by early onset GBS disease. Pregnancy-related physiological changes can alter pharmacokinetics. To estimate the intrapartum pharmacokinetics of penicillin, women (n = 12) at risk of GBS disease were enrolled. A fixed regimen of intravenous benzylpenicillin 3 g at onset of labor and 1.5 g every 4 h until delivery was used. Benzylpenicillin concentrations in plasma and umbilical cord were quantified. A nonparametric population pharmacokinetic model was fitted to the data and regimens that optimized drug exposure (fC_min > MIC for 100% of the dosing interval) were determined using Monte Carlo simulation. Benzylpenicillin pharmacokinetics were well described using a two-compartment model with a linked umbilical cord compartment. The mean volume of the central compartment and first-order clearance were 16.55 L and 41.24 L/h, respectively. Simulations showed that a lower regimen of benzylpenicillin 2.4 g followed by 1.2 g every 4 h resulted in adequate drug exposure-with plasma fC_min > 0.125 mg/L for 100% of the dosing interval in > 90% of the simulated population. Simulations of a continuous infusion of benzylpenicillin resulted in higher target attainment rates when compared to intermittent dosing. Alternative intrapartum regimens of penicillin that are efficacious but require less total daily drug amounts appear feasible. Further research evaluating alternative regimens on clinical outcomes is required.