P49 A pharmacokinetic evaluation of oral clavulanic acid in term newborns

Abstract

Background Clavulanic acid is an irreversible beta-lactamase inhibitor which has a weak antibacterial action. When combined with a beta-lactam antibiotic such as amoxicillin, it is effective against a broad range of bacteria. Despite its widespread use, little is known on the mechanism of action and target levels. A few studies on oral clavulanic acid in adults are available reporting great variance (AUC median 4.99 mg h/ L [0.44-8.31])1 and a short elimination half-time (1.08h).2 Observations in neonates are currently lacking. We therefore evaluated the pharmacokinetics of oral clavulanic acid coadministered with amoxicillin in term newborns. Methods As part of a multicenter RCT (Clinicaltrials.gov: NCT03247920) evaluating neonatal intravenous-to-oral switch therapy in probable bacterial infection, we measured serum levels in patients allocated to the intervention group. They switched to amoxicillin/clavulanic acid suspension (25/6.25 mg/ kg tid), after 48 hours of intravenous penicillin/gentamicin. Two blood samples from different dosing intervals, were obtained and directly stored at -80°C. Initially, and to ensure that amoxicillin levels were attained as safety marker, levels in the second part of the timeframe (4-8 h after administration) were collected. For the second batch, peak levels (1-2 h after administration) were collected. Analysis was performed using Liquid Chromatography and Mass Spectrometry. Results At submission, samples of the first 15 patients were analysed (first batch). Samples were collected 6.0 ± 1.3 h (mean,S.D.) after antibiotic administration. Clavulanic acid levels were detected in all patients but a great variance was observed (median: 1.4 mg/L; range: 0.20-4.82 mg/L). Extrapolation would lead to an AUC of at least 8.4 mg h/L. Conclusions Oral clavulanic acid is absorbed in term newborns, but great variance is seen in trough levels (4-8 h after administration). Extrapolation predicts at least an AUC comparable to those of adults. Peak levels in the first part of the time interval (0-4h) are needed to further build confidence on this conclusion.