Beta-lactam exposure and safety in intermittent or continuous infusion in critically ill children: an observational monocenter study

The aim of this study was to assess the pharmacokinetic (PK) exposure and clinical toxicity for three beta-lactams: cefotaxime, piperacillin/tazobactam, and meropenem, depending on two lengths of infusion: continuous and intermittent, in critically ill children. This single center observational prospective study was conducted in a pediatric intensive care unit. All hospitalized children who had one measured plasma concentration of the investigated antibiotics were included. Plasma antibiotic concentrations were interpreted by a pharmacologist, using a Bayesian approach based on previously published population pharmacokinetic models in critically ill children. Exposure was considered optimal, low, or high according to the PK target 100% f(T>4xMIC) and a trough concentration below the toxic concentration (50 mg.L-1 for cefotaxime, 150 mg. L-1 for piperacillin, and 44 mg.L-1 for meropenem). Between May 2019 and January 2020, 80 patients were included and received 106 antibiotic courses: 74 (70%) were administered in intermittent infusion (II) and 32 (30%) in continuous infusion (CI). Compared to II, CI provided more optimal PK exposure (n=22/32, 69% for CI versus n=35/74, 47% for II, OR 1.2, 95%CI 1.01-1.5, p =0.04), less underexposure (n=4/32, 13% for CI versus n=36/74, 49% for II, OR 0.7, 95%CI 0.6-0.84, p < 0.001), and more overexposure (n= 6/32, 19% for CI versus n=3/74, 4% for II, OR 1.2, 95%CI 1.03-1.3, p=0.01). Five adverse events have been reported during the study period, although none has been attributed to beta-lactam treatment. Conclusion: CI provided a higher probability to attain an optimal PK target compared to II, but also a higher risk for overexposure. Regular therapeutic drug monitoring is recommended in critically ill children receiving beta-lactams, regardless of the length of infusion.