Optimization of β-Lactam Dosing Regimens in Neonatal Infections: Continuous and Extended Administration versus Intermittent Administration.

Abstract

In neonates, β-Lactam antibiotics are almost exclusively administered by intermittent infusion. However, continuous or prolonged infusion may be more beneficial because of the time-dependent antibacterial activity. In this pharmacokinetic/pharmacodynamic simulation study, we aimed to compare treatment with continuous, extended and intermittent infusion of β-lactam antibiotics for neonates with infectious diseases. We selected population pharmacokinetic models of penicillin G, amoxicillin, flucloxacillin, cefotaxime, ceftazidime and meropenem, and performed a Monte Carlo simulation with 30,000 neonates. Four different dosing regimens were simulated: intermittent infusion in 30min, prolonged infusion in 4h, continuous infusion, and continuous infusion with a loading dose. The primary endpoint was 90% probability of target attainment (PTA) for 100% ƒT>MIC during the first 48h of treatment. For all antibiotics except cefotaxime, continuous infusion with a loading dose resulted in a higher PTA compared with other dosing regimens. Sufficient exposure (PTA>90%) using continuous infusion with a loading dose was reached for amoxicillin (90.3%), penicillin G (PTA 98.4%), flucloxacillin (PTA 94.3%), cefotaxime (PTA 100%), and ceftazidime (PTA 100%). Independent of dosing regimen, higher meropenem (PTA for continuous infusion with a loading dose of 85.5%) doses might be needed to treat severe infections in neonates. Ceftazidime and cefotaxime dose might be unnecessarily high, as even with dose reductions, a PTA >90% was retained. Continuous infusion after a loading dose leads to a higher PTA compared with continuous, intermittent or prolonged infusion, and therefore has the potential to improve treatment with β-lactam antibiotics in neonates.