The Hague Hospital Pharmacy, The Hague, The Netherlands.
Department of Hospital Pharmacy, Haga Teaching Hospital, The Hague, The Netherlands.
Clin Pharmacokinet. 2023 May;62(5):715-724. doi: 10.1007/s40262-023-01230-w. Epub 2023 Mar 27.
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 30 min, prolonged infusion in 4 h, 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 48 h 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.
在新生儿中，β-内酰胺类抗生素几乎仅通过间歇性输注给药。然而，由于时间依赖性抗菌活性，连续或延长输注可能更有益。在这项药代动力学/药效学模拟研究中，我们旨在比较连续、延长和间歇性输注β-内酰胺类抗生素治疗感染性疾病新生儿的效果。
我们选择了青霉素 G、阿莫西林、氟氯西林、头孢噻肟、头孢他啶和美罗培南的群体药代动力学模型，并对 30000 名新生儿进行了蒙特卡罗模拟。模拟了四种不同的给药方案：30 分钟间歇性输注、4 小时延长输注、连续输注和连续输注加负荷剂量。主要终点是治疗的前 48 小时内 100%ƒT>MIC 的 90%概率达到目标（PTA）。
除头孢噻肟外，所有抗生素连续输注加负荷剂量均比其他给药方案具有更高的 PTA。连续输注加负荷剂量可使阿莫西林（PTA90.3%）、青霉素 G（PTA98.4%）、氟氯西林（PTA94.3%）、头孢噻肟（PTA100%）和头孢他啶（PTA100%）达到足够的暴露（PTA>90%）。无论给药方案如何，治疗新生儿严重感染可能需要更高剂量的美罗培南（连续输注加负荷剂量的 PTA 为 85.5%）。头孢他啶和头孢噻肟的剂量可能过高，因为即使减少剂量，PTA>90%仍可保留。
与连续、间歇性或延长输注相比，连续输注加负荷剂量可导致更高的 PTA，因此有可能改善新生儿β-内酰胺类抗生素的治疗效果。
