Institute for Infection and Immunity, St George's, University of London, London, UK.
St George's University Hospitals NHS Foundation Trust, London, UK.
J Antimicrob Chemother. 2020 Dec 1;75(12):3625-3634. doi: 10.1093/jac/dkaa363.
The pharmacokinetics of β-lactam antibiotics in critical illness remain poorly characterized, particularly in neonates, children and the elderly. We undertook a pharmacokinetic study of commonly used β-lactam antibiotics in critically ill patients of all ages. The aims were to produce a whole-life β-lactam pharmacokinetic model and describe the extent to which standard doses achieve pharmacokinetic/pharmacodynamic targets associated with clinical cure.
A total of 212 critically ill participants with an age range from 1 day (gestational age 24 weeks) to 90 years were recruited from a UK hospital, providing 1339 pharmacokinetic samples. Population pharmacokinetic analysis was undertaken using non-linear mixed-effects modelling (NONMEM) for each drug. Pooled data were used to estimate maturation and decline of β-lactam pharmacokinetics throughout life.
Pharmacokinetic models for eight drugs were described, including what is thought to be the first benzylpenicillin model in critically ill adults. We estimate that 50% of adult β-lactam clearance is achieved by 43 weeks post-menstrual age (chronological plus gestational age). Fifty percent of decline from peak adult clearance occurs by 71 years. Paediatric participants were significantly less likely than adults to achieve pharmacokinetic/pharmacodynamic targets with standard antibiotic doses (P < 0.01).
We believe this to be the first prospective whole-life antibiotic pharmacokinetic study in the critically ill. The study provides further evidence that standard antibiotic doses fail to achieve pharmacokinetic/pharmacodynamic targets associated with clinical success in adults, children and neonates. Maturation and decline parameters estimated from this study could be adopted as a standard for future prospective studies.
β-内酰胺类抗生素在危重病患者中的药代动力学仍未得到充分描述，尤其是在新生儿、儿童和老年人中。我们对所有年龄段的危重症患者中常用的β-内酰胺类抗生素进行了药代动力学研究。目的是建立一个全生命周期的β-内酰胺类抗生素药代动力学模型，并描述标准剂量达到与临床治愈相关的药代动力学/药效学目标的程度。
从英国一家医院共招募了 212 名年龄在 1 天（胎龄 24 周）至 90 岁的危重症患者，共提供了 1339 个药代动力学样本。采用非线性混合效应模型（NONMEM）对每种药物进行群体药代动力学分析。使用合并数据来估计β-内酰胺药代动力学在整个生命周期中的成熟和下降。
描述了 8 种药物的药代动力学模型，包括我们认为是首次在危重病成人中描述的苄青霉素模型。我们估计，50%的成人β-内酰胺清除率在月经后 43 周（胎龄加实际年龄）时达到。从成人清除率峰值下降 50%发生在 71 岁。与成人相比，儿科患者使用标准抗生素剂量达到药代动力学/药效学目标的可能性显著降低（P<0.01）。
我们认为这是第一项在危重病患者中进行的前瞻性全生命周期抗生素药代动力学研究。该研究进一步证明，标准抗生素剂量无法达到与成人、儿童和新生儿临床成功相关的药代动力学/药效学目标。本研究中估计的成熟和下降参数可以作为未来前瞻性研究的标准。
