Department of Pharmacology and Toxicology and Department of Intensive Care, Radboud Institute of Health Sciences, Radboudumc, Geert Grooteplein Zuid 10, 6525 GA, Nijmegen, The Netherlands.
Royal Dutch Pharmacists Association (KNMP), Den Haag, The Netherlands.
Paediatr Drugs. 2020 Aug;22(4):433-444. doi: 10.1007/s40272-020-00400-8.
The Dutch Pediatric Formulary (DPF) increasingly bases its guidelines on model-based dosing simulations from pharmacokinetic studies. This resulted in nationwide dose changes for vancomycin, gentamicin, and tobramycin in 2015.
We aimed to evaluate target attainment of these altered, model-based doses in critically ill neonates and children.
This was a retrospective cohort study in neonatal intensive care unit (NICU) and pediatric ICU (PICU) patients receiving vancomycin, gentamicin, or tobramycin between January 2015 and March 2017 in two university hospitals. The first therapeutic drug monitoring concentration for each patient was collected, as was clinical and dosing information. Vancomycin and tobramycin target trough concentrations were 10-15 and ≤ 1 mg/L, respectively. Target gentamicin trough and peak concentrations were < 1 and 8-12 mg/L, respectively.
In total, 482 patients were included (vancomycin [PICU] n = 62, [NICU] n = 102; gentamicin [NICU] n = 97; tobramycin [NICU] n = 221). Overall, median trough concentrations were within the target range for all cohorts but showed large interindividual variability, causing nontarget attainment. Trough concentrations were outside the target range in 66.1%, 60.8%, 14.7%, and 23.1% of patients in these four cohorts, respectively. Gentamicin peak concentrations were outside the range in 69% of NICU patients (term neonates 87.1%, preterm infants 57.1%). Higher creatinine concentrations were associated with higher vancomycin and tobramycin trough concentrations.
This study illustrates the need to validate model-based dosing advice in the real-world setting as both sub- and supratherapeutic concentrations of vancomycin, gentamicin, and tobramycin were very prevalent. Our data underline the necessity for further individualization by addressing the high interindividual variability to improve target attainment.
荷兰儿科处方集（DPF）越来越多地根据药代动力学研究的基于模型的剂量模拟来制定指南。这导致 2015 年万古霉素、庆大霉素和妥布霉素在全国范围内调整剂量。
我们旨在评估这些改变后的基于模型的剂量在危重症新生儿和儿童中的目标达标情况。
这是一项回顾性队列研究，纳入了 2015 年 1 月至 2017 年 3 月期间在两所大学医院接受万古霉素、庆大霉素或妥布霉素治疗的新生儿重症监护病房（NICU）和儿科重症监护病房（PICU）患者。收集每位患者的首次治疗药物监测浓度，以及临床和给药信息。万古霉素和妥布霉素的目标谷浓度分别为 10-15 和≤1mg/L。目标庆大霉素谷浓度和峰浓度分别为<1 和 8-12mg/L。
共纳入 482 名患者（PICU 万古霉素组 n=62，NICU 组 n=102；NICU 庆大霉素组 n=97；NICU 妥布霉素组 n=221）。总体而言，所有队列的谷浓度中位数均在目标范围内，但个体间差异较大，导致目标未达标。这四个队列的患者中，分别有 66.1%、60.8%、14.7%和 23.1%的患者谷浓度不在目标范围内。NICU 患者中，庆大霉素峰浓度不在目标范围内的比例为 69%（足月新生儿 87.1%，早产儿 57.1%）。肌酐浓度较高与万古霉素和妥布霉素谷浓度较高相关。
本研究表明，需要在真实环境中验证基于模型的剂量建议，因为万古霉素、庆大霉素和妥布霉素的谷浓度和峰浓度均非常普遍。我们的数据强调了通过解决个体间的高变异性来进一步个体化治疗以提高目标达标率的必要性。
