Louvain Centre for Toxicology and Applied Pharmacology, Université Catholique de Louvain (UCL), Brussels, Belgium; Louvain Drug Research Institute, Université Catholique de Louvain (UCL), Brussels, Belgium.
Department of Infectious Diseases, Cliniques Universitaires de Bruxelles Erasme, Université Libre de Bruxelles (ULB), Brussels, Belgium.
Int J Antimicrob Agents. 2020 Oct;56(4):106113. doi: 10.1016/j.ijantimicag.2020.106113. Epub 2020 Jul 25.
Optimal loading doses of β-lactams to rapidly achieve adequate drug concentrations in critically ill patients are unknown. This was a post-hoc analysis of a prospective study that evaluated broad-spectrum β-lactams [piperacillin (PIP), ceftazidime (CAZ), cefepime (FEP) and meropenem (MEM)] pharmacokinetics (PKs) in patients with sepsis or septic shock (n = 88). Monte Carlo simulation was performed for 1000 virtual patients using specific sets of covariates for various dosing regimens and different durations of administration. Pharmacodynamic (PD) targets were considered as drug concentrations exceeding at least 50% of time above four times the minimum inhibitory concentration (T) of Pseudomonas aeruginosa, according to EUCAST criteria, for PIP, 70%T for CAZ and FEP and 40%T for MEM. The probability of target attainment (PTA) was derived by calculating the percentage of patients who attained the PK/PD target at each MIC. The optimal loading dose was defined as the one associated with a ≥90% probability to achieve the PD targets. Our simulation model identified an optimal loading dose for PIP of 8 g given as a 3-h infusion (PTA of 96.2%), for CAZ and FEP of 4 g given as a 3-h infusion (PTA of 96.5% and 98.4%, respectively), and for MEM of 2 g given as a 30-min infusion (PTA of 93.4%), with the following antibiotic dose administered 6 h thereafter regardless of the drug. A higher first dose of broad-spectrum β-lactams should be given to adequately treat less-susceptible pathogens in septic patients. These findings need to be validated in a prospective study.
在危重症患者中，快速达到适当药物浓度的β-内酰胺类药物最佳负荷剂量尚不清楚。这是一项对评估广谱β-内酰胺类药物（哌拉西林（PIP）、头孢他啶（CAZ）、头孢吡肟（FEP）和美罗培南（MEM））药代动力学（PK）的前瞻性研究的事后分析，纳入了脓毒症或感染性休克患者（n=88）。使用各种剂量方案和不同给药时间的特定协变量集，对 1000 名虚拟患者进行了蒙特卡罗模拟。药效学（PD）目标被认为是根据 EUCAST 标准，药物浓度超过铜绿假单胞菌最低抑菌浓度（MIC）的 4 倍以上时间至少 50%（PIP）、70%T（CAZ 和 FEP）和 40%T（MEM）。通过计算每个 MIC 下达到 PK/PD 目标的患者百分比来得出目标达到率（PTA）。最佳负荷剂量被定义为与≥90%概率达到 PD 目标相关的剂量。我们的模拟模型确定了 PIP 的最佳负荷剂量为 8 g，以 3 小时输注（PTA 为 96.2%），CAZ 和 FEP 的最佳负荷剂量为 4 g，以 3 小时输注（PTA 分别为 96.5%和 98.4%），MEM 的最佳负荷剂量为 2 g，以 30 分钟输注（PTA 为 93.4%），此后 6 小时给予相同剂量的抗生素，无论药物如何。在脓毒症患者中，应该给予更高的首剂广谱β-内酰胺类药物，以充分治疗敏感性较低的病原体。这些发现需要在前瞻性研究中得到验证。
