Institute of Experimental and Clinical Pharmacology and Toxicology, University of Lübeck, Lübeck, Germany.
Department of Pharmacy, University Hospital Schleswig-Holstein, Campus Lübeck, Lübeck, Germany.
Naunyn Schmiedebergs Arch Pharmacol. 2019 Feb;392(2):229-241. doi: 10.1007/s00210-018-1573-6. Epub 2018 Oct 27.
Infections are a major problem in patients with burn diseases. Mortality is high despite antibiotic therapy as studies are controversial concerning drug underdosing. The aims of this prospective, observational study were to monitor plasma concentrations of piperacillin during standard piperacillin/tazobactam treatment in 20 burn patients and 16 controls from the intensive care unit (ICU) and to optimize doses by in silico analyses. Piperacillin/tazobactam (4/0.5 g, tid) was administered over 0.5 h. Blood samples were taken at 1, 4, and 7.5 h after the end of the infusion. Free piperacillin plasma concentrations were determined. Pharmacokinetic parameters and in silico analysis results were calculated using the freeware TDMx. The primary target was defined as percentage of the day (fT; fT) when piperacillin concentrations exceeded 1xMIC/4xMIC (minimum inhibitory concentration), considering a MIC breakpoint of 16 mg/L for Pseudomonas aeruginosa. In an off-label approach, two burn patients were treated with 8/1 g piperacillin/tazobactam, 3 h qid. fT (55 ± 22% vs. 77 ± 24%) and fT (17 ± 11% vs. 30 ± 11%) were lower in burn than in ICU patients after 4/0.5 g, 0.5 h, tid. In silico analyses indicated that fT (93 ± 12% burn, 97 ± 4% ICU) and fT (62 ± 23% burn, 84 ± 19% ICU) values increase by raising the piperacillin dosage to 8/1 g qid and prolonging the infusion time to 3 h. Off-label treatment results were similar to in silico data for burn patients (84%fT and 47%fT). Standard dosage regimens for piperacillin/tazobactam resulted in subtherapeutic piperacillin concentrations in burn and ICU patients. Dose adjustments via in silico analyses can help to optimize antibiotic therapy and to predict respective concentrations in vivo. Trial registration: NCT03335137, registered 07.11.2017, retrospectively.
感染是烧伤患者的主要问题。尽管抗生素治疗，但死亡率仍然很高，因为研究表明药物剂量不足存在争议。这项前瞻性、观察性研究的目的是监测 20 名烧伤患者和 16 名重症监护病房（ICU）对照患者在标准哌拉西林/他唑巴坦治疗期间的哌拉西林血浆浓度，并通过计算机模拟分析来优化剂量。哌拉西林/他唑巴坦（4/0.5 g，tid）在 0.5 小时内输注。在输注结束后 1、4 和 7.5 小时采集血样。测定游离哌拉西林的血浆浓度。使用免费软件 TDMx 计算药代动力学参数和计算机模拟分析结果。主要目标是当哌拉西林浓度超过 1xMIC/4xMIC（最小抑菌浓度）时，计算超过一天的百分比（fT；fT），考虑铜绿假单胞菌的 MIC 截断值为 16mg/L。在一种非标签方法中，两名烧伤患者接受了 8/1 g 哌拉西林/他唑巴坦，每 3 小时静脉滴注一次。与 ICU 患者相比，烧伤患者在接受 4/0.5 g、0.5 小时、tid 后，fT（55±22% vs. 77±24%）和 fT（17±11% vs. 30±11%）较低。计算机模拟分析表明，fT（93±12%烧伤，97±4% ICU）和 fT（62±23%烧伤，84±19% ICU）值通过将哌拉西林剂量提高到 8/1 g qid 并将输注时间延长至 3 小时而增加。非标签治疗结果与烧伤患者的计算机模拟数据相似（84%fT 和 47%fT）。标准哌拉西林/他唑巴坦治疗方案导致烧伤和 ICU 患者的哌拉西林浓度低于治疗浓度。通过计算机模拟分析进行剂量调整有助于优化抗生素治疗，并预测体内相应的浓度。试验注册：NCT03335137，于 2017 年 11 月 7 日注册，为回顾性研究。
