Optimization of linezolid therapy in the critically ill: the effect of adjusted infusion regimens
Optimization of linezolid therapy in the critically ill: the effect of adjusted infusion regimens
复制标题
重症患者利奈唑胺治疗的优化：调整输注方案的效果
DOI：
10.1093/jac/dkx149
复制
发表时间：
2017
影响因子：
5.2
通讯作者：
M. Zoller
中科院分区：
文献类型：
--
作者：
M. Taubert;J. Zander;S. Frechen;C. Scharf;L. Frey;M. Vogeser;U. Fuhr;M. Zoller
目标
在接受标准给药的ICU患者中经常观察到利奈唑胺水平不足，这与较差的结局相关。尽管已经讨论了克服这些不足水平的策略，但仍需确定适当的替代给药方案。
方法
在67 000例ICU患者中模拟了不同的输注方案（1200-3600 mg/d; q6 h、q8 h、q12 h和连续）。达到药效学目标的概率（T >MIC ≥ 85%，AUC/MIC ≥100，金黄色葡萄球菌和肠球菌的累积应答分数，PTA的MIC为0.5-4 mg/L）以及避免毒性浓度和浓度持续低于MIC（缺乏抗生素作用）或突变体选择窗口内（抗性发展）。
结果
根据T >MIC，连续输注观察到最佳目标达到，其次是q6 h，q8 h和q12 h。在急性呼吸窘迫综合征（ARDS）患者中观察到目标达到率大幅降低。在无ARDS的患者中，无论何种方案，1200 mg/天的剂量都是不够的，而1400 mg/天的剂量q6 h或连续输注提供了可接受的目标实现（例如，关于T >MIC ≥93%的累积应答分数）。与q6 h输注（1400 mg/天，无ARDS患者）相比，连续输注观察到潜在毒性谷浓度（28% vs 12%）和恒定在突变体选择窗内的浓度（15% vs <0.1%）的发生率更高。
结论
无论方案如何，1200 mg/天利奈唑胺可能不足以治疗ICU患者。无ARDS的患者可能特别受益于q6 h输注，增加每日剂量（例如1400 mg/天）。
Objectives
Insufficient linezolid levels, which are associated with a poorer outcome, are often observed in ICU patients who receive standard dosing. Although strategies to overcome these insufficient levels have been discussed, appropriate alternative dosing regimens remain to be identified.
Methods
Various infusion regimens (1200-3600 mg/day; q6h, q8h, q12h and continuous) were simulated in 67 000 ICU patients. The probability of attaining pharmacodynamic targets ( T >MIC ≥85%, AUC/MIC ≥100, cumulative fraction of response for Staphylococcus aureus and Enterococcus spp., PTA for an MIC of 0.5-4 mg/L) as well as the avoidance of toxic concentrations and concentrations constantly below the MIC (lack of antibiotic effect) or inside a mutant selection window (resistance development) were evaluated.
Results
Best target attainment according to T >MIC was observed for continuous infusions, followed by q6h, q8h and q12h. A substantially reduced target attainment was observed in patients with acute respiratory distress syndrome (ARDS). In patients without ARDS, 1200 mg/day was insufficient irrespective of the regimen, while a dose of 1400 mg/day administered q6h or by continuous infusions provided an acceptable target attainment (e.g. cumulative fraction of response with regards to T >MIC ≥93%). Higher rates of potentially toxic trough concentrations (28% versus 12%) and concentrations constantly inside the mutant selection window (15% versus <0.1%) were observed with continuous infusions compared with q6h infusions (1400 mg/day, patients without ARDS).
Conclusions
Irrespective of the regimen, 1200 mg/day linezolid might be insufficient for the treatment of ICU patients. Patients without ARDS might particularly benefit from q6h infusions with increased daily doses (e.g. 1400 mg/day).