Taubert Max, Zoller Michael, Maier Barbara, Frechen Sebastian, Scharf Christina, Holdt Lesca-Miriam, Frey Lorenz, Vogeser Michael, Fuhr Uwe, Zander Johannes
Department of Pharmacology, Clinical Pharmacology Unit, Hospital of the University of Cologne, Cologne, Germany.
Department of Anesthesiology, Hospital of the Ludwig Maximilians University of Munich, Munich, Germany
Antimicrob Agents Chemother. 2016 Aug 22;60(9):5254-61. doi: 10.1128/AAC.00356-16. Print 2016 Sep.
Adequate linezolid blood concentrations have been shown to be associated with an improved clinical outcome. Our goal was to assess new predictors of inadequate linezolid concentrations often observed in critically ill patients. Fifty-two critically ill patients with severe infections receiving standard dosing of linezolid participated in this prospective observational study. Serum samples (median, 32 per patient) were taken on four consecutive days, and total linezolid concentrations were quantified. Covariates influencing linezolid pharmacokinetics were identified by multivariate analysis and a population pharmacokinetic model. Target attainment (area under the concentration-time curve over 12 h [AUC12]/MIC ratio of >50; MIC = 2 mg/liter) was calculated for both the study patients and a simulated independent patient group (n = 67,000). Target attainment was observed for only 36% of the population on both days 1 and 4. Independent covariates related to significant decreases of linezolid concentrations included higher weight, creatinine clearance rates, and fibrinogen and antithrombin concentrations, lower concentrations of lactate, and the presence of acute respiratory distress syndrome (ARDS). Linezolid clearance was increased in ARDS patients (by 82%) and in patients with elevated fibrinogen or decreased lactate concentrations. In simulated patients, most covariates, including fibrinogen and lactate concentrations and weight, showed quantitatively minor effects on target attainment (difference of ≤9% between the first and fourth quartiles of the respective parameters). In contrast, the presence of ARDS had the strongest influence, with only ≤6% of simulated patients reaching this target. In conclusion, the presence of ARDS was identified as a new and strong predictor of insufficient linezolid concentrations, which might cause treatment failure. Insufficient concentrations might also be a major problem in patients with combined alterations of other covariate parameters. (This study has been registered at ClinicalTrials.gov under registration number NCT01793012.).
已证明利奈唑胺的血药浓度充足与临床结局改善相关。我们的目标是评估重症患者中经常观察到的利奈唑胺浓度不足的新预测因素。52例接受标准剂量利奈唑胺治疗的重症感染患者参与了这项前瞻性观察研究。连续4天采集血清样本（每位患者中位数为32份），并对利奈唑胺总浓度进行定量分析。通过多变量分析和群体药代动力学模型确定影响利奈唑胺药代动力学的协变量。计算了研究患者和模拟独立患者组（n = 67,000）的目标达成率（12小时浓度-时间曲线下面积[AUC12]/MIC比值>50；MIC = 2 mg/L）。在第1天和第4天，仅36%的患者达到目标。与利奈唑胺浓度显著降低相关的独立协变量包括体重增加、肌酐清除率、纤维蛋白原和抗凝血酶浓度升高、乳酸浓度降低以及急性呼吸窘迫综合征（ARDS）的存在。ARDS患者和纤维蛋白原升高或乳酸浓度降低的患者中利奈唑胺清除率增加（82%）。在模拟患者中，大多数协变量，包括纤维蛋白原和乳酸浓度以及体重，对目标达成率的影响在数量上较小（各参数第一和第四四分位数之间的差异≤9%）。相比之下，ARDS的存在影响最强，只有≤6%的模拟患者达到该目标。总之，ARDS的存在被确定为利奈唑胺浓度不足的一个新的强预测因素，这可能导致治疗失败。浓度不足在其他协变量参数合并改变的患者中也可能是一个主要问题。（本研究已在ClinicalTrials.gov注册，注册号为NCT01793012。）
