Tikiso Tjokosela, Fuhrmann Valentin, König Christina, Jarczak Dominik, Iwersen-Bergmann Stefanie, Kluge Stefan, Wicha Sebastian G, Grensemann Jörn
Department of Clinical Pharmacy, Institute of Pharmacy, University of Hamburg, Bundesstraße 45, 20146, Hamburg, Germany.
Department of Intensive Care Medicine, University Medical Center Hamburg-Eppendorf, Martinistraße 52, 20246, Hamburg, Germany.
Ann Intensive Care. 2023 Sep 12;13(1):83. doi: 10.1186/s13613-023-01184-z.
In acute-on-chronic liver failure (ACLF), adequate antibiotic dosing is challenging due to changes of drug distribution and elimination. We studied the pharmacokinetics of linezolid in critically ill patients with ACLF during continuous renal replacement therapy compared to patients without concomitant liver failure (NLF).
In this prospective cohort study, patients received linezolid 600 mg bid. Linezolid serum samples were analyzed by high-performance liquid chromatography. Population pharmacokinetic modelling was performed followed by Monte-Carlo simulations of 150 mg bid, 300 mg bid, 450 mg bid, 600 mg bid, and 900 mg bid to assess trough concentration target attainment of 2-7 mg/L.
Eighteen patients were included in this study with nine suffering from ACLF. Linezolid body clearance was lower in the ACLF group with mean (standard deviation) 1.54 (0.52) L/h versus 6.26 (2.43) L/h for NLF, P < 0.001. A trough concentration of 2-7 mg/L was reached with the standard dose of 600 mg bid in the NLF group in 47%, with 42% being underexposed and 11% overexposed versus 20% in the ACLF group with 77% overexposed and 3% underexposed. The highest probability of target exposure was attained with 600 mg bid in the NLF group and 150 mg bid in the ACLF group with 53%.
Linezolid body clearance in ACLF was markedly lower than in NLF. Given the overall high variability, therapeutic drug monitoring (TDM) with dose adjustments seems required to optimize target attainment. Until TDM results are available, a dose reduction may be considered in ACLF patients to prevent overexposure.
在慢加急性肝衰竭（ACLF）中，由于药物分布和消除的变化，给予足够的抗生素剂量具有挑战性。我们研究了与无肝衰竭（NLF）的患者相比，在接受持续肾脏替代治疗的ACLF重症患者中利奈唑胺的药代动力学。
在这项前瞻性队列研究中，患者接受600 mg bid的利奈唑胺治疗。通过高效液相色谱法分析利奈唑胺血清样本。进行群体药代动力学建模，随后对150 mg bid、300 mg bid、450 mg bid、600 mg bid和900 mg bid进行蒙特卡洛模拟，以评估2-7 mg/L的谷浓度目标达成情况。
本研究纳入了18例患者，其中9例患有ACLF。ACLF组的利奈唑胺体内清除率较低，平均（标准差）为1.54（0.52）L/h，而NLF组为6.26（2.43）L/h，P<0.001。NLF组600 mg bid的标准剂量达到2-7 mg/L谷浓度的比例为47%，暴露不足的比例为42%，暴露过度的比例为11%；而ACLF组相应比例分别为20%、77%和3%。NLF组600 mg bid和ACLF组150 mg bid达到目标暴露的概率最高，均为53%。
ACLF患者的利奈唑胺体内清除率明显低于NLF患者。鉴于总体变异性较高，似乎需要进行治疗药物监测（TDM）并调整剂量以优化目标达成情况。在获得TDM结果之前，可考虑降低ACLF患者的剂量以防止暴露过度。
