Polymyxin B (PB) and Polymyxin E (PE, also called colistin) are used as the last treatment resort for multidrug-resistant Gram-negative bacterial infections. The nephrotoxicity and neurotoxicity of polymyxins limit their clinical use, and guidelines recommend therapeutic drug monitoring (TDM) to optimize efficacy and reduce toxicity. However, there are limited analytical methods available for the determination of PB and PE. This study aimed to develop a simple and robust liquid chromatography with tandem mass spectrometry (LC-MS/MS) analytical method for determining the main compounds of PB and PE, namely PB1, PB2, ile-PB1, PE1, and PE2, in human plasma and to investigate of their pharmacokinetics in critically ill patients with the use of PB and PE, respectively. Plasma PB1, PB2, ile-PB1, PE1, and PE2 were chromatographically separated on a Welch LP-C18 column and detected using electrospray ionization mode coupled with multiple reaction monitoring. The calibration curve showed acceptable linearity over 20–10,000 ng/mL for PB1, PE1, and PE2 and 10–5000 ng/mL for PB2 and ile-PB1 in the plasma, respectively. After validation following approved guidelines, this method was successfully applied for PB and PE pharmacokinetic analysis and TDM in critically ill patients. Additionally, the composition of PB1, PB2, ile-PB1, PE1, and PE2 remains unchanged from 0 to 12 h after entering the patient’s body.

中文翻译：

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液相色谱-串联质谱法测定人血浆中多粘菌素B1、B2、ile-B1、E1和E2的建立和验证及其临床药代动力学应用


多粘菌素 B (PB) 和多粘菌素 E (PE，也称为粘菌素) 被用作多重耐药革兰氏阴性细菌感染的最后治疗手段。多粘菌素的肾毒性和神经毒性限制了其临床使用，指南建议进行治疗药物监测（TDM）以优化疗效并降低毒性。然而，可用于测定 PB 和 PE 的分析方法有限。本研究旨在开发一种简单而可靠的液相色谱串联质谱 (LC-MS/MS) 分析方法，用于测定人体中 PB 和 PE 的主要化合物，即 PB1、PB2、ile-PB1、PE1 和 PE2。血浆并分别使用 PB 和 PE 研究其在危重患者中的药代动力学。血浆 PB1、PB2、ile-PB1、PE1 和 PE2 在 Welch LP-C18 色谱柱上进行色谱分离，并使用电喷雾电离模式结合多反应监测进行检测。血浆中 PB1、PE1 和 PE2 的校准曲线显示可接受的线性范围为 20–10,000 ng/mL，PB2 和 ile-PB1 的线性范围为 10–5000 ng/mL。根据批准的指南进行验证后，该方法成功应用于危重患者的 PB 和 PE 药代动力学分析以及 TDM。此外，PB1、PB2、ile-PB1、PE1和PE2的成分在进入患者体内后0至12小时内保持不变。