Optimizing Clinical Use of Polymyxin B: Teaching an Old Drug to Treat Superbugs

 描述（由申请人提供）：多重耐药（MDR）革兰氏阴性“超级细菌”正在全球迅速蔓延，多粘菌素B和粘菌素（多粘菌素E）通常是唯一有效的抗生素。自20世纪50年代多粘菌素B上市以来，其药代动力学、药效学、毒理学（PK/PD/TD）尚未明确。最近对多粘菌素的药理学研究主要集中在甲磺酸粘菌素（CMS，粘菌素的无活性前药），并证明CMS具有显著的局限性。因此，多粘菌素B越来越被视为优选的多粘菌素。不幸的是，最近开发的基于科学的CMS给药建议不能也不应该应用于多粘菌素B，因为后者作为其活性实体给药。因此，有必要确定多粘菌素B在危重患者中的PK/PD/TD，优化最佳给药方案，并开发用户友好的自适应反馈控制（AFC）临床工具。具体目标是：1）开发多粘菌素B的群体PK模型; 2）研究多粘菌素B的PK、治疗持续时间和患者特征与肾毒性的发生和时间之间的关系;并使用下一代蛋白质组学来鉴定多粘菌素B相关肾毒性的最具预测性的生物标志物;并开发群体PK/TD模型; 3）建立多粘菌素B PK、细菌敏感性和患者特征之间的关系，以及达到临床和细菌学结果的可能性和时间; 4）利用目标1-3的模型和蒙特卡罗模拟，科学地发展-基于多粘菌素B的剂量方案，并为未来的个体患者开发AFC算法。研究设计：将在美国的三个临床研究中心和新加坡的一个临床研究中心确定接受静脉多粘菌素B治疗的患者。患者（n = 250）将在治疗的第1天和第5天之间的多粘菌素B剂量周围的不同时间收集血液。将检查肾毒性的发生、临床反应和细菌学反应。将测定多粘菌素B的总血浆浓度和游离血浆浓度。将检查细菌分离株是否出现多粘菌素耐药性。将使用药理学分析评估多粘菌素B PK、PD和TD终点（例如，临床和细菌学应答、毒性和耐药性的发生）之间的关系。最后，所获得的信息将用于应用Monte Carlo模拟，以检查各种患者特征和其他因素对多粘菌素B PK、PD和TD的影响，以便为个体危重患者建立最佳剂量方案和AFC算法。意义：多年来，没有新的抗生素可用于革兰氏阴性“超级细菌”。这项具有里程碑意义的多中心研究将为优化多粘菌素B在危重患者中的使用提供重要信息，同时最大限度地减少耐药性和毒性。这项建议 完全符合NIAID的优先事项“教老药新把戏”和白宫最近的行政命令，以打击抗生素耐药性。

 DESCRIPTION (provided by applicant): Multidrug-resistant (MDR) Gram-negative 'superbugs' are rapidly spreading around the world, and polymyxin B and colistin (polymyxin E) are often the only effective antibiotics. Since polymyxin B was released in the 1950s, its pharmacokinetics, pharmacodynamics, toxicodynamics (PK/PD/TD) have never been defined. Recent pharmacological research on polymyxins has predominantly focused on colistin methanesulfonate (CMS, an inactive prodrug of colistin) and demonstrates that CMS has significant limitations. Thus, polymyxin B is increasingly being viewed as the preferred polymyxin. Unfortunately, recently developed scientifically-based dosing recommendations for CMS cannot and should not be applied to polymyxin B, as the latter is administered as its active entity. Therefore, it is essential to determine the PK/PD/TD of polymyxin B in critically-ill patients, refine optimal dosage regimens, and develop the user-friendly adaptive feedback control (AFC) clinical tool. The Specific Aims are: 1) To develop a population PK model for polymyxin B; 2) To investigate relationships between the PK of polymyxin B, duration of therapy and patient characteristics, with the development and timing of nephrotoxicity; and to use next-generation proteomics to identify the most predictive biomarker(s) of polymyxin B associated nephrotoxicity; and to develop the population PK/TD model; 3) To establish the relationships between polymyxin B PK, bacterial susceptibility and patient characteristics, with the probability of attaining and time to achieving clinical and bacteriological outcomes; and 4) To employ the models from Aims 1-3 and Monte Carlo simulation to develop scientifically-based dosage regimens of polymyxin B and to develop an AFC algorithm for future individual patients. Research Design: Patients being treated with intravenous polymyxin B will be identified at three clinical sites in the USA and one in Singapore. Patients (n = 250) will have blood collected at various times surrounding a dose of polymyxin B between days 1 and 5 of therapy. Development of nephrotoxicity, clinical response, and bacteriological response will be examined. Total and free plasma concentrations of polymyxin B will be determined. Bacterial isolates will be examined for the emergence of polymyxin resistance. The relationships between polymyxin B PK, PD and TD end-points (e.g. clinical and bacteriological responses, development of toxicity and resistance) will be assessed using pharmacometric analyses. Finally, the obtained information will be used to apply Monte Carlo simulation to examine the impact of various patient characteristics and other factors on polymyxin B PK, PD and TD, in order to establish optimal dosage regimens and AFC algorithms for individual critically-ill patients. Significance: No new antibiotics will be available for Gram-negative 'superbugs' for many years. This landmark multicenter study will provide essential information for optimizing polymyxin B use in critically-ill patients, while minimizing resistance and toxicity. This proposal aligns perfectly with the NIAID priority "To teach old drugs new tricks" and the recent Executive Order of the White House to combat antibiotic resistance.