Pharmacology of intrathecal/intraventricular polymyxins: A systems-based approach

项目摘要/摘要 背景：世界正面临着来自细菌出现的巨大且日益严重的威胁 ‘超级细菌’。如果细菌继续以目前的速度和速度对多种抗生素产生耐药性 在抗生素管道继续枯竭的同时，可能会产生灾难性的成本 医疗保健和全球社会。世界各地的许多医院都经历了感染的暴发 由多重耐药鲍曼不动杆菌、铜绿假单胞菌和克雷伯菌引起 肺炎。所有这些病原体都在美国传染病学会(IDSA)的 六种最优先的危险细菌，需要紧急关注才能发现新的抗生素。治疗的方法 耐多药革兰氏阴性菌引起的中枢神经系统(CNS)感染是有问题的，并与 死亡率很高。多粘菌素B和粘菌素是针对这些非常有问题的MDR的最后一线疗法 革兰氏阴性病原体。静脉注射多粘菌素治疗中枢神经系统感染的临床应用受阻 由于它们的肾毒性和对中枢神经系统的有限渗透。在对抗快速崛起的战斗中 我们不能再依赖于新抗生素的发现。我们必须优化利用现有的 系统药理学与药代动力学相结合应用抗菌药物 /药效学(PK/PD)，以提高疗效，同时将毒性和耐药性降至最低。交付 多粘菌素抗生素直接进入中枢神经系统显示出非常有希望的感染治疗潜力 由细菌“超级细菌”引起的。不幸的是，目前鞘内给药的建议和 由于缺乏PK/PD数据，脑室内(ITH/IVT)多粘菌素完全是经验的，重要的是， 目前还没有关于潜在神经毒性的数据。 研究设计：这项多学科研究旨在阐明人格特质和潜能的机制。 用前沿成像和系统药理学研究ITH/IVT多粘菌素的毒性，并优化 大鼠中枢神经系统感染模型的治疗。其具体目的是：(1)研究脑脊液的药代动力学 多粘菌素在鲍曼不动杆菌、铜绿假单胞菌和肺炎克雷伯菌中枢神经系统感染模型中的作用 用尖端成像技术阐明多粘菌素在神经细胞和中枢神经系统组织中的分布 技术；(3)利用系统药理学研究ITH/IVT多粘蛋白的潜在神经毒性； (4)优化ITH/IVT多粘菌素治疗革兰氏阴性中枢神经系统感染的剂量方案 大鼠中枢神经系统模型及基于机制的PK/PD模型 意义：我们的创新方案将提供有史以来第一个PK/PD和毒性数据，以支持更安全和 多粘菌素ITH/IVT治疗革兰氏阴性致命性中枢神经系统感染更有效 ‘超级细菌’。它将在改善世界各地的临床实践方面具有巨大的潜力。

PROJECT SUMMARY/ABSTRACT Background: The world is facing an enormous and growing threat from the emergence of bacterial `superbugs'. If bacteria continue developing resistance to multiple antibiotics at the present rate and at the same time the antibiotic pipeline continues to dry up, there could be catastrophic costs to healthcare and society globally. Numerous hospitals worldwide have experienced outbreaks of infections caused by multidrug-resistant (MDR) Acinetobacter baumannii, Pseudomonas aeruginosa and Klebsiella pneumoniae. All of these pathogens are on the Infectious Diseases Society of America (IDSA) `hit list' of the six top-priority dangerous bacteria that require urgent attention to discover new antibiotics. The treatment of central nervous system (CNS) infections due to MDR Gram-negative bacteria is problematic and is associated with high mortality rates. Polymyxin B and colistin are the last-line therapy against these very problematic MDR Gram-negative pathogens. The clinical utility of intravenous polymyxins for CNS infections is hindered by their nephrotoxicity and limited penetration into the CNS. In the battle against rapidly emerging resistance we can no longer rely on the discovery of new antibiotics. We must optimise the use of existing antibiotics through the application of systems pharmacology combined with pharmacokinetics /pharmacodynamics (PK/PD) to increase efficacy while minimising toxicity and resistance. Delivery of polymyxin antibiotics directly into the CNS shows very promising potential for the treatment of infections caused by bacterial `superbugs'. Unfortunately, current dosing recommendations of intrathecal and intraventricular (ITH/IVT) polymyxins are entirely empirical due to the lack of PK/PD data and, importantly, there are no data on potential neurotoxicity. Research Design: This multi-disciplinary project aims to elucidate the mechanism of disposition and potential toxicity of ITH/IVT polymyxins using cutting-edge imaging and systems pharmacology, and to optimise the therapy in a rat CNS infection model. The Specific Aims are to: (1) investigate the CSF pharmacokinetics of ITH/IVT polymyxins in a rat CNS infection model with A. baumannii, P.aeruginosa and K. pneumoniae; (2) elucidate the disposition of polymyxins in neuronal cells and CNS tissue using cutting-edge imaging techniques; (3) investigate the potential neurotoxicity of ITH/IVT polymyxins using systems pharmacology; and (4) optimise dosage regimens of ITH/IVT polymyxins for the treatment of Gram-negative CNS infections using a rat CNS model and mechanism-based PK/PD modelling. Significance: Our innovative proposal will provide the first-ever PK/PD and toxicity data to support safer and more efficacious ITH/IVT therapy of polymyxins for life-threatening CNS infections due to Gram-negative `superbugs'. It will have a significant potential in improving clinical practice worldwide.