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

鞘内/脑室内多粘菌素的药理学：基于系统的方法

• 批准号: 10652982
• 负责人: Gauri G Rao
• 金额: $ 27.43万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-08 至 2023-08-16
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10652982
• 关键词: Acinetobacter baumannii; Aminoglycosides; Anti-Bacterial Agents; Antibiotic Resistance; Antibiotic Therapy; Antibiotics; Antimicrobial Resistance; Apoptotic; Attention; Back; Bacteria; Binding Proteins; Biological Models; Blood - brain barrier anatomy; Carbapenems; Cells; Centers for Disease Control and Prevention (U.S.); Central Nervous System; Central Nervous System Infections; Cephalosporins; Cerebrospinal Fluid; Cessation of life; Clinical; Colistin; Combating Antibiotic Resistant Bacteria; Communicable Diseases; Dangerousness; Data; Development; Disease Outbreaks; Dose; Dose Limiting; Drug Delivery Systems; Drug Kinetics; Dryness; Economics; Fiber; Generations; Gram-Negative Bacteria; Growth; Health; Healthcare; Hospitals; Human; Image; Imaging Techniques; Infection; International; Intravenous; Intraventricular; Klebsiella pneumoniae; Life; Light; Limes; Medical; Mesylates; Modeling; Multi-Drug Resistance; Multidrug-resistant Acinetobacter; National Institute of Allergy and Infectious Disease; Nature; Neurons; Outcome; Penetration; Pharmaceutical Preparations; Pharmacodynamics; Pharmacology; Physicians; Plasma Proteins; Polymyxin B; Polymyxins; Pseudomonas aeruginosa; Rattus; Recommendation; Regimen; Research; Research Design; Research Priority; Research Proposals; Resistance; Resistance development; Societies; Superbug; System; Therapeutic; Time; Tissues; Toxic effect; clinical efficacy; clinical practice; cost; dosage; experience; global health; improved; innovation; lipophilicity; model development; mortality; multidisciplinary; nephrotoxicity; neurotoxicity; novel; pathogen; pharmacodynamic model; pharmacokinetics and pharmacodynamics; pharmacologic; pre-clinical; treatment optimization

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.

项目摘要/摘要 背景：由于细菌的出现，世界正面临着巨大的威胁 “超级细菌”。如果细菌继续以目前的速率和AT产生对多种抗生素的抗性 同时，抗生素管道继续干燥，可能会有灾难性的成本 全球医疗保健和社会。全球许多医院经历了感染的爆发 由多药耐药（MDR）鲍曼尼（Baumannii），铜绿假单胞菌和克雷伯氏菌引起 肺炎。所有这些病原体都在美国传染病协会（IDSA）的“命中列表”上 六种高优先级危险细菌，需要紧急注意才能发现新的抗生素。处理 MDR革兰氏阴性细菌引起的中枢神经系统（CNS）感染是有问题的，并且是相关的 死亡率高。多霉菌素B和结肠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。 CNS感染的静脉多碳素的临床实用性受到阻碍 通过它们的肾毒性和有限的渗透到中枢神经系统中。在与快速新兴的战斗中 抗药性我们不再依赖于新抗生素的发现。我们必须优化现有的使用 通过应用系统药理学与药代动力学结合的抗生素 /药效学（PK/PD），以提高功效，同时最大程度地减少毒性和耐药性。交付 直接进入中枢神经系统的多牙蛋白抗生素显示出非常有希望的感染潜力 由细菌“超级细菌”引起。不幸的是，目前的鞘内服用建议和 脑室室（ITH/IVT）多粘毒素完全是经验的，这是由于缺乏PK/PD数据，并且重要的是 没有关于潜在神经毒性的数据。 研究设计：这个多学科项目旨在阐明处置机制和潜力机制 使用尖端成像和系统药理学的ITH/IVT多碳素的毒性，并优化 大鼠中枢神经系统感染模型中的治疗。具体目的是：（1）研究CSF药代动力学的 大鼠CNS感染模型中的ITH/IVT多霉菌素与A. baumannii，p.aeruginosa和K.肺炎； （2） 使用最先进的成像阐明多聚淋巴素在神经元细胞和CNS组织中的处置 技术； （3）研究使用系统药理学的ITH/IVT多碳素的潜在神经毒性；和 （4）优化使用ITH/IVT多氧合素的剂量方案，用于使用革兰氏阴性中心感染治疗使用 大鼠CNS模型和基于机制的PK/PD建模。 意义：我们的创新提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 由于革兰氏阴性造成的，对威胁生命的中枢神经系统感染的多碳素的ITH/IVT治疗更有效 “超级细菌”。它将在改善全球临床实践方面具有巨大的潜力。