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.

项目概要/摘要 背景：世界正面临细菌出现带来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，可能会带来灾难性的成本 全球医疗保健和社会。全球多家医院爆发感染 由多重耐药 (MDR) 鲍曼不动杆菌、铜绿假单胞菌和克雷伯氏菌引起 肺炎杆菌。所有这些病原体都在美国传染病学会 (IDSA) 的“打击名单”上。 六种最重要的危险细菌需要紧急关注以发现新的抗生素。治疗 由 MDR 革兰氏阴性菌引起的中枢神经系统 (CNS) 感染是一个问题，并且与 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到阻碍 由于其肾毒性和对中枢神经系统的渗透有限。在对抗快速崛起的战斗中 我们不能再依赖新抗生素的发现来对抗耐药性。我们必须优化利用现有资源 通过应用系统药理学与药代动力学相结合的抗生素 /药效学 (PK/PD) 以提高疗效，同时最大限度地减少毒性和耐药性。交付 直接进入中枢神经系统的多粘菌素抗生素在治疗感染方面显示出非常有前途的潜力 由细菌“超级细菌”引起。不幸的是，目前鞘内注射和 由于缺乏 PK/PD 数据，心室内 (ITH/IVT) 多粘菌素完全是经验性的，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倾向和潜力的机制 使用尖端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中的治疗。具体目标是：（1）研究脑脊液药代动力学 ITH/IVT 多粘菌素在鲍曼不动杆菌、铜绿假单胞菌和肺炎克雷伯菌感染大鼠 CNS 模型中的作用； (2) 使用尖端成像阐明多粘菌素在神经元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多粘菌素的潜在神经毒性；和 (4)优化ITH/IVT多粘菌素治疗革兰氏阴性CNS感染的剂量方案 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、更安全的研究。 多粘菌素 ITH/IVT 治疗革兰氏阴性菌引起的危及生命的中枢神经系统感染更有效 “超级细菌”。它将在改善全球临床实践方面具有巨大潜力。