Adjuvant heat treatment for catheter salvage in central line associated bloodstream infection (HEATSAVE)

中心导管相关血流感染导管抢救的辅助热处理 (HEATSAVE)

• 批准号: 10440832
• 负责人: J SCOTT VANEPPS
• 金额: $ 55.65万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-10 至 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10440832
• 关键词: Adjuvant; Adopted; Animals; Antibiotics; Bacteria; Biomass; Blood Vessels; Caring; Catheters; Centers for Disease Control and Prevention (U.S.); Cessation of life; Clinical; Clinical Trials; Complication; Coupled; Data; Device Removal; Devices; Dialysis procedure; Disease; Dose; End stage renal failure; Excision; Functional disorder; Future; Geometry; Goals; Hemodialysis; Human; Immune response; In Situ; Incidence; Infection; Life; Liquid substance; Mechanics; Medical Economics; Medical Errors; Microbial Biofilms; Modeling; Morbidity - disease rate; Nature; Patients; Phase; Physiological; Population; Preparation; Procedures; Publishing; Rattus; Recommendation; Regimen; Reporting; Risk; Role; Sepsis; Specific qualifier value; Standardization; Surface; System; Temperature; Therapeutic heat application; Time; Translating; Translations; Uncertainty; Vancomycin; Venous; Work; antimicrobial; clinical practice; comorbidity; cost; experimental study; fluid flow; healthcare-associated infections; heat injury; high risk; infection management; instrumentation; life-sustaining therapy; mortality; research clinical testing; therapy development; therapy duration; treatment optimization; treatment strategy; trend

PROJECT SUMMARY: Central line associated bloodstream infections (CLABSI), now considered a medical error, remain a significant contributor to healthcare associated infections (HAIs) and associated morbidity and mortality. Despite ongoing initiatives to adopt or adhere to specific recommendations and increased use of antibiotic impregnated catheters, the incidence trend for CLABSIs has remained flat or increasing. The underlying pathophysiology is related to biofilm formation on catheter surfaces which offer significant protection from host response and antimicrobial therapy. Thus, definitive therapy often requires removal and replacement of catheters. However, the patients at greatest risk for CLABSI (i.e., hemodialysis patients) also have high risk associated with catheter replacement owing to: limited other vascular access points; life-sustaining nature of hemodialysis; and significant co-morbidity increasing complication risk of instrumentation procedures. Our long-term goal is to develop an effective catheter salvage strategy that removes biofilms from catheters in situ in patients whose condition precludes device removal and replacement. We have found that modest elevations in temperature: (1) soften biofilms, making them more likely to be mechanically dispersed; (2) reduce the total biomass from a surface; and (3) augment antibiotic killing of constituent bacteria within a biofilm. Our preliminary data also show that biomass dispersed by heat retains significant viability that can be completely mitigated by traditional antibiotics. In a proof-of-principle experiment, we have shown that in-and-out cycling of a heated perfusate reduces catheter-adhered biomass in a rat model of CLABSI. This work suggests that the application of heat in conjunction with antibiotics is a promising catheter-salvage treatment strategy that could be quickly translated to clinical practice. The objective of this study is to optimize the treatment parameters for the application of heat and antibiotics for in situ CLABSI therapy in preparation for phase 1 human clinical trials. We hypothesize that the addition of heat in combination with catheter lock and system antibiotics will reduce bacterial load on the catheter and systemic dissemination. Our aims are to: (1) Determine the dose and duration of heat therapy that maximizes biofilm dispersal and minimizes thermal injury; (2) Define a generalizable description of the heat delivery required for biofilm eradication to allow translation from the rat to the human setting; and (3) Determine the appropriate antibiotic regimen to be used in combination with the heat therapy developed in Aim 1. Completion of these aims will provide a robust description of the heat flux required to achieve biofilm eradication without thermal injury and the parameters required to administer that treatment in a human dialysis catheter infection application. These parameters will form the basis for future phase 1 clinical testing.

项目概要： 中心静脉导管相关血流感染 (CLABSI) 现在被认为是医疗错误，但仍然是一个重大问题 导致医疗保健相关感染 (HAI) 以及相关发病率和死亡率。尽管正在进行 采取或遵守具体建议的举措以及增加抗生素浸渍的使用 导管，CLABSI 的发病率趋势保持平稳或增加。潜在的病理生理学是 与导管表面生物膜的形成有关，该生物膜提供了针对宿主反应的重要保护，并且 抗菌治疗。因此，确定性治疗通常需要移除和更换导管。然而， CLABSI 风险最高的患者（即血液透析患者）也具有与以下相关的高风险 由于其他血管接入点有限而需要更换导管；血液透析的生命维持性质；和 显着的合并症增加了仪器操作的并发症风险。我们的长期目标是 开发一种有效的导管抢救策略，可以在患者体内原位去除导管上的生物膜 该情况不允许设备拆卸和更换。我们发现温度适度升高： (1)软化生物膜，使其更容易被机械分散； (2) 减少总生物量 表面; (3)增强抗生素对生物膜内组成细菌的杀灭作用。我们的初步数据还 表明通过热量分散的生物质保留了显着的生存能力，而传统的方法可以完全缓解这种生存能力 抗生素。在原理验证实验中，我们证明了加热灌注液的进出循环 减少 CLABSI 大鼠模型中导管粘附的生物量。这项工作表明，应用热 与抗生素联合使用是一种有前途的导管抢救治疗策略，可以快速实现 转化为临床实践。本研究的目的是优化治疗参数 应用热和抗生素进行原位 CLABSI 治疗，为 1 期人体临床试验做准备。 我们假设加热与导管锁和系统抗生素相结合将减少 导管上的细菌负荷和全身传播。我们的目标是： (1) 确定剂量和 热疗持续时间可最大限度地促进生物膜分散并最大限度地减少热损伤； (2) 定义一个 消除生物膜所需的热量传递的一般性描述，以允许从大鼠到 人文环境； (3) 确定与以下药物联合使用的适当抗生素治疗方案： 目标 1 中开发的热疗法。完成这些目标将为热通量提供可靠的描述 在没有热损伤的情况下实现生物膜根除所需的参数以及执行该操作所需的参数 在人体透析导管感染治疗中的应用。这些参数将成为未来的基础 一期临床测试。