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： 中心线相关血流感染（CLABSI），现在被认为是一个医疗错误，仍然是一个重大的 导致医疗相关感染（HAI）和相关的发病率和死亡率。虽然各方不断 采取或遵守具体建议的举措，并增加使用抗生素浸渍剂， 导管，CLABSI的发生率趋势保持平稳或增加。潜在的病理生理学是 与导管表面上的生物膜形成相关，可提供显著的保护，免受宿主反应的影响， 抗菌治疗因此，确定性治疗通常需要移除和更换导管。然而，在这方面， 处于CLABSI最大风险的患者（即，血液透析患者）也具有与以下相关的高风险： 由于以下原因更换导管：其他血管接入点有限;血液透析的生命维持性质;以及 显著的合并症增加了内固定手术的并发症风险。我们的长期目标是 制定有效的导管挽救策略，从患者的导管原位去除生物膜， 这种情况排除了器械取出和更换。我们发现，温度的适度升高： (1)软化生物膜，使它们更容易被机械分散;（2）减少总生物量， 表面;和（3）增加生物膜内组成细菌的抗生素杀灭。我们的初步数据还 表明通过加热分散的生物质保留了显着的生存能力，可以通过传统的方法完全缓解 抗生素在原理验证实验中，我们已经表明，加热灌注液的进出循环 减少CLABSI大鼠模型中的导管粘附生物量。这项工作表明， 与抗生素联合使用是一种很有前途的导管挽救治疗策略， 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，加热结合导管锁定和系统抗生素将减少 导管上的细菌负荷和全身传播。我们的目标是：（1）确定剂量， 最大化生物膜扩散并最小化热损伤的热治疗持续时间;（2）定义 生物膜根除所需的热传递的一般性描述，以允许从大鼠翻译到 人类环境;和（3）确定与抗生素联合使用的适当抗生素方案。 目的1中开发的热疗法。这些目标的完成将提供一个强大的描述热通量 所需的参数，以实现生物膜根除没有热损伤和所需的参数， 在人体透析导管感染应用中的治疗。这些参数将构成未来 第一阶段临床试验。