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: 10620335
• 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/10620335
• 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; Economics; End stage renal failure; Excision; Functional disorder; Future; Geometry; Goals; Hemodialysis; Human; Immune response; In Situ; Incidence; Infection; Life; Liquid substance; Mechanics; Medical; Medical Errors; Microbial Biofilms; Modeling; Morbidity - disease rate; Nature; Patients; Phase; 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; improved; 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.

项目摘要： 中央线相关的血液感染（CLABSI）现在被认为是医疗错误，仍然是显着的 医疗保健相关感染（HAI）以及相关的发病率和死亡率的贡献者。尽管正在进行 采用或遵守特定建议并增加使用抗生素的倡议 导管，Clabsis的发病率趋势保持平坦或增加。潜在的病理生理学是 与导管表面上的生物膜形成相关，这些形成可为宿主反应和 抗菌治疗。因此，确定的治疗通常需要去除和替换导管。然而， CLABSI风险最大的患者（即血液透析患者）也具有高风险 造成的导管更换：有限的其他血管接入点；血液透析的生命性质；和 合并大大增加了仪器程序的并发症风险。我们的长期目标是 制定一种有效的导管救助策略，该策略可去除现场导管的生物膜 条件排除了设备去除和更换。我们发现温度的适度海拔高度： （1）软化生物膜，使它们更有可能在机械上分散； （2）减少来自A的总生物量 表面; （3）增强生物膜内组成细菌的抗生素杀死。我们的初步数据 表明热量分散的生物质保留了显着的生存能力，传统可以完全缓解 抗生素。在原理证明实验中，我们表明，加热的灌注液的循环中 在CLABSI大鼠模型中还原导管粘附的生物量。这项工作表明热量的应用 与抗生素结合使用是一种有希望的导管溶剂治疗策略，可以很快 翻译成临床实践。这项研究的目的是优化 将热量和抗生素应用于原位CLABSI治疗，以准备1阶段的人类临床试验。 我们假设加热与导管锁和系统抗生素结合使用将减少 导管和全身传播的细菌负荷。我们的目标是：（1）确定剂量和 热疗法的持续时间可最大化生物膜分散并最大程度地减少热损伤； （2）定义a 消除生物膜所需的热量的可概括描述，以使大鼠翻译成 人类环境； （3）确定合适的抗生素方案 在目标1中开发的热疗法。这些目标的完成将提供对热通量的强大描述 在没有热损伤的情况下消除生物膜的必需品以及管理所需的参数 在人透析导管感染应用中的治疗。这些参数将构成未来的基础 第1阶段临床测试。