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

项目总结： 中心线相关性血流感染(CLABSI)，现在被认为是一个医疗错误，仍然是一个重要的 医疗保健相关感染(HAI)以及相关发病率和死亡率的贡献者。尽管仍在进行 通过或遵守具体建议和增加使用浸渍抗生素的倡议 在导尿管方面，CLABSI的发病率趋势持平或上升。潜在的病理生理学是 与导管表面的生物膜形成有关，它提供了显著的保护，使其免受宿主的反应和 抗菌治疗。因此，明确的治疗通常需要拔除和更换导管。然而， CLABSI风险最高的患者(即血液透析患者)也有与 更换导管的原因：其他血管进入点有限；血液透析的生命维持性；以及 严重的并发症，增加了器械操作的并发症风险。我们的长期目标是 开发一种有效的导管挽救策略，在以下患者中原位清除导管中的生物膜 情况不允许拆卸和更换设备。我们已经发现，气温的适度上升： (1)软化生物膜，使其更容易被机械分散；(2)从 (3)增强抗生素对生物膜内组成细菌的杀灭作用。我们的初步数据也 表明通过加热分散的生物质保留了相当大的生命力，这可以通过传统的 抗生素。在原理验证实验中，我们已经证明了加热灌流液的进出循环 减少CLABSI大鼠模型中导管粘连的生物量。这项工作表明，加热的应用 与抗生素联合使用是一种有希望的导管挽救治疗策略，可能会很快 转化为临床实践。本研究的目的是优化红斑狼疮的治疗参数。 热和抗生素在CLABSI原位治疗中的应用为人类临床试验1期做准备。 我们假设，加温加上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)确定剂量和 最大限度地分散生物膜并将热损伤降至最低的热疗持续时间；(2)定义 消除生物膜所需的热传递的概括性描述，以允许从大鼠到 人类环境；以及(3)确定适当的抗生素方案与 在目标1中开发的热疗。完成这些目标将提供对热通量的强有力的描述 在没有热损伤的情况下实现生物膜根除所需的条件以及实施这一要求所需的参数 治疗在一例人体透析导管感染中的应用。这些参数将构成未来的基础 第一阶段临床试验。

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.