Staphylococcus aureus Infections in VAD Patients

VAD 患者的金黄色葡萄球菌感染

• 批准号: 7312563
• 负责人: FRANKLIN D LOWY
• 金额: $ 49.37万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-01 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7312563
• 关键词: Staphylococcus aureus; Staphylococcus infection; auxiliary heart prosthesis; bacteria infection mechanism; bacterial endocarditis; bacterial proteins; bacterial vaccines; biomaterial interface interaction; cardiovascular disorder epidemiology; cardiovascular infection; communicable disease control; congestive heart failure; human subject; human therapy evaluation; laboratory mouse; longitudinal human study; medical implant science; outcomes research; polymerase chain reaction; postoperative complications; serology /serodiagnosis; therapy adverse effect; topical drug application; vaccine evaluation; virulence

The ventricular assist device (LVAD) has become a major form of therapy for patients with congestive heart failure. Originally introduced as a bridge to cardiac transplantation, it has recently been approved for "destination therapy": a means to improve survival and the quality of life in patients with heart failure refractory to medical therapy. A serious limitation to the prolonged use of LVADs has been the high incidence of device-related infections. These infections, ranging from driveline infections to device-associated endocarditis, occur in 28-48% of patients and entail significant morbidity and mortality. A combination of factors is responsible for the high incidence of infection, including immunocompromised hosts, lengthy hospitalizations with numerous invasive procedures, and the long-term presence of a large prosthetic device. While the nature of LVAD-associated infections has been well described, less attention has been devoted to their epidemiology and pathogenesis. Critical to the initiation of most bacterial infections is the colonization step where bacteria adhere to the host cellular or extracellular matrix. For Staphylococcus aureus, a primary pathogen in these infections, a family of structurally related surface proteins facilitates this initial step. The importance of these proteins has been demonstrated in a number of experimental models of infection. The contribution of these proteins to LVAD infections has not been previously investigated. If left ventricular assist devices (LVADs) are to become a more established form of therapy, the incidence of infections must be reduced. The goals of this proposal are to perform clinical trials that will investigate the pathogenesis of these infections while assessing promising strategies for preventing them. The proposal will focus on S. aureus because of its prominence as a pathogen in this setting and its unique virulence. The most lethal of the LVAD infections -- "pump endocarditis" -- will be a particular focus. Our specific aims are summarized below. 1) Develop clinical intervention strategies to prevent LVAD-related infections. 2) Characterize the nature of S. aureus - LVAD surface interactions by identifying both the S. aureus adhesins and the LVAD cellular and matrix surface components that mediate these interactions in vitro. 3) Examine the role of specific S. aureus adhesins in a mouse model of prosthetic intravascular infection.

心室辅助装置（LVAD）已成为充血性心力衰竭患者的一种主要治疗形式。它最初是作为心脏移植的桥梁引入的，最近已被批准用于“目的地疗法”：改善心力衰竭患者的生存和生活质量的手段。长时间使用LVAD的严重局限是与设备相关的感染的高发生率。这些感染范围从传动系统感染到与装置相关的心内膜炎，发生在28-48％的患者中，并具有明显的发病率和死亡率。多种因素的组合是导致感染的高发病率，包括免疫功能低下的宿主，冗长的住院治疗以及许多侵入性手术以及长期存在大型假体装置。尽管已经很好地描述了与LVAD相关的感染的性质，但较少的关注对它们的流行病学和发病机理。对大多数细菌感染的开始至关重要的是定植步骤，其中细菌粘附在宿主细胞或细胞外 矩阵。对于金黄色葡萄球菌，这些感染中的主要病原体，结构相关的表面蛋白家族促进了这一初步步骤。这些蛋白质的重要​​性已在许多感染的实验模型中得到了证明。这些蛋白质对LVAD感染的贡献尚未得到研究。如果左心室辅助装置（LVADS）将成为一种更确定的治疗形式，则必须降低感染的发生率。该建议的目标是进行临床试验，以研究这些感染的发病机理，同时评估预防它们的有希望的策略。该提议将重点放在金黄色葡萄球菌上 它独特的毒力。 LVAD感染最致命的“泵心内膜炎”将是一个特别的重点。我们的具体目标总结在下面。 1）制定临床干预策略，以防止LVAD相关感染。 2）通过鉴定金黄色葡萄球菌粘附蛋白以及LVAD细胞和基质表面成分，可以在体外介导这些相互作用。 3）检查特异性金黄色葡萄球菌在肢体内血管内的小鼠模型中的作用 感染。