Staphylococcus aureus Infections in VAD Patients

心脏辅助装置(LVAD)已成为充血性心力衰竭患者的主要治疗手段。它最初是作为心脏移植的桥梁引入的，最近被批准用于“目的疗法”：一种改善内科治疗难治的心力衰竭患者存活率和生活质量的手段。长期使用LVAD的一个严重限制是与设备相关的感染的高发生率。这些感染，从传动系统感染到与设备相关的心内膜炎，在28-48%的患者中发生，并导致显著的发病率和死亡率。感染的高发生率是多种因素综合作用的结果，包括免疫功能受损的宿主、因许多侵入性手术而长时间住院，以及长期使用大型假肢装置。虽然LVAD相关感染的性质已被很好地描述，但对其流行病学和发病机制的关注较少。大多数细菌感染开始的关键是细菌附着于宿主细胞或细胞外的定植步骤 矩阵。对于这些感染的主要病原体金黄色葡萄球菌来说，一系列结构上相关的表面蛋白有助于这一初始步骤。这些蛋白质的重要性已经在一些感染的实验模型中得到了证明。这些蛋白在LVAD感染中的作用以前还没有被研究过。如果左心室辅助装置(LVAD)要成为一种更成熟的治疗形式，就必须减少感染的发生率。这项提议的目标是进行临床试验，调查这些感染的发病机制，同时评估有希望的预防策略。该提案将重点关注金黄色葡萄球菌，因为它在这种情况下是一种突出的病原体， 它独特的致命性。最致命的LVAD感染--“泵性心内膜炎”--将是一个特别的焦点。我们的具体目标概括如下。 1)制定预防LVAD相关感染的临床干预策略。 2)通过鉴定金黄色葡萄球菌的粘附素以及在体外介导这种相互作用的细胞和基质表面成分，来表征金黄色葡萄球菌与左心室AD表面相互作用的性质。 3)检测特定的金黄色葡萄球菌粘附素在人工血管内小鼠模型中的作用 感染。

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.