Staphylococcus aureus Infections in VAD Patients

心室辅助装置（LVAD）已成为充血性心力衰竭患者的主要治疗形式。最初作为心脏移植的桥梁引入，最近已被批准用于“目的地治疗”：一种提高药物治疗难治性心力衰竭患者生存率和生活质量的方法。长期使用LVAD的一个严重限制是器械相关感染的高发生率。这些感染，从传动系统感染到器械相关性心内膜炎，发生在28-48%的患者中，并导致显著的发病率和死亡率。多种因素的结合导致了感染的高发病率，包括免疫功能低下的宿主、大量侵入性手术的长期住院以及大型假体装置的长期存在。虽然LVAD相关感染的性质已得到充分描述，但对其流行病学和发病机制的关注较少。对于大多数细菌感染的起始至关重要的是定殖步骤，其中细菌粘附到宿主细胞或细胞外， 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始步骤。这些蛋白质的重要性已在许多感染实验模型中得到证实。这些蛋白质对LVAD感染的贡献以前没有研究过。如果左心室辅助装置（LVAD）成为一种更成熟的治疗形式，感染的发生率必须降低。该提案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。该提案将集中在S。金黄色葡萄球菌，因为它在这种情况下作为病原体的突出地位， 其独特的毒性。最致命的LVAD感染-“泵心内膜炎”-将是一个特别的焦点。我们的具体目标概述如下。 1)制定临床干预策略以预防LVAD相关感染。 2)刻画了S.金黄色葡萄球菌- LVAD表面相互作用，通过鉴定S.金黄色葡萄球菌粘附素和介导这些体外相互作用的LVAD细胞和基质表面成分。 3)检查特定S的作用。金黄色葡萄球菌粘附素在人工血管内移植小鼠模型中的作用 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.