VENOUS: A translational study of enterococcal bacteremia

摘要 肠球菌是最顽固的医院相关病原体之一，因为它对许多 临床上使用的抗生素与免疫功能低下的一些无法治愈的感染有关 个人。美国疾病控制与预防中心保守地估计，万古霉素耐药肠球菌(VRE)与 仅在美国，每年就有2万人感染，1300人死亡。VRE通常会影响患有 多种并存或免疫系统严重受损，包括实体器官移植 患者和血液系统恶性疾病患者等。令人惊讶的是，尽管频繁 在这些易感人群中发生VRE，评估VRE的实际临床影响 由这些细菌引起的感染是罕见的，限制了指导治疗的临床信息的可用性。 这些顽固不化的感染。此外，缺乏可靠的抗菌药选择来治疗重症 疾病是最令人担忧的问题。事实上，肠球菌已经对几乎所有的抗肠球菌药物产生了抗药性。 临床实践中可用的抗生素。目前，脂质体抗生素达托霉素(DAP)已成为 一线治疗由于其杀菌活性和安全性，尽管没有FDA对此的批准 指示。然而，MIC测试性能、DAP断点和适当剂量的不确定性 对于肠球菌来说，使用这种抗生素对抗VRE是主要限制。此外，阻力和耐受性 为了在治疗过程中通过编码LianFSR系统的基因的染色体突变而容易出现DAP，a 控制肠球菌细胞膜应激反应的三组分调控系统。为了 填补这一重大的知识真空，优化肠球菌菌血症的管理，我们有 集合静脉队列(万古霉素耐药肠球菌结局研究)，一个独特的前景 目前在美国17家医院(7个城市)招募的肠球菌菌血症患者队列 在南美洲(n=2)和欧洲(n=2)增加4家医院。我们最重要的假设是，深层次的 对VRE血流感染的临床和微生物学方面的了解以及VRE血流感染的动力学 感染分离株的种群结构对设计新的诊断方法和治疗方法至关重要 改善这些难以治疗的感染的结果的治疗方案。利用我们建议的静脉研究 一)描述VRE菌血症的临床影响，二)剖析引起VRE的人群结构 血液感染，以及，iii)开发一种新的最小抑制浓度(MIC)非依赖的诊断方法 测试以评估DAP的敏感性，寻求用一种新的工具来指导临床医生，以允许准确地识别 DAP敏感菌株，改善DAP的使用及与β-内酰胺类药物的联合应用 有机体。这项提案的结果可能会提供急需的和稳健的数据，以优化 VRE感染的治疗，提供必要的信息，以计划未来的干预研究和开发 创新的诊断方法，以彻底改变这些危及生命的感染的管理。

ABSTRACT Enterococci are one of the most recalcitrant hospital-associated pathogens due to resistance to many antibiotics used in clinical practice with some untreatable infections occurring in immunocompromised individuals. The CDC conservatively estimates that vancomycin-resistant enterococci (VRE) are associated with 20,000 infections and 1,300 deaths per year in the US alone. VRE typically affect patients who have multiple comorbidities or with important compromise of the immune system, including solid organ transplant patients and those with hematological malignancies, among others. Surprisingly, despite the frequent occurrence of VRE in these vulnerable populations, prospective studies assessing the actual clinical impact of infections due to these organisms are scarce, limiting the availability of clinical information to guide treatment for these recalcitrant infections. Furthermore, the paucity of reliable antimicrobial options to treat severe disease is of major concern. Indeed, enterococci have developed resistance to virtually all anti-enterococcal antibiotics available in clinical practice. Currently, the lipopetide antibiotic daptomycin (DAP) has become the first-line therapy due to its bactericidal activity and safety profile, despite lacking FDA approval for this indication. However, uncertainties on the performance of MIC testing, DAP breakpoint and appropriate dosing for enterococci are major limitations for using this antibiotic against VRE. Additionally, resistance and tolerance to DAP readily emerge during therapy via chromosomal mutations in genes encoding the LiaFSR system, a three component regulatory system that controls the enterococcal cell membrane stress response. In order to fill this major vacuum in knowledge and optimize the management of enterococcal bacteremia, we have assembled the VENOUS cohort (Vancomycin-Resistant ENterococci OUtcomes Study), a unique prospective cohort of patients with enterococcal bacteremia currently recruiting in 17 hospitals in the USA (7 cities) and additional 4 hospitals in South America (n=2) and Europe (n=2). Our overarching hypothesis is that a deep understanding of the clinical and microbiological aspects of VRE bloodstream infections and dynamics of the population structure of infecting isolates is crucial to help design novel diagnostic approaches and treatment regimens to improve the outcomes of these difficult-to-treat infections. Using the VENOUS study we propose to i) characterize the clinical impact of VRE bacteremia, ii) dissect the population structure of VRE causing bloodstream infections and, iii) develop a new minimal inhibitory concentration (MIC)-independent diagnostic test to assess DAP susceptibility, seeking to guide clinicians with a novel tool to allow accurate identification of DAP-susceptible isolates and improve the use of DAP and combination with β-lactams against these organisms. The results of this proposal are likely to provide much needed and robust data to optimize the treatment of VRE infections, deliver the necessary information to plan future interventional studies and develop innovative diagnostic approaches to revolutionize the management of these life-threatening infections.