VENOUS: A translational study of enterococcal bacteremia

摘要 肠球菌是最易感染的医院相关病原体之一， 在临床实践中使用的抗生素，在免疫功能低下的患者中发生一些无法治疗的感染 个体CDC保守估计，万古霉素耐药肠球菌（VRE）与 仅在美国每年就有2万人感染，1,300人死亡。VRE通常会影响患有 多种合并症或免疫系统严重受损，包括实体器官移植 患者和血液恶性肿瘤患者等。令人惊讶的是，尽管经常 这些脆弱人群中VRE的发生率，前瞻性研究评估VRE的实际临床影响 由于这些微生物引起的感染很少，限制了指导治疗的临床信息的可用性 治疗这些寄生虫感染此外，缺乏可靠的抗菌药物选择来治疗严重的 疾病是一个主要问题。事实上，肠球菌已经对几乎所有的抗肠球菌药物产生了耐药性。 临床实践中可用的抗生素。目前，脂肽抗生素达托霉素（DAP）已成为 由于其杀菌活性和安全性，尽管缺乏FDA批准， 适应症然而，MIC检测、DAP断点和适当剂量的性能存在不确定性 肠球菌感染是使用这种抗生素对抗VRE的主要限制。此外，抵抗力和耐受性 在治疗过程中，通过编码LiaFSR系统的基因中的染色体突变，很容易出现DAP，这是一种 控制肠球菌细胞膜应激反应的三组分调节系统。为了 填补这一知识的主要真空，并优化肠球菌菌血症的管理，我们有 收集静脉队列（万古霉素耐药肠球菌结局研究），一项独特的前瞻性研究， 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， 南美（n=2）和欧洲（n=2）的另外4家医院。我们的首要假设是， 了解VRE血流感染的临床和微生物学方面以及 感染分离株的种群结构对于帮助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。通过静脉研究，我们建议 i）描述VRE菌血症的临床影响，ii）分析VRE引起的人群结构 iii）开发新的最小抑菌浓度（MIC）独立的诊断方法， 测试，以评估DAP的敏感性，寻求指导临床医生与一种新的工具，以允许准确识别 DAP敏感菌株，并改善DAP的使用以及与β-内酰胺类药物的联合使用，以对抗这些菌株 有机体该提案的结果可能会提供急需的可靠数据，以优化 治疗VRE感染，提供必要的信息，以规划未来的干预性研究，并制定 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.