VENOUS: A translational study of enterococcal bacteremia

静脉：肠球菌菌血症的转化研究

• 批准号: 10197036
• 负责人: Cesar Augusto Arias
• 金额: $ 78.56万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-17 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10197036
• 关键词: Affect; Ampicillin; Antibiotics; Bacteremia; Blood; Cell membrane; Cell surface; Centers for Disease Control and Prevention (U.S.); Cessation of life; Characteristics; Cities; Clinical; Clinical Microbiology; Critical Illness; DNA Sequence Rearrangement; Daptomycin; Data; Detection; Diagnosis; Diagnostic; Diagnostic tests; Disease; Enterococcus; Enterococcus faecium; Epidemiology; Europe; Evolution; Extracellular Protein; FDA approved; Failure; Future; Genes; Genetic; Genetic Heterogeneity; Genome; Genomics; Geographic Locations; Hematologic Neoplasms; Hospitals; Immune system; Immunocompromised Host; In Vitro; Individual; Infection; Intervention Studies; Knowledge; Life; Linezolid; Location; Mediating; Methods; Microbiology; Monobactams; Multi-Drug Resistance; Multivariate Analysis; Mutation; Organ Transplantation; Organism; Outcome; Outcome Study; Patient-Focused Outcomes; Patients; Performance; Population; Population Dynamics; Predisposition; Prospective Studies; Prospective cohort; Public Health; Recurrence; Reproducibility; Resistance; Resistance development; Safety; Sepsis; Solid; South America; Structure; Survival Analysis; System; Testing; Therapeutic; Transplant Recipients; Treatment Protocols; Uncertainty; Vacuum; Vancomycin resistant enterococcus; Vulnerable Populations; antimicrobial; appropriate dose; bactericide; beta-Lactams; biological adaptation to stress; clinical practice; cohort; comorbidity; design; genomic variation; improved; improved outcome; innovation; insight; microorganism; minimal inhibitory concentration; mortality; multi-drug resistant pathogen; novel; novel diagnostics; novel strategies; novel therapeutics; pathogen; prospective; public health relevance; recruit; response; tool; translational study; treatment optimization; virtual

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.

抽象的 肠球菌是最顽固的医院相关病原体之一，因为它对许多 临床实践中使用抗生素治疗免疫功能低下者发生的一些无法治疗的感染 CDC 保守估计与万古霉素耐药肠球菌 (VRE) 有关。 仅在美国，每年就有 20,000 例感染和 1,300 例死亡，VRE 通常会影响患有 VRE 的患者。 多种合并症或免疫系统严重受损，包括实体器官移植 令人惊讶的是，尽管这种情况经常发生，但仍存在于患者和患有血液恶性肿瘤的患者中。 VRE 在这些弱势群体中的发生，前瞻性研究评估了 VRE 的实际临床影响 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 此外，缺乏可靠的抗菌药物来治疗严重感染。 事实上，肠球菌已经对几乎所有抗肠球菌药物产生了耐药性。 目前，脂肽类抗生素达托霉素（DAP）已成为临床应用的抗生素。 尽管尚未获得 FDA 批准，但因其杀菌活性和安全性而成为一线治疗 然而，MIC 测试、DAP 断点和适当剂量的性能存在不确定性。 对于肠球菌来说，使用这种抗生素对抗 VRE 的主要限制是耐药性和耐受性。 DAP 在治疗过程中很容易通过编码 LiaFSR 系统的基因的染色体突变而出现， 控制肠球菌细胞膜应激反应的三部分调节系统。 为了填补这一知识真空并优化肠球菌菌血症的管理，我们有 组建了 VENOUS 队列（万古霉素耐药肠球菌结果研究），这是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 另外 4 家医院位于南美洲 (n=2) 和欧洲 (n=2)。 了解 VRE 血流感染的临床和微生物学方面以及 VRE 的动态 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至关重要 我们建议使用 VENOUS 研究来改善这些难以治疗的感染的结果。 i) 描述 VRE 菌血症的临床影响，ii) 剖析导致 VRE 菌血症的群体结构 血流感染和感染，iii) 开发一种新的独立于最小抑菌浓度 (MIC) 的诊断方法 测试评估 DAP 敏感性，寻求使用新颖的工具来准确识别 DAP 敏感分离株并改进 DAP 的使用以及与 β-内酰胺的组合来对抗这些 该提案的结果可能会提供急需且可靠的数据来优化生物体。 治疗 VRE 感染，提供必要的信息以规划未来的干预研究并制定 创新的诊断方法彻底改变这些危及生命的感染的管理。