VENOUS: A translational study of enterococcal bacteremia

静脉：肠球菌菌血症的转化研究

基本信息

批准号：
10593508
负责人：
Cesar Augusto Arias
金额：
$ 78.31万
依托单位：
METHODIST HOSPITAL RESEARCH INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-06-17 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10593508
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 diagnostic strategy 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

项目摘要

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.

抽象的肠球菌是由于对许多人的抵抗力，是最顽固的医院相关病原体之一在临床实践中使用的抗生素，在免疫功能低下发生了一些不可治疗的感染个人。 CDC保守地估计，抗性霉素肠球菌（VRE）是相关的仅在美国，每年就有20,000次感染和1,300人死亡。 vre通常会影响患者多种合并症或对免疫系统的重要妥协，包括固体器官移植患者和血液系统恶性肿瘤等。令人惊讶的是，频率在这些脆弱人群中，VRE发生，前瞻性研究评估了由于这些生物而引起的感染很少，限制了临床信息的可用性来指导治疗对于这些顽固感染。此外，可靠的抗菌选择的匮乏来治疗严重疾病是主要关注的。实际上，肠球菌已经对几乎所有抗enteroccal产生了抵抗力抗生素可用于临床实践。目前，脂生物胺抗生素daptomycin（DAP）已成为一线疗法由于其细菌活性和安全性，拼命缺乏FDA批准指示。但是，关于MIC测试，DAP断点和适当给药的性能的不确定性对于肠球菌是使用这种抗生素针对VRE的主要局限性。另外，抵抗力和公差通过编码LIAFSR系统的基因中的染色体突变，在治疗过程中很容易出现DAP，A 控制肠球菌细胞膜应力反应的三个组件调节系统。为了在知识中填充这个主要真空并优化肠细菌的管理，我们有组装了静脉队列（抗性霉素肠球菌结果研究），这是一个独特的前瞻性目前在美国17家医院（7个城市）和南美（n = 2）和欧洲（n = 2）的另外4家医院。我们的总体假设是一个深了解VRE血液感染的临床和微生物方面和动力学感染分离株的种群结构对于帮助设计新型诊断方法和治疗至关重要改善这些难以治疗感染的结果的方案。使用静脉研究我们建议 i）表征VRE细菌的临床影响，ii）剖析引起的VRE的种群结构血流感染和iii）发展了新的最小抑制浓度（MIC）独立诊断测试以评估DAP易感性，寻求使用新颖的工具指导临床医生，以准确识别可启发性DAP的分离株，并改善DAP和与β-内酰胺的结合使用有机体。该提案的结果可能会提供急需和强大的数据以优化治疗VRE感染，提供必要的信息以计划未来的介入研究并进行开发创新的诊断方法彻底改变了对这些威胁生命的感染的管理。