Dynamics of Colonization and Infection by Multidrug-resistant Pathogens in Immunocompromised and Critically Ill Patients (DYNAMITE)

免疫功能低下和危重患者中多重耐药病原体定植和感染的动态 (DYNAMITE)

• 批准号: 10226283
• 负责人: Cesar Augusto Arias
• 金额: $ 237.88万
• 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: 2020-08-01 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10226283
• 关键词: Affect; Antibiotic Resistance; Antimicrobial Resistance; Bacteria; Clinical; Clostridium difficile; Collaborations; Communities; Community Hospitals; Critical Illness; Data; Development; Diagnosis; Disease; Extended-spectrum β-lactamase; Functional disorder; Gastrointestinal tract structure; Genome; Genomics; Goals; Hospitals; Immunocompromised Host; Individual; Infection; Intensive Care Units; Intervention; Intestines; Investigation; Knowledge; Longitudinal Studies; Mediating; Medical center; Metagenomics; Multi-Drug Resistance; Multiple Bacterial Drug Resistance; Names; Nature; Organism; Patients; Play; Population; Positioning Attribute; Predisposition; Prevention; Preventive; Prospective cohort; Recording of previous events; Resistance; Resources; Ribosomal RNA; Risk; Role; Sampling; Signal Transduction; Site; Stem cell transplant; System; Texas; Therapeutic; Transplant Recipients; United Nations; Vancomycin resistant enterococcus; antimicrobial; base; carbapenem resistance; carbapenem-resistant Enterobacteriaceae; clinical epidemiology; clinical risk; cohort; combat; commensal microbes; genomic epidemiology; gut colonization; gut microbiota; high risk; host microbiome; host microbiota; member; metaproteomics; microbial; microbiome; microbiome composition; microbiome research; microbiota; multi-drug resistant pathogen; novel; novel diagnostics; pathobiont; pathogen; patient population; patient subsets; programs; public health priorities; public health relevance; stool sample; tool; trait

ABSTRACT - OVERALL Dynamics of Colonization and Infection by Multidrug-Resistant Pathogens in Immunocompromised and Critically Ill Patients (DYNAMITE) Program. Antimicrobial resistance (AMR) in community and hospital-associated pathogens has been named one of the most pressing public health priorities by the United Nations. Among the most relevant multidrug-resistant (MDR) bacteria, vancomycin-resistant enterococci (VRE), extended spectrum β-lactamase producing/carbapenem-resistant Enterobacteriaceae (ESBL-E/CRE) and Clostridiodes difficile are considered high priority inasmuch as these organisms commonly infect severely ill and immunocompromised patients, and there is a paucity of therapeutic options to treat infections caused by these bacteria. For each of these key pathogens, the intestines are the site of initial colonization and, under the influence of broad- spectrum antimicrobial therapies, these organisms can “dominate” the gastrointestinal tract increasing the risk of clinical disease. Importantly, it is becoming progressively clear that colonization of the intestines by either VRE, ESBL-E/CRE, or C. difficile is markedly associated with subsequent colonization by other members of this group, but whether pathogen-to-pathogen signaling plays a role is not known. Further, data generated from microbiome-based studies to date has not allowed for clinically impactful interventions due to the imprecise identification of high-risk patients and it is currently unclear why only a subset of patients, under apparently similar conditions, develop colonization/disease. Our overarching hypothesis is that patient susceptibility to gut-derived nosocomial colonization and subsequent infection is critically dependent on functional microbiota- pathogen interactions that can be detected via a holistic combination of pathogen, host, and commensal microbiota analyses. The DYNAMITE program (Dynamics of Colonization and Infection by Multidrug-Resistant Pathogens in Immunocompromised and Critically Ill Patients) seeks to fill these important gaps in knowledge. Indeed, we have identified keystone microbiota features that are broadly protective against gut-derived pathogens via previously unappreciated antimicrobial mechanisms suggesting that lack of such organisms may be a critical factor in determining pathogen colonization and infection. The aims of the program are, i) dissect the main microbial, clinical and antimicrobial resistance determinants that impact colonization and infection by VRE, ESBL-E/CRE and C. difficile, ii) evaluate the role of the commensal microbiota in VRE, ESBL-E/CRE and C. difficile colonization, and iii) define the functional aspects of keystone microbiota and mechanisms of protection against colonization/infection. Our strong history of multi-institutional collaboration on AMR and microbiome science with centralized state-of-the art facilities, administrative resources, and access to two major cohorts of critically ill and immunocompromised patients in the Texas Medical Center, place our team in a unique and ideal position to achieve the goals. We expect that the findings of our high impact, complementary projects will provide critical platforms for the development of novel diagnostic, preventive, and therapeutic approaches to combat gut-derived AMR organisms affecting critically ill individuals.

摘要 - 总体 免疫功能低下的多药病原体的定植和感染动力学 和重症患者（炸药）计划。 社区和医院相关病原体中的抗菌抗性（AMR）已被任命为其中之一 联合国最紧迫的公共卫生优先事项。最相关的多饮用 （MDR）细菌，万古霉素耐药的肠球菌（VRE），延伸光谱β-内酰胺酶 产生/抗碳青霉烯型肠杆菌科（ESBL-E/CRE）和梭状芽胞杆菌艰难梭菌是 这些生物通常被认为是高度优先级的 患者，并且缺乏治疗这些细菌引起的感染的治疗选择。每个 这些关键的病原体，肠道是初始定植的部位，在广泛的影响下 光谱抗菌疗法，这些生物可以“主导”胃肠道增加风险 重要的是，越来越清楚的是，肠道的殖民化 VRE，ESBL-E/CRE或艰难梭菌与其他成员的随后定植显着相关 这组，但是病原体对病原体信号传导是否起作用。此外，从 迄今为止，基于微生物组的研究由于浸渍而不允许进行临床影响的干预措施 鉴定高危患者，目前尚不清楚为什么只有一部分患者，显然只有一部分 类似的条件，发展定植/疾病。我们的总体假设是患者对 肠道衍生的医院定殖和随后的感染取决于功能性微生物群 病原体相互作用，可以通过病原体，宿主和共生的整体组合检测到的病原体相互作用 微生物群分析。炸药程序（抗性和抗性的动力学感染动力学 免疫功能低下和重症患者中的病原体试图填补这些重要的知识差距。 确实，我们已经确定了广泛保护肠道衍生的基石菌群特征 通过以前未经批准的抗菌机制病原体，表明缺乏这种生物可能 是确定病原体定植和感染的关键因素。该程序的目的是，i）剖析 主要的微生物，临床和抗菌耐药性决定了影响定植和感染 VRE，ESBL-E/CRE和C.艰难梭菌，ii）评估Comensal Microbiota在VRE，ESBL-E/CRE中的作用 艰难梭菌定植，以及iii）定义了Keystone微生物群的功能方面和机制 防止殖民/感染。我们在AMR和 微生物组科学，具有集中的最先进的设施，行政资源，并访问两个 德克萨斯医学中心的重症病患者和免疫功能低下的患者的主要同类，将我们的团队放入 实现目标的独特而理想的位置。我们希望我们的高影响力的发现， 完全项目将为开发新颖的诊断，预防和 抗击肠道衍生的AMR生物的治疗方法，影响重症患者。