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

摘要-总体 免疫功能低下患者多药耐药病原体的定植和感染动态 重症患者（Critically Ill Patients，简称CRIITE） 社区和医院相关病原体的抗菌药物耐药性（AMR）已被命名为 联合国最紧迫的公共卫生优先事项。在最相关的多药耐药 (MDR)细菌，万古霉素耐药肠球菌，超广谱β-内酰胺酶 产/碳青霉烯耐药肠杆菌科（ESBL-E/CRE）和艰难梭菌是 由于这些微生物通常感染严重疾病和免疫功能低下的人， 患者，并且缺乏治疗这些细菌引起的感染的治疗选择。中的每 这些关键的病原体，肠道是最初的殖民地，并在广泛的影响下， 如果使用广谱抗菌药物治疗，这些微生物可以“支配”胃肠道，增加风险 临床疾病。重要的是，越来越清楚的是， VRE、ESBL-E/CRE或C.艰难梭菌与随后的其他成员的殖民化显著相关。 这一组，但是否病原体-病原体信号转导发挥作用是未知的。此外，从 迄今为止，基于微生物组的研究由于不精确， 目前尚不清楚为什么只有一部分患者， 类似的条件，发展殖民/疾病。我们的总体假设是， 肠道源性医院定植和随后的感染严重依赖于功能性微生物群- 病原体相互作用，可以通过病原体、宿主和寄生虫的整体组合来检测 微生物群分析。多药耐药菌的定殖和感染动力学（Dynamics of Colonization and Infection by Multidrug Resistant 免疫功能低下和危重病患者的病原体）试图填补这些重要的知识空白。 事实上，我们已经确定了主要的微生物群特征，这些特征广泛地保护了肠道源性疾病。 病原体通过以前未被认识到的抗菌机制，这表明缺乏这种微生物可能 是确定病原体定殖和感染的关键因素。该计划的目的是，i）剖析 影响定植和感染的主要微生物、临床和抗菌素耐药性决定因素， VRE、ESBL-E/CRE和C.艰难梭菌，ii）评价肠道微生物群在VRE、ESBL-E/CRE中的作用 和C.艰难定植，和iii）定义关键微生物群的功能方面和 防止定植/感染。我们在AMR方面的多机构合作历史悠久， 微生物组科学与集中国家的最先进的设施，行政资源，并获得两个 德克萨斯州医疗中心的重症和免疫功能低下患者的主要队列，将我们的团队置于 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， 互补项目将为开发新的诊断、预防和治疗方法提供关键平台。 治疗方法，以打击肠源性AMR生物体影响危重病人。

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.