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

摘要--总体 免疫低下患者多药耐药病原菌的定植和感染动态 和危重病人(炸药)计划。 社区和医院相关病原菌的抗菌素耐药(AMR)已被命名为 联合国最紧迫的公共卫生优先事项。最相关的多药耐药 耐多药菌、耐万古霉素肠球菌、超广谱β-内酰胺酶 产/耐碳青霉烯类肠杆菌科(ESBL-E/CRE)和艰难梭菌属 被认为是高度优先的，因为这些微生物通常感染严重的疾病和免疫受损 患者，治疗这些细菌引起的感染的治疗选择很少。对于每一个 这些关键病原体，肠道是最初定植的地方，在广泛的- 广谱的抗菌治疗，这些细菌可以“支配”胃肠道，增加风险 临床疾病。重要的是，越来越清楚的是，任一种肠道的定植 VRE、ESBL-E/Cre或艰难梭菌与其他成员随后的定植显著相关 这一组，但病原体对病原体信号是否发挥作用尚不清楚。此外，从以下位置生成的数据 到目前为止，基于微生物组的研究还没有考虑到临床上有效的干预措施，因为 高危患者的识别，目前尚不清楚为什么只有一小部分患者，显然 类似的条件，会发展成殖民化/疾病。我们最重要的假设是，患者对 肠道来源的医院定植和随后的感染严重依赖于功能微生物区系- 病原体相互作用可以通过病原体、宿主和共生的整体组合来检测 微生物区系分析。爆炸性计划(多药耐药的定植和感染动态 免疫受损和危重病人中的病原体)试图填补这些重要的知识空白。 事实上，我们已经确定了Keystone微生物区系的特征，这些特征对肠道来源的微生物具有广泛的保护作用 病原体通过以前不为人知的抗菌机制表明，缺乏这样的微生物可能 是决定病原体定植和感染的关键因素。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和艰难梭菌，II)评估共生微生物群在VRE、ESBL-E/Cre中的作用 和艰难梭菌的定植，以及iii)定义了Keystone微生物区系的功能方面和 针对殖民/感染的保护。我们在AMR和AMR方面的多机构合作历史悠久 微生物组科学，拥有集中的最先进的设施、管理资源和访问两个 德克萨斯医疗中心的危重和免疫缺陷患者的主要队列，将我们的团队置于 一个实现目标的独特而理想的位置。我们预计，我们的高影响力的发现， 补充性项目将为开发新的诊断、预防和 对抗影响危重患者的肠道AMR生物的治疗方法。

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.