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

摘要 - 总体 免疫功能低下者中多重耐药病原体的定植和感染动态 和危重病人 (DYNAMITE) 计划。 社区和医院相关病原体中的抗菌素耐药性（AMR）已被列为最重要的问题之一。 联合国最紧迫的公共卫生优先事项。其中最相关的多重耐药性 (MDR) 细菌、耐万古霉素肠球菌 (VRE)、超广谱 β-内酰胺酶 产/碳青霉烯类耐药肠杆菌 (ESBL-E/CRE) 和艰难梭菌 被认为是高度优先的，因为这些生物体通常会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。对于每个 这些关键病原体的肠道是最初定植的场所，并且在广泛的影响下 频谱抗菌疗法，这些微生物可以“控制”胃肠道，增加风险 的临床疾病。重要的是，越来越清楚的是，肠道中的定植 VRE、ESBL-E/CRE 或艰难梭菌与随后的其他成员的定植显着相关。 这一群体，但病原体间信号传导是否发挥作用尚不清楚。此外，数据生成自 迄今为止，基于微生物组的研究由于不精确而无法进行具有临床影响的干预措施 识别高风险患者，目前尚不清楚为什么只有一小部分患者明显处于危险状态 相似的条件下，会发生定植/疾病。我们的首要假设是患者对 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 可以通过病原体、宿主和共生体的整体组合来检测病原体的相互作用 微生物群分析。 DYNAMITE 计划（多重耐药菌的定植和感染动力学 免疫功能低下和危重患者中的病原体）试图填补这些重要的知识空白。 事实上，我们已经确定了关键的微生物群特征，这些特征可以广泛保护肠道来源的微生物 病原体通过以前未被认识到的抗菌机制表明，缺乏这种生物体可能会 是决定病原体定植和感染的关键因素。该计划的目标是，i）剖析 影响定植和感染的主要微生物、临床和抗菌药物耐药性决定因素 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 和艰难梭菌定植，以及 iii) 定义关键微生物群的功能方面和机制 防止定植/感染。我们在抗微生物药物耐药性和耐药性方面拥有悠久的多机构合作历史 微生物组科学拥有集中的最先进的设施、管理资源以及两个 德克萨斯医疗中心的主要重症和免疫功能低下患者群体，将我们的团队安排在 实现目标的独特且理想的位置。我们期望我们的研究结果具有高度影响力， 补充项目将为开发新型诊断、预防和治疗提供重要平台 对抗影响危重患者的肠道源性 AMR 微生物的治疗方法。

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.