Longitudinal Analysis of the Fecal Microbiome and Resistome of Patients with Multidrug-Resistant Urinary Tract Infections and Predictors of Recurrence

项目摘要/ABSTRCT 多药耐药生物(MDRO)是对人类健康的主要威胁，导致200万人感染 仅在美国每年就有2.3万人死亡。尿路感染(UTI)是最常见的 由MDRO引起的感染。预防和治疗MDRO尿路感染的选择很少，没有干预措施 逆转粪便MDRO定植，并采取有限的策略来识别有复发风险的患者。本研究 将解决复发MDRO UTI和粪便MDRO领域的科学进步的关键障碍 通过描述宿主微生物群落和MDRO特征来提高科学知识 与MDRO定植和复发性尿路感染有关。 为了推进我以病人为中心的研究事业，并在基因组研究方面追求更多的专业知识，我将 对MDRO尿路感染患者进行前瞻性队列试验，并确定他们的大便和尿液特征 利用微生物培养和基因组技术的标本。我们将评估 应用基因测序技术鉴定MDRO尿路感染患者粪便微生物组 与持久MDRO定植和复发性UTI相关的分类群和功能，并将此信息联系起来 有详细的临床数据。这里描述的建议将促进对微生物的理解 粪便微生物群的生态学及其在MDRO感染中的作用，并将为我提供获得 研究实施、纵向数据分析和基因组数据分析方面的知识和技能。我有过 组建了一个由导师和合作者组成的团队来指导我早期的研究生涯，并就 对通过试点研究创建的现有存储标本进行评估，并持续招募患者用于 前瞻性队列试验。我们将对样本进行分析，以回答以下问题： 1)多药耐药尿路感染患者的粪便微生物群和耐药菌群在抗菌药物治疗后的变化轨迹如何 治疗？ 2)与MDRO有关的粪便微生物组有分类和功能成分吗？ 移居和反复感染？ 3)抗菌药物治疗如何影响耐药基因和细菌的浓度 毒力因子，以及它们与复发的多药耐药尿路感染有什么关系？ 将使用基因组方法和经典微生物学技术来评估菌株类型、微生物 在MDRO尿路感染患者的粪便微生物组中发现分类、功能和抗生素耐药基因。这个 这些研究的结果将提供必要的数据，以推动合理设计检测和 防止粪便MDRO定植和MDRO尿路感染。这项研究的发现将广泛适用于 UTIS，因为我们将确定粪便MDRO定植与反复感染之间的关系。

PROJECT SUMMARY/ABSTRCT Multidrug-resistant organisms (MDRO) are major threats to human health, responsible for >2 million infections and 23,000 deaths per year in the US alone. Urinary tract infections (UTI) are the most common types of infections caused by MDROs. There are few options to prevent and treat MDRO UTIs, no interventions to reverse fecal MDRO colonization, and limited strategies to identify patients at risk for recurrence. This study will address critical barriers to scientific progress in the fields of recurrent MDRO UTI and fecal MDRO colonization, and improve scientific knowledge by delineating the host microbial communities and MDRO traits that are associated with MDRO colonization and recurrent UTI. To advance my patient-oriented research career and pursue additional expertise in genomic research, I will conduct a prospective cohort trial of patients with MDRO UTIs and characterize their stool and urine specimens utilizing microbiologic culture and genomic techniques. We will assess longitudinal changes in the fecal microbiome of patients with MDRO UTI utilizing metagenomic shotgun sequencing to identify microbial taxa and functions associated with persistent MDRO colonization and recurrent UTI, and link this information with detailed clinical data. The proposals delineated here will advance the understanding of the microbial ecology of the fecal microbiome and its role in MDRO infections, and will provide me the opportunity to gain knowledge and skills in study implementation, longitudinal data analysis, and genomic data analysis. I have assembled a team of mentors and collaborators to guide my early research career and advise on the evaluation of existing stored specimens created through a pilot study, and ongoing recruitment of patients for the prospective cohort trial. We will analyze the specimens to answer the following questions: 1) What is the trajectory of the fecal microbiome and resistome in patients with MDRO UTIs after antimicrobial treatment? 2) Are there taxonomic and functional compositions of the fecal microbiome associated with MDRO colonization and recurrent infection? 3) How does antimicrobial treatment impact the concentration of antibiotic resistance genes and bacterial virulence factors, and what is their relationship to recurrent MDRO UTI? Genomic approaches and classic microbiologic techniques will be used to assess the strain types, microbial taxa, function, and antibiotic resistance genes found in the fecal microbiome of patients with MDRO UTIs. The culmination of these studies will provide essential data to drive the rational design of methods to detect and prevent fecal MDRO colonization and MDRO UTIs. The findings in this study will be broadly applicable beyond UTIs, as we will determine the relationship between fecal MDRO colonization and recurrent infections.