Loss of Gastrointestinal Colonization Resistance and Antibiotic-Resistant Infections in the Intensive Care Unit

7.项目总结/摘要 该提案详细说明了一个全面的四年培训计划，以扩大我的临床和翻译 与胃肠道定植抵抗力丧失和随后发展相关的研究 重症监护病房（ICU）中的多药耐药（MDR）细菌感染，以及广泛的教学和 生物统计学和微生物组分析及方法学方面的实验室培训。的中心假设 该研究建议ICU中的抗生素耐药性是人类胃肠道的问题， 微生物组，以及微生物组内胃肠道定植抗性的丧失导致抗生素- 高危患者的耐药感染。虽然不能在体内直接测量定殖抗性，但它 可以通过替代标记进行评估：正常粪便生物多样性的丧失，多药- 耐药微生物（MDRO），以及抗生素耐药基因的总负担增加， 胃肠道微生物组。研究的总体目标是确定临床和肠道微生物组- 相关因素，有助于殖民抵抗力的损失，以促进战略，以防止肠道， ICU中的MDR感染。为了实现这一目标，我将在ICU进行一项前瞻性队列研究 患者在ICU入院时和72小时后采集样本和临床数据。使用 收集的样本和数据，然后确定（1）导致胃肠功能丧失的临床暴露 ICU中的定植抗性;（2）保持胃肠道定植的特定细菌分类群 ICU中的耐药性;（3）抗生素对胃肠道抗生素总负荷的影响 在ICU的抵抗。这项研究的结果将描绘殖民损失的关键风险因素 耐药性，并将成为未来预防MDR感染的多中心试验的基础。 ICU和其他高危环境中。通过提出的补充职业发展计划，我将获得 高级统计分析方面的额外培训，以及 为了制定长期研究计划，以了解 肠道微生物组与MDR或其他机会性感染之间的关系。在整个研究过程中 在这些职业发展活动中，我将接受蒂莫西·王博士领导的团队的指导， 国际公认的科学家和专家，研究胃肠道微生物如何引起人类 疾病我致力于作为一个独立的研究人员在以病人为导向的研究的职业生涯， 我制定了我的培训计划，以提供所需的知识和技能，为 识别和改变肠道源性感染的风险因素。

7. PROJECT SUMMARY/ABSTRACT This proposal details a comprehensive four year training program to expand my clinical and translational research related to loss of gastrointestinal colonization resistance and the subsequent development of multidrug resistant (MDR) bacterial infections in the intensive care unit (ICU), as well as extensive didactic and laboratory-based training in biostatistics and microbiome analysis and methodology. The central hypothesis of this research proposal is that antibiotic resistance in the ICU is a problem of the human gastrointestinal microbiome, and that loss of gastrointestinal colonization resistance within the microbiome leads to antibiotic- resistant infections in at-risk patients. Although colonization resistance cannot be directly measured in vivo, it can be assessed through surrogate markers: loss of normal fecal biodiversity, domination by multidrug- resistant organisms (MDROs), and a rise in the total burden of antibiotic resistance genes within the gastrointestinal microbiome. The overall goal of the research is to identify the clinical and gut microbiome- related factors that contribute to loss of colonization resistance in order to facilitate strategies to prevent gut- derived MDR infections in the ICU. To accomplish this, I will perform a prospective cohort study in ICU patients with collection of samples and clinical data at the time of ICU admission and 72 hours later. Using the samples and data collected, I will then determine (1) the clinical exposures that lead to loss of gastrointestinal colonization resistance in the ICU; (2) the specific bacterial taxa that preserve gastrointestinal colonization resistance in the ICU; and (3) the impact of antibiotics on the total burden of gastrointestinal antibiotic resistance in the ICU. The results of this research will delineate the key risk factors for loss of colonization resistance, and will form the foundation for future multicenter trials for the prevention of MDR infections in the ICU and in other at-risk settings. Through the proposed complementary career development plan, I will gain additional training in advanced statistical analysis, and the laboratory-based and didactic training in the analysis of the microbiome necessary in order to develop a long-term research program to understand the relationship between the gut microbiome and MDR or other opportunistic infections. Throughout this research and these career development activities, I will be mentored by a team led by Dr. Timothy Wang, an internationally recognized scientist and expert in how gastrointestinal microorganisms can cause human disease. I am committed to a career as an independent investigator in patient oriented research and have constructed my training plan to provide the knowledge and skills needed to make substantial contributions to identifying and modifying the risk factors for gut-derived infections.