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

重症监护室胃肠道定植抵抗力丧失和抗生素耐药性感染

• 批准号: 9222133
• 负责人: Daniel E. Freedberg
• 金额: $ 16.77万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-02-17 至 2020-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9222133
• 关键词: Admission activity; Analysis of Variance; Antibiotic Resistance; Antibiotics; Award; BLR1 gene; Bacteria; Bacterial Infections; Biodiversity; Biometry; Cessation of life; Clinical; Clinical Data; Clinical Research; Critical Illness; Data; Development; Development Plans; Discriminant Analysis; Distal; Dose; Enrollment; Exposure to; Foundations; Future; Goals; Gram-Negative Bacteria; Grant; Healthcare; Hour; Human; Individual; Infection; Inpatients; Intensive Care Units; International; Intestines; Knowledge; Laboratories; Lead; Linear Regressions; Logistic Regressions; Measures; Medical; Mentors; Methodology; Modeling; Morbidity - disease rate; Multi-Drug Resistance; Multicenter Trials; Nosocomial Infections; Opportunistic Infections; Organism; Patient risk; Patients; Pattern; Plasmids; Prevention strategy; Prevention trial; Prospective cohort study; Research; Research Personnel; Research Proposals; Resistance; Risk; Risk Factors; Sampling; Scientist; Sepsis; Statistical Data Interpretation; Surrogate Markers; Swab; Testing; Time; Training; Training Programs; Translational Research; Vancomycin resistant enterococcus; Work; bacterial resistance; base; career; career development; cohort; cost; design; gastrointestinal; genome sequencing; gut microbiome; high risk; human disease; in vivo; methicillin resistant Staphylococcus aureus; microbial; microbiome; microorganism; mortality; multi-drug resistant pathogen; multidisciplinary; novel; pathogen; patient oriented research; prevent; proctolin; programs; prospective; rRNA Genes; rectal; resistance gene; sample collection; skills; whole genome

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.

7. 项目概要/摘要 该提案详细介绍了一个为期四年的综合培训计划，以扩展我的临床和转化能力 与胃肠道定植抵抗力丧失及后续发展相关的研究 重症监护病房 (ICU) 中的多重耐药 (MDR) 细菌感染，以及广泛的说教和治疗 生物统计学和微生物组分析和方法方面的实验室培训。中心假设为 这项研究建议是，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抵抗力的丧失导致抗生素- 高危患者的耐药感染。尽管无法在体内直接测量定植抗性，但 可以通过替代标记进行评估：正常粪便生物多样性的丧失、多种药物的支配 耐药生物（MDRO），以及抗生素耐药基因总负担的增加 胃肠道微生物组。该研究的总体目标是确定临床和肠道微生物组 导致定植抵抗力丧失的相关因素，以促进预防肠道菌群的策略 ICU 中衍生的 MDR 感染。为了实现这一目标，我将在 ICU 中进行一项前瞻性队列研究 患者进入 ICU 时和 72 小时后收集样本和临床数据。使用 收集样本和数据后，我将确定（1）导致胃肠道损失的临床暴露 ICU 中的定植抵抗； (2) 维持胃肠道定植的特定细菌类群 ICU 内的阻力； (3)抗生素对胃肠道抗生素总负担的影响 ICU 内的阻力。这项研究的结果将描述导致殖民化丧失的关键风险因素 耐药性，并将为未来预防 MDR 感染的多中心试验奠定基础 ICU 和其他高危环境。通过建议的互补职业发展计划，我将获得 高级统计分析方面的额外培训以及基于实验室和教学的培训 为了制定长期研究计划以了解微生物组所必需的分析 肠道微生物组与耐多药或其他机会性感染之间的关系。在整个研究过程中 以及这些职业发展活动，我将得到由 Timothy Wang 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导致人类 疾病。我致力于作为一名独立调查员从事以患者为导向的研究，并拥有 制定了我的培训计划，以提供做出重大贡献所需的知识和技能 识别和改变肠道源性感染的危险因素。