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; 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。项目摘要/摘要 该建议详细介绍了一项全面的四年培训计划，以扩大我的临床和翻译 与胃肠道造成抗性丧失以及随后发展有关的研究 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 基于实验室的生物统计学和微生物组分析和方法学培训。中心假设 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抗原抗性的丧失会导致抗生素 - 处于危险患者中的抗性感染。尽管不能直接在体内测量定植的抗性，但 可以通过替代标记来评估：正常粪便生物多样性的丧失，多饮用 抗性生物（MDROS），以及抗生素抗性基因的总负担上升 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 - 有助于丧失定殖抗性的相关因素，以促进策略以防止肠道 ICU中的MDR感染。为此，我将在ICU进行一项前瞻性队列研究 在ICU入院时和72小时后，具有样品和临床数据收集的患者。使用 然后收集的样品和数据，然后我将确定（1）导致胃肠道丧失的临床暴露 ICU中的定殖抗性； （2）保留胃肠道定殖的特定细菌分类单元 ICU中的抗性； （3）抗生素对胃肠道抗生素总负担的影响 ICU中的阻力。这项研究的结果将描述丧失殖民的关键风险因素 抵抗力，并将为预防MDR感染的未来多中心试验奠定基础 ICU和其他高危设置。通过拟议的互补职业发展计划，我将获得 高级统计分析的其他培训以及基于实验室的教学培训 分析所需的微生物组，以制定长期研究计划以了解 肠道微生物组与MDR或其他机会感染之间的关系。在整个研究中 以及这些职业发展活动，我将由由蒂莫西·王（Timothy Wang）博士领导的团队指导 国际认可的科学家和专家，胃肠道微生物如何引起人类 疾病。我致力于从事以患者为导向研究的独立调查员的职业，并且 构建了我的培训计划，以提供为做出重大贡献所需的知识和技能 识别和修改肠道衍生感染的危险因素。