Precision characterization of antimicrobial resistance gene dynamics in bloodstream infection risk after hematopoietic stem cell transplantation

造血干细胞移植后血流感染风险中抗菌药物耐药基因动态的精确表征

• 批准号: 10487458
• 负责人: Tessa Andermann
• 金额: $ 20.26万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-10 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10487458
• 关键词: Accounting; Antibiotic Resistance; Antibiotic-resistant organism; Antibiotics; Antimicrobial Resistance; Award; Bacteria; Bacterial Antibiotic Resistance; Basic Science; Bioinformatics; Blood Circulation; Cancer Center; Cessation of life; Clinical; Clinical Research; Clinical Trials; Clonal Expansion; Communicable Diseases; Communities; Complex; Complication; Culture-independent methods; Data; Databases; Development; Disease; Doctor of Philosophy; Emerging Technologies; Enrollment; Environment; Exhibits; Feasibility Studies; Feces; Fellowship; Foundations; Frequencies; Funding; Future; Gene Transfer; Genes; Genome; Goals; Hematologic Neoplasms; Hematopoietic Stem Cell Transplantation; Home; Horizontal Gene Transfer; Immunocompromised Host; Infection; Infection prevention; Inpatients; Institution; Intervention; Knowledge; Leadership; Location; Malignant Neoplasms; Medical; Medicine; Mentored Patient-Oriented Research Career Development Award; Mentors; Metagenomics; Methods; Microbe; Minority; Modeling; Multi-Drug Resistance; Multicenter Studies; Nature; North Carolina; Organism; Outpatients; Patients; Population; Randomized Controlled Trials; Research; Resistance development; Risk; Sampling; Scientist; Sepsis; Shotgun Sequencing; Shotguns; Specialist; Systemic infection; Technology; Time; Training; Translational Research; Transplant Recipients; Transplantation; Universities; Validation; Wages; Work; biobank; bioinformatics tool; career; cohort; colonization resistance; design; gut bacteria; gut colonization; gut microbes; gut microbiome; gut microbiota; in vivo; infection risk; interest; microbial; microbial genomics; mortality; multi-drug resistant pathogen; nanopore; next generation sequencing; novel; novel sequencing technology; pathogen; patient oriented research; post-transplant; prevent; professor; prospective; resistance gene; stool sample

PROJECT SUMMARY Candidate: Tessa M. Andermann, MD, MPH is a fellowship-trained Infectious Diseases specialist who has been involved in patient-oriented research throughout her medical training. As an Assistant Professor of Medicine at UNC, she has specific interests in translational research and is invested in precisely tracking the development and dissemination of antibiotic resistant organisms in immunocompromised patients in order to prevent untreatable infections. The specific training objectives for the proposed award include gaining expertise in: 1) applying next-generation sequencing technologies to characterize antibiotic resistance genes in gut flora, and 2) designing clinical studies to prevent infections with multidrug-resistant organisms in patients with cancer. Her expert team of mentors include Drs. Jonathan Juliano, MD, and Anthony Fodor, PhD. Environment: As one of the nation's premier research institutions, the University of North Carolina provides an optimal environment for the proposed research. The Division of Infectious Diseases is home to a number of extremely accomplished basic, clinical, and translational research scientists; within the Division, there is active work investigating antimicrobial resistance that will provide Dr. Andermann ample guidance and leadership. The UNC research community's collegial nature is demonstrated in the seamless incorporation of experts in cancer, the gut microbiome, and microbial genomics with whom Tessa has developed the necessary relationships to accomplish the proposed research. UNC, in kind, has demonstrated its support of Tessa's research career by providing the salary support that allowed her to develop this current proposal. Research: Patients undergoing hematopoietic stem cell transplantation (HCT) whose gut flora are colonized with antibiotic-resistant bacteria have a higher frequency of bloodstream infections (BSI), and an increased mortality. Despite the significant burden of antimicrobial resistance (AMR) in this population, knowledge of how antibiotic-resistant bacteria develop and disseminate in patients is limited. Prior studies in HCT recipients have not yet investigated the acquisition and transfer of AMR genes within and between gut bacteria that may contribute to infection. The overarching goal of the proposed research is to assess the impact of gut AMR gene dynamics on the risk of systemic infections using novel sequencing technologies. The specific aims are to determine: 1) the timing of AMR gene acquisition relative to transplant, 2) the extent of AMR gene transfer and dissemination between bacteria in the gut, and 3) the relationship between AMR gene burden and BSI risk after HCT. To accomplish this, next-generation sequencing will be performed on stool samples from 70 HCT recipients at two different institutions. We hypothesize that the increased antibiotic resistance gene burden in the gut resistome after transplant is due primarily to expansion of pre-transplant AMR genes and is associated with an increased risk of BSI after HCT. We expect that this research will yield a greater understanding of how antimicrobial resistance develops in gut bacteria that can be used to prevent infections in patients with cancer.

项目摘要 候选人：Tessa M. Andermann，医学博士，公共卫生硕士是一位受过奖学金培训的传染病专家， 在她的医学训练中一直参与以病人为导向的研究。作为助理教授， 她对转化研究有着特殊的兴趣，并致力于精确跟踪 在免疫功能低下患者中产生和传播抗生素耐药微生物， 预防无法治愈的感染。拟议奖项的具体培训目标包括获得 专业知识：1）应用下一代测序技术来表征抗生素耐药基因 肠道植物群，以及2）设计临床研究，以预防患者感染多重耐药微生物 得了癌症她的专家导师团队包括Jonathan Juliano博士和Anthony Fodor博士。 环境：作为全国首屈一指的研究机构之一，北卡罗来纳州大学提供了一个 为研究提供最佳环境。传染病科是许多 非常有成就的基础，临床和转化研究科学家;在该部门内，有活跃的 研究抗菌素耐药性的工作将为Andermann博士提供充分的指导和领导。 研究社区的合议性质体现在专家的无缝结合， 癌症，肠道微生物组和微生物基因组学，Tessa与他们一起开发了必要的 为完成拟议的研究。以实物形式，证明了它对泰莎 研究生涯提供的工资支持，使她能够发展目前的建议。 研究：接受造血干细胞移植（HCT）的患者肠道植物群定植 具有抗药性细菌的人有更高的血液感染频率（BSI）， mortality.尽管该人群中存在显著的抗菌素耐药性（AMR）负担，但了解如何 耐药细菌在患者体内的发展和传播是有限的。先前在HCT接受者中的研究 尚未研究AMR基因在肠道细菌内和肠道细菌之间的获得和转移， 有助于感染。这项研究的总体目标是评估肠道AMR基因对 使用新的测序技术对系统性感染风险的动态研究。具体目标是 确定：1）AMR基因获得相对于移植的时间，2）AMR基因转移的程度， 肠道中细菌之间的传播，以及3）AMR基因负荷与BSI风险之间的关系 HCT后为了实现这一点，将对70 HCT的粪便样本进行下一代测序 在两个不同的机构。我们假设，增加的抗生素耐药基因负担， 移植后的肠道耐药基因组主要是由于移植前AMR基因的扩增， HCT后BSI的风险增加。我们希望这项研究能更好地了解 在肠道细菌中产生了抗菌素耐药性，可用于预防癌症患者的感染。