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

项目总结 候选人：Tessa M.Andermann，医学博士，公共卫生硕士，是一名接受过团契培训的传染病专家， 在整个医学培训期间，她一直参与以病人为中心的研究。作为麻省理工学院的助理教授 在北卡罗来纳大学学习医学，她对翻译研究有特殊的兴趣，并致力于精确跟踪 在免疫功能低下的患者中发展和传播抗生素耐药性细菌，以便 预防无法治愈的感染。拟议奖项的具体培训目标包括获得 专长：1)应用下一代测序技术来表征抗生素耐药性基因 肠道菌群，以及2)设计临床研究以预防患者感染多重耐药菌 得了癌症。她的专家导师团队包括医学博士Jonathan Juliano和博士博士Anthony Fodor。 环境：作为美国最重要的研究机构之一，北卡罗来纳大学提供了 为拟议的研究提供最佳环境。传染病科有许多 非常优秀的基础、临床和转化型研究科学家；在该司内，有活跃的 研究抗菌素耐药性的工作将为安德曼博士提供充分的指导和领导。 北卡罗来纳大学研究界的合议性体现在专家们在 癌症、肠道微生物组和微生物基因组学，特萨与这些微生物基因组学一起开发了必要的 关系，以完成拟议的研究。北卡罗来纳大学以实物形式展示了它对特萨的支持 通过提供工资支持，使她能够开发目前的提案，从而研究职业生涯。 研究：接受造血干细胞移植(HCT)的患者肠道菌群定植 与抗生素耐药细菌有更高的血液感染(BSI)的频率，并增加 死亡率。尽管抗菌素耐药性(AMR)在这个人群中造成了沉重的负担，但关于如何 耐药细菌在患者体内的发展和传播是有限的。先前对HCT接受者的研究有 尚未调查AMR基因在肠道细菌内部和之间的获取和转移，这可能 会导致感染。拟议研究的首要目标是评估肠道AMR基因的影响 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)相对于移植获得AMR基因的时间，2)AMR基因转移的程度和 肠道细菌间的传播，以及3)AMR基因负荷与BSI风险的关系 在HCT之后。为了做到这一点，将对来自70个HCT的粪便样本进行下一代测序 两个不同机构的受助人。我们假设，增加的抗生素耐药性基因负担在 移植后的肠道耐药主要是由于移植前AMR基因的扩增，并与 HCT后发生BSI的风险增加。我们期望这项研究能够更好地理解 抗菌素耐药性在肠道细菌中产生，可用于预防癌症患者的感染。

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.