Elucidating transmission of plasmids harboring blaKPC among carbapenem-resistant Enterobacteriaceae using long-range sequencing

使用长程测序阐明携带 blaKPC 的质粒在碳青霉烯类耐药肠杆菌科细菌中的传播

• 批准号: 10057217
• 负责人: Angela Gomez-Simmonds
• 金额: $ 19.47万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-12-01 至 2022-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10057217
• 关键词: Academic Medical Centers; Accounting; Admission activity; Advisory Committees; Age; Antibiotic Resistance; Antibiotics; Bacteria; Bioinformatics; Biometry; Carbapenems; Career Mobility; Caring; Clinical; Cluster Analysis; Collection; Communicable Diseases; Complex; Control Groups; Detection; Disease Outbreaks; Enterobacter cloacae; Enterobacteriaceae; Environment; Epidemic; Evolution; Funding; Genome; Genomics; Geography; Goals; High Prevalence; Hospitals; In Vitro; Incidence; Infection; Infection Control; Interruption; Intervention; Klebsiella pneumoniae; Laboratories; Link; Location; Master' s Degree; Mediating; Mediation; Medical; Mentors; Methods; Microbiology; Mobile Genetic Elements; Molecular; Molecular Epidemiology; Multi-Drug Resistance; New York City; Patient Isolators; Patients; Phylogenetic Analysis; Phylogeny; Physicians; Plasmids; Protocols documentation; Public Health; Publications; Publishing; Research; Research Design; Research Personnel; Resistance; Risk; Risk Factors; Role; Scientist; Sequence Analysis; Signal Transduction; Site; Surface; Technology; Training; United States; United States National Institutes of Health; antibiotic resistant infections; attributable mortality; base; carbapenem resistance; carbapenem-resistant Enterobacteriaceae; carbapenemase; career development; case control; clinical epidemiology; clinical risk; comparative; cross-species transmission; genome sequencing; genomic epidemiology; individual patient; multidisciplinary; next generation sequencing; pathogen; patient population; prospective; rectal; resistance gene; resistance mechanism; sequencing platform; sex; spatiotemporal; tertiary care; tool; transmission process; uptake; whole genome

PROJECT SUMMARY/ABSTRACT: Rationale: Resistance to broad-spectrum carbapenem antibiotics has spread rapidly among Enterobacteriaceae since the early 1990s, posing an escalating threat to medical care. While Klebsiella pneumoniae comprise the majority of CRE in the United States, recent evidence suggests that CRE are rapidly diversifying. This reflects the ability of carbapenem resistance genes to spread to between different strains of Enterobacteriaceae via mobile genetic elements, particularly plasmids. Despite their important infection control implications, the mechanisms by which these plasmids spread have not been fully elucidated. Candidate: As an infectious diseases clinician with a masters’ degree in biostatistics, Dr. Angela Gomez-Simmonds’ previous publications characterize the clinical and molecular epidemiology of CRE. Formal training in advanced bioinformatics and genomic epidemiology will be critical for the completion of the proposed research and the advancement of her career. With primary mentor Dr. Anne-Catrin Uhlemann, she has assembled a multidisciplinary advisory team of experts to guide her training and research progress. Dr. Gomez-Simmonds’ long-term goal is to become an NIH-funded independent researcher using next-generation sequencing to understand links between the bacterial evolution, resistance mechanisms, and clinical epidemiology of multidrug-resistant Gram-negative nosocomial pathogens. Environment: The Uhlemann laboratory at Columbia University Medical Center (CUMC) has the microbiology and sequencing tools necessary to carry out the proposed research, as well as a large retrospective collection of CRE clinical isolates from diverse sites to perform genomic studies. CUMC has a strong track record of supporting the career development of young physician-scientists. Approach: We hypothesize that horizontal transfer of plasmids encoding blaKPC, the dominant carbapenem resistance gene in the United States, is an important contributor to the spread of CRE within hospitals. To overcome limitations in previous genomics studies using traditional sequencing platforms such as Illumina, we will perform long-range plasmid sequencing. Plasmid-mediated transmission of blaKPC will be characterized through three aims. In Aim 1 we will systematically assess the contribution of horizontal transfer to the spread of CRE in a large retrospective collection of CRE isolates collected between 2009-2016. In Aim 2 we will perform a case-control-control study to assess unique clinical risk factors associated with horizontal transfer versus clonal spread; a third control group will consist of CRE-negative patients. In Aim 3 we will determine whether hospital environmental surfaces such as sink drains are reservoirs for blaKPC- harboring plasmids. Phylogenetic analyses will be used to assess links between plasmid sequences from clinical and environmental CRE and published genomes. In addition to elucidating the role of plasmids in the diversification and spread of CRE, this research may contribute to the integration of long-range sequencing in effective infection surveillance and control protocols to account for plasmid-mediation CRE transmission.

项目摘要/摘要： 理由：对广谱碳青霉烯抗生素的抵抗力已迅速扩散 自1990年代初以来，肠杆菌科构成了对医疗护理的不断升级的威胁。而克莱伯斯ella 肺炎在美国完成了大多数CRE，最近的证据表明，CRE迅速 多样化。这反映了碳青霉烯耐药基因扩散到不同菌株之间的能力 肠杆菌科通过移动遗传因素，尤其是质粒。尽管具有重要的感染控制 含义，这些质粒扩散的机制尚未完全阐明。候选人：AS Angela Gomez-Simmonds博士以前 出版物是CRE的临床和分子流行病学的特征。高级培训 生物信息学和基因组流行病学对于完成拟议的研究和 她的职业发展。与主要导师Anne-Catrin Uhlemann博士一起，她聚集了 多学科专家咨询团队指导她的培训和研究进度。 Gomez-Simmonds博士 长期目标是使用下一代测序成为NIH资助的独立研究人员 了解细菌进化，抗性机制和临床流行病学之间的联系 耐多药的革兰氏阴性医学院病原体。环境：Uhlemann实验室 哥伦比亚大学医学中心（CUMC）具有携带所需的微生物学和测序工具 提出了拟议的研究，以及来自不同站点的CRE临床分离株的大量回顾性收集 进行基因组研究。 CUMC在支持年轻的职业发展方面有很强的记录 身体科学家。方法：我们假设编码blakpc的质粒的水平转移， 在美国，主要的碳青霉烯耐药基因是CRE传播的重要贡献者 在医院内。使用传统测序平台克服以前的基因组学研究的局限性 例如Illumina，我们将执行远程质粒测序。质粒介导的blakpc的传播将 通过三个目标来表征。在AIM 1中，我们将系统地评估水平的贡献 在2009 - 2016年间收集的大量回顾性CRE分离株中，转移到CRE的传播中。 在AIM 2中，我们将进行一项病例对照控制研究，以评估与 水平转移与克隆扩散；第三个对照组将由CRE阴性患者组成。在目标3中 我们将确定医院环境表面（例如水槽排水管）是否是Blakpc-的水库 - 藏有质粒。系统发育分析将用于评估质粒序列之间的联系 临床和环境CRE以及已发表的基因组。除了阐明质粒在 CRE的多元化和传播，这项研究可能有助于远程测序的整合 有效的感染监视和控制方案，以说明质粒流失CRE的传播。