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.

项目概要/摘要： 理由：对广谱碳青霉烯类抗生素的耐药性已在人群中迅速传播 自 20 世纪 90 年代初以来，肠杆菌科细菌对医疗保健构成了不断升级的威胁，而克雷伯氏菌则对医疗保健构成了不断升级的威胁。 在美国，肺炎链球菌占 CRE 的大部分，最近的证据表明，CRE 正在迅速蔓延 这反映了碳青霉烯类抗性基因在不同菌株之间传播的能力。 肠杆菌科通过移动遗传元件，特别是质粒，尽管它们具有重要的感染控制作用。 影响，这些质粒传播的机制尚未完全阐明。 安吉拉·戈麦斯·西蒙兹 (A​​ngela Gomez-Simmonds) 博士是一位传染病临床医生，拥有生物统计学硕士学位 出版物描述了 CRE 的临床和分子流行病学正规培训。 生物信息学和基因组流行病学对于完成拟议的研究和 在她的主要导师 Anne-Catrin Uhlemann 博士的帮助下，她组建了一个团队。 多学科专家顾问团队指导戈麦斯-西蒙兹博士的培训和研究进展。 长期目标是成为一名 NIH 资助的独立研究人员，利用下一代测序技术 了解细菌进化、耐药机制和临床流行病学之间的联系 多重耐药革兰氏阴性医院病原体 环境：Uhlemann 实验室。 哥伦比亚大学医学中心 (CUMC) 拥有携带所需的微生物学和测序工具 提出了拟议的研究，以及来自不同地点的 CRE 临床分离株的大量回顾性收集 CUMC 在支持年轻人的职业发展方面有着良好的记录。 方法：我们捕获了编码 blaKPC（即 blaKPC）的质粒的水平转移。 美国显性碳青霉烯类耐药基因，是CRE传播的重要贡献者 克服以前使用传统测序平台进行基因组学研究的局限性。 例如 Illumina，我们将进行 blaKPC 的远程质粒测序。 在目标 1 中，我们将系统地评估横向的贡献。 在 2009 年至 2016 年期间收集的大量回顾性 CRE 分离株中，转移到了 CRE 的传播。 在目标 2 中，我们将进行病例对照对照研究，以评估与以下疾病相关的独特临床风险因素： 水平转移与克隆扩散；第三个对照组将由目标 3 中的 CRE 阴性患者组成。 我们将确定医院环境表面（例如水槽排水管）是否是 blaKPC- 的储存库 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，此外还阐明了质粒在疾病中的作用。 CRE 的多样化和传播，这项研究可能有助于长程测序的整合 有效的感染监测和控制方案，以解决质粒介导的 CRE 传播。