The molecular basis of the carbapenem resistance epidemic

碳青霉烯类耐药流行的分子基础

• 批准号: 10065482
• 负责人: BARRY Neal KREISWIRTH
• 金额: $ 66.74万
• 依托单位: HACKENSACK UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-01 至 2022-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10065482
• 关键词: Address; Antibiotic Resistance; Antibiotics; Area; Automobile Driving; Biological; Boronic Acids; Carbapenems; Clinical; Collection; Country; Data; Enterobacteriaceae; Enzymes; Epidemic; Epidemiology; Europe; Evolution; Family; Far East; Gene Transfer; Genes; Genetic; Genomics; Goals; Hospitals; Incidence; Infection; Institution; Klebsiella; Klebsiella pneumoniae; Lipopolysaccharides; Maps; Mediating; Membrane Proteins; Molecular; Molecular Diagnostic Testing; Molecular Epidemiology; Molecular Evolution; Mutation; Nature; New York City; Organism; Outcome; Phenotype; Plasmids; Polysaccharides; Prevalence; Reporting; Resistance; South America; Specificity; Surveys; Techniques; Testing; Therapeutic Agents; Therapeutic Index; Treatment Failure; United States; Urban Hospitals; base; beta-Lactamase; carbapenem resistance; carbapenemase; comparative; comparative genomics; design; detection assay; diagnostic platform; genome sequencing; genomic data; genomic epidemiology; human pathogen; indexing; inhibitor/antagonist; innovation; insight; novel; novel therapeutics; prospective; resistance gene; resistance mechanism; resistant Klebsiella pneumoniae; resistant strain; trait; transmission process; whole genome

Summary A common theme in bacterial evolution is how the acquisition of antibiotic resistance can rapidly change the epidemiologic landscape of major human pathogens. Carbapenem Resistant Klebsiella pneumoniae (CRKp), first documented in 1996, is now epidemic in New York City (NYC) hospitals and is reported globally. CRKp infections often result in poor therapeutic indices; thus curbing the incidence of CRKp infections is now a national priority. Currently, three overlapping CRKp epidemics with three different classes of carbapenemases are spreading in different continents. Accelerating these epidemics is the ability of carbapenemase genes, harbored on conjugative plasmids, to spread across the Enterobacteriaceae family. A critical, poorly understood aspect of the CRKp epidemic is the relative contribution of plasmid-mediated transfer and clonal dissemination to driving the regional and global epidemiology. Previously, we used whole genome sequencing (WGS) to dissect the molecular epidemiology and evolution of the main US epidemic CRKp sequence type (ST) 258. Interrogating strains and resistance harboring plasmids within our network of NYC hospitals we found that the majority of ST258 CRKp strains harbor one of three common plasmids carrying a particular class of carbapenemase enzyme, KPC. These data suggest the spread of CRKp is likely the consequence of plasmid-mediated gene transfer and subsequent clonal spread. We therefore hypothesize that this epidemic is primarily due to transmission of resistance harboring plasmids uniquely adapted to specific host genetic backgrounds. In Aim 1, we expand our NYC network to include a large US consortium and to examine the genomic epidemiology of CRKp strains and plasmids across the US. Aim 2 builds on the insights and techniques developed in our previous studies to interrogate the global epidemiology of CRKp via a large clinical isolate collection from over 62 countries, with the goal of constructing a phylogeographic map of strains, plasmids and carbapenemase genes. In this Aim we will also directly test the basis of CRKp strain-plasmid association by comparative transmission efficiency studies of different carbapenemase gene-harboring plasmids into diverse strain backgrounds. Using robust CRKp genomic data obtained in Aims 1 and 2, we will develop a rapid molecular detection assay to identify and track CRKp strains and plasmids in clinical settings. Aim 3 will characterize non-carbapenemase factors that contribute to high-level carbapenemase resistance in CRKp isolates, such as mutations in outer membrane proteins, which result in very poor clinical outcomes. Based on this characterization, some of these highly carbapenemase resistant strains will be selected to build a new, well-curated panel of strains for testing novel antibiotic agents. Taken together, ours is an innovative approach with the potential to make a substantial impact in the field of CRKp epidemiology, develop critically needed diagnostic platforms, and explore efficacy of novel antibiotics against these organisms.

总结

项目成果

Genomic Epidemiology of Global Carbapenemase-Producing Enterobacter spp., 2008-2014.

• DOI: 10.3201/eid2406.171648
• 发表时间: 2018-06
• 期刊: Emerging infectious diseases
• 影响因子: 11.8
• 作者: Peirano G;Matsumura Y;Adams MD;Bradford P;Motyl M;Chen L;Kreiswirth BN;Pitout JDD
• 通讯作者: Pitout JDD

RpoE is a Putative Antibiotic Resistance Regulator of Salmonella enteric Serovar Typhi.

RpoE 是一种公认​​的肠伤寒沙门氏菌抗生素耐药性调节剂。

• DOI: 10.1007/s00284-015-0983-7
• 发表时间: 2016
• 期刊: Curr Microbiol
• 作者: Xie Xiaofang;Zhang Haifang;Zheng Yi;Li Aiqing;Wang Min;Zhou Huiqin;Zhu Xueming;Schneider Zachary;Chen Liang;Kreiswirth Barry N;Du Hong（杜鸿）
• 通讯作者: Du Hong（杜鸿）

Colistin- and Carbapenem-Resistant Escherichia coli Harboring mcr-1 and blaNDM-5, Causing a Complicated Urinary Tract Infection in a Patient from the United States.

• DOI: 10.1128/mbio.01191-16
• 发表时间: 2016-08-30
• 期刊: mBio
• 影响因子: 6.4
• 作者: Mediavilla JR;Patrawalla A;Chen L;Chavda KD;Mathema B;Vinnard C;Dever LL;Kreiswirth BN
• 通讯作者: Kreiswirth BN

Two for the price of one: emerging carbapenemases in a returning traveller to New York City.

• DOI: 10.1136/bcr-2018-225440
• 发表时间: 2018-07-18
• 期刊: BMJ case reports
• 影响因子: 0.9
• 作者: Mittal, Jaimie;Szymczak, Wendy A;Nori, Priya
• 通讯作者: Nori, Priya

Evaluation of Remel Spectra CRE Agar for Detection of Carbapenem-Resistant Bacteria from Rectal Swabs Obtained from Residents of a Long-Term-Care Facility.

对 Remel Spectra CRE 琼脂用于检测长期护理机构居民直肠拭子中的碳青霉烯类耐药细菌的评估。

• DOI: 10.1128/jcm.00789-15
• 发表时间: 2015
• 期刊: Journal of clinical microbiology
• 影响因子: 9.4
• 作者: LaBombardi,VincentJ;Urban,CarlM;Kreiswirth,BarryN;Chen,Liang;Osorio,Giuliana;Kopacz,Joanna;Labaze,Georges;Segal-Maurer,Sorana
• 通讯作者: Segal-Maurer,Sorana