Bacterial Characteristics of Community-associated Carbapenem-Resistant Enterobacteriaceae

群落相关碳青霉烯类耐药肠杆菌科细菌的特征

• 批准号: 10328871
• 负责人: DAVID VAN DUIN
• 金额: $ 38.12万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-02-13 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10328871
• 关键词: Active Sites; Antibiotics; Argentina; Australia; Bacterial Drug Resistance; Biological; Biological Assay; Carbapenems; Cell Adhesion; Cell Line; Cells; Censuses; Characteristics; Chile; China; Clinical; Clostridium difficile; Colombia; Communities; Community Hospitals; Data; Diagnosis; Early identification; Enrollment; Enterobacteriaceae; Enterobacteriaceae Infections; Epidemiology; Evaluation; Extended-spectrum β-lactamase; Funding; Gene Cluster; Gene Expression; Gene Family; Genes; Genetic; Genome; Health Care Costs; Health care facility; Healthcare; Healthcare Systems; Home; Hospitalization; Hospitals; Human; In Vitro; Infection; Infrastructure; International; Intestines; Klebsiella; Lead; Leadership; Long-Term Care; Measures; Mobile Genetic Elements; Modeling; Molecular Epidemiology; Morbidity - disease rate; Mus; New Zealand; Nicaragua; Outcome; Pathway interactions; Patients; Persons; Phenotype; Plasmids; Play; Public Health; Recording of previous events; Resistance; Role; Singapore; Site; Staphylococcus aureus; Work; acute care; antimicrobial; bacterial genetics; base; carbapenem resistance; carbapenem-resistant Enterobacteriaceae; carbapenemase; community setting; community transmission; dysbiosis; genetic analysis; genome analysis; genome sequencing; gut colonization; healthcare-associated infections; high risk; human microbiota; indexing; interest; methicillin resistant Staphylococcus aureus; mortality; multi-drug resistant pathogen; overexpression; pressure; prevent; prospective; response; transmission process; type 1 fimbriae; whole genome

Carbapenem-resistant Enterobacteriaceae (CRE) represent an immediate public health threat that requires urgent and aggressive action. To date, most CRE infections are healthcare associated (HA). However, the molecular epidemiology of other multidrug resistant organisms (MDRO) such as methicillin-resistant Staphylococcus aureus (MRSA) and Clostridium difficile suggests that progression to community-associated (CA) CRE is an imminent threat. Early recognition of potential CA-CRE strains and a clear biological understanding of mechanisms resulting in community transmission is essential for an appropriate response. The Consortium on Resistance against Carbapenems in Klebsiella and other Enterobacteriaceae (CRACKLE) is a prospective, international, multicenter, observational ongoing study for which Dr. van Duin is the PI. CRACKLE is federally funded through and data-shares with the Antibacterial Resistance Leadership Group (ARLG). In CRACKLE, all patients at participating hospitals who have CRE isolated from a clinical culture during hospitalization are included. Our preliminary data from CRACKLE indicate an increase in the US in possible CA-CRE infections. Our overall hypothesis is that enhanced intestinal colonization is a final common pathway for community spread of CRE strains that are responsible for increasing CA-CRE infections in the US. Enhanced ability to establish intestinal colonization, especially in the absence of antimicrobial-induced dysbiosis is proposed to be a prerequisite for successful community spread of CRE. In line with this hypothesis, our preliminary data shows a relative lack of fimE in CRE from patients admitted from home without obvious healthcare exposures. Absence of fimE results in over-expression of type 1 fimbriae, which are known to be involved in intestinal colonization. In this proposal, we will use CRACKLE infrastructure to evaluate current CA-CRE infections in the US and study CRE spread in the community (Aim 1). The intestinal colonization potential of various CRE strains will be determined in human intestinal cell adhesion and murine intestinal colonization assays with increasing antibiotic pressures (Aim 2). Finally, we will determine which bacterial chromosomal and/or plasmid genetic characteristics are associated with the CA-CRE phenotype, by performing whole genome analysis and plasmid analysis (Aim 3). This genetic analysis will focus on gene families that are known to play a role in intestinal colonization such as fim. Together, these studies will allow for early discovery of CRE strains and/or carbapenemase gene-carrying plasmids with potential for community spread resulting in guided efforts to prevent widespread community dissemination of CRE.

碳青霉烯类耐药肠杆菌科（CRE）代表了一种直接的公共卫生威胁， 紧急和积极的行动。到目前为止，大多数CRE感染是医疗保健相关的（HA）。但 其他多重耐药微生物（MDRO）的分子流行病学，如耐甲氧西林 金黄色葡萄球菌（MRSA）和艰难梭菌表明，社区相关的进展， (CA)CRE是迫在眉睫的威胁。早期识别潜在的CA-CRE菌株， 了解导致社区传播的机制对于采取适当对策至关重要。 克雷伯菌属和其他肠杆菌科细菌碳青霉烯类耐药联合体（CRACKLE） 是一项前瞻性、国际性、多中心、观察性正在进行的研究，货车Duin博士是该研究的主要研究者。 CRACKLE由联邦政府资助，并与抗菌素耐药性领导小组共享数据 （ARLG）。在CRACKLE中，参与医院中从临床培养物中分离出CRE的所有患者 住院期间，包括。我们来自CRACKLE的初步数据表明， 可能的CA-CRE感染。我们的总体假设是，增强肠道定植是一个最终的共同点， CRE菌株的社区传播途径，导致美国CA-CRE感染增加。 增强建立肠道定植的能力，特别是在没有抗菌剂诱导的情况下 生态失调被认为是CRE成功社区传播的先决条件。根据这一 假设，我们的初步数据显示，从家里入院的患者中CRE相对缺乏fimE 没有明显的医疗风险fimE的缺失导致1型菌毛的过度表达， 已知与肠道定植有关。在本提案中，我们将使用CRACKLE基础设施来 评估美国目前的CA-CRE感染，并研究CRE在社区中的传播（目标1）。肠 各种CRE菌株的定殖潜力将在人肠细胞粘附和鼠肠细胞粘附中测定。 增加抗生素压力的肠道定殖测定（目的2）。最后，我们将确定 细菌染色体和/或质粒遗传特征与CA-CRE表型相关， 进行全基因组分析和质粒分析（目的3）。这种遗传分析将集中在基因 已知在肠道定植中起作用的家族如FIM。这些研究将使 用于早期发现CRE菌株和/或携带碳青霉烯酶基因的质粒， 传播导致指导努力，以防止社区广泛传播的CRE。