Molecular Epidemiology of Carbapenem-Resistant Klebsiella pneumoniae

耐碳青霉烯类肺炎克雷伯菌的分子流行病学

• 批准号: 8975488
• 负责人: ROBERT A. BONOMO
• 金额: $ 20.91万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-06-25 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8975488
• 关键词: Admission activity; Antibiotic Resistance; Antibiotics; Antimicrobial Resistance; Bacterial Drug Resistance; Biological Preservation; Carbapenems; Characteristics; Clinical; Clinical Markers; Colistin; Data; Development; Epidemic; Funding; Future; Genes; Genetic; Genetic Markers; Genomics; Goals; Great Lakes Region; Health; Health Care Costs; Healthcare Systems; Hospital Mortality; Hospitals; Human; In Vitro; Individual; Infection; Institutes; Intervention; Klebsiella pneumonia bacterium; Leadership; Length of Stay; Life; Link; Long-Term Care; Maps; Measures; Medical Genetics; Mobile Genetic Elements; Modeling; Molecular; Molecular Epidemiology; Organism; Outcome; Patient risk; Patients; Pattern; Plasmids; Polysaccharides; Positioning Attribute; Predisposition; Public Health; Recommendation; Recording of previous events; Reporting; Resistance; Resistance development; Resort; Risk; Risk Factors; Structure; System; Time; Toxic effect; Variant; base; carbapenem resistance; carbapenem-resistant Enterobacteriaceae; clinical risk; colistin resistance; epidemiologic data; fight against; genetic element; genetic variant; genome sequencing; in vitro activity; interest; novel; pathogen; primary outcome; prospective; public health relevance; resistant strain; therapy design; tigecycline

 DESCRIPTION (provided by applicant): Antimicrobial resistance is "one of the greatest threats to human health worldwide" and carbapenem-resistant enterobacteriaceae (CRE) represent an immediate public health threat that requires urgent and aggressive action. In the US, infections caused by resistant organisms add $21-$34 billion to healthcare costs annually. Carbapenem-resistant Klebsiella pneumoniae (CRKP) are the most commonly encountered CRE in the US. CRKP are resistant to most antibiotics and clinical outcomes with CRKP infections are generally poor. The globally endemic CRKP strain ST258 is responsible for most CRKP infections in the US. The overarching hypothesis of this R21 proposal is that ST258 strains of CRKP carry specific genes that are associated with poor clinical outcomes and that these genetic elements are nonuniformly distributed among the isolates. Using whole genome sequencing we will seek to identify genetic and clinical markers of poor outcomes and transmissibility by comparison of colonizing isolates versus those that cause infection. We have already determined that ST258 strains from the Great Lakes region can be grouped based on the presence of two plasmids carrying the blaKPC gene. In addition, the two plasmids are associated with distinct chromosomal backgrounds that differ in many genes including those that encode the capsular polysaccharide structure. Finding the links between these observations will help stratify at risk patients by determining which CRKP isolates and what genetic signatures have the most clinical impact. To obtain these answers, we will join our established multicenter CRKP consortium, which currently consists of 9 hospital systems, covering more than 2 million people living in the Great Lakes region with the genomics expertise of JCVI. Since January of 2012, more than 500 unique patients with greater than 750 admissions and over 850 CRKP culture episodes have been included in this consortium; so far, we have analyzed 57 strains by WGS. We have 2 specific aims. 1) To discover molecular characteristics that are associated with clinical outcomes in patients infected with ST258 strains of CRKP. We will determine the genomic sequences of CRKP isolates collected from patients with extensive clinical information, treatment history, and outcome data. The primary outcome of interest will be association of genetic variants with hospital mortality. Secondary measures will include variants associated with post-infection length of stay, ICU admission, and readmissions. 2) To study the interplay between clinical risk factors and molecular characteristics leading to tigecycline and colistin resistance in CRKP isolates. We will determine the mechanisms of resistance of strains with reduced in vitro susceptibility to tigecycline and/or colistin and whethr specific genetic backgrounds in the context of specific clinical settings - such as antibiotic exposure or stay in long term care - are associated with tigecycline and/or colistin resistance. Molecular results combined with clinical/epidemiologic data will inform these models. Our unique approach will provide the necessary understanding that is crucial in the design of interventions to curb the CRKP epidemic.

 描述（由申请人提供）：抗生素耐药性是“全世界人类健康面临的最大威胁之一”，碳青霉烯类耐药肠杆菌科细菌（CRE）代表了直接的公共卫生威胁，需要采取紧急和积极的行动。在美国，耐药性引起的感染。耐碳青霉烯类肺炎克雷伯菌 (CRKP) 是美国最常见的 CRE，CRKP 对大多数细菌都有耐药性。 R21 提案的总体假设是，CRKP 感染的 ST258 菌株携带与不良临床结果相关的特定基因。并且这些遗传元件在分离株中分布不均匀，我们将通过比较定植分离株与引起感染的分离株来寻求识别不良结果和传播性的遗传和临床标记。确定来自五大湖地区的 ST258 菌株可以根据携带 blaKPC 基因的两个质粒的存在进行分组。此外，这两个质粒与许多基因（包括编码荚膜多糖结构的基因）不同的不同染色体背景相关。找到这些观察结果之间的联系将有助于通过确定哪些 CRKP 分离株以及哪些基因特征具有最大的临床影响来对高危患者进行分层。为了获得这些答案，我们将加入我们已建立的多中心。 CRKP 联盟目前由 9 个医院系统组成，利用 JCVI 的基因组学专业知识覆盖五大湖地区超过 200 万人，自 2012 年 1 月以来，已有 500 多名独特患者入院，并进行了 850 多个 CRKP 培养。到目前为止，我们已经通过 WGS 分析了 57 个菌株，我们有 2 个具体目标：1) 发现与临床结果相关的分子特征。我们将确定从具有广泛临床信息、治疗史和结果数据的患者中收集的 CRKP 分离株的基因组序列，主要结果是遗传变异与医院死亡率的关联。将包括与感染后住院时间、ICU 入住和再入院相关的变异。 2) 研究导致 CRKP 菌株替加环素和粘菌素耐药的临床危险因素和分子特征之间的相互作用。体外对替加环素和/或粘菌素敏感性降低的菌株的耐药性以及特定临床环境中的特定遗传背景（例如抗生素暴露或长期护理）是否与替加环素和/或粘菌素耐药性相关。结果与临床/流行病学数据相结合将为这些模型提供信息，我们独特的方法将提供必要的理解，这对于设计遏制 CRKP 流行的干预措施至关重要。