Molecular Epidemiology of Carbapenem-Resistant Klebsiella pneumoniae

 说明(申请人提供)：抗菌素耐药性是“全球对人类健康的最大威胁之一”，耐碳青霉烯类肠杆菌科细菌(CRE)是一种直接的公共健康威胁，需要采取紧急和积极的行动。在美国，由耐药微生物引起的感染每年增加210亿至340亿美元的医疗费用。耐碳青霉烯类肺炎克雷伯菌(CRKP)是美国最常见的CRE。CRKP对大多数抗生素具有耐药性，CRKP感染的临床结果通常较差。全球流行的CRKP毒株ST258是美国大多数CRKP感染的原因。这一R21建议的首要假设是，ST258 CRKP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。使用全基因组测序，我们将寻求通过比较定植分离株和引起感染的分离株来识别不良结局和可传播性的遗传和临床标记。我们已经确定来自大湖区的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，这两个质粒与不同的染色体背景有关，这些背景在许多基因上都不同，包括那些编码胶囊多糖结构的基因。发现这些观察之间的联系将有助于通过确定哪些CRKP分离株和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，我们将加入我们建立的多中心CRKP联盟，该联盟目前由9个医院系统组成，覆盖生活在大湖区的200多万人，拥有JCVI的基因组学专业知识。自2012年1月以来，该联盟已经包括了500多名独特的患者，超过750名入院患者和超过850例CRKP培养病例；到目前为止，我们已经分析了WGS的57种菌株。我们有两个具体目标。1)发现感染ST258株CRKP的患者的分子特征与临床转归有关。我们将确定从具有广泛的临床信息、治疗历史和结果数据的患者中收集的CRKP分离株的基因组序列。令人感兴趣的主要结果将是基因变异与医院死亡率之间的关联。次要措施将包括与感染后住院时间、ICU入院和再入院相关的变量。2)研究临床危险因素与CRKP分离株产生替格环素和粘菌素耐药性的分子特征之间的相互作用。我们将确定体外对替环素和/或粘菌素敏感性降低的菌株的耐药性机制，以及特定临床环境下的特定遗传背景--如抗生素暴露或长期护理--是否与替环素和/或粘菌素耐药性有关。结合临床/流行病学数据的分子结果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流行病的干预措施至关重要。

 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.