Regional genomic epidemiology to identify drivers of resistance, transmission and infection with carbapenem-resistant Klebsiella pneumoniae

抗生素耐药微生物的出现和世界范围内的传播代表了一个重大的挑战。 对全球公共卫生的威胁。一个有机体，集中体现了与之相关的紧迫性和挑战， 这种威胁是耐碳青霉烯类肺炎克雷伯氏菌（CRKP）。CRKP首次在临床病例中观察到 1996年在北卡罗来纳州的一家医院里从那时起，CRKP的成功血统已经遍布世界各地， 地球仪，成为许多地区医疗保健网络的地方病。CRKP患病率的增加 对住院患者的风险很大，因为CRKP感染的粗死亡率可能超过50%。 此外，与CRKP有关的威胁继续升级，有许多关于CRKP的报告， 甚至对最后一线的抗生素都有抗药性，使受影响的患者的治疗选择有限。轻重 CRKP的流行导致美国疾病控制中心和世界卫生组织 将其列为最紧迫的抗生素耐药性威胁。然而，尽管对CRKP给予了关注， 在许多地区仍然非常普遍。我们的核心假设是，我们无法有效控制CRKP， 以及其他紧迫的抗生素耐药性威胁，是由于缺乏对临床和 推动抗生素耐药微生物在区域间出现和传播的流行病学因素 医疗保健网络。在这里，我们试图克服这一知识差距，首先应用全基因组 按顺序构建CRKP的区域传播网络，然后覆盖丰富的流行病学和 临床元数据，以确定区域间传播、耐药性演变和感染的驱动因素 医疗保健设施。这些目标将通过以下三个目标来实现：1）应用系统发育 方法来重建区域传输网络，并进行数据分析和建模，以确定 医院内和医院间传播的驱动因素，2）确定对最后一条线耐药的遗传决定因素 抗生素和分析的背景下，区域传播网络和临床元数据，以确定 与抗性的进化和获得相关的因素; 3）确定遗传决定因素 与CRKP感染相关，并在区域传播网络和患者背景下进行分析 元数据，以确定与不良患者相关的毒性亚系和会聚变异 结果。这些目标的整体将提供关键的洞察因素驱动传输，耐药性， CRKP的演变和感染，因为它在区域医疗保健网络中传播。此外，我们相信， 一种整合基因组、临床和流行病学数据研究抗生素耐药菌增殖的方法 区域一级的威胁可以应用于其他情况，以帮助指导区域感染预防。

The emergence and worldwide dissemination of antibiotic resistant organisms represents a significant threat to global public health. An organism that epitomizes both the urgency and challenges associated with this threat is carbapenem-resistant Klebsiella pneumoniae (CRKP). CRKP was first observed in a clinical case in 1996 in a hospital in North Carolina. Since that time, successful lineages of CRKP have spread across the globe, becoming endemic in healthcare networks in many regions. This increasing prevalence of CRKP poses a great risk to hospitalized patients, as crude mortality rates for CRKP infections can be upwards of 50%. Moreover, the threat associated with CRKP continues to escalate, with numerous reports of CRKP that are resistant to even last-line antibiotics, leaving affected patients with limited treatment options. The seriousness of the CRKP epidemic has led to both the U.S. Centers for Disease Control and the World Health Organization ranking it as their most urgent antibiotic resistant threat. However, despite the attention given to CRKP, it remains highly prevalent in many areas. Our central hypothesis is that our inability to effectively control CRKP, as well as other urgent antibiotic resistant threats, is due to a lack of understanding of the clinical and epidemiologic factors that drive the emergence and spread of antibiotic resistant organisms across regional healthcare networks. Here, we seek to overcome this knowledge gap by first applying whole-genome sequencing to construct regional transmission networks for CRKP, and then overlaying rich epidemiologic and clinical meta-data to identify drivers of transmission, resistance evolution and infection across regional healthcare facilities. These goals will be accomplished through the following three aims: 1) apply phylogenetic methods to reconstruct regional transmission networks, and perform data analysis and modeling to identify drivers of transmission within and between hospitals, 2) identify genetic determinants of resistance to last line antibiotics and analyze in the context of the regional transmission network and clinical metadata to identify factors associated with both the evolution and acquisition of resistance and 3) identify genetic determinants associated with CRKP infection and analyze in the context of the regional transmission networks and patient meta-data to identify virulent sub-lineages and convergent variation that are associated with poor patient outcomes. The totality of these aims will provide critical insight into the factors driving transmission, resistance evolution and infection with CRKP as it spreads across regional healthcare networks. Moreover, we believe our approach of integrating genomic, clinical and epidemiologic data to study the proliferation of antibiotic resistant threats at a regional level can be applied in other contexts to help guide regional infection prevention.