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Integrated modeling of Klebsiella pneumoniae infections based on bacterial genotype, patient factors and colonization status

基于细菌基因型、患者因素和定植状态的肺炎克雷伯菌感染综合模型

基本信息

批准号：
10092078
负责人：
Michael Abbott Bachman
金额：
$ 41.72万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-02-15 至 2023-01-31
项目状态：
已结题

项目摘要

Abstract Klebsiella pneumoniae is a leading cause of hospital-acquired infections in the United States and the most common Carbapenem-resistant Enterobacteriaceae (CRE) and Extended-Spectrum Beta-lactamase (ESBL) species. Infections with CRE cause up to 50% mortality from sepsis, and both ESBL and CRE infections are a significant cause of excess morbidity and hospital costs. Our preliminary data from 1765 patients indicates that patients with K. pneumoniae gastrointestinal colonization are at a high risk of subsequent disease (Odds ratio 4.0; p<0.0001) and become infected with their colonizing strain. Antibiotic therapy can be life-saving but choosing the correct regimen requires antimicrobial susceptibility data that is available days after the onset of disease. Testing for colonization could provide an ideal opportunity for intervention: physicians can identify at- risk patients and use antibiotic susceptibility data from their colonizing strain to make rational choices for empiric therapy. High-risk patients could be targeted for intervention, but how the complex interaction of patient and bacterial factors leads to disease is unknown. To close this gap in knowledge, we have assembled a multi- disciplinary team of physician-scientists, epidemiologists, bioinformaticians, and statisticians with expertise in clinical microbiology, microbial pathogenesis and infectious diseases. The objective of this proposal is to identify the bacterial and host factors that predict K. pneumoniae infections in colonized patients. Our central hypothesis is that K. pneumoniae strains vary in their virulence potential, and the combination of K. pneumoniae genotype and host susceptibility determines the risk of disease in a colonized patient. To test this hypothesis, we validated a novel genome comparison method called Pathogenicity-Associated Loci sequencing (PAL-Seq) to identify K. pneumoniae genes in variable genomic regions that are associated with infection. We also developed a preliminary clinical model of patient risk factors for K. pneumoniae infection. We will test our hypothesis and meet the objective of this proposal through the following specific aims: Aim 1: Define patient risk factors for K. pneumoniae infection in colonized patients. We will use electronic medical records and culture samples in cohorts from three hospitals to build and validate models based on patient characteristics and colonization density as risk factors for infection in colonized patients, and test the models in the subgroup of ESBL and CRE colonized patients. Aim 2: Identify K. pneumoniae genes that predict the risk of disease in colonized patients. Using colonizing and invasive isolates, we will apply our PAL-Seq pipeline to identify bacterial genes associated with infection, validate them in animal models and an independent cohort, and test candidate virulence genes in ESBL and CRE colonized patients. The positive impact of this work will be immediate and substantial. We will rapidly advance our understanding of K. pneumoniae pathogenesis based on both clinical and animal studies, and develop predictive models that could be used to identify high- risk patients for prevention or rapid treatment of K. pneumoniae infection.

摘要肺炎克雷伯菌是美国医院获得性感染的主要原因，也是最常见的原因常见碳青霉烯类耐药肠杆菌科（CRE）和超广谱β-内酰胺酶（ESBL）物种CRE感染可导致高达50%的败血症死亡率，ESBL和CRE感染均是导致CRE感染的主要原因。是导致发病率和住院费用过高的重要原因。我们对1765名患者的初步数据表明，患者K。肺炎胃肠道定植导致后续疾病的风险很高（比值比 4.0; p<0.0001）并被其定殖菌株感染。抗生素治疗可以挽救生命，选择正确的治疗方案需要在疾病发生后数天内获得抗菌药物敏感性数据。疾病定植检测可以提供理想的干预机会：医生可以识别- 风险患者和使用抗生素敏感性数据，从他们的殖民菌株，作出合理的选择，经验疗法高风险患者可以作为干预的目标，但如何复杂的相互作用，而细菌因素导致的疾病是未知的。为了弥补这一知识差距，我们组建了一个多- 由医学科学家、流行病学家、生物信息学家和统计学家组成的学科团队，临床微生物学、微生物发病机制和传染病。这项建议的目的是确定预测K的细菌和宿主因素。肺炎感染的患者。我们的中央假设是K。pneumoniae菌株的毒力潜力各不相同，并且K. 肺炎基因型和宿主易感性决定了定植患者的疾病风险。为了验证这一假设，我们验证了一种新的基因组比较方法，称为致病性相关基因座测序（PAL-Seq）以鉴定K.与肺炎相关的可变基因组区域中的基因，感染我们还开发了一个初步的临床模型的病人的危险因素K。肺炎感染。我们将通过以下具体目标检验我们的假设并实现本提案的目标：目标1：定义K的患者风险因素。肺炎感染的患者。我们将使用电子医疗来自三家医院的队列记录和培养样本，以建立和验证基于患者特征和定植密度作为定植患者感染的风险因素，并在 ESBL和CRE定植患者亚组。目标2：识别K。肺炎的基因预测的风险殖民地患者的疾病。使用定殖和侵入性分离株，我们将应用我们的PAL-Seq管道，鉴定与感染相关的细菌基因，在动物模型和独立队列中验证它们，并在ESBL和CRE定植患者中检测候选毒力基因。这项工作的积极影响将是直接的和实质性的。我们将迅速推进我们对K的理解。肺炎发病机制基于临床和动物研究，并开发预测模型，可用于识别高对高危患者进行预防或快速治疗。肺炎感染。