Carbapenem-resistant bacterial colonization and infection after liver transplant

肝移植后碳青霉烯类耐药细菌定植和感染

基本信息

批准号：
9053590
负责人：
Anne-Catrin Uhlemann
金额：
$ 15.7万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-01-14 至 2019-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9053590
关键词：
Academic Medical Centers Accounting Address Adult Affect Antibiotic-resistant organism Antibiotics Bacteria Bacterial Genome Biological Categories Centers for Disease Control and Prevention (U.S.)Clinical Cohort Studies Comorbidity Containment Cox Proportional Hazards Models Data Diagnostic Disease Outbreaks Drug Exposure Enabling Factors Enrollment Enterobacteriaceae Enterobacteriaceae Infections Epidemiology Evolution Fatal Outcome Feces Genetic Variation Genomics Genotype Goals Health Healthcare Hospital Units Hospitals Individual Infection Intervention Intestines Investigation Klebsiella pneumonia bacterium Knowledge Lead Life Link Measures Methods Monitor Morbidity - disease rate Multi-Drug Resistance New York City Operative Surgical Procedures Organ Transplantation Organism Outcome Pathway interactions Patients Phylogenetic Analysis Pilot Projects Population Prevention strategy Preventive Process Public Health Recording of previous events Reporting Research Research Design Resistance Resolution Risk Risk Factors Role Sampling Sequence Analysis Solid Structure Survival Analysis Swab Taxon Techniques Technology Testing Time Transplant Recipients Transplantation Treatment Protocols Virulence adverse outcome carbapenem resistance carbapenem-resistant Enterobacteriaceae cohort effective therapy genome sequencing high risk innovation interdisciplinary approach liver transplantation modifiable risk mortality multi-drug resistant pathogen novel pathogen genome patient population prevent programs prospective rectal tool trait transmission process whole genome

项目摘要

DESCRIPTION (provided by applicant): Multifaceted approaches are needed to limit carbapenem-resistant Enterobacteriaceae (CRE) infections, including Klebsiella pneumoniae, which have emerged as a worldwide public health problem. These multidrug- resistant organisms are associated with high morbidity and mortality that often exceeds 50%, as highly effective and non-toxic treatment regimens are lacking. While intestinal colonization with CREs has been proposed as a potential risk factor for infections during CRE outbreaks, its actual contribution to infection remains incompletely understood. Moreover, there is a fundamental gap in knowledge on how these antibiotic resistant organisms transition from colonization to infection within affected hosts. The long-term goal of this application is to elucidate at the bacterial genome level how CRE infections emerge and spread. Understanding these processes is critical to developing intervention and real-time clinical monitoring approaches to limit the impac of CRE infections at an individual and population level. We will focus our study on patients after liver transplantation who are at very high risk for CRE infections and adverse outcomes. Our central hypothesis is that the intestine provides a microenvironment in which CRE can expand and adapt with small genetic variations and subsequently lead to infections. To address these questions we propose to establish a cohort study of adult patients undergoing liver transplant, and track CREs within affected patients and across the hospital. In this prospective cohort we will enroll 300 patients pre-transplant, collect stool samples to ascertain intestinal colonization pre- and repeatedly post-transplant, and assess patients for CRE infections over a 6-month period. Our study design will allow us to execute the following Aims: 1) Define the rate and role of colonization on CRE infection in liver transplant patients; 2) Evaluate the within-host evolutio from CRE colonization to infection; and 3) Investigate the spread of CRE between liver transplant and other patient populations in the hospital. In Aim 1 we will test the contribution of CRE colonization to infection and characterize outcomes using Kaplan-Meier survival analyses and a Cox proportional hazard model. In Aim 2 we will apply 16S and whole-genome sequencing to answer whether CRE colonization dominance develops prior to infection and how modifiable risk factors (e.g. certain antibiotics) relate to these adaptations. We will also define the clonal diversity of colonizing CRE and assess whether infectious isolates arise from dominant colonizing clones or acquire novel virulence traits. In Aim 3 we will assess the within-hospital evolution and spread of CRE infections by extending whole-genome sequence analyses to infections that occurred in non- liver transplant patients. Our multidisciplinary approach is innovative in its combination of high-resolution genomics with detailed epidemiological investigations to monitor the evolution of CRE infections in real time. This research is significant with direct translational impact in establishing a framework to track the emergence of multi-drug resistant Enterobacteriaceae and to ultimately devise novel containment strategies for CREs.

描述（由适用提供）：需要多面方法来限制耐碳青霉烯肠杆菌科（CRE）感染，包括肺炎克雷伯氏菌肺炎，这些感染已成为全球公共卫生问题。由于缺乏高效和无毒治疗方案，这些多药耐药的生物与高发病率和死亡率相关，通常超过50％。虽然已经提出了用CRE的肠道定植作为CRE爆发期间感染的潜在危险因素，但其对感染的实际贡献仍未完全理解。此外，了解这些抗生素抗生素的生物如何从殖民化到受影响宿主内的感染有根本的差距。该应用的长期目标是在细菌基因组水平上阐明CRE感染如何出现和扩散。了解这些过程对于开发干预和实时临床监测方法至关重要，以限制个人和人群水平上CRE感染的影响。我们的研究将重点放在肝移植后的患者上，这些患者患有CRE感染和不良后果的风险很高。我们的中心假设是肠提供了一种微环境，在该环境中，CRE可以扩展和适应较小的遗传变异，然后导致感染。为了解决这些问题，我们提出了对接受肝移植的成年患者的队列研究，并追踪受影响的患者和整个医院内的CRE。在此前瞻性队列中，我们将招募300名患者预移植，收集粪便样品以确定肠道定植移植前后，并评估了6个月内CRE感染的患者。我们的研究设计将使我们能够执行以下目的：1）定义肝移植患者中定植对CRE感染的速度和作用； 2）评估从CRE定殖到感染的宿主内部演变； 3）研究医院中肝移植和其他患者种群之间CRE的扩散。在AIM 1中，我们将测试使用Kaplan-Meier生存分析和COX比例危害模型，将CRE定植至感染并表征结局。在AIM 2中，我们将应用16S和全基因组测序，以回答CRE定植在感染之前的支配性发展以及与这些适应性相关的可修改风险因素（例如某些抗生素）的修改。我们还将定义克隆的殖民CRE的克隆多样性和评估是来自主导殖民克隆的传染性分离株还是获得新的病毒特征。在AIM 3中，我们将通过将全基因组序列分析扩展到非肝移植患者中发生的感染来评估院内的进化和CRE感染的扩散。我们的多学科方法具有创新的高分辨率基因组学与详细的流行病学研究的结合，以实时监测CRE感染的演变。这项研究具有重大的转化影响，在建立一个框架中，以跟踪耐多药的肠杆菌科的出现并最终设计了CRES的新型遏制策略。