Rapid Identification of Neutropenic Patients at High Risk of CRE Bacteremia

快速识别 CRE 菌血症高风险中性粒细胞减少症患者

• 批准号: 8982215
• 负责人: Michael Joseph Satlin
• 金额: $ 17.61万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-12-09 至 2019-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8982215
• 关键词: Acute leukemia; Admission activity; Anti-Bacterial Agents; Antibiotic Resistance; Antibiotic Therapy; Antibiotic susceptibility; Antibiotics; Area; Award; Bacteremia; Bacteria; Bacterial Infections; Biological Assay; Biometry; Carbapenems; Caring; Centers for Disease Control and Prevention (U.S.); Clinical; Clinical Microbiology; Clinical Research; Code; Country; Data; Detection; Development; Diagnosis; Diagnostic Procedure; Early Diagnosis; Ensure; Enterobacteriaceae; Enterobacteriaceae Infections; Enzymes; Epidemiologic Studies; Epidemiology; Feces; Fever; Fluoroquinolones; Fostering; Foundations; Genes; Genetic; Goals; Gram-Negative Bacteria; Health; Hematologic Neoplasms; Hematopoietic Stem Cell Transplantation; High Prevalence; Immunocompromised Host; Individual; Infection; Infectious Diseases Research; Inguinal region; Institution; Intensive Care Units; Investigation; Klebsiella pneumonia bacterium; Knowledge; Laboratories; Lactams; Lead; Learning; Left; Malignant Neoplasms; Master' s Degree; Mediating; Mentors; Mentorship; Molecular; Molecular Diagnostic Techniques; Molecular Epidemiology; Molecular Genetics; Multi-Drug Resistance; Nephrotoxic; Neutropenia; New York City; Outcome; Patients; Physicians; Polymyxin Resistance; Polymyxins; Population; Positioning Attribute; Prevalence; Prevention; Public Health; Reporting; Research; Research Personnel; Research Project Grants; Resistance; Risk; Risk Factors; Role; Scientist; Specimen; Surveillance Program; Swab; Testing; Time; Training; Writing; antimicrobial; antimicrobial drug; bactericide; base; carbapenem-resistant Enterobacteriaceae; carbapenemase; career; career development; chemotherapy; combat; design; experience; gastrointestinal; high risk; killings; lectures; meetings; molecular diagnostics; mortality; novel; novel strategies; oncology; pathogen; programs; rapid detection; screening; skills; skills training; success; symposium; targeted treatment; transmission process

DESCRIPTION (provided by applicant): The candidate's career goal is to become a physician-scientist and direct an academic research program that focuses on the prevention, diagnosis, and treatment of infections caused by multidrug-resistant (MDR) bacteria in immunocompromised patients. The candidate has laid the foundation for achieving this goal by obtaining a Master's Degree in Clinical and Translational Investigation, gaining clinical expertise in caring for this population, and conducting clinical epidemiologic studies of MDR bacterial infections. However, in order for the candidate to achieve his career goal, he needs to enhance and expand upon his clinical research skills and acquire laboratory skills in clinical microbiology, molecular diagnostics, and molecular epidemiology. A critical component of the candidate's training will be conducting the proposed research project on car- bapenem-resistant Enterobacteriaceae (CRE) in neutropenic patients with hematologic malignancies. CRE are MDR bacteria that are emerging worldwide and are classified by the CDC as an "urgent" antibiotic resistance threat. Neutropenic patients lack the ability to combat bacterial infections, and thus rely on immediate treatment with antibiotics that kill infecting bacteria. However, CRE are resistant to the antibiotic therapies that are recommended for fever in neutropenic patients, and it takes 2-4 days to identify CRE from cultures. The candidate found that 50-70% of neutropenic patients who develop bacteremia due to CRE died from these infections and there were long delays from the onset of infection until receipt of active antibiotics. Polymyxins are the only antibiotics that are consistently active against CRE and are appropriate for the treatment of bacteremia. However, they are highly nephrotoxic and widespread use may lead to polymyxin resistance. The primary goals of this research project are to develop a strategy to rapidly identify neutropenic patients who are at high risk of CRE bacteremia, and thus should receive immediate therapy with a polymyxin when they develop fever, and to characterize the molecular epidemiology of CRE in this population. We hypothesize that detection of asymptomatic colonization with CRE portends a high risk of subsequent CRE bacteremia. The specific aims of this project are: 1) Identify risk factors for CRE acquisition and CRE bacteremia in neutropenic patients; 2) Rapidly detect CRE colonization in neutropenic patients; and 3) Determine the genetic relatedness of CRE isolates in neutropenic patients. Fecal and inguinal/perianal swab specimens will be collected on admission and weekly from two groups of patients with prolonged neutropenia: those with acute leu- kemia who receive chemotherapy and those who receive a hematopoietic stem cell transplant. These patients will be followed to determine factors that lead to CRE acquisition and bacteremia. The candidate will also evaluate a novel molecular test to rapidly identify CRE colonization from swab specimens and genetically characterize colonizing and infecting CRE isolates. The study will be conducted in two large oncology centers that are uniquely located in an area that has the highest prevalence of CRE in the country. This project proposes a five-year, multi-faceted training plan under the mentorship of Drs. Thomas Walsh and Barry Kreiswirth. Dr. Walsh has extensive expertise and experience in conducting clinical and translational infectious diseases research in immunocompromised patients and Dr. Kreiswirth has expertise in molecular diagnostics and molecular characterization of MDR bacteria. These mentors and a team of collaborators will meet regularly with the candidate throughout this award to ensure success of his research project and guide his career development. Through "hands-on" training in Dr. Kreiswirth's laboratory, the candidate will not only learn to perform relevant molecular typing and diagnostic techniques, but he will gain an understanding of the strengths and limitations of each of these tests. This mentored training will be supplemented by coursework in molecular genetics, molecular diagnostic methods, and biostatistics, guidance from a scientific advisory board of experts, attending local and national conferences, giving lectures and writing reviews on MDR bacteria, and serving on a national committee for antibiotic susceptibility testing. The completion of the proposed project will lead to an understanding of the role of screening for gastrointestinal CRE colonization in identifying neutropenic patients at high risk for CRE bacteremia and the development of a test to rapidly identify CRE colonization. Furthermore, an understanding of the genetic relatedness of CRE isolates will inform the degree to which CRE are spread among oncology patients. After completion of this project, the candidate will be poised to submit a competitive R01 proposal of a multi-institutional trial of rapid detection of CRE colonization and targeted therapy, to determine whether this approach decreases mortality rates of neutropenic patients with CRE infections. The candidate's mentors and institution are committed to his success, both in completing this project, and ensuring that he achieves his career goal of becoming an independent clinical researcher in MDR bacterial infections.

描述(由申请人提供)： 应聘者的职业目标是成为一名内科科学家，并指导一个学术研究计划，重点是预防、诊断和治疗免疫受损患者的多药耐药(MDR)细菌感染。候选人通过获得临床和翻译调查硕士学位，获得护理这一人群的临床专业知识，以及进行MDR细菌感染的临床流行病学研究，为实现这一目标奠定了基础。然而，为了实现他的职业目标，他需要提高和扩大他的临床研究技能，并获得临床微生物学、分子诊断学和分子流行病学的实验室技能。 候选人培训的一个关键部分将是进行拟议的研究项目，即中性粒细胞减少的血液恶性肿瘤患者的卡培南耐药肠杆菌科(CRE)。CRE是一种在全球范围内出现的MDR细菌，CDC将其列为“紧急”的抗生素耐药性威胁。中性粒细胞减少的患者缺乏对抗细菌感染的能力，因此需要立即使用抗生素治疗，以杀死感染细菌。然而，Cre对推荐用于中性粒细胞减少症患者发烧的抗生素治疗具有抵抗力，需要2-4天才能从培养中鉴定出Cre。候选人发现，由于CRE而出现菌血症的中性粒细胞减少症患者中，有50%-70%死于这些感染，从感染开始到接受活性抗生素治疗有很长的延迟。 多粘菌素是唯一对Cre持续有效的抗生素，适用于菌血症的治疗。然而，它们具有高度的肾脏毒性，广泛使用可能会导致多粘菌素耐药。这项研究项目的主要目标是开发一种策略，以快速识别中性粒细胞减少症患者，这些患者是Cre菌血症的高危人群，因此当他们出现发烧时应该立即接受多粘菌素治疗，并描述Cre在这一人群中的分子流行病学特征。我们假设，检测到Cre无症状定植预示着随后Cre菌血症的高风险。该项目的具体目标是：1)确定收购CRE的风险因素，并 Cre在中性粒细胞减少患者中的菌血症；2)快速检测Cre在中性粒细胞减少患者中的定植；以及3)确定中性粒细胞减少患者中Cre分离株的遗传相关性。在入院时和每周收集两组长期中性粒细胞减少症患者的粪便和腹股沟/肛周拭子样本：接受化疗的急性白血病患者和接受造血干细胞移植的患者。这些患者将被跟踪以确定导致CRE获得性和菌血症的因素。候选人还将评估一种新的分子测试，以快速从拭子样本中识别Cre定植，并对定植和感染Cre分离株进行遗传学表征。这项研究将在两个大型肿瘤学中心进行，这两个中心位于全国CRE患病率最高的地区。 该项目提出了一个在Thomas Walsh博士和Barry Kreiswirth博士的指导下进行的为期五年、多方面的培训计划。沃尔什博士在免疫受损患者的临床和转化性传染病研究方面拥有丰富的专业知识和经验，Kreiswirth博士在多药耐药细菌的分子诊断和分子特征方面拥有专业知识。这些导师和合作者团队将在整个奖项期间定期与候选人会面，以确保他的研究项目成功并指导他的职业发展。通过在Kreiswirth博士的实验室进行的实践培训，应聘者不仅将学习执行相关的分子分型和诊断技术，而且他还将了解每种测试的优点和局限性。这一辅导性培训将补充分子遗传学、分子诊断方法和生物统计学的课程，由专家组成的科学咨询委员会提供指导，出席地方和国家会议，发表关于耐多药细菌的演讲和撰写评论，并在国家抗生素敏感性测试委员会任职。 拟议项目的完成将使人们了解胃肠道Cre定植筛查在确定中性粒细胞减少症高风险Cre菌血症患者方面的作用，并开发一种快速确定Cre定植的测试。此外，了解CRE分离株的遗传相关性将有助于了解CRE在肿瘤患者中的传播程度。在这个项目完成后，候选人将准备提交一份竞争性的R01提案，即快速检测CRE定植和靶向治疗的多机构试验，以确定这种方法是否降低了患有CRE感染的中性粒细胞减少患者的死亡率。候选人的导师和机构致力于他的成功，既完成了这个项目，又确保他实现了成为MDR细菌感染的独立临床研究人员的职业目标。