Impact of early gut microbiome features on risk of neutropenic fever and bloodstream infection in hematologic malignancy

早期肠道微生物组特征对血液恶性肿瘤中中性粒细胞减少性发热和血流感染风险的影响

• 批准号: 10335245
• 负责人: Matthew Ziegler
• 金额: $ 19.49万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-02-13 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10335245
• 关键词: Accounting; Address; Admission activity; Adult; Advanced Development; Adverse event; Advisory Committees; Affect; Anaerobic Bacteria; Antibiotic Prophylaxis; Antibiotic Therapy; Antibiotics; Benchmarking; Bioinformatics; Biological Markers; Biometry; Characteristics; Child; Clinical; Collection; Data; Development; Development Plans; Event; Exposure to; Fever; Foundations; Future; Goals; Gut Mucosa; Health; Hematologic Neoplasms; Hematology; Impairment; Infection prevention; Inflammation; International; Investigation; Knowledge; Length of Stay; Levaquin; Life; Link; Longitudinal cohort study; Measurement; Measures; Mentored Patient-Oriented Research Career Development Award; Mentors; Methods; Microbe; Molecular Epidemiology; Monobactams; Morbidity - disease rate; Mucositis; Mucous Membrane; Neutropenia; Neutropenic Fever; Oncology; Outcome; Pathogenesis; Pathway interactions; Patients; Population; Populations at Risk; Prevention; Preventive measure; Prophylactic treatment; Prospective cohort study; Proteobacteria; Provider; Public Health; Research; Research Personnel; Research Support; Resistance; Resources; Risk; Risk Marker; Role; Sampling; Sepsis; Series; Serum; Stem cell transplant; Taxon; Time; Toll-like receptors; Training; Training and Education; Work; advanced analytics; bacterial community; bacteriome; base; care costs; career; career development; chemotherapy; cohort; colonization resistance; commensal bacteria; experience; gastrointestinal; gut bacteria; gut dysbiosis; gut microbiome; high risk; high risk population; individual patient; infection risk; microbiome; microbiome research; mortality; outcome prediction; patient oriented research; patient population; patient subsets; preference; prevent; programs; prophylactic; skills; statistics; symposium; therapy design; transplantation therapy; treatment duration; treatment strategy

PROJECT SUMMARY/ ABSTRACT Both neutropenic (NTP) fever and bloodstream infections (BSIs) are common complications in patients receiving treatment for hematologic malignancy and are associated with increased length of stay, cost of care, and mortality. Chemotherapy and neutropenia result in the disruption of the gastrointestinal mucosa, leading to translocation of commensal bacteria from the gut, causing NTP fever, and in some cases BSI. The study of the impact of the gut microbiome is critical to understanding the pathogenesis of, and risk for, NTP fever. To prevent BSIs and treat NTP fever, patients are exposed to both prophylactic and empiric broad-spectrum antibiotics. However, the decision for antibiotic prophylaxis and the choice of therapy with empiric antibiotics are typically based on provider preference. This is due to a lack of data to inform antibiotic treatment and selection of specific agents for individual patients. Utilizing the gut microbiome to predict NTP fever and BSI may allow for personalized antibiotic decisions, to determine which patients will benefit most from antibiotic prophylaxis while limiting excess antibiotic exposures in those at low risk of NTP fever and BSI. The candidate plans to study the ability of the early gut microbiome before and change after chemotherapy to predict NTP fever (Aim 1.1). This includes an investigation of the impact of the gut microbiome on measures of gut mucosal integrity and microbe-induced inflammation. This proposal also aims to discriminate microbiome features of patients with NTP fever who ultimately develop BSI from those patients who do not (Aim 1.2). This will be accomplished through longitudinal collection of patient samples, focusing on a broad patient population at risk of these events, specifically patients admitted for chemotherapy and stem cell transplantation for treatment of hematologic malignancy. In addition, the candidate will investigate the impact of specific antibiotic exposures on the gut microbiome over the course of admission to understand how specific antibiotic choices, including prophylaxis, impact the gut microbiome (Aim 2). The results of this study may allow future clinicians to utilize early gut microbiome features in patients receiving treatment for hematologic malignancy to predict NTP fever and BSI. This knowledge will help inform the decision for antibiotic prophylaxis using individual patient factors and will help guide selection of specific antibiotics used for the treatment of NTP fever that also reduce the risk of microbiome disruption. The aims are combined with a robust training plan that includes formal training and education in bioinformatics, molecular epidemiology, and biostatistics, the development of advanced analytic skills for microbiome data, formal benchmarks for progress including presentation at seminars and international conferences, and extensive research experience under the guidance of an expert mentoring and advisory team. This proposal will form a strong foundation for the candidate's continued development toward a career as an independent investigator with a program of research focused on the prevention of infection in patients with hematologic malignancy.

项目摘要/摘要 中性粒细胞减少症（NTP）热和血液感染（BSI）都是患者常见并发症 接受血液系统恶性肿瘤治疗，并与住院时间增加，护理成本相关， 和死亡率。化学疗法和中性粒细胞减少会导致胃肠道粘膜中断，导致 来自肠道的共生细菌的易位，导致NTP热，在某些情况下BSI。研究 肠道微生物组的影响对于理解NTP发烧的发病机理和风险至关重要。到 预防BSI和治疗NTP热，患者暴露于预防和经验性广谱 抗生素。但是，对预防抗生素的决定和经验性抗生素的治疗选择 通常基于提供商的偏好。这是由于缺乏为抗生素治疗提供信息的数据而引起的 为个别患者选择特定药物。利用肠道微生物组预测NTP热和BSI 可能允许个性化的抗生素决定，以确定哪些患者将从抗生素中受益最大 预防性在限制NTP发烧和BSI风险低的患者中限制过量的抗生素暴露。 候选人计划在之前研究早期肠道微生物组的能力，然后更改 预测NTP热的化学疗法（AIM 1.1）。这包括对肠道影响的调查 微生物组对肠粘膜完整性和微生物诱导的炎症的测量值。该提议也旨在 区分NTP热患者的微生物组特征，这些特征最终从这些患者中发展为BSI 谁没有（目标1.2）。这将通过纵向的患者样本收集来实现，重点是 有这些事件风险的广泛患者人群，特别是接受化学疗法和干细胞的患者 用于治疗血液系统恶性肿瘤的移植。此外，候选人将调查 在入院过程中，肠道微生物组的特定抗生素暴露，以了解特定 抗生素选择，包括预防，会影响肠道微生物组（AIM 2）。 这项研究的结果可能使未来的临床医生能够在患者中使用早期的肠道微生物组特征 接受血液系统恶性肿瘤的治疗方法，以预测NTP热和BSI。这些知识将有助于告知 使用单个患者因素做出预防抗生素的决定，并将有助于指导特定的选择 用于治疗NTP发烧的抗生素也降低了微生物组破坏的风险。目的是 结合强大的培训计划，包括生物信息学的正式培训和教育，分子 流行病学和生物统计学，开发微生物组数据的先进分析技能，正式 进度的基准，包括在研讨会和国际会议上演讲，并广泛 在专家指导和咨询团队的指导下进行的研究经验。该建议将形成 候选人持续发展的强大基础，成为独立调查员的职业 通过一项研究计划，重点是预防血液系统恶性肿瘤患者的感染。