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

项目总结/摘要 血小板减少性（NTP）发热和血流感染（BSI）是患者常见的并发症 接受恶性血液病治疗，并与住院时间延长，护理费用增加， and mortality.化疗和中性粒细胞减少导致胃肠道粘膜破坏，导致 肠道细菌移位，导致NTP发热，在某些情况下还导致BSI。的研究 肠道微生物组的影响对于理解NTP发热的发病机制和风险至关重要。到 预防BSI和治疗NTP发热，患者暴露于预防性和经验性广谱 抗生素然而，抗生素预防的决定和经验性抗生素治疗的选择 通常基于供应商偏好。这是由于缺乏数据来告知抗生素治疗， 为个别患者选择特定药物。利用肠道微生物组预测NTP发热和BSI 可以允许个性化的抗生素决定，以确定哪些患者将从抗生素中获益最多 预防，同时限制NTP发热和BSI低风险人群的过量抗生素暴露。 候选人计划研究早期肠道微生物组的能力之前和之后的变化 化疗预测NTP发热（目的1.1）。这包括对肠道影响的调查 微生物组对肠道粘膜完整性和微生物诱导的炎症的测量。该提案还旨在 区分最终发生BSI的NTP发热患者与这些患者的微生物组特征 而不是（目标1.2）。这将通过纵向收集患者样本来实现，重点是 存在这些事件风险的广泛患者人群，特别是接受化疗和干细胞治疗的患者 用于治疗恶性血液病的移植。此外，候选人还将调查 在入院过程中肠道微生物组的特定抗生素暴露，以了解具体 抗生素的选择，包括预防，影响肠道微生物组（目的2）。 这项研究的结果可能使未来的临床医生能够利用患者的早期肠道微生物组特征 接受恶性血液病治疗以预测NTP发热和BSI。这些知识将有助于 使用个体患者因素决定抗生素预防，并将有助于指导特定 用于治疗NTP发热的抗生素，也可降低微生物组破坏的风险。其宗旨是 结合强大的培训计划，包括生物信息学的正式培训和教育，分子生物学 流行病学和生物统计学，微生物组数据的高级分析技能的发展，正式 进展基准，包括在研讨会和国际会议上介绍情况， 在专家指导和咨询团队的指导下进行研究。该提案将构成一个 为候选人继续发展成为独立调查员奠定坚实的基础 该研究项目的重点是预防恶性血液病患者的感染。

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.