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

项目摘要/摘要

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.