Precision characterization of antimicrobial resistance gene dynamics in bloodstream infection risk after hematopoietic stem cell transplantation

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PROJECT SUMMARY Candidate: Tessa M. Andermann, MD, MPH is a fellowship-trained Infectious Diseases specialist who has been involved in patient-oriented research throughout her medical training. As an Assistant Professor of Medicine at UNC, she has specific interests in translational research and is invested in precisely tracking the development and dissemination of antibiotic resistant organisms in immunocompromised patients in order to prevent untreatable infections. The specific training objectives for the proposed award include gaining expertise in: 1) applying next-generation sequencing technologies to characterize antibiotic resistance genes in gut flora, and 2) designing clinical studies to prevent infections with multidrug-resistant organisms in patients with cancer. Her expert team of mentors include Drs. Jonathan Juliano, MD, and Anthony Fodor, PhD. Environment: As one of the nation's premier research institutions, the University of North Carolina provides an optimal environment for the proposed research. The Division of Infectious Diseases is home to a number of extremely accomplished basic, clinical, and translational research scientists; within the Division, there is active work investigating antimicrobial resistance that will provide Dr. Andermann ample guidance and leadership. The UNC research community's collegial nature is demonstrated in the seamless incorporation of experts in cancer, the gut microbiome, and microbial genomics with whom Tessa has developed the necessary relationships to accomplish the proposed research. UNC, in kind, has demonstrated its support of Tessa's research career by providing the salary support that allowed her to develop this current proposal. Research: Patients undergoing hematopoietic stem cell transplantation (HCT) whose gut flora are colonized with antibiotic-resistant bacteria have a higher frequency of bloodstream infections (BSI), and an increased mortality. Despite the significant burden of antimicrobial resistance (AMR) in this population, knowledge of how antibiotic-resistant bacteria develop and disseminate in patients is limited. Prior studies in HCT recipients have not yet investigated the acquisition and transfer of AMR genes within and between gut bacteria that may contribute to infection. The overarching goal of the proposed research is to assess the impact of gut AMR gene dynamics on the risk of systemic infections using novel sequencing technologies. The specific aims are to determine: 1) the timing of AMR gene acquisition relative to transplant, 2) the extent of AMR gene transfer and dissemination between bacteria in the gut, and 3) the relationship between AMR gene burden and BSI risk after HCT. To accomplish this, next-generation sequencing will be performed on stool samples from 70 HCT recipients at two different institutions. We hypothesize that the increased antibiotic resistance gene burden in the gut resistome after transplant is due primarily to expansion of pre-transplant AMR genes and is associated with an increased risk of BSI after HCT. We expect that this research will yield a greater understanding of how antimicrobial resistance develops in gut bacteria that can be used to prevent infections in patients with cancer.