Rapid Identification of Neutropenic Patients at High Risk of CRE Bacteremia

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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.