Impact of anti-anaerobic antibiotics on clinical outcomes and the microbiome in hospitalized Veterans

Candidate: This is a Career Development proposal for Dr. Rishi Chanderraj, an Infectious Diseases physician with a Master's degree in Clinical Research Design and Biostatistics and expertise in integrating microbiome and clinical data for translational research. Specific aims: This proposal aims to test the hypothesis that depletion of gut anaerobes with anti-anaerobic

antibiotics leads to translocation of Enterobacteriaceae, inflammation, nosocomial infection, and death among hospitalized Veterans with two complementary studies. Aim 1 will determine if anti-anaerobic antibiotics may cause increased 30-day mortality. Dr. Chanderraj will leverage the resources of the Corporate Data

Warehouse (CDW) to conduct a retrospective cohort study of 87,321 patients treated with anti-anaerobic piperacillin-tazobactam or anaerobe-sparing cefepime. A natural experiment caused by concurrent drug shortages of piperacillin-tazobactam and cefepime will allow for estimating causal effects with a difference-in-

differences analysis. Aim 2 will investigate the microbiologic and immunologic consequences of gut anaerobe depletion on hospitalized Veterans. Dr. Chanderraj will conduct a prospective cohort study of 30 piperacillin- tazobactam-treated patients and 30 cefepime-treated patients, characterizing microbiota in the gut, skin, and

upper respiratory tract on hospital days 0, 2, and 4. He will collect time-matched markers of gut permeability (intestinal fatty-acid binding protein and lipopolysaccharide-binding protein) and inflammation (IL-6 and CRP). Regression modeling will determine whether anaerobe depletion precedes gut Enterobacteriaceae domination,

intestinal permeability, and systemic inflammation. Impact: The proposal aligns with key VA research priorities of the Offices of Research and Development and Clinical Science Research and Development in that it 1) increases the real-world impact of VA research, as the study's results will impact current antibiotic practices and guide clinicians in reducing avoidable harm related to

antibiotic use, 2) puts VA data to work for Veterans by leveraging the vast resources of the Corporate Data Warehouse, and 3) improves treatment optimization by characterizing clinical, microbiologic, and physiologic changes associated with antibiotic use, ultimately guiding clinicians to avoid harm related to antibiotic use.

Career Development: With directed mentorship and didactic coursework, Dr. Chanderraj will complete his training aims of 1) gaining mentored experience in the conduct of prospective, hands-on, patient-oriented translational research, 2) learning new methods of interrogating host-microbiome interactions, 3) developing

new skills in big data analytics, and 4) developing expertise in methods of causal inference. Completion of this proposal will equip Dr. Chanderraj with the necessary skills and preliminary data to conduct Merit studies that use big data analytics to investigate the impact of "common shocks" on antibiotic use and outcomes, as well as

multi-center prospective studies to evaluate the impact of antibiotics on the microbiome and host physiology. It will allow him to become an independent VA investigator with skills across the translational spectrum, molecularly interrogating antibiotic treatment's microbiologic and physiologic consequences and translating

findings into improved care for Veterans. Environment: Dr. Chanderraj's mentorship team consists of international leaders in microbiome science, translational research, big-data analytics, and advanced causal inference methods. Dr. Chanderraj will perform this research at the Ann Arbor VA and will benefit from the extensive research infrastructure of the VA Center

for Clinical Management Research, as well as the rich scientific environment of The University of Michigan and the Michigan Microbiome Project, further bolstering his research capabilities.