Beyond Febrile Neutropenia: Risks Associated with Antibiotic Choice in Children with Leukemia that Undergo Transplant
Background: A subset of children with high-risk leukemia require stem cell transplant in order to cure their disease. Due to the profound immunosuppression associated with this procedure, children undergoing transplant receive a substantial number of antibiotics. However, the implications of such extensive antibiotic exposures are not well understood.
Project Goal: This study proposes to evaluate the adverse events associated with antibiotics through complementary aims that specifically strive to understand if there is risk variability across classes of antibiotics that are otherwise considered interchangeable with regards to their anti-infectious properties. This proposal focuses on three common post-transplant complications that lead to significant morbidity: (1) graft-versus-host disease, the major immunologic complication of transplant, (2) clostridium difficile infection, an infection associated with considerable mortality in immunocompromised hosts; and (3) acute kidney injury, an organ toxicity that limits the delivery of other necessary post-transplant medications. Identification of differential risk with regards to one or more of these outcomes will be immediately actionable, factoring into decision-making about antibiotic choice by clinicians at the bedside. Through investigating the adverse outcomes associated with this common exposure, we can immediately influence clinical practice to promote rational and individualized antibiotic selection in children with leukemia, and limit the toxicity that is associated with cure.
Project Update 2022: With the funding provided by this grant mechanism, we performed a large, multicenter study that convincingly demonstrates that patients who receive carbapenem antibiotics, particularly early in the transplant course, are more likely to develop severe graft versus host disease. These data suggest that gastrointestinal tract microbiota, and antibiotic-induced microbiome disruption that occurs over the course of SCT, may predict or even contribute to the pathogenesis of these immune-related outcomes, including graft-versus-host disease. Future directions will focus on better understanding the microbiome disruption that underlies the association identified in this project. These data add to the literature and immediately impact patient care by suggesting that specific classes of antibiotics may have detrimental off-target effects and that clinicians should be thoughtful about their use. In addition, the funding provided by this grant established two unique and powerful datasets that will facilitate future research in pediatric stem cell transplantation. The first is a merger of data from the Pediatric Health Information Service and the Center for International Blood and Marrow Transplantation Research (CIBMTR). This dataset includes high quality data on demographics, transplant characteristics and outcomes, as well as daily level resource utilization data and will be used in several upcoming planned studies in collaboration with CIBMTR. The second dataset leverages a procedure for automated data extraction from the electronic medical record to supplement the CIBMTR data back to centers interface with increasing granular information related to medication usage, vital signs, and laboratory values, again broadening the scope of analyses that can be performed with CIBMTR data alone.
