Abstract Bloodstream infections (BSI) caused by bacteria translocating across injured mucosa are a significant cause of morbidity and mortality in the 25,000 patients undergoing stem cell transplantation (SCT) in the United States each year. BSI secondary to translocation of oral organisms through damaged oral mucosaoccurs in nearly 16% of SCT recipients in the first three weeks after SCT despite current routine oral care. There are currently no known strategies to prevent post-SCT BSI from the translocation of bacteria through an injured mucosa. There is a critical need to identify preventive strategies to reduce BSI, and the oral mucosa as a specific route of entry has not been evaluated. In the absence of such information, SCT patients will continue to develop BSI from translocation of bacteria from mucosal barrier injury. Our long-term goal is to develop and disseminate clinically relevant and easily adoptable strategies to prevent BSI and improve outcomes after SCT. The overall objective of this proposal is to identify a clinically effective strategy to prevent or reduce BSI secondary to bacterial translocation through injured mucosa in the mouth. The rationale for the study is based on our baseline and pilot intervention data. The central hypothesis is that dental xylitol use, in addition to current oral care practice, are effective at reducing BSI from oral organisms, and decreasing the incidence of gingivitis, oral plaque, and oral ulcerations after SCT. Apart from our preliminary data, we are well-positioned to carry out the proposed work as we have a multicenter collaborative team consisting of pediatric bone marrow transplant physicians, dentists, and infectious disease specialists with focus and expertise in microbiome analyses. The following specific aims are proposed: AIM 1: Determine the effectiveness of twice-daily xylitol-wipe application on reducing BSI from oral organisms through a randomized, multicenter, double-blind, placebo-controlled study in pediatric SCT recipients. AIM 2: Determine the effectiveness of twice-daily xylitol-wipe application in reducing dental plaque, mucositis, oral GVHD, and gingival inflammation. AIM 3: Evaluate the influence of twice-daily xylitol-wipe application on oral microbiome diversity and saliva levels of pathogenic microbial species. The innovation of this proposal lies in the simplicity and affordability of the intervention. Xylitol is commercially available, inexpensive ($0.15 per application), non-toxic, and can be rapidly adopted into practice. If our hypotheses are proven, xylitol application could reduce the morbidity and mortality associated with BSI and decrease healthcare-associated costs of an estimated $40,000 per infection. At the successful completion of the proposed research, our expectation is to have demonstrated a significant reduction of bacteremia from oral organisms (Aim 1); decreased oral dental plaque, gingivitis, and oral ulceration (Aim 2); and preserved oral microbiome...