#17 Gut decontamination, the microbiome, and the risk of bloodstream infections during pediatric allogeneic hematopoietic cell transplantation
Authors: Severyn Chris 
Published: June 2022

Abstract

Background
Gut decontamination (GD) is the practice of using antibiotics to eradicate intestinal microbes before and during hematopoietic cell transplantation (HCT). Pre-clinical studies suggest that GD may be protective against acute graft-versus-host-disease (aGVHD), although no studies have focused on the potential impact of GD on non-aGVHD treatment related illnesses. Recently, we completed a randomized controlled trial of GD in pediatric patients. We report the results of an exploratory analysis of the impact of gut decontamination on the incidence of bloodstream infections (BSI) in pediatric HCT patients.

Method
We conducted a randomized phase 2 trial (ClinicalTrials.gov NCT02641236) of GD in pediatric patients undergoing allo-HCT with the primary objective to characterize the gut microbiota at 2-weeks post-HCT. Patients were randomized to receive the GD regimen (Arm A, n=10) (oral vancomycin-polymyxin B from day -5 through neutrophil engraftment) or not receive GD (no-GD; Arm B, n=10). Serial stool samples were collected from patients in both arms and subsequently underwent shotgun metagenomic sequencing to characterize the gut microbiome. In an exploratory, post-hoc analysis, stool metagenomic sequences were compared against the assembled sequence of a BSI isolate for any patient with a BSI in the first 100 days using a population average nucleotide identity (popANI) metric. Assembled BSI contigs and binned contigs from stool metagenomic sequences were profiled for antibiotic resistance genes (ARGs) with the Comprehensive Antibiotic Resistance Database (CARD) and the Resistance Gene Identifier (RGI) using default parameters.

Results
There was no statistical difference between the two arms in Shannon diversity of the gut microbiota at 2 weeks post-transplant for either genus (p=0.80) or species level (p=0.44). Six patients had a total of nine BSI episodes in the first 100 days post-HCT. We observed fewer BSI (1 vs. 5, Fig. 1A, p=0.048) in the GD vs no-GD arm, respectively. Using strain-specific analysis of BSI-causing bacteria and temporal association with the stool microbiome from patients who developed BSIs, we identified BSI-causing pathogens in 7 of 9 BSI episodes in the gut microbiome in the no-GD arm (Fig. 1B), including the genus Staphylococcus (Fig. 1C) in 2 patients. The 1 BSI in the GD arm was not derived from the gut (Fig. 1B). The number of unique colistin-, polymyxin B-, and vancomycin-ARGs were similar between the two arms (Fig. 1D).

Conclusion
Shannon diversity was similar in patients with or without GD, possibly due to the prevalent use of systemic antibiotics in the no-GD arm. Staphylococcus was found in the gut suggesting the need for an expanded definition of non-mucosal barrier injury (MBI) pathogens in HCT. All gut-localized BSIs were found in the non-GD arm suggesting that GD may protect against BSI in HCT patients by decreasing the prevalence or abundance of pathogens that can translocate across the mucosal barrier and subsequently cause gut-derived BSIs.