Stool-based genomic surveillance identifies post-engraftment expansion of multidrug-resistant pathogens in haematopoietic stem cell transplant patients in India

Background Patients undergoing haematopoietic stem cell transplantation (HSCT) are highly susceptible to bloodstream infections (BSIs) caused by antimicrobial resistant (AMR) pathogens, yet the temporal dynamics and clinical relevance of intestinal AMR reservoirs remain poorly defined, particularly in high-burden settings. Methods We conducted prospective longitudinal surveillance of 81 HSCT recipients in India using targeted enrichment-based stool metagenomics, coupled with whole genome sequencing of bloodstream isolates and strain-level tracking. Results Across 252 samples, we identified a restructuring of the gut-associated resistome, characterised by depletion during conditioning and a marked post-engraftment expansion of non-efflux AMR determinants, including plasmid-borne carbapenemase and ESBL genes ( bla NDM, bla OXA). This expansion defined a previously underappreciated window of vulnerability during early immune recovery. Over 50% of patients harboured multidrug-resistant organisms, and carriage of bla NDM was associated with increased odds of subsequent infection. Strain-resolved analyses provided genomic evidence linking gut colonisation to bloodstream infection in a subset of cases, demonstrating the feasibility of non-invasive prediction of invasive disease. Patients with AMR-BSIs experienced high mortality (> 40%). Conclusions These findings establish that dynamic changes in the gut resistome following HSCT can identify periods of heightened infection risk and provide a foundation for predictive, genomics-guided surveillance and antimicrobial stewardship strategies in high-burden settings.