Clinical implementation of routine whole-genome sequencing for hospital infection control of multi-drug resistant pathogens

Background: Prospective whole-genome sequencing (WGS)-based surveillance may be the optimal approach to rapidly identify transmission of multi-drug resistant (MDR) bacteria in the healthcare setting. Materials/methods: We prospectively collected methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant enterococci (VRE), carbapenem-resistant Acinetobacter baumannii (CRAB), extended-spectrum beta-lactamase (ESBL-E) and carbapenemase-producing Enterobacterales (CPE) isolated from blood cultures, sterile sites or screening specimens across three large tertiary referral hospitals (2 adult, 1 paediatric) in Brisbane, Australia. WGS was used to determine in silico multi-locus sequence typing (MSLT) and resistance gene profiling via a bespoke genomic analysis pipeline. Putative transmission events were identified by comparison of core genome single nucleotide polymorphisms (SNPs). Relevant clinical meta-data were combined with genomic analyses via customised automation, collated into hospital-specific reports regularly distributed to infection control teams. Results: Over four years (April 2017 to July 2021) 2,660 isolates were sequenced. This included MDR gram-negative bacilli (n=293 CPE, n=1309 ESBL), MRSA (n=620) and VRE (n=433). A total of 379 clinical reports were issued. Core genome SNP data identified that 33% of isolates formed 76 distinct clusters. Of the 76 clusters, 43 were contained to the three target hospitals, suggesting ongoing transmission within the clinical environment. The remaining 33 clusters represented possible inter-hospital transmission events or strains circulating in the community. In one hospital, proven negligible transmission of non-multi-resistant MRSA enabled changes to infection control policy. Conclusions: Implementation of routine WGS for MDR pathogens in clinical laboratories is feasible and can enable targeted infection prevention and control interventions.