Background: Genomic epidemiology which combines whole genome sequencing (WGS) of bacterial isolates with patient movement data, promises improved detection, prevention, and management of infection transmission, enhancing patient safety and reducing healthcare costs. However, evidence on its cost-effectiveness and clinical utility remains limited, as initial studies were restricted to selected pathogens and based on extrapolated assumptions from partial WGS data. Methods: We conducted a 28-month observational study at Rigshospitalet, a 1 200-bed tertiary hospital in Copenhagen. The study involved collecting patient movement and WGS data for clinical isolates of 19 bacterial species, regardless of their site of isolation, or antibiotic susceptibility profile. This included sequencing of 18 940 clinical isolates from 7 760 patients. Findings: We found that 27.1 % of culture-positive hospitalized patients harboured a pathogen ge-netically related to another patients isolate. 69 % had an epidemiological link, indicating transmis-sion between patients, with Enterococcus faecium being the most prevalent. Notably, there were 2.2 times more transmissions of antibiotic-susceptible than resistant isolates. We estimated that prevention based on genomic epidemiology could potentially generate net savings of 1.25 million Euros annually and avoid more than 750 disability adjusted life years (DALYs). Interpretation: Our holistic, proactive genomic epidemiology approach reveals previously unex-plored transmission landscapes. We discovered that transmission is widespread, varies significantly between species, and is not limited to resistant isolates. Our results highlight the potential for WGS-informed infection control, greater savings by including susceptible isolates, and an incremen-tal cost-effectiveness ratio (ICER) classification by pathogen species.

Martin Lucas Joergensen, Theiss Bendixen and Roshkan Srinathan were employed by Nordic Healthcare Group, Copenhagen, a private company during the study period.

This work was funded by Department of Clinical Microbiology, Rigshospitalet, Denmark, Beta.Health (ID:1188), Den Frie Forskningsfond (DFF) (3101-00040B), and the Novo Nordisk Foundation (NNF Laureate Grant 18OC0033946). The funders had no role in designing and conducting the study, analysis, and interpretation the data, or the writing, review, and approval of the manuscript.

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Approval from the Ethical Committee was not necessary. Approval from the Center for Sundhed was sufficient and has been obtained according to Danish law (journaldata.center-forsundhed@ regionh.dk) The extraction of data from registries was approved by the local data protection agency (Journal-nr.: R-21015888) and registered in Pactius (P-2020-743).

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