Abstract Background Hospital infection control requires timely detection and identification of organisms, and their antimicrobial susceptibility. We describe a hybrid modeling approach to evaluate whole genome sequencing of pathogens for improving clinical decisions during a 2017 hospital outbreak of OXA-181 carbapenemase-producing Escherichia coli and the associated economic effects. Methods Combining agent-based and discrete-event paradigms, we built a hybrid simulation model to assess hospital ward dynamics, pathogen transmission and colonizations. The model was calibrated to exactly replicate the real-life outcomes of the outbreak at the ward-level. Seven scenarios were assessed including genome sequencing (early or late) and no sequencing (usual care). Model inputs included extent of microbiology and sequencing tests, patient-level data on length of stay, hospital ward movement, cost data and local clinical knowledge. The main outcomes were outbreak size and hospital costs. Model validation and sensitivity analyses were performed to address uncertainty around data inputs and calibration. Results An estimated 197 patients were colonized during the outbreak with 75 patients detected. The total outbreak cost was US$318,654 with 6.1% of total costs spent on sequencing. Without sequencing, the outbreak was estimated to result in 352 colonized patients costing US$531,109. Microbiology tests were the largest cost component across all scenarios. Conclusion A hybrid simulation approach using the advantages of both agent-based and discrete-event modeling successfully replicated a real-life bacterial hospital outbreak as a foundation for evaluating clinical outcomes and efficiency of outbreak management. Whole genome sequencing of a potentially serious pathogen appears effective in containing an outbreak and minimizing hospital costs.