Multi-drug-resistant organisms (MDROs) are adept at transmitting in clinical environments, negatively impacting patients by prolonging admission times and increasing mortality. Identifying MDRO transmission is essential for targeted infection prevention and control (IPC) measures. Genomics is superior to routine microbiology methods, providing high-resolution data to detect these transmission events. To investigate the impact that genomics has on IPC, we implemented prospective routine MDRO sequencing at five hospital networks in Victoria, Australia. Four target MDROs were included: vanA VRE, MRSA, ESBL Escherichia coli (ESBL-Ec) and ESBL Klebsiella pneumoniae (ESBL-Kp). Putative transmission events were detected in near-real-time using a reference-free bioinformatic pipeline. Genomic results were provided to IPC staff via a secure online platform (AusTrakka) and fortnightly reports. Over the 16-month study period a total of 1,945 eligible samples were collected from 1,841 patients. Genomics identified putative transmission for all four MDROS with 18.5% of ESBL-Ec, 25.3% of ESBL-Kp, 31.4% of MRSA and 81.5% of VRE being highly similar to another isolate, indicating possible transmission, which was then investigated by IPC staff. Median turn-around-time from sample collection to result availability was 18-days. Genomics identified 23 isolate clusters involving more than 5 patients and 5 with more than 10 patients. Genomics aided IPC staff identify 236 additional epidemiological links, resulting in implementation and redirection of IPC measures such as environmental cleaning and staff education. Prospective MDRO sequencing and interactive reporting empowered IPC teams with high-resolution data to direct interventions for maximum effect, resulting in improved patient safety.