Sampling and Host–Strain Interactions Shape Detection of Staphylococcus aureus Transmission in Hospitals

BACKGROUND: In principle, whole-genome sequencing of Staphylococcus aureus in hospitals is most effective when used prospectively, but its practical limits are unclear. METHODS: We performed large-scale genomic surveillance across two interconnected hospitals, sequencing 4,779 S. aureus isolates from admission screening and clinical cultures. Integration of genomic and epidemiologic data identified 361 transmission events undetected by standard surveillance. RESULTS: Despite dense sampling, most events (90%) were detected only at readmission, indicating that transmission escapes recognition during the index hospitalization. Serial or discharge screening is likely required to capture transmission. Detection depended on sampling: clinical isolates alone were insufficient, and nearly all events required screening and repeated sampling. CONCLUSIONS: Because such approaches are unlikely to scale if applied universally, surveillance must be targeted. Transmission concentrated in methicillin-resistant strains, and it increased when healthcare exposure coincided with hospital-associated strain lineage. These findings help define the limits of prospective genomic surveillance and provide a framework for targeted detection.