BACKGROUND: Clinicians often start unnecessarily broad-spectrum empiric Gram-negative antibiotics out of the concern that delaying effective therapy could lead to a worse clinical outcome. This study examined the consequences of delayed initiation of broad-spectrum Gram-negative antibiotics. METHODS: In a retrospective cohort of adult inpatients from 928 US hospitals, we compared clinical outcomes after (1) empiric narrow-spectrum antibiotics escalated to broad-spectrum antibiotics (delayed broad-spectrum therapy, DBT) and (2) empiric broad-spectrum antibiotics continued for at least 5 days (early broad-spectrum therapy, EBT) using Win Ratios. DBT and EBT patients were matched on hospital, admitting diagnosis, and propensity scores incorporating 28 clinical variables. The outcome of interest was a ranked composite of mortality, readmission, and adverse drug events. RESULTS: Out of 746,880 inpatients, 82,276 (11%) received DBT and 664,604 (89.0%) received EBT. Among the 67,046 with DBT who were matched to 67,046 with EBT, mortality was 8.7% after DBT and 9.5% after EBT (p=0.022), readmission was 10.5% after DBT and 11.8% after EBT (p<
0.0001), and the rate of adverse drug events was 8.4% after DBT and 7.2% after EBT (p<
0.0001). Among matched patients, clinical outcomes were superior after DBT than after EBT (win-ratio 1.06
p <
0.0001). CONCLUSIONS: On average, among a large sample of adult inpatients who ultimately received broad-spectrum antibiotic therapy, delaying initiation of a broad-spectrum antibiotic was not associated with worse outcomes. Though broad-spectrum empiric therapy is undoubtedly sometimes warranted, this finding challenges the common belief that is it safer to err towards overly broad-spectrum empiric antibiotic therapy.