Association Between Delayed Broad-Spectrum Gram-negative Antibiotics and Clinical Outcomes: How Much Does Getting It Right With Empiric Antibiotics Matter?

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 as post-empiric therapy (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 = .022), readmission was 10.5% after DBT and 11.8% after EBT (P < .0001), and the rate of adverse drug events was 8.4% after DBT and 7.2% after EBT (P < .0001). Among matched patients, clinical outcomes were superior after DBT compared with EBT (win-ratio 1.06; P < .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. Although 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.