Objective To assess trends in antibiotic use across a large cohort of extremely low birth-weight (<1000 g; ELBW) infants admitted to academic and community neonatal intensive care units (NICUs) across the USA over a 13-year period.

Design Repeated cross-sectional cohort study.

Setting Premier Health Database, a comprehensive administrative database of inpatient encounters from academic and community hospitals across the US.

Patients ELBW inborn infants admitted to NICUs from 1 January 2009 to 31 December 2021.

Interventions N/A

Main outcome measures Absolute and relative changes in (1) proportion of ELBW infants with antibiotic exposure and (2) days of therapy (DOT) per 1000 patient days, over time. Average annual differences were estimated using generalised linear regression with 95% CI. Disposition trends were also measured.

Results Among 36 701 infants admitted to 402 NICUs, the proportion exposed to antibiotics was essentially unchanged (89.9% in 2009 to 89.3% in 2021; absolute reduction of −0.6%); generalised linear regression estimated an annual absolute difference of −0.3% (95% CI (−0.6%) to (−0.07%); p=0.01). DOT per 1000 patient days decreased from 337 in 2009 to 210 in 2021, a 37.8% relative difference and annual relative difference of −4.3% ((−5.2%) to (−3.5%); p<0.001). Mortality was unchanged during the study period.

Conclusions We found a substantial reduction in antibiotic DOT despite no substantive change in the proportion of infants exposed to antibiotics. This suggests the success of stewardship efforts aimed at antibiotic duration and highlight the need for improved approaches to identifying ELBW infants at highest risk of infection.