Importance Gram-negative bacteremia is a global health concern, and optimizing the transition from intravenous (IV) to oral antibiotics is a critical step in improving patient treatment and resource utilization.

Objective To assess the association of switching to oral antibiotics within 4 days after initial blood culture with 90-day all-cause mortality compared with prolonged IV antibiotic treatment for patients with uncomplicated gram-negative bacteremia.

Design, Setting, and Participants This cohort study conducted using the target trial emulation framework included observational data from adults with uncomplicated gram-negative bacteremia in 4 hospitals in Copenhagen, Denmark, from January 1, 2018, through December 31, 2021. The duration of follow-up was 90 days. Eligibility criteria included a blood culture positive for growth of gram-negative bacteria, clinical stability within 4 days of initial blood culture, an available susceptibility report on day 4, and initiation of appropriate empirical IV antibiotic treatment within 24 hours of blood culture.

Exposure Switching to oral antibiotics within 4 days after initial blood culture compared with continuing IV antibiotic treatment for at least 5 days after initial blood culture.

Main Outcomes and Measures The main outcome was 90-day all-cause mortality. Inverse probability of treatment weighting was applied to adjust for confounding. Intention-to-treat and per-protocol analyses were performed using pooled logistic regression to estimate absolute risk, risk difference (RD), and risk ratio (RR); 95% CIs were computed using bootstrapping.

Results A total of 914 individuals were included in the target trial emulation analysis (512 [56.0%] male; median age, 74.5 years [IQR, 63.3-83.2 years]); 433 (47.4%) transitioned early to oral antibiotic treatment, and 481 (52.6%) received prolonged IV treatment. Ninety-nine individuals (10.8%) died during follow-up. The proportion of individuals who died was higher in the group receiving prolonged IV treatment (69 [14.3%] vs 30 [6.9%]). In the intention-to-treat analysis, 90-day all-cause mortality risk was 9.1% (95% CI, 6.7%-11.6%) for the early-switch group and 11.7% (95% CI, 9.6%-13.8%) for the group receiving prolonged IV treatment; the RD was −2.5% (95% CI, −5.7% to 0.7%) and RR was 0.78 (95% CI, 0.60-1.10). In the per-protocol analysis, the RD was −0.1% (95% CI, −3.4% to 3.1%) and RR was 0.99 (95% CI, 0.70-1.40).

Conclusions and Relevance In this cohort study of uncomplicated gram-negative bacteremia, early transition to oral antibiotics within 4 days of initial blood culture was associated with 90-day all-cause mortality risk comparable to that of continuing IV antibiotic treatment and may be an effective alternative to prolonged IV treatment.