Comparative Effectiveness of Long-Acting Lipoglycopeptides vs Standard-of-Care Antibiotics in Serious Bacterial Infections

Importance: Serious bacterial infections such as bacteremia, endocarditis, osteomyelitis, and septic arthritis typically require prolonged intravenous antibiotics. Long-acting lipoglycopeptides (laLGPs), such as dalbavancin and oritavancin, offer extended treatment intervals for gram-positive infections that may benefit populations with barriers to traditional treatment, including persons who use drugs (PWUD individuals). Objective: To assess the effectiveness of laLGPs in managing serious bacterial infections in both PWUD and non-PWUD populations compared with standard-of-care (SOC) antibiotics. Design, Setting, and Participants: This comparative effectiveness study using a target trial emulation framework included data extracted from the US Cerner Real World Data platform. Individuals hospitalized and discharged for serious bacterial infections between October 1, 2015, and October 1, 2022, were included in the analysis. Data were analyzed from July 7, 2023, to February 28, 2025. Intervention: Receipt of an laLGP (dalbavancin or oritavancin) vs SOC antibiotics. Main Outcome and Measures: The primary outcome measure was a composite of readmission, emergency department visit, and inpatient death or discharge to hospice within 90 days post discharge from the index admission. Analyses were stratified by PWUD and non-PWUD status. Clone censor weighting was used to emulate a per-protocol analysis. Hazard ratios (HR) of time to the composite event and 95% CIs were calculated using bootstrapping. Results: Among 42 067 included individuals, median age was 61 (IQR, 47-73) years, 24 704 were male (58.7%), and 5047 (12.0%) were classified as PWUD. laLGPs were prescribed in 825 individuals (2.0%). There was no statistically significant difference in the composite outcome between the laLGP and SOC groups in both the PWUD (HR, 1.01; 95% CI, 0.88-1.13) and non-PWUD (HR, 0.93; 95% CI, 0.86-1.00) participants. Conclusions and Relevance: In this study of laLGPs vs SOC, findings suggested that laLGPs were effective as step-down treatment of serious gram-positive bacterial infections, offering comparable outcomes to those of SOC antibiotics in PWUD and non-PWUD individuals. Clinicians may consider laLGPs as alternative step-down options to SOC antibiotics for the treatment of serious gram-positive bacterial infections.