Effect of adequacy of empirical antibiotic therapy for hospital-acquired bloodstream infections on ICU patient prognosis: a causal inference approach using data from the Eurobact2 study

Objectives: Hospital-acquired bloodstream infections (HA-BSI) in the intensive care unit (ICU) are common life-threatening events. We wanted to investigate the association between early adequate antibiotic therapy and 28-day mortality in ICU patients surviving for at least 1 day after the onset of HA-BSI. Methods: We used individual data from a prospective, observational, multicenter, intercontinental cohort study (Eurobact2). We included patients followed for ≥1 day for whom time-to-appropriate treatment was available. We used an adjusted frailty-Cox proportional hazard model to assess the effect of time-to-treatment-adequacy on 28-day mortality. Infection- and patient-related variables identified as confounders by the Directed Acyclic Graph were used for adjustment. Adequate therapy within 24 hours was used for primary analysis. Secondary analyses were performed for adequate therapy within 48 and 72 hours and for identified patient subgroups. Results: Among the 2,418 patients included in 330 centers worldwide, 28-day mortality was 32.8% (n=402/1226) in patients who were adequately treated within 24 hours after HA-BSI onset and 40% (n=477/1192) in inadequately treated patients (p<0.01). Adequacy within 24 hours was more common in young, immunosuppressed patients, and with HA-BSI due to Gram-negative pathogens. Antimicrobial adequacy was significantly associated with 28-day survival (aHR 0.83, 95% CI 0.72-0.96, p=0.01). The estimated population attributable fraction (PAF) of 28-day mortality of inadequate therapy was 9.15% (95% CI 1.9%-16.2%). Conclusions: In patients with HA-BSI admitted in ICU, the PAF of 28-day mortality of inadequate therapy within 24 hours was 9.15%. This estimate should be used when hypothesizing the possible benefit of any intervention aiming at reducing the time-to-appropriate antimicrobial therapy in HA-BSI.