(1552) Association Between Sequence of Beta-Lactam and Vancomycin Administration and Mortality in Sepsis

Introduction: Timely antibiotic initiation is a cornerstone of sepsis management, but less attention has been paid to the sequence of antibiotic administration in patients prescribed vancomycin and β-lactam therapy and whether this affects outcomes.

Methods: We retrospectively analyzed adults admitted to 5 US hospitals between 2015-2022 with suspected sepsis (defined as a blood culture collected and acute organ dysfunction) who received vancomycin and a broad-spectrum β-lactam (ceftriaxone, ampicillin-sulbactam, cefepime, ceftazidime, piperacillin-tazobactam, meropenem, or imipenem) within 24h of arrival. We estimated the association between β-lactam first vs vancomycin first strategies and in-hospital mortality using inverse probability weighting (IPW) to adjust for demographics, encounter characteristics, comorbidities, initial vital signs, laboratory data, infection site, and time to first antibiotic.

Results: The cohort included 25,391 patients with suspected sepsis, of whom 21,449 (84.4%) received β-lactams first and 3,942 (15.6%) vancomycin first. Patient characteristics were generally similar between both groups, with the notable exception of more skin/musculoskeletal infections (20.0% vs 7.8%) and longer time to first (median 175 vs 133 min from arrival) and second antibiotics (median 339 vs 242 min) relative to ED arrival in the vancomycin first group. Overall, patients in the vancomycin first group received β-lactams a median of 3.5 hours later vs the β-lactam first group. On IPW analysis, the β-lactam first strategy was associated with lower mortality (adjusted OR 0.89, 95% CI 0.80-0.99). A similar trend was seen in patients with positive blood cultures (n=4,009 [16.1% of the cohort]; adjusted OR 0.80, 95% CI 0.62-1.04). Only 3.4% of the cohort (n=868) had positive MRSA clinical cultures; the β-lactam first strategy was associated with similar mortality in this subgroup (adjusted OR 0.91, 95% CI 0.55-1.51).

Conclusions: Among patients with suspected sepsis prescribed vancomycin and β-lactam therapy, β-lactam administration before vancomycin was associated with a 11% lower odds of in-hospital　mortality. These findings support prioritizing β-lactam therapy in most patients with sepsis but merit affirmation in randomized trials given the risk of residual confounding in observational analyses.