Association Between the Sequence of β-lactam and Vancomycin Administration and Mortality in Patients with Suspected Sepsis.

Background: Timely antibiotic initiation is critical to sepsis management, but there are limited data on the impact of giving β-lactams first vs vancomycin first amongst patients prescribed both agents.

Methods: We retrospectively analyzed all adults admitted to 5 US hospitals from 2015-2022 with suspected sepsis (blood culture collected, antibiotics administered, and organ dysfunction) treated with vancomycin and a broad-spectrum β-lactam within 24h of arrival. We estimated associations between β-lactam vs vancomycin first strategies and in-hospital mortality using inverse probability weighting (IPW) to adjust for potential confounders.

Results: Amongst 25,391 patients with suspected sepsis, 21,449 (84.4%) received β-lactams first and 3,942 (15.6%) received vancomycin first. Compared to the β-lactam first group, patients administered vancomycin first tended to be less severely ill, had more skin/musculoskeletal infections (20.0% vs 7.8%), and received β-lactams a median of 3.5h later relative to ED arrival. On IPW analysis, the β-lactam first strategy was associated with lower mortality (aOR 0.89, 95% CI 0.80-0.99). Point estimates were directionally similar but non-significant in a sensitivity analysis using propensity score-matching rather than IPW (aOR 0.94, 95% CI 0.82-1.07) and in subgroups of patients with positive blood cultures, MRSA cultures, and those administered antipseudomonal β-lactams.

Conclusions: Among patients with suspected sepsis prescribed vancomycin and β-lactam therapy, β-lactam administration before vancomycin was associated with a modest reduction 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.