Association Between the Sequence of β-Lactam and Vancomycin Administration and Mortality in Patients With Suspected Sepsis

Abstract

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. Conclusion 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.