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Sepsis: The Beta-lactam goes first. Now, which one is that?

Reviewed by S. Shaefer Spires, MD, Duke Center for Antimicrobial Stewardship and Infection Prevention, Durham, NC

I will spare you the statistics on how mortal bloodstream infections (BSI) can be and how earlier administration of antibiotics reduces that mortality, especially in severe sepsis. You would not be reading this brief if you did not already know that.  However, there are still controversies over many aspects of their care, such as what are the optimal diagnostic criteria (quick SOFA or SIRS) and do early antimicrobials improve outcomes in less than severe sepsis presentations.  Nonetheless, this study published by Amoah et al. seems to provide some clarity on the next logical question, does the sequence of antibiotics matter when using a combination of vancomycin and a beta-lactam for those with BSIs?

The authors performed a multicenter, observational study including 3,376 patients ≥ 13 years with BSIs to evaluate the sequence of antibiotic administration with 7-day mortality.  They used inverse probability of treatment weighting based on propensity scores using a robust set of variables collected from the EHR. They found administration of the beta-lactam agent prior to vancomycin protected against 7-day mortality (adjusted OR, 0.48 [95% CI, 0.24-0.83]).  Even in their sensitivity analysis restricted to those patients with a BSI from MRSA, there was no harm seen with initial beta-lactam, nor was there a benefit with initial vancomycin.

When you consider the predominance of Gram-negative organisms as the underlying cause of sepsis, there is a logical argument for an earlier administration of the beta-lactam. In addition, when you take in to account the time it takes to administer a beta-lactam (5 minutes for a push or 30 minutes for IV piggyback) vs vancomycin IV (>60 minutes) then you might also see why there is no harm even in those patients with MRSA BSIs.

The patients in this study were sick, with over 41% of them admitted to the ICU within 24 hours, and they still found a reduction in mortality of 52% due to simply administering the beta-lactam agent prior to vancomycin. There are some generalizability questions. For example, would the same benefit be seen in other types of infections causing sepsis or whether your region’s BSI antibiogram would allow for appropriate selection of a beta-lactam?  Nonetheless, the small to no downsides, the reported mortality benefit, and the biological plausibility of giving a beta-lactam first make this a simple but clinically important intervention to consider.

But the next steps include implementation and education. Many of us trying to implement this simple intervention in our hospitals found that when the combination of iv vancomycin plus a beta-lactam is ordered, traditionally the iv vancomycin is administered first.  When asked why, vancomycin was typically thought of as the most powerful or most important drug.  Thus, understanding current practices and the impetus behind them is important as you consider rolling out this clinical intervention system wide.


Joe Amoah et al., “Administration of a β-Lactam Prior to Vancomycin as the First Dose of Antibiotic Therapy Improves Survival in Patients with Bloodstream Infections,” Clinical Infectious Diseases, no. ciab865 (October 4, 2021).

James B Cutrell and James M Sanders, “‘The Early Beta-Lactam Catches the Germ’: Empiric Antimicrobial Sequence in Bloodstream Infections,” Clinical Infectious Diseases 75, no. 1 (July 1, 2022): 105–6.

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