Does Order of Antibiotic Administration Matter?

Hello Everyone,

Today I’ll be discussing whether the order of antibiotic administration in patients requiring multiple antibiotics matters. In patients who are critically ill with concern for bloodstream infections, two types of antibiotics are given as standard of care: 1) anti-pseudomonal / broad-spectrum beta-lactam coverage (typically cefepime or piperacillin-tazobactam) and 2) anti-MRSA coverage (typically vancomycin). A 2021 study was conducted to determine whether the order of administration of these antibiotics matters- spoiler: it makes a difference.

Link to study: https://academic.oup.com/cid/article/75/1/98/6381106?login=false

Rationale:
-Early antibiotic administration in sepsis has been proven to reduce mortality. Mortality increases with each hourly delay in antibiotic administration.
-Early in the ED course, patients often have limited IV access. If multiple antibiotics are required, there is no established preferential order of administration.
-Vancomycin takes 1 hour to administer. Cefepime and pipericillin-tazobactam take 15-30 minutes each to administer. Given the hour-to-hour increase in mortality with antibiotic delays, these timings could be significant if one antibiotic is preferential.
-Theoretically, gram negative bacteria may cause more serious infection due to exotoxin release and profound inflammatory response. Broad-spectrum anti-pseudomonal antibiotics may provide better coverage early in infection course over anti-MRSA coverage, which covers for a more narrow spectrum of pathogens.

Clinical Question:
Does the sequence of antibiotic administration in patients with suspected blood stream infection have an effect on 48-hr and 7-day mortality?

Study Details:
-Multicenter retrospective observational study from July 2016-2020 in Baltimore, MD
-N = 3376 patients total
-Inclusion: Patients older than 13, all suspected blood stream infections
-Exclusion: Patients who did not receive at least one dose of antibiotic within the first 6 hours of treatment, overlapping antibiotics, previously on antibiotics, contaminant organisms in blood cultures, and non-bacterial organisms in blood cultures
-Groups: Beta lactam first (including cephalosporin, piperacillin-tazobactam, carbapenems, or monobactams) vs. Vancomycin first

Discussion/Conclusion
-Administration of a beta-lactam antibiotic prior to vancomycin is protective against 48-hr and 7-day mortality (reduced odds of 7-day mortality by 52%)
-Strengths: large sample size, generalizability
-Limitations: retrospective study, non-randomized
-Recommendations: further prospective studies can provide additional evidence

Next time when ordering antibiotics for a critically ill patient with concern for blood stream infection, based on this study, consider the sequence of administration as well (and communicate with nursing!). Prioritizing beta lactam administration may significantly impact mortality for our patients. It’s a simple step, but it can make a big difference.

Best,

Lekha Reddy