Dose Order Matter? Which Antibiotic to Give First for a Bloodstream Infection

Background

Early antibiotics are recommended for treatment of many infections, including patients with sepsis or septic shock [1]. Critically-ill patients and those with a suspected infection at risk for severe illness are generally administered two (or more) empiric antibiotics in the emergency department (ED) which cover a wide range of potential pathogens. A typical approach includes utilizing a broad-spectrum antibiotic (frequently a beta-lactam such as cefepime or piperacillin-tazobactam) plus an anti-MRSA agent (typically vancomycin).

Early in the patient’s hospital stay they may have limited IV access, so the question often arises as to which antibiotic to give first, the broad-spectrum antimicrobial or the anti-MRSA agent. Additionally, though the overall risk of an allergic reaction is relatively low with most antimicrobials, when multiple agents are given simultaneously it can be difficult to ascertain which one may have caused a reaction and lead to incorrectly documented allergies, so it can be important to consider if the initial doses should be administered separately. However, there isn’t strong data to guide practice in terms of giving the initial antibiotics concurrently vs consecutively, from an allergy perspective. To further complicate the issue, patients may also develop delayed reactions so a strong causal relationship cannot always be determined. In practice, there are times (increasingly so with rising ED patient volumes) when we give antibiotics one at a time simply for logistical reasons. So that begs the question, which antibiotic should be given first?

Evidence

In patients with sepsis or septic shock, early antibiotics significantly decrease mortality [1]. This relationship is strongest for patients with septic shock, where the odds of in-hospital mortality was increased by 1.04-1.16 for each hour antibiotics were delayed [2-4]. Notably, broad spectrum antibiotics are deemed such as they cover both gram positive and gram negative pathogens, therefore the addition of an anti-MRSA agent contributes a relatively smaller amount of coverage and is primarily targeted at resistant gram-positive bacteria. Additionally, gram-negative pathogens tend to cause a higher degree of illness and mortality, so it would be reasonable to give the broad-spectrum antibiotic first [5-7]. As both cefepime and piperacillin-tazobactam are recommended to be infused over 30 minutes (though this can vary based on institutional policies) and vancomycin is typically infused over 1 hour for each gram, if vancomycin is administered first, patients may wait hours to receive a broad spectrum agent.

A recent study now supports this practice. This is an observational trial which evaluated 3,376 patients with a blood stream infection, 2,685 patients received a beta-lactam first and 691 patients received vancomycin first [8]. They found that patients who received a beta-lactam prior to vancomycin had significantly improved 48-hour and 7-day mortality. Further review of this article may be found on the JournalFeed blog post.

Bonus tip: Having antibiotics stocked on the unit reduces time to administration [9].

Bottom Line

• Antibiotic delays lead to increased mortality, especially in patients with septic shock.
• For patients with a suspected bloodstream infection, administering the broad-spectrum antibiotic first, instead of the anti-MRSA agent, has the potential to reduce mortality at 48 hours and 7 days. This should be the general approach for treatment of all infections when two or more antimicrobial agents are indicated.

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References

1. Evans L, Rhodes A, Alhazzani W, et al. Surviving sepsis campaign: international guidelines for management of sepsis and septic shock 2021. Crit Care Med. 2021;49(11):e1063-e1143. PMID: 34605781. doi: 10.1097/CCM.0000000000005337.
2. Seymour CW, Gesten F, Prescott HC, et al. Time to treatment and mortality during mandated emergency care for sepsis. N Engl J Med. 2017;376(23):2235-2244. PMID: 28528569. doi: 10.1056/NEJMoa1703058.
3. Liu VX, Fielding-Singh V, Greene JD, et al. The timing of early antibiotics and hospital mortality in sepsis. Am J Respir Crit Care Med. 2017;196(7):856-863. PMID: 28345952. doi: 10.1164/rccm.201609-1848OC.
4. Peltan ID, Brown SM, Bledsoe JR, et al. Ed door-to-antibiotic time and long-term mortality in sepsis. Chest. 2019;155(5):938-946. PMID: 30779916. doi: 10.1016/j.chest.2019.02.008.
5. Abe R, Oda S, Sadahiro T, et al. Gram-negative bacteremia induces greater magnitude of inflammatory response than Gram-positive bacteremia. Crit Care. 2010;14(2):R27. PMID: 20202204. doi: 10.1186/cc8898.
6. Alexandraki I, Palacio C. Gram-negative versus Gram-positive bacteremia: what is more alarmin(G)? Crit Care. 2010;14(3):161. PMID: 20550728. doi: 10.1186/cc9013. 
7. Morgan MP, Szakmany T, Power SG, et al. Sepsis patients with first and second-hit infections show different outcomes depending on the causative organism. Front Microbiol. 2016;7:207. PMID: 26955367. doi: 10.3389/fmicb.2016.00207.
8. Amoah J, Klein EY, Chiotos K, Cosgrove SE, Tamma PD, CDC Prevention Epicenters Program. Administration of a β-lactam prior to vancomycin as the first dose of antibiotic therapy improves survival in patients with bloodstream infections. Clin Infect Dis. Published online October 4, 2021:ciab865. PMID: 34606585. doi: 10.1093/cid/ciab865.
9. Lo A, Zhu JN, Richman M, Joo J, Chan P. Effect of adding piperacillin-tazobactam to automated dispensing cabinets on promptness of first-dose antibiotics in hospitalized patients. Am J Health Syst Pharm. 2014;71(19):1663-1667. PMID: 25225451. doi: 10.2146/ajhp130694.

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