Background: Patients with sepsis are routinely treated with empiric broad-spectrum antibiotics while awaiting source identification, as recommended by the surviving sepsis campaign.2 Vancomycin, in combination with either piperacillin-tazobactam or cefepime, is commonly used for empiric treatment in these cases. Literature comparing the two regimens has largely focused on the adverse effects of each medication, rather than on overall efficacy. In 2021, Buckley et. al. found no difference in mortality in critical care patients treated with vancomycin and piperacillin-

tazobactam compared to vancomycin and cefepime or meropenem.3 The same year, Ross et. al. compared cefepime to piperacillin-tazobactam in a cohort of 250 patients with septic shock and found a signal toward higher mortality in those receiving cefepime.4 The 2023 ACORN Trial (covered here on REBEL EM) randomized 2,511 patients requiring antipseudomonal coverage to receive either cefepime or piperacillin-tazobactam. Investigators found no statistically significant difference in the incidence of acute kidney injury (AKI) or death at 14 days, however, those who received cefepime had higher rates of neurologic dysfunction.5 Interestingly, while the effects of piperacillin-tazobactam and cefepime on rates of organ dysfunction have been explored, there are far fewer studies evaluating all-cause mortality as a primary endpoint, which Chanderraj et. al. address in the article discussed below.

Article: Chanderraj R, Admon AJ, He Y, et al. Mortality of Patients With Sepsis Administered Piperacillin-Tazobactam vs Cefepime. JAMA Intern Med. 2024;184(7):769-777. PMID: 38739397

Clinical Question: In adult patients with suspected sepsis treated empirically, does the administration of piperacillin-tazobactam compared to cefepime affect 90-day mortality?

What They Did:

Investigators performed a retrospective cohort study in the Emergency Department at the University of Michigan between July 1, 2014 through December 31, 2018.
They analyzed the electronic health records of patients presenting to the ED who met modified Center for Disease Control and Prevention (CDC) sepsis surveillance criteria and received empiric treatment with either vancomycin/piperacillin-tazobactam or vancomycin/cefepime.
When determining inclusion and exclusion criteria, only the first 24 hours were considered to better emulate a randomized controlled trial.
Evaluated data 90-day mortality and organ-failure free days, comparing unadjusted data to that adjusted for patient demographics and comorbidities.
Ran an instrumental variable analysis, using the piperacillin-tazobactam shortage to simulate a randomized control trial in a retrospective manner
Performed a subgroup analysis, comparing patients that received anaerobic coverage (i.e. Piperacillin-tazobactam or Cefepime and Metronidazole) and those that did not (i.e. Cefepime only)
In response to the publication of the ACORN trial, they repeated their analysis, only looking at the first 14 days

Population:

Inclusion Criteria:

Age ≥18, presenting to the ED
Met the modified Centers for Disease Control and Prevention sepsis surveillance criteria
Blood samples drawn for culture on arrival
Evidence of acute organ dysfunction within the first 24 hours
Antibiotics given for at least 1 day

Exclusion Criteria:

Patients with an indication for anti-anaerobic therapy
- Necrotizing infections, intra-abdominal infections, head and neck infections
CNS infections
Transfers from outside hospitals
Missing data around the source of infection or antibiotic administration

Intervention: Administration of cefepime in combination with vancomycin in the setting of a piperacillin-tazobactam shortage.

Comparator: Empiric therapy with piperacillin-tazobactam and vancomycin for treatment of suspected sepsis.

Outcomes:

Primary outcome: All-cause mortality within 90 days of ED presentation

Secondary outcomes: Organ-failure-free days at 28 days, that is how many days in the first 28 after arriving in the ED not requiring mechanical ventilation, vasopressors, or dialysis.

Results:

Patient Selection:

28,627 Screening admissions (July 2014 – December 2018)
- 9,794 Excluded
  - 1,297 Outside hospital transfers
  - 8,497 Repeat admissions
18,833 First admission via emergency department
- 8,958 Excluded
  - 6,491 Vancomycin not administered
  - 2,467 Neither piperacillin-tazobactam nor cefepime administered
9,875 Administration of vancomycin and either piperacillin-tazobactam or cefepime
- 2,306 Excluded
  - 1,583 Intra-abdominal infection
  - 438 Necrotizing infection
  - 24 Head and neck infection
  - 22 Central nervous system infection
  - 239 Multiple excluded d...