The ACORN Trial: Battle of the Gorilla-Cillins (Cefepime vs Piperacillin-Tazobactam)

Background: Acutely ill adults presenting to the hospital with suspected infection commonly receive empiric, broad-spectrum antibiotics as part of their initial management including coverage of both MRSA and pseudomonas species.  MRSA coverage includes the use of vancomycin while anti-pseudomonal coverage is often with cefepime or piperacillin-tazobactam. Both cefepime and piperacillin-tazobactam have similar gram-negative bacterial coverage (efficacy) but have differences in potential adverse effects (safety). Cefepime has potential neurotoxicity (i.e. agitation, coma, etc…) while piperacillin-tazobactam has the potential for acute kidney injury (especially with concurrent use of vancomycin). Head to head comparisons of these two agents in patients with acute infection are lacking making selecting the ideal agent challenging for clinicians.

Paper: Qian ET et al. Cefepime vs Piperacillin-Tazobactam in Adults Hospitalized with Acute Infection: The ACORN Randomized Clinical Trial. JAMA 2023. PMID: 37837651

Clinical Question: Does the use of cefepime or piperacillin-tazobactam affect the risks of AKI or neurologic dysfunction in adults hospitalized with acute infection?

What They Did:

  • The Antibiotic Choice on Renal Outcomes (ACORN) Trial
  • Pragmatic, open-label, parallel-group, randomized, comparative safety clinical trial
  • Single center trial at Vanderbilt University Medical Center in the ED and ICU
  • Occurred between Nov 2021 to Oct 2022
  • Adult patients initiated on anti-pseudomonal antibiotics within 12 hours of presentation to the hospital in the ED or ICU were randomized to:
    • Cefepime: 2g IV over 5min q8hr
    • Piperacillin-tazobactam: 3.375g IV bolus over 30 min (Initial dose); 3.375g q8hr infused over 4hrs (Subsequent doses)


  • Primary: Highest stage of acute kidney injury or death by day 14
    • 0 = No new or worsening AKI
    • 1 = Creatinine 1.5 – 1.9x baseline or increase ≥0.3mg/dL
    • 2 = Cr 2.0 – 2.9x baseline
    • 3 = Cr ≥3.0x baseline, Cr ≥4.0mg/dL or new RRT
    • 4 = Death
  • Secondary:
    • Incidence of any major adverse kidney events at day 14
    • Number of days alive and free of delirium and coma within 14 days


  • Adults (≥18 years of age)
  • In the ED or medical ICU
  • Initiated on cefepime or piperacillin-tazobactam w
  • ithin 12 hours of presentation to the hospital


  • Allergy to cephalosporins or penicillins
  • Received more than 1 dose of anti-pseudomonal cephalosporin or penicillin within the previous 7 days (Patients who had received other anti-pseudomonal antibiotics were eligible)
  • Incarcerated
  • Treating clinician determined that 1 of the 2 drugs represented a better treatment option for that patient


  • 2511 patients included in primary analysis
    • 7% enrolled in ED
    • 2% receiving vancomycin at enrollment
    • Median time between presentation and enrollment = 1.2hrs
    • Most common sources of infection
      • Intra-abdominal: 26 vs 23%
      • Pulmonary: 21 vs 23%
      • Sepsis (As per Sepsis-3): 54 vs 54%
      • Mechanical Ventilation: 9 vs 7%
      • Vasopressors: 13 vs 13%
      • CKD: 20 vs 20%
    • Assigned antibiotic was received for median of 3d in each group
  • Highest stage of acute kidney injury or death by day 14
    • Cefepime:
      • Stage 3 AKI: 7.0%
      • Death: 7.6%
    • Piperacillin-Tazobactam:
      • Stage 3 AKI: 7.5%
      • Death: 6.0%
    • OR 0.95; 95% CI 0.80 to 1.13; p = 0.56
    • Results remained consistent in adjusted analyses and all prespecified sensitivity analyses
  • Incidence of major adverse kidney events at day 14
    • Cefepime: 10.2%
    • Piperacillin-Tazobactam: 8.8%
    • 95% CI 01.0 to 3.8%
  • Days alive and free of delirium at 14 days
    • Cefepime: 11.9d
    • Piperacillin-tazobactam: 12.2d
    • OR 0.79; 95% CI 0.65 to 0.95
    • Delirium or Coma Incidence
      • Cefepime 20.8%
      • Piperacillin-Tazobactam: 17.3%
      • 95% CI 0.3 to 6.6


  • Asks a clinically important question about two antibiotics commonly used as empiric treatment of septic adult patients
  • Good methodology
    • Large randomized clinical trial
    • Concealment of group assignment until enrollment to prevent selection bias
    • Enrollment occurring at a median of 1hr after hospital presentation to minimize exposure to antibiotics prior to enrollment
  • Overseen by an independent data and safety monitoring board
  • >95% of patients received the antibiotic for which they were randomized to
  • Groups fairly balanced at baseline
  • Just under 50% of enrolled patients already had some form of kidney injury at the time of enrollment. These patients are at the highest risk of worsening kidney injury and death
  • Included a large portion of patients receiving concurrent vancomycin at enrollment


  • Treating clinicians determined the duration of anti-pseudomonal antibiotic therapy and whether to administer additional antibiotics (i.e. vancomycin or metronidazole) which could alter the number of days an antibiotic could be received
  • Single center trial may limit generalizability at other institutions
  • Patients and clinicians were not blinded to group assignment (open-label) which could affect subjective clinical assessments (i.e. RASS and CAM-ICU)
  • 1in 5 patients in each group received at least 1 dose of unassigned antibiotic within the first 14 days which decreases the separation between groups and increases risk of facility to detect a true between-group difference in outcomes
  • Pre-illness creatinine was not available for all patients (≈99% had a pre-creatinine level available)
  • Patients only received a median of 3 days of treatment with antibiotics, which might minimize risk of AKI or neurologic dysfunction
  • Piperacillin-tazobactam was administered as an extended infusion (The results of this trial may not apply at institutions that use a different dosing strategy)
  • Unclear if outcome assessors were blinded
  • Non-consecutive enrollment
  • Clinicians could exclude patients from the trial if they felt one agent was superior to another for that particular patient. This biases the result towards the null.  This is particularly true with piperacillin-tazobactam where clinicians may have excluded patients from the trial who they felt were at risk for renal adverse events


  • Receipt of piperacillin-tazobactam did not appear to affect the risk of AKI at any of the measured time points, overall, nor among patients receiving vancomycin at enrollment
  • Receipt of cefepime did seem to cause increased delirium and coma compared to piperacillin-tazobactam. Neurotoxicity of cefepime can include coma, delirium, encephalopathy, and seizures

Author Conclusion: “Among hospitalized adults in this randomized clinical trial, treatment with piperacillin-tazobactam did not increase the incidence of acute kidney injury or death.  Treatment with cefepime resulted in more neurological dysfunction.”

Clinical Take Home Point: In this large single-center randomized clinical trial piperacillin-tazobactam did not increase the incidence of AKI and/or death compared to cefepime.  Cefepime, however, did result in more neurologic dysfunction when compared to piperacillin-tazobactam. Given similar efficacy of the two medications (bacterial coverage), and barring any contra-indications, it seems empiric treatment in septic patients with piperacillin-tazobactam is a better way to go.


  1. Qian ET et al. Cefepime vs Piperacillin-Tazobactam in Adults Hospitalized with Acute Infection: The ACORN Randomized Clinical Trial. JAMA 2023. PMID: 37837651

Post-Peer Reviewed By: Anand Swaminathan, MD (Twitter/X: @EMSwami)

Cite this article as: Salim Rezaie, "The ACORN Trial: Battle of the Gorilla-Cillins (Cefepime vs Piperacillin-Tazobactam)", REBEL EM blog, April 25, 2024. Available at:

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