ACORN: Cefepime vs Piperacillin-Tazobactam in Hospitalized Adults (2023)

“Among hospitalized adults in this randomized clinical trial, cefepime, compared with piperacillin-tazobactam, did not improve the primary outcome of the highest stage of acute kidney injury or death by day 14.”

— The ACORN Trial Investigators

1. Publication Details

  • Trial Title: Cefepime vs Piperacillin-Tazobactam in Hospitalized Adults With Suspected Infection: The ACORN Randomized Clinical Trial.
  • Citation: Qian ET, Rhee C, D’Silva KM, et al; for the ACORN Trial Investigators. Cefepime vs Piperacillin-Tazobactam in Hospitalized Adults With Suspected Infection: The ACORN Randomized Clinical Trial. JAMA. 2023;330(15):1446-1455. doi:10.1001/jama.2023.19582.
  • Published: October 17, 2023, in the Journal of the American Medical Association (JAMA).
  • Author: Edward T. Qian, M.D., M.Sc.
  • Funding: National Institutes of Health (NIH).

2. Keywords

Antibiotics, Cefepime, Piperacillin-Tazobactam, Acute Kidney Injury (AKI), Neurological Dysfunction, Sepsis, Randomized Controlled Trial.

3. The Clinical Question

In hospitalized adults with suspected infection (Population), does treatment with cefepime (Intervention) compared to piperacillin-tazobactam (Comparison) result in a lower incidence of acute kidney injury or death at 14 days (Outcome)?

4. Background and Rationale

  • Existing Knowledge: Cefepime and piperacillin-tazobactam are two of the most commonly used broad-spectrum antibiotics in hospitals. Observational studies had suggested that piperacillin-tazobactam was associated with a higher risk of acute kidney injury (AKI), while cefepime was associated with a higher risk of neurological dysfunction.
  • Knowledge Gap: There was no large-scale, pragmatic randomized trial to directly compare the safety of these two common antibiotics and determine which one was associated with a lower risk of adverse outcomes.
  • Proposed Hypothesis: The authors hypothesized that the use of cefepime would result in a lower incidence of AKI and death compared to piperacillin-tazobactam.

5. Study Design and Methods

  • Design: A large, pragmatic, multicenter, randomized, open-label, crossover trial.
  • Setting: A single large academic medical center in the United States (Vanderbilt University Medical Center).
  • Trial Period: Enrollment from October 2019 to October 2021.
  • Population:
    • Inclusion Criteria: Adult patients (≥18 years) for whom a clinician ordered at least one dose of cefepime or piperacillin-tazobactam in the emergency department or medical ICU.
    • Exclusion Criteria: Known allergies to either drug, pregnancy, incarceration, or receiving renal replacement therapy.
  • Intervention: Cefepime Group: Patients received cefepime as the primary antibiotic.
  • Control: Piperacillin-Tazobactam Group: Patients received piperacillin-tazobactam as the primary antibiotic.
  • Management Common to Both Groups: The choice of antibiotic was determined by the randomization of the clinical unit, but clinicians could override the assigned drug if clinically indicated. All other aspects of care were at the discretion of the clinical team.

6. Key Results

  • Enrollment and Baseline: 2511 patients were randomized (1214 to cefepime and 1297 to piperacillin-tazobactam). The groups were well-matched at baseline.
  • Trial Status: The trial was completed as planned.
  • Primary Outcome: There was no significant difference in the primary outcome of the highest stage of AKI or death by day 14. The event occurred in 34.6% of patients in the cefepime group and 34.1% in the piperacillin-tazobactam group.
  • Secondary Outcomes: Patients in the cefepime group had significantly fewer days alive and free of delirium and coma within 14 days compared to the piperacillin-tazobactam group (a median of 11.9 days vs 12.2 days), suggesting more neurological dysfunction with cefepime.
  • Adverse Events: The incidence of major adverse kidney events at 30 days (MAKE-30) was similar between the groups.

7. Medical Statistics

  • Analysis Principle: An intention-to-treat analysis was performed.
  • Statistical Tests Used: The primary outcome was analyzed using a multivariable logistic regression model.
  • Key Statistic(s) Reported:
    • Primary Outcome (AKI or Death): Adjusted Odds Ratio (OR) 1.04 (95% CI, 0.88 to 1.23; P=0.64).
  • Interpretation of Key Statistic(s):
    • Odds Ratio (OR):
      • Formula: Conceptually, OR = (Odds of event in Intervention Group) / (Odds of event in Control Group).
      • Calculation: The paper reports the adjusted OR as 1.04.
      • Clinical Meaning: An OR of 1.04 means that the odds of experiencing the primary outcome (AKI or death) were 4% higher in the cefepime group, a difference that is not statistically significant.
    • Confidence Interval (CI):
      • Formula: Conceptually, CI = (Point Estimate) ± (Margin of Error).
      • Calculation: The reported 95% CI was 0.88 to 1.23.
      • Clinical Meaning: Since the 95% CI broadly crosses the line of no effect (1.0), ranging from a 12% benefit to a 23% harm, it confirms that the result is not statistically significant and is consistent with chance.
    • P-value:
      • Calculation: The reported p-value was 0.64.
      • Clinical Meaning: The p-value of 0.64 is very high, far above the 0.05 threshold, confirming the lack of a statistically significant difference between the two antibiotics for the primary outcome.

8. Strengths of the Study

  • Pragmatic Design: The trial’s design, embedded within the electronic health record, allowed for the rapid randomization of a large, real-world population, increasing its generalizability.
  • Large Sample Size: The study was large enough to provide a precise estimate of the effect on the primary outcome.
  • Important Clinical Question: The trial addressed a very common and important clinical decision for which high-quality evidence was lacking.

9. Limitations and Weaknesses

  • Single-Center Study: Although large, the trial was conducted at a single academic medical center, which may limit generalizability to other types of hospitals.
  • Open-Label Design: Clinicians were aware of the treatment allocation, which could have introduced bias.
  • Other: The primary outcome was a composite of death and a laboratory-based endpoint (AKI), which can sometimes be difficult to interpret.

10. Conclusion of the Authors

“Among hospitalized adults with suspected infection, treatment with cefepime compared with piperacillin-tazobactam did not significantly improve the primary outcome of incidence of AKI or death.”

11. To Summarize

  • Impact on Current Practice: This was a major “negative” trial that provided strong evidence to refute the common belief that piperacillin-tazobactam causes more kidney injury than cefepime. It also provided randomized trial evidence to support the concern that cefepime is associated with more neurological dysfunction.
  • Specific Recommendations:
    • Patient Selection: For hospitalized adults requiring broad-spectrum antibiotic coverage with either cefepime or piperacillin-tazobactam.
    • Actionable Intervention: The choice between these two antibiotics should not be based on a concern for differential effects on kidney function. In patients at high risk for delirium or neurological complications, piperacillin-tazobactam may be a safer choice.
  • What This Trial Does NOT Mean: This trial does not mean that one antibiotic is superior to the other for all patients. The choice should still be guided by local antibiograms, the suspected source of infection, and patient-specific factors.

12. Context and Related Studies

  • Building on Previous Evidence: The ACORN trial was designed to provide a definitive, randomized answer to the safety concerns raised by numerous prior observational studies about both piperacillin-tazobactam (nephrotoxicity) and cefepime (neurotoxicity).
  • Influence on Subsequent Research: This trial provides a high-quality, pragmatic framework for conducting future comparative effectiveness trials of other common hospital interventions.

13. Unresolved Questions & Future Directions

  • Unresolved Questions: What is the precise mechanism by which cefepime is associated with worse neurological outcomes? Are there specific patient populations who are more susceptible to this effect?
  • Future Directions: Future research may focus on understanding the mechanisms of antibiotic-associated neurotoxicity and on developing strategies to mitigate this risk.

14. External Links

15. Framework for Critical Appraisal

  • Clinical Question: The question was highly relevant, addressing a very common clinical decision with significant safety implications.
  • Methods: The pragmatic, randomized, crossover design was innovative and highly efficient, allowing for a large trial to be conducted with minimal research infrastructure.
  • Results: The trial had a clear neutral result for its primary outcome, refuting the hypothesis that cefepime was safer for the kidneys. The finding of worse neurological outcomes with cefepime was a key secondary result.
  • Conclusions and Applicability: The authors’ conclusion is a direct and fair interpretation of the data. The results are highly applicable and should influence the choice of antibiotic for hospitalized adults, particularly those at risk for delirium.

16. Disclaimer and Contact

This summary is provided by the Academic Committee of ESBICM (ACE) to facilitate the understanding of this study; readers are advised to refer to the original trial document for a deeper understanding. If you find any information incorrect, or missing, or it needs an update or have a request for a specific critical care trial summary, kindly write to us at academics[at]esbicm.org.

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