Patients in the emergency department and intensive care unit who are suspected of having infections are treated with antibiotics. Most patients received either cefepime or piperacillin-tazobactam, antibiotics targeting resistant gram-negative bacteria. The two antibiotics are believed to have different risks. Cefepime may cause “neurotoxicity” (symptoms like agitation or coma). Piperacillin-tazobactam may cause kidney injury. To learn whether cefepime or piperacillin-tazobactam affects the chances of experiencing neurotoxicity or kidney injury, we conducted a research study called the ACORN study. A total of 1,172 patients receiving antibiotics for resistant gram-negative bacteria in the Vanderbilt Emergency Department or Intensive Care Unit participated in the study. The results of the study suggested that cefepime does cause neurotoxicity but piperacillin- tazobactam does not cause kidney injury and may be a safer alternative for patients being treated in the emergency department or intensive care unit.

Importance

Cefepime and piperacillin-tazobactam are commonly administered to hospitalized adults for empirical treatment of infection. Although piperacillin-tazobactam has been hypothesized to cause acute kidney injury and cefepime has been hypothesized to cause neurological dysfunction, their comparative safety has not been evaluated in a randomized clinical trial.

Objective

To determine whether the choice between cefepime and piperacillin- tazobactam affects the risks of acute kidney injury or neurological dysfunction. Design, setting, and participants: The Antibiotic Choice on Renal Outcomes (ACORN) randomized clinical trial compared cefepime vs piperacillin-tazobactam in adults for whom a clinician initiated an order for antipseudomonal antibiotics within 12 hours of presentation to the hospital in the emergency department or medical intensive care unit at an academic medical center in the US between November 10, 2021, and October 7, 2022. The final date of follow-up was November 4, 2022.

Interventions

Patients were randomized in a 1:1 ratio to cefepime or piperacillin- tazobactam.

Main outcomes and measures

The primary outcome was the highest stage of acute kidney injury or death by day 14, measured on a 5-level ordinal scale ranging from no acute kidney injury to death. The 2 secondary outcomes were the incidence of major adverse kidney events at day 14 and the number of days alive and free of delirium and
coma within 14 days.

Results

There were 2511 patients included in the primary analysis (median age, 58 years [IQR, 43-69 years]; 42.7% were female; 16.3% were Non-Hispanic Black; 5.4% were Hispanic; 94.7% were enrolled in the emergency department; and 77.2% were receiving vancomycin at enrollment). The highest stage of acute kidney injury or death was not significantly different between the cefepime group and the piperacillin-tazobactam group; there were 85 patients (n = 1214; 7.0%) in the cefepime group with stage 3 acute kidney injury and 92 (7.6%) who died vs 97 patients (n = 1297; 7.5%) in the piperacillin- tazobactam group with stage 3 acute kidney injury and 78 (6.0%) who died (odds ratio, 0.95 [95% CI, 0.80 to 1.13], P = .56). The incidence of major adverse kidney events at day 14 did not differ between groups (124 patients [10.2%] in the cefepime group vs 114 patients [8.8%] in the piperacillin-tazobactam group; absolute difference, 1.4% [95% CI, -1.0% to 3.8%]). Patients in the cefepime group experienced fewer days alive and free of delirium and coma within 14 days (mean [SD], 11.9 [4.6] days vs 12.2 [4.3] days in the piperacillin-tazobactam group; odds ratio, 0.79 [95% CI, 0.65 to 0.95]).

Conclusions and relevance

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.

ClinicalTrials.gov Identifier: NCT05094154.
Manuscript Title: Cefepime vs Piperacillin-Tazobactam in Adults Hospitalized With
Acute Infection: The ACORN Randomized Clinical Trial.
Journal: JAMA
PMID: 37837651