Cefepime vs Piperacillin-Tazobactam in Adults Hospitalized With Acute Infection: The ACORN Randomized Clinical Trial

Abstract

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.

Trial registration: ClinicalTrials.gov Identifier: NCT05094154.

Figure 1.. Flow of Participants Through the ACORN Trial

ACORN indicates Antibiotic Choice on Renal Outcomes. ^aA tool in the electronic health record screened all patients presenting to the study hospital for the presence of inclusion criteria (≥18 years of age; being treated in participating emergency department or intensive care unit; <12 hours since presentation to the hospital; and order initiated for antipseudomonal cephalosporin or penicillin). ^bIncluded clinician preference, metronidazole shortage, and no reason recorded.

Figure 2.. Receipt of Antibiotics by Group

Patients may have received both cefepime and piperacillin-tazobactam on a study day when switching from one antibiotic to the other; 32 patients (1.3%) received both antibiotics on more than 1 consecutive study day.

Figure 3.. Effect Modification of the Primary and Secondary Outcomes

The results of tests for interaction appear in eTables 14, 21, and 22 in Supplement 2. ^aThe primary outcome was the highest stage or death by day 14 (score range, 0 [alive without acute kidney injury] to 4 [dead]). An odds ratio (OR) <1.0 indicates a better outcome with cefepime. ^bDefined as a composite of death, receipt of new kidney replacement therapy, or final creatinine level that was at least 2 times the baseline level. An OR <1.0 indicates a better outcome with cefepime. ^cThe number of days from randomization to day 14. An OR >1.0 indicates a better outcome with cefepime. ^dClinician uncertain about the suspected source of infection at enrollment. ^ePresence or absence at enrollment.