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Protocol and statistical analysis plan for the Antibiotic Choice On ReNal outcomes (ACORN) randomised clinical trial
Edward Tang Qian1, Jonathan D Casey2, Adam Wright3
1Division of Allergy, Pulmonary, and Critical Care Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA edward.t.qian@vumc.org.
Introduction:
Antibiotics are time-critical in the management of sepsis. When infectious organisms are unknown, patients are treated with empiric antibiotics to include coverage for gram-negative organisms, such as antipseudomonal cephalosporins and penicillins. However, in observational studies, some antipseudomonal cephalosporins (eg, cefepime) are associated with neurologic dysfunction while the most common antipseudomonal penicillin (piperacillin-tazobactam) is associated with acute kidney injury (AKI). No randomised control trials have compared these regimens. This manuscript describes the protocol and analysis plan for a trial designed to compare the effects of antipseudomonal cephalosporins and antipseudomonal penicillins among acutely ill patients receiving empiric antibiotics.
Methods And Analysis:
The Antibiotic Choice On ReNal outcomes trial is a prospective, single-centre, non-blinded randomised trial being conducted at Vanderbilt University Medical Center. The trial will enrol 2500 acutely ill adults receiving gram-negative coverage for treatment of infection. Eligible patients are randomised 1:1 to receive cefepime or piperacillin-tazobactam on first order entry of a broad-spectrum antibiotic covering gram-negative organisms. The primary outcome is the highest stage of AKI and death occurring between enrolment and 14 days after enrolment. This will be compared between patients randomised to cefepime and randomised to piperacillin-tazobactam using an unadjusted proportional odds regression model. The secondary outcomes are major adverse kidney events through day 14 and number of days alive and free of delirium and coma in 14 days after enrolment. Enrolment began on 10 November 2021 and is expected to be completed in December 2022.
Ethics And Dissemination:
The trial was approved by the Vanderbilt University Medical Center institutional review board (IRB#210591) with a waiver of informed consent. Results will be submitted to a peer-reviewed journal and presented at scientific conferences.
Trial Registration Number:
NCT05094154.
Insights
This trial compares cefepime and piperacillin-tazobactam for sepsis, evaluating acute kidney injury (AKI) and death. Results will guide antibiotic choice in critically ill patients.
Area of Science:
- Critical care medicine
- Infectious diseases
- Nephrology
Background:
- Sepsis management requires timely antibiotics, often empiric gram-negative coverage.
- Observational studies link cephalosporins (e.g., cefepime) to neurologic issues and penicillins (e.g., piperacillin-tazobactam) to acute kidney injury (AKI).
- No randomized trials have directly compared these common empiric antibiotic regimens.
Purpose of the Study:
- To compare the safety and efficacy of cefepime versus piperacillin-tazobactam in acutely ill patients receiving empiric gram-negative antibiotic coverage.
- To assess the incidence of acute kidney injury (AKI) and death in patients treated with either cefepime or piperacillin-tazobactam.
- To evaluate secondary outcomes including major adverse kidney events and neurological/cognitive function.
Main Methods:
- Prospective, single-centre, non-blinded randomized trial (Antibiotic Choice On ReNal outcomes trial).
- Enrolling 2500 acutely ill adults randomized 1:1 to cefepime or piperacillin-tazobactam.
- Primary outcome: highest stage of AKI and death within 14 days post-enrolment, analyzed via proportional odds regression.
Main Results:
- Data collection ongoing; results not yet available as enrollment is expected to complete December 2022.
- Primary outcome analysis will compare AKI and mortality between the two antibiotic groups.
- Secondary outcomes include major adverse kidney events and delirium-free days.
Conclusions:
- The trial protocol is established to address a critical knowledge gap in sepsis antibiotic management.
- Findings will inform clinical decision-making regarding empiric antibiotic selection for gram-negative coverage in critically ill patients.
- This study aims to optimize patient outcomes by clarifying the risks and benefits of commonly used antibiotic regimens.
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