By Samuel Nadler, MD, PhD
Clinical Instructor, University of Washington, Seattle
SYNOPSIS: There was no significant difference in the incidence of acute kidney injury in patients given piperacillin-tazobactam vs. cefepime for sepsis.
SOURCE: Qian ET, Casey JD, Wright A, et al. Cefepime vs piperacillin-tazobactam in adults hospitalized with acute infection: The ACORN randomized clinical trial. JAMA 2023;330:1557-1567.
Rapid identification of infection and sepsis leading to early empiric antibiotics saves lives. Both cefepime and piperacillin-tazobactam are broad-spectrum antibiotics commonly used for the treatment of sepsis. Each therapy has been associated with adverse effects in patients, including acute kidney injury (AKI) with piperacillin-tazobactam and delirium with cefepime. The Antibiotic Choice on Renal Outcomes (ACORN) study is a randomized, prospective study comparing the incidence of these adverse effects.
ACORN enrolled patients aged 18 years or older who presented with suspected infection in the emergency department or medical intensive care unit (ICU). Patients were randomized within 12 hours of presentation and were excluded if they had allergies to either antibiotic or had received either antibiotic with seven days of randomization. Participants received either cefepime at 2 g intravenous push over five minutes every eight hours or piperacillin-tazobactam at 3.375 g intravenously over four hours every eight hours after an initial bolus over 30 minutes.
The primary outcome was the highest stage of AKI or death within 14 days. Two prespecified secondary outcomes included: the composite of death, new renal replacement therapy (RRT), or persistent kidney dysfunction; and the number of days alive and free of delirium or coma. Overall, 2,511 patients were enrolled. Median age was 58 years and 54.2% presented with sepsis, most commonly from intra-abdominal and pulmonary sources. Most patients in each group also received vancomycin on the day of enrollment, 77.6% and 76.9% in the cefepime and piperacillin-tazobactam groups, respectively. There was a male predominance, and most patients identified as non-Hispanic white.
The primary outcome of the ACORN study was the highest stage of AKI as measured by Kidney Disease: Improving Global Outcomes (KDIGO) criteria based on creatinine level. There was no significant difference in the primary outcome between the cefepime and piperacillin-tazobactam groups (odds ratio [OR], 0.95; 95% confidence interval [CI], 0.8-1.13; P = 0.56).
Regarding secondary outcomes, there was no statistically significant difference in the composite outcome of death, RRT, or persistent kidney dysfunction between the cefepime and piperacillin-tazobactam groups (10.2% vs. 8.8%; 95% CI, -1.0 to 3.8%), but there were fewer days alive and free of delirium in the cefepime group compared with the piperacillin-tazobactam group (11.9 vs. 12.2 days; OR, 0.79; 95% CI, 0.64-0.95). Overall, 20.8% and 17.3% of patients who received cefepime or piperacillin-tazobactam, respectively, experienced coma or delirium based on Confusion Assessment Method for the ICU (CAM-ICU)/Richmond Agitation Sedation Scale (RASS) scoring.
COMMENTARY
Several recent studies raised the concern that the concomitant administration of vancomycin and piperacillin-tazobactam increased the risk for AKI. Buckley et al conducted a propensity scored-matched study that demonstrated higher incidence of AKI defined by serum creatinine in patients receiving vancomycin with piperacillin-tazobactam compared with cefepime or meropenem.1 Subsequently, Miano et al confirmed an elevation in serum creatinine with the combination of vancomycin and piperacillin-tazobactam, but noted other biomarkers, such as cystatin C, were similar, raising the question of whether piperacillin-tazobactam affects creatinine levels only without changes in glomerular filtration rate.2
The current study failed to demonstrate significant elevations in serum creatinine in patients receiving both piperacillin-tazobactam and vancomycin. More importantly, this study showed no difference in outcomes, such as persistent renal dysfunction or the need for hemodialysis. This provides evidence that the combination of piperacillin-tazobactam and vancomycin may not cause persistent renal dysfunction.
Like previous studies, ACORN redemonstrated a higher incidence of delirium in patients receiving cefepime as compared with piperacillin-tazobactam. On average, compared with piperacillin-tazobactam, cefepime led to 0.3 days more of delirium without effects on mortality, ICU length of stay, or hospital-free days. Cefepime crosses the blood-brain barrier and inhibits gamma-aminobutyric acid receptors. This is thought to be worsened by sepsis degrading the blood-brain barrier and is predisposed in patients with underlying renal dysfunction. Interestingly, effect modification analysis showed neither sepsis nor AKI at enrollment made the likelihood of delirium worse in this study.
Overall, the ACORN study provides reassurance that the combination of piperacillin-tazobactam and vancomycin may be used without causing long-term renal dysfunction. Cefepime clearly leads to a higher incidence of delirium but did not markedly affect outcomes such as mortality or length of stay. Decisions regarding preferential use of either cefepime or piperacillin-tazobactam for sepsis should be made based on other factors.
REFERENCES
- Buckley MS, Komerdelj IA, D’Alessio PA, et al. Vancomycin with concomitant piperacillin/tazobactam vs. cefepime or meropenem associated acute kidney injury in the critically ill: A multicenter propensity score-matched study. J Crit Care 2022;67:134-140.
- Miano TA, Hennessy S, Yang W, et al. Association of vancomycin plus piperacillin-tazobactam with early changes in creatinine versus cystatin C in critically ill adults: A prospective cohort study. Intensive Care Med 2022;48:1144-1155.
