Reference: JAMA. 2023 Oct 24;330(16):1557-1567
Practice Point: Piperacillin-tazobactam seems slightly less dangerous than cefepime for hospitalized patients needing pseudomonas coverage.
EBM Pearl: Randomized trials inherently have less systematic bias than observational studies.
The recently published ACORN (Antibiotic Choice on Renal Outcomes) trial in JAMA is generating buzz among hospitalists heading into respiratory season. This randomized trial compared the safety of piperacillin-tazobactam (pip-tazo) to cefepime in acutely ill adults. It found similar incidences of AKI but an increased risk of neurotoxicity with cefepime. Given that both cefepime and pip-tazo are thought to provide equal anti-pseudomonal coverage, the choice of either empiric antibiotic often comes down to the risks of adverse effects. Cefepime and other antipseudomonal cephalosporins have generally been preferred to pip-tazo due to their lower observed incidence of AKI, especially when compared to pip-tazo combined with vancomycin. This is complicated, however, by concerns about potential neurotoxicity with cefepime and up until now, only informed by observational data.
Researchers took 2,634 adults presenting to the ED or medical ICU who required empiric anti-pseudomonal coverage and randomized them 1:1 to either cefepime 2g IV Q8H or pip-tazo 3.375g IV Q8H. Treatment teams determined treatment duration and need for additional antibiotics. The primary outcome was the highest stage of AKI according to the KDIGO (Kidney Disease: Improving Global Outcomes) creatinine-based criteria or death at 2 weeks. Secondary outcomes included the occurrence of major adverse kidney events and number of days alive and without delirium or coma at 2 weeks. At enrollment, 54% had sepsis, attributable to pulmonary or intra-abdominal sources in a majority of cases, and about 77% of participants in both groups were receiving IV vancomycin. The median duration of antibiotic use was 3 days.
The primary intention-to-treat analysis included 2,511 adults (95%) (median age 58 years, 57% male). At 14 days there were no significant differences between the groups for the highest stage AKI or death or the occurrence of major adverse kidney events. Participants who received pip-tazo, however, experienced slightly fewer days of delirium and/or coma than those who received cefepime (12.2 [4.3] vs 11.9 [4.6] mean [SD] days, respectively, odds ratio 0.79 [95% CI 0.65-0.95]).
Based on this randomized trial, pip-tazo appears to be the less harmful of the two options, albeit by a small margin. As in every study, there are limitations. The study was unblinded, so clinicians may have been prone to diagnose delirium or coma in cefepime-treated patients. In addition, around 20% of participants received at least one cross-over dose of the other group's antibiotic, increasing the risk of a type II error. Limitations aside, however, these results strongly counter observational data which suggest nephrotoxicity is more common with pip-tazo. How do we reconcile this? Well, much of the observational data is based on creatinine-defined AKI, but not more patient-oriented outcomes like the need for renal replacement therapy or mortality. The current trial underscores the value of randomized trials and makes a good case for a change in practice — to preferentially choose pip-tazo over cefepime for empiric anti-pseudomonal coverage in acutely ill adults to slightly reduce the risk of neurotoxicity.
For more information, see the topic Bacteremia With Gram-negative Bacilli in DynaMed.
DynaMed EBM Focus Editorial Team
This EBM Focus was written by Nicole Jensen, MD, Family Physician at WholeHealth Medical. Edited by Alan Ehrlich, MD, Executive Editor at DynaMed and Associate Professor in Family Medicine at the University of Massachusetts Medical School; Katharine DeGeorge, MD, MS, Senior Deputy Editor at DynaMed and Associate Professor of Family Medicine at the University of Virginia; Dan Randall, MD, Deputy Editor at DynaMed; Vincent Lemaitre, PhD, Medical Editor at DynaMed; Elham Razmpoosh, PhD, Postdoctoral fellow at McMaster University; and Sarah Hill, MSc, Medical Writer at DynaMed.