In adults hospitalized for acute infections, cefepime and piperacillin-tazobactam turned out to be equally safe in terms of serious kidney outcomes, although the latter antibiotic showed a lower risk for coma and delirium, an open-label randomized trial found.
Cefepime versus piperacillin-tazobactam for suspected infection resulted in no significant difference in the study’s primary endpoint, the highest stage of acute kidney injury (AKI) or death at 14 days (OR 0.95, 95% CI 0.80-1.13, P=0.56), Edward Qian, MD, of Vanderbilt University Medical Center in Nashville, Tennessee, reported here during a late-breaking abstract session at IDWeek.
In addition, major adverse kidney events (10.2% vs 8.8%, respectively) and deaths (7.6% vs 6.0%) were similar between groups, while those taking piperacillin-tazobactam had fewer days of delirium and coma (11.9 vs 12.2 days with cefepime; OR 0.79, 95% CI 0.65-0.95), according to the findings, which were simultaneously published in JAMA.
Findings from the so-called ACORN (Antibiotic Choice on Renal Outcomes) trial — performed in over 2,500 acutely ill patients at a single U.S. center — should help put clinicians’ minds at ease when deciding between the two treatment protocols, he told MedPage Today. “Clinicians who are starting antibiotics on these patients can feel comfortable with either regimen.”
Additionally, Qian said during his presentation, piperacillin-tazobactam “did not cause any kidney injury in any of the prespecified subgroups, including the 1,939 patients who were receiving concurrent vancomycin.”
Both antibiotics have been associated with risks: neurotoxicity in the case of cefepime, while AKI has been linked to piperacillin-tazobactam plus vancomycin in observational data, leading to an FDA warning and a “cultural shift away from the empirical use” of the antibiotic combination, noted Steven Tong, PhD, of the University of Melbourne in Australia, and colleagues.
“Because institutions must make decisions about which antibiotics to position on medical wards for rapid administration in patients meeting sepsis criteria, these data should offer solace that if the choice is made to use piperacillin-tazobactam, there is not an increased risk of AKI,” the group wrote in an accompanying editorial.
But the editorialists noted some limitations to the study as well, including that the small between-group difference when it came to days alive and free of delirium and coma (0.3 days) was of questionable clinical significance, and the high rate of crossover (19% in the cefepime arm and 17% in the piperacillin-tazobactam arm), despite electronic health record reminders.
Tong’s group also pointed to the possibility of bias, given the open-label design, and said the dosing regimens used “may not reflect broader clinical use.”
“Importantly, cefepime was administered via rapid intravenous push, which is associated with enhanced toxic effects compared with intermittent or extended infusions,” they wrote. “Thus, the dosing regimens may have reduced the risk of AKI with piperacillin-tazobactam due to the lower dose used and exaggerated the risk of neurotoxicity with cefepime due to the rapid intravenous push.”
ACORN was a randomized safety study of 2,511 adults who presented with a suspected infection to the emergency department (95%) or intensive care unit (5%) at Vanderbilt University Medical Center.
Patients had a median age of 58 years, a majority were men, and 54% had confirmed sepsis at baseline. About half in each group had no baseline AKI.
They were randomized to the institution’s standard doses of either cefepime (2 g IV push over 5 minutes every 8 hours) or piperacillin-tazobactam (3.375 g bolus over 30 minutes for the initial administration followed by an extended infusion of 3.375 g every 8 hours, infused over 4 hours), with the dosage determined by a clinical decision support tool based on the patient’s estimated glomerular filtration rate. Median time for antibiotic initiation was 1.2 hours.
Along with the crossover of study drugs, about 7% of each group also received other extended-spectrum gram-negative antibiotics (most often an aminoglycoside or carbapenem) and about 77% of each group were getting IV vancomycin when they entered the trial and remained on it for a median of 2 days thereafter.
At 14 days of treatment, AKI between the cefepime and piperacillin-tazobactam arms, respectively, occurred at the following rates:
- Stage 1 AKI: 7.1% vs 7.7%
- Stage 2 AKI: 3.4% vs 5.4%
- Stage 3 AKI: 7% vs 7.5%
In all, 20.8% in the cefepime group and 17.3% in the piperacillin-tazobactam group experienced coma or delirium at some time during the 14 days of treatment.
Disclosures
The study was supported by the National Heart, Lung, and Blood Institute, the NIH, U.S. Department of Defense, and the Vanderbilt Institute for Clinical and Translational Research, among others.
Qian had no conflicts of interest. Co-authors reported relationships with Fisher & Paykel Healthcare, the Infectious Diseases Society of America, the American Society of Nephrology, Novartis, UptoDate, the Eastern Association for Surgery of Trauma, Bristol Myers Squibb, Baxter International, the American College of Chest Physicians, the American Society of Parenteral and Enteral Nutrition, Cumberland Pharmaceuticals, Cytovale, and Sanofi.
Tong reported a relationship with Roivant Sciences. Co-authors of the editorial disclosed relationships with AbbVie, Basilea, Baxter Institutional, Ferring, GSK, Melinta, Merck, the National Health and Medical Research Council, and Shionogi.
Primary Source
JAMA
Source Reference: Qian ET, et al “Cefepime vs piperacillin-tazobactam in adults hospitalized with acute infection: the ACORN randomized clinical trial” JAMA 2023; DOI: 10.1001/jama.2023.20583.
Secondary Source
JAMA
Source Reference: Tong SYC, et al “Acute kidney injury with empirical antibiotics for sepsis” JAMA 2023; DOI: 10.1001/jama.2023.18591.
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