Two antibiotics, both alike in efficacy, are commonly prescribed for empirical treatment of infection in hospitalized adults.
Yet each drug – cefepime and piperacillin-tazobactam (Zosyn) – has its own baggage in terms of suspected associated toxicities: Cefepime has been implicated in neurologic dysfunction, and piperacillin-tazobactam has been associated with acute kidney injury (AKI).
The true nature of toxicities associated with each agent in clinical practice has been unclear, however – until now. As results of the randomized ACORN (Antibiotic Choice on Renal Outcomes) trial showed, but cefepime was indeed associated with a higher incidence of neurologic dysfunction as measured by freedom from delirium and coma.
The findings, by Edward T. Qian, MD MSc and colleagues at Vanderbilt University Medical Center, Nashville, Tenn.e, were published in JAMA.
Questioning a common practice
In an interview, Dr. Qian said that he and his colleagues conducted the pragmatic trial to seek answers to an important issue.
“We noticed a change in practice patterns as people were afraid of using Zosyn as empiric antibody therapy because they were afraid of the risks of AKI,” he said. “And as that practice shifted with a lower quality of evidence, just from observational studies, we started using more cefepime and we started seeing more patients with this rare phenomenon called ‘cefepime neurotoxicity.’ ”
To see whether the choice of one antibiotic over the other would affect the risk for either AKI or neurologic dysfunction, the investigators enrolled adults for whom a clinician ordered antipseudomonal antibiotics with 12 hours of when they were seen in the ED or medical ICU.
The patients were randomized on a 1:1 basis to receive either cefepime or piperacillin-tazobactam.
A total of 2,511 patients treated from Nov. 10, 2021, to Oct. 7, 2022, were included in the primary analysis. A large majority of the patients (94.7%) were enrolled in the ED, and 77.2% of patients were also receiving vancomycin at the time of enrollment.
No added AKI risk
The investigators found that there was no significant difference between the drugs for the primary outcome of the highest stage of AKI or death within 14 days of the start of treatment.
In the cefepime arm, 85 of 1,214 patients (7.0%) had stage 3 AKI, and 92 (7.6%) died.
In the piperacillin-tazobactam arm, 97 of 1,297 patients (7.5%) had stage 3 AKI, and 78 (6%) died. As noted, the difference was not statistically significant.
In addition, there was no significant difference between the groups in the secondary endpoint of the incidence of major adverse kidney events at day 14, with 10.2% in the cefepime arm and 8.8% in the piperacillin-tazobactam arm having an event.
As noted before, however, there was a significant difference in the secondary outcome of the number of days alive and free of delirium and coma within 14 days.
Patients on cefepime had a mean 11.9 days free of delirium and coma, compared with 12.2 days for patients on piperacillin-tazobactam. This difference translated into an odds ratio of 0.79 (95% confidence interval, 0.65-0.95).
Dr. Qian said that he and his colleagues stop short of calling the neurologic dysfunction that they observed “cefepime neurotoxicity,” but added that it warrants further study.