If you work in the emergency department, you’re out there in the trenches “suspecting sepsis” on a daily basis. Adhering to guideline recommendations, considered by some hand in hand with “quality,” requires prudent empiric antibiotic coverage. Vancomycin remains the typical straightforward choice for patients in whom methicillin-resistant Staphylococcus aureus coverage is indicated. However, the choice for antipseudomonal coverage is muddier; the split between cefepime and piperacillin-tazobactam is more or less equal in current practice.¹

Surely, these two differing antibiotic formulations cannot possibly be interchangeable?There must be a difference favoring one over the other? These are among the questions at the forefront in the exciting world of infectious disease. The opening volley in the debate came from the Antibiotic Choice On ReNal outcomes (ACORN) trial, which tested these two antibiotics against a primary outcome of acute kidney injury (AKI) or death by day 14 of treatment.² A secondary prespecified outcome included measures of days alive and free of delirium and coma, a nod to the observed increase in neurotoxicity suspected with cefepime.

Nearly 95 percent of the 2,511 patients included in this trial were enrolled in the emergency department, with the most common sources of infection suspected to be intra-abdominal or pulmonary. Most patients received the antibiotic as per randomization, though the number of patients receiving the study antibiotic dropped steadily through the first three days. By study day four, fewer than 40 percent of the original cohorts were still hospitalized and receiving the antibiotic exposures of interest.

Grossly speaking, the results were a wash. Small differences, not reaching statistical significance, favor piperacillin-tazobactam, including renal outcomes, neurotoxicity, and death. It is probably not reliable to focus on these small differences in renal outcomes and mortality, as there are differences in the baseline characteristics of patients enrolled that potentially contributed to the skew. Most prominently, there was a two percent absolute excess of intensive care unit patients and mechanically ventilated patients randomized into the cefepime. Without further parsing through baseline characteristics, this is enough of an indicator that the non-significant excess mortality should not be emphasized. By any stretch, however, there are no clear signals of harm associated with piperacillin-tazobactam.

Unfortunately, the suspected association of cefepime with neurotoxicity was likely confirmed. While the measure of days “alive and free of delirium and coma” was skewed by the increased mortality seen in the cefepime cohort, further analyses still demonstrate an excess of delirium and coma. These various post-hoc analyses required accounting for receipt of sedation and varying alternative definitions of delirium and coma, but do little to refute the prevailing notion of increased neurotoxicity relating to cefepime.