A Common Hospital Antibiotic Linked to Rare ‘I Am Dead’ Delusion—and to Delirium in a Major Trial

A 76-year-old woman undergoing dialysis became convinced that she had died. Her doctors traced the delusion—a rare syndrome known as Cotard’s—to cefepime, a widely used hospital antibiotic she was taking for a wound infection following ankle surgery and a urinary tract infection. Once the drug was discontinued and dialysis helped clear it from her system, her symptoms faded quickly.

The case, reported in the August 2025 issue of Annals of Internal Medicine: Clinical Cases, is an extreme example. Yet it represents one end of a broader problem that a large randomized trial measured among ordinary hospitalized patients.

In the ACORN trial, published in JAMA in 2023, adults treated with cefepime were more likely to experience delirium or coma than those given piperacillin-tazobactam, another antibiotic used in similar situations.

A Routine Choice in Hospitals Every Day

Cefepime and piperacillin-tazobactam—commonly shortened to pip-tazo—are foundational antibiotics. Clinicians often begin one of them in emergency departments and intensive care units before the causative bacteria are known, since both are effective against dangerous pathogens such as Pseudomonas.

Each drug carried its own suspected drawback. Earlier research had raised concerns that pip-tazo, particularly when paired with vancomycin, might harm the kidneys, while cefepime had a long-standing reputation for affecting the brain.

To settle the question, researchers at Vanderbilt University Medical Center designed the ACORN trial to compare the two drugs directly. Between November 2021 and October 2022, they randomly assigned adults to cefepime or pip-tazo within 12 hours of their arrival in the emergency department or medical intensive care unit; 2,511 patients were ultimately included in the main analysis. Cefepime was administered as a 2-gram intravenous push every eight hours. First author Edward Qian presented the findings at IDWeek 2023, coinciding with the paper’s publication.

Kidneys Spared, Brain at Greater Risk

The primary result resolved one concern. Pip-tazo did not increase the risk of acute kidney injury or death compared with cefepime.

The neurological findings pointed in the opposite direction. Within 14 days, 20.8% of patients in the cefepime group developed delirium or coma, compared with 17.3% of those on pip-tazo, according to an analysis of the trial published by Relias Media. Patients given cefepime also spent slightly fewer days alive and free of delirium and coma—an average of 11.9 days versus 12.2.

The gap is modest, roughly 3.4 percentage points. Still, spread across the large population of hospitalized patients who receive these antibiotics, it could translate into a substantial number of additional episodes of confusion.

The study had limitations. It was conducted at a single U.S. medical center, neither clinicians nor patients were blinded to the drug they received, and about 18% of patients in each group received at least one dose of the antibiotic to which they had not been assigned. At enrollment, the cefepime group also showed slightly higher baseline rates of coma and delirium. Moreover, delirium and coma were secondary outcomes rather than the trial’s central question.

Why Impaired Kidneys Raise the Risk with Cefepime

Cefepime is cleared primarily by the kidneys, so it can accumulate when renal function declines. Researchers believe the drug crosses into the brain and blocks GABA-A receptors, which normally dampen nerve activity—a mechanism described in a 2023 report of another cefepime-associated case of Cotard’s syndrome.

In that case, reported by physicians at the University of Pittsburgh Medical Center, a 48-year-old woman developed difficulty speaking three days after beginning cefepime. After the drug was stopped, she told her doctors she had died: “I’m sure you can’t hear my heart since I’m dead.”

The 76-year-old patient’s experience fits a wider pattern. A 2017 systematic review of 135 published cases of cefepime-induced neurotoxicity found a median patient age of 69, with 80% of patients affected by kidney dysfunction. About one in four developed symptoms despite receiving appropriate doses—evidence that adjusting the dose lowers the risk but does not eliminate it.

The U.S. Food and Drug Administration has issued warnings for years. A 2012 Drug Safety Communication described 59 cases of nonconvulsive status epilepticus—a seizure state without visible convulsions—among cefepime users. Fifty-eight of those patients had kidney dysfunction, and in 56 cases the dose had not been properly adjusted for renal function.

When Confusion Is Actually a Medication Side Effect

In the 76-year-old woman, laboratory tests and imaging revealed nothing abnormal, but an electroencephalogram showed a pattern consistent with toxic-metabolic encephalopathy—brain dysfunction caused by drugs or metabolic disturbances rather than a primary psychiatric disorder.

Her case illustrates how cefepime toxicity can masquerade as mental illness. In an older hospitalized patient, sudden confusion is easily attributed to age, infection, or simply the hospital environment itself. The ACORN trial suggests the antibiotic should be added to that list of possible causes.

Neither the case report nor the trial implies that cefepime should be avoided. It remains a vital treatment for serious infections, and the appropriate choice depends on the infection, the likely bacteria, and the individual patient. Dosing tailored to kidney function is essential.

Family members of hospitalized loved ones—especially those with kidney disease—can ask whether a new antibiotic might be contributing to sudden confusion, unusual beliefs, or drowsiness. The FDA advises caregivers to seek medical attention immediately if altered mental status, confusion, or reduced responsiveness develops during cefepime treatment.

Key Questions Answered

What happened to the woman?

A 76-year-old dialysis patient developed Cotard’s syndrome, believing she had died, while taking cefepime. Her symptoms resolved after the drug was stopped and cleared through dialysis.

What did the ACORN trial find?

Among 2,511 hospitalized adults, cefepime was associated with more delirium or coma than piperacillin-tazobactam, at 20.8% versus 17.3%.

Did pip-tazo damage kidneys in the trial?

No. It did not increase acute kidney injury or death compared with cefepime.

Who is most at risk of cefepime neurotoxicity?

Older adults and people with reduced kidney function, particularly when the dose is not adjusted accordingly.

Is cefepime unsafe?

No. It remains an important antibiotic, but doses must match kidney function, and new confusion should prompt a medication review.

What should families watch for?

Sudden confusion, strange beliefs, decreased responsiveness, or seizures in someone receiving cefepime.

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