As a fourth-generation cephalosporin, Cefepime is a powerful antibiotic frequently used to combat severe infectious diseases like pneumonia, meningitis, and skin or intra-abdominal infections [1]. While effective, it can cause Cefepime-induced encephalopathy (CIE), a condition classified as a type-1 antibiotic-associated encephalopathy [1]. The incidence of CIE is reported to be between 1% and 15% [2]. Patients with CIE present with a range of clinical features, including altered mental status that can progress from confusion and disorientation to more severe states like delirium and coma. Other symptoms include agitation, aphasia, myoclonic jerks, and epileptic seizures [1]. Predisposing factors for CIE include a high Cefepime dosage, reduced drug renal clearance, and older age [1,3].

We present this case to highlight the importance of early recognition and prompt cessation of Cefepime by monitoring for mental status changes in all treated patients.

An 85-year-old female with a history of hypertension, gastroesophageal reflux disease (GERD) and lumbar disc herniation. She was recently admitted to general internal medicine department with progressive back pain and difficulty walking.

Two days later, the patient reported slight back pain relief, but also noted the onset of dysuria. Urinalysis findings revealed a positive Nitrite (baseline negative), 3+ Leukocytes (baseline negative), a white blood cell count of 609/uL (baseline 0-25/ uL), and bacteria of 24,324/uL (baseline 0-130/ uL). She was diagnosed with a urinary tract infection and was started on Cefepime at a dose of 2g three times a day. At this time, the patient's renal function was creatinine of 0.94 mg/dL (baseline 0.51-1.35 mg/dL), BUN of 23.9 mg/dL (baseline 7-18 mg/dL) and CrCl of 29.9 ml/min.

On the seventh day of hospitalization, the patient began to exhibit myoclonic jerks, primarily in the face. The condition subsequently worsened, and she was admitted to the neurology department with severe symptoms.

During the physical examination, the patient's eyes were open spontaneously, but she was non-responsive and in a restless, agitated state, refusing to lie still. We noted continuous chewing movements and tremors in all four limbs, as well as slurred speech. She had not slept for three days. She exhibited extrapyramidal hypertonia in all four limbs and the neck, with generalized rigidity. Deep tendon reflexes were hyperactive in all four limbs (3+ in the upper extremities and 2+ in the lower). The pupillary light reflex was present, but the pupils were unequal in size (4mm on the right and 3mm on the left). The 12 pairs of cranial nerves were intact. Examination of other organs was within normal limits.

She was also found to have AKI with elevated creatinine of 1.45 mg/dL, BUN of 38.6 mg/dL, and decreased CrCl of 19.4. Liver function tests were within normal limits with an AST of 41 U/L (baseline 0-35 U/L) and an ALT of 11 U/L (baseline 0-35 U/L). Electrolyte levels were serum sodium 142.4 mmol/L (baseline 135 - 145 mmol/L), serum potassium 4.6 mmol/L (baseline 3.5-5 mmol/L), serum chloride 112.2 mmol/L (baseline 95-106 mmol/L), and serum calcium 2.5 mmol/L (baseline 2.1-2.6 mmol/L). Urinalysis showed improvement with a negative result for both nitrite and leukocytes. The white blood cell count was 1/uL, and bacteria were 5/uL. Magnetic resonance imaging of the brain revealed no acute cerebral infarction or hemorrhage. Findings were consistent with age-related cerebral atrophy and white matter signal abnormalities in both hemispheres due to small vessel disease.

Figure 1: Axial DWI and Axial ADC.

Figure 2: Axial T2 FLAIR.

Additionally, an extended electroencephalogram (EEG) was ordered. The EEG showed asymmetric background slowing, which was more prominent over the left hemisphere. There were intermittent multifocal epileptiform discharges, including spikes and sharp-and-slow waves, located in the frontal regions (F3, F4, F7, and F8). The background rhythm consisted of a poorly organized, low-amplitude 11 Hz alpha rhythm distributed predominantly over the posterior region, along with low-amplitude 21 Hz beta activity over the frontocentral regions. The following result was abnormal, showing epileptiform activity during the recording.

Figure 3: EEG findings in a Cefepime-induced encephalopathy patient with background slowing, multifocal sharp waves, and generalized periodic discharges.

Based on the patient's clinical course, a suspicion of Cefepime-induced encephalopathy began to arise. After assessment, we recognized the infection was controlled and decided to discontinue intravenous Cefepime. Unfortunately, due to the general conditions in Vietnam and the specific circumstances of our hospital, we are unable to perform a serum Cefepime level test. Our treatment protocol focused on fluid resuscitation to rehydrate, along with calcium and vitamin supplementation. To stabilize heart rate and manage agitation, we used Propranolol. Valproic acid was administered to control facial myoclonus. Midazolam was also considered for use in cases of continued patient agitation. Within two days of stopping antibiotic, her mental status returned to the baseline. The antiepileptic drug was stopped with no further seizures noted. In addition, her renal function was recovered with a Creatinine Level of 0.7 mg/dL, BUN of 17.2 mg/dL and CrCl of 40.2 ml/min. The patient then received an injection of Diprospan (Betamethasone disodium phosphate, Betamethasone dipropionate) mixed with Lidocaine into the paravertebral muscles at the L4-L5 and L5-S1 levels to alleviate her back pain. The patient was discharged one day later.

Beta-lactam antibiotics, including Penicillin, Cephalosporins, and Carbapenems, are recognized for their broad therapeutic window and high safety profile. Yet, the neurotoxic side effects of Cefepime, a fourth-generation cephalosporin commonly administered to critically ill patients, were first documented in 1999 [4]. Risk factors of CIE are a high Cefepime dosage, reduced drug renal clearance, and older age. CIE is characterized by symptoms like confusion, delirium, seizures, and myoclonus. It occurs when Cefepime crosses the blood-brain barrier and interferes with GABA receptors, leading to neurotoxicity, particularly in patients with renal dysfunction. Diagnosis involves identifying Cefepime exposure approximately 1-10 days after the first dose of Cefepime, and ruling out other causes of encephalopathy, supported by EEG findings consistent with CIE. Treatment primarily involves discontinuing the antibiotic, which usually resolves symptoms within 2-7 days [5]. For severe cases involving refractory seizures, anti-epileptic medications may be utilized. In certain severe circumstances, continuous renal replacement therapy (CRRT) may also be considered to enhance the clearance of Cefepime from the blood [3,4].

The patient in this clinical case was an 85-year-old woman. Due to her advanced age and a creatinine clearance (CrCl) of only 29.9 mL/min, her kidney function was significantly impaired. However, she was prescribed Cefepime at a very high dose of 6g/day. This mismatch between the drug dosage and her kidney function led to drug accumulation in her body, resulting in a high risk of developing CIE.

Table 1: Cefepime dasage in renal failure [6,7].

Five days after beginning treatment for a urinary tract infection with Cefepime, the patient started to experience myoclonic jerks. The symptoms then progressed to include confusion, agitation, and aphasia. These clinical manifestations were consistent with symptoms previously described in the medical literature [4,6]. Moreover, the most common EEG findings include diffuse background slowing, multifocal sharp waves, and generalized periodic discharges (with or without a triphasic morphology) [8]. Our patient’s presentation was nearly identical, and upon considering a diagnosis of CIE, we noted that the urinary tract infection had resolved and decided to discontinue the antibiotic. The patient’s consciousness gradually recovered, returning to normal on the third day after ceasing Cefepime administration. Both the time to symptom onset (5 days after taking the medication) and the time to recovery (3 days after discontinuation) were consistent in the reports, which typically range from 1-10 days and 2-7 days, respectively [3-5]. Based on previous literature, antiepileptic medications and benzodiazepines can provide partial control of symptoms [3,4,6]. Therefore, we added valproic acid and midazolam to our treatment protocol.

This case underscores the crucial importance of antibiotic stewardship and vigilant monitoring for signs of Cefepime-induced encephalopathy, particularly in patients with impaired renal function, where careful dose adjustment based on estimated creatinine clearance is imperative.

Careful consideration should be given to prescribing Cefepime, as the incidence of drug-induced encephalopathy may be higher than anticipated in older adults. If a patient is on multiple medications and has renal insufficiency, the risk is even greater, potentially leading to increased mortality and other serious complications.

Written patient consent for publication was not required, as the patient's details were fully de-identified to ensure their identity could not be ascertained.

Funding Information

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Data Availability

All data supporting the conclusions of this article are included within the article.

Competing Interests

The authors declare that they have no competing interests.

1. Jeon JY, Cho YW, Moon HJ. Cefepime-Induced Encephalopathy in a Tertiary Medical Center in Korea. J Clinical Neurology. 2020; 16: 408-415.
2. Crow S, Alagha Z, Abdeen AMZ, Al-Astal AY. Cefepime-Induced Encephalopathy Mimicking Brainstem Injury. Chest. 2024; 166: A2658-A2659.
3. Lichak BP, Lawal O, Polimera HV, Garg A, Kaur G. A Case of Cefepime-Induced Neurotoxicity: Renal Function Missing in Action. Cureus. 13: e13368.
4. Keerty D, Shareef NA, Ramsakal A, Haynes E, Syed M. Cefepime-Induced Encephalopathy. Cureus. 2021; 13: e13125.
5. Kenzaka T, Matsumoto M. Cefepime-induced encephalopathy. BMJ Case Rep. 2018; 2018: bcr2017223954.
6. Taylor J, Gunter HM, Cohen K. Cefepime-induced neurotoxicity. Southern African J Infectious Diseases. 2025; 40: 4.
7. Khole AV, Dionne E, Zitek-Morrison E, Campion M. Cefepime extended infusion versus intermittent infusion: Clinical and cost evaluation. Antimicrobial Stewardship and Healthcare Epidemiology. 2023; 3: e119.
8. Tsai IH, Wang YC. Cefepime-induced encephalopathy in an older patient with polypharmacy and renal insufficiency: a case report. J Int Med Res. 2024; 52: 03000605241244743.