Cefepime-induced neurotoxicity

The patient

An 87-year-old man with a medical history significant for hypertension, hyperlipidemia, severe aortic stenosis treated with aortic valve replacement 13 years ago, coronary artery disease, nonischemic cardiomyopathy, ventricular fibrillation leading to cardiac arrest and a single-chamber implantable cardioverter defibrillator, ischemic stroke, and stage 3b chronic kidney disease presented to the ED from a transitional care center. The patient was confused and speaking nonsensically, with decreased responsiveness. A seizure was suspected.

The patient had been discharged from the hospital three days before this presentation after an eight-day hospitalization for right fourth metatarsal osteomyelitis due to Enterobacter cloacae, which had been treated with IV cefepime. A peripherally inserted central catheter (PICC) was put in to continue the antimicrobial agent for a total of six weeks. He had been fully alert and oriented at discharge.

Physical exam on the present admission revealed a healing right toe wound that was appropriately dressed. The neurological exam was significant for the patient being awake and alert to self but disoriented to time and place without evidence of myoclonus or other abnormal movements. The remainder of the physical exam was normal. Significant laboratory data included a blood urea nitrogen level of 54 mg/dL (reference range, 6 to 24 mg/dL), a creatinine level of 1.8 mg/dL (baseline, 1.2 to 1.4 mg/dL; reference range, 0.8 to 1.3 mg/dL), an estimated glomerular filtration rate (GFR) of 35.9 mL/min/1.73 m² (reference >60 mL/min/1.73 m²), an albumin level of 2.9 g/dL (reference range, 3.4 to 5.4 g/dL), an aspartate aminotransferase level of 50 U/L (reference range, 8 to 33 U/L), and a hemoglobin level of 11.4 g/dL (reference range, 13.2 to 16.6 g/dL). Urinalysis showed 1+ protein but was negative for leukocyte esterase, nitrites, and bacteria.

A CT of the head without contrast revealed no significant findings. Interrogation of the patient's permanent pacemaker was negative for acute arrhythmias. Electroencephalogram (EEG) showed excessive theta waves consistent with toxic metabolic encephalopathy. An ultrasound of the kidneys, obtained given the patient's ongoing acute kidney injury, showed simple cysts in the left kidney with no hydronephrosis or renal calculi. Peripheral blood cultures remained negative. With an antibiotic change from cefepime to ertapenem, his mental status improved back to baseline within two days. Given the lack of alternative diagnosis and improvement in mental status with antibiotic change, the etiology was felt to be cefepime-induced even though cefepime levels were not obtained.

The diagnosis

The diagnosis is cefepime-induced neurotoxicity. Cefepime is a fourth-generation cephalosporin that is commonly used as an empiric first-line treatment for many severe bacterial infections, particularly in critically ill patients. The primary mechanism of cefepime-induced neurotoxicity is thought to be through the concentration-dependent competitive inhibition of the γ-aminobutyric acid (GABA) receptor, which can both lower the seizure threshold and lead to encephalopathy. EEG monitoring can be useful for diagnosis as nearly all patients with cefepime-induced neurotoxicity have abnormal findings, including generalized slowing, triphasic waves, multifocal sharp waves, and epileptiform activity.

Cefepime can freely cross the blood-brain barrier, making neurotoxicity a rare but known complication of therapy, occurring in up to 0.15% of all patients and 15% of ICU patients treated with cefepime. Presentation varies, however, and symptoms are often delayed, by a median of four days from initiation of treatment. The most common presenting signs and symptoms of neurotoxicity are diminished level of consciousness (80%), disorientation (47%), myoclonus (40%), nonconvulsive status epilepticus (31%), seizures (11%), and aphasia (9%). One of the primary risk factors for cefepime-induced neurotoxicity is renal dysfunction. Renal dysfunction leads to proteinuria, albuminuria, and altered-protein binding, which increases the unbound, biologically active form of cefepime in the blood. Unfortunately, it is difficult to predict what degree of renal impairment predisposes a patient to a higher risk of toxicity, as GFR is difficult to accurately assess in critically ill patients. Systemic inflammation, including sepsis, disrupts the integrity of the blood-brain barrier, allowing for greater penetration of cefepime, from 10% in normal conditions up to 45%.

Treatment of cefepime neurotoxicity is centered around stopping the offending agent, managing seizure activity with antiepileptics, and in some cases, initiating hemodialysis. Emergent or urgent hemodialysis can shorten recovery time by approximately one day and is most often indicated for prompt resolution of seizure activity

As the risk of toxicity increases with serum concentrations of cefepime, it may be appropriate to routinely monitor cefepime levels in high-risk patients. Patients considered to be at high risk for cefepime toxicity include those with renal impairment (GFR ≤60 mL/min/1.73 m²), critical illness, sepsis, uremia, prior central nervous system infections, or older age. Studies have shown that patients who developed cefepime-induced neurotoxicity had higher levels of blood urea nitrogen. Generally, a trough of 5 to 10 mg/L is considered to be therapeutic. The toxic level of cefepime has yet to be clearly defined, though studies have suggested that the probability of cefepime neurotoxicity increases exponentially around a plasma concentration of 22 mg/L. However, it is important to recognize that cefepime toxicity can occur despite appropriate dosage, and a lower dose should not preclude its inclusion as a differential diagnosis for encephalopathy, particularly in critically ill patients with renal failure.

Pearls

• Cefepime competitively antagonizes the GABA receptors in the brain, leading to central overexcitation that results in confusion, myoclonus, seizures, reduced levels of consciousness, and coma.
• Disruptions of the blood-brain barrier, caused by renal dysfunction, sepsis, uremia, or prior central nervous system infection, allow increased central nervous system penetration of cefepime.