Case Presentation: A 48-year-old man presented with 3 days of confusion, excessive drowsiness, and upper extremity twitching. He denied any fever, headache, or neck stiffness. History was notable for kidney transplant on chronic immunosuppression. Three weeks prior, the patient was started on a course of cefepime for pseudomonal osteomyelitis of the tibia.Vital signs were normal. The patient was hypersomnolent and offered no response to voice. He had intermittent myoclonic jerks in both arms and hyperreflexia in the lower extremities. There was no nuchal rigidity or jolt accentuation. Serum creatinine was 2.9 mg/dL (estimated GFR 29 mL/min/1.73m2), elevated from a baseline of 1.2 mg/dL. Blood cultures were negative. Cerebrospinal fluid showed white blood cells of 46/μL with 62% lymphocytes, red blood cells of 8/μL, glucose of 74 mg/dL, protein of 70 mg/dL, and no organisms on Gram stain. CT scan of the head was unremarkable. EEG demonstrated diffuse slowing and rare triphasic waveforms, but no epileptiform activity.Despite the addition of broad-spectrum antibiotics for meningitis and cessation of potentially neurotoxic medications such as gabapentin, baclofen, and tacrolimus, mentation failed to improve. The patient became nonverbal by hospital day five. Cefepime was then switched to ciprofloxacin. Within 24 hours, the patient became fully alert and oriented, with normal conversational ability and resolution of the myoclonus. He was discharged to a skilled nursing facility.
Discussion: Cefepime, a fourth-generation cephalosporin with broad activity against Gram-positive and Gram-negative bacteria including Pseudomonas aeruginosa, is associated with neurotoxicity in up to 15% of ICU patients. Given its ubiquity in the inpatient setting, cefepime’s potentially severe neurologic effects should be acknowledged by internists and intensivists alike.Common manifestations include decreased consciousness, confusion, and seizures, with median onset at 4 days after initiation. Myoclonus occurs in 40% of cases. EEG abnormalities are nonspecific but include triphasic waves, focal sharp waves, and non-convulsive status epilepticus. Effects may be attributable to cefepime’s concentration-dependent gamma-aminobutyric acid (GABA) antagonism, which blocks the central nervous system’s main inhibitory neurotransmitter pathway and lowers the seizure threshold.The kidneys excrete 85% of cefepime in the unmetabolized form, making renal failure the strongest risk factor for developing neurotoxicity. Serum drug concentrations greater than 20 mg/L have been associated with a five-fold risk increase, but laboratory assays for cefepime monitoring are not widely available.In 90% of cases, discontinuing cefepime leads to reversal of neurologic symptoms within 1-3 days. In the setting of unexplained encephalopathy, providers should consider switching cefepime to an acceptable alternative while awaiting additional workup. Severe cases may benefit from hemodialysis. Importantly, cefepime neurotoxicity will likely become more widely recognized in the near future, as some physicians now favor vancomycin/cefepime over vancomycin/piperacillin-tazobactam for empiric sepsis treatment due to the latter’s association with acute kidney injury.
Conclusions: Patients with renal failure are at highest risk for cefepime-induced neurotoxicityManifestations include decreased consciousness, confusion, myoclonus, and seizures. Discontinuing cefepime typically leads to resolution of symptoms.