Mechanism of Cefepime-Induced Neurotoxicity
Cefepime causes neurotoxicity primarily through concentration-dependent antagonism of γ-aminobutyric acid (GABA) receptors in the central nervous system, combined with its ability to cross the blood-brain barrier, particularly when drug accumulation occurs in the setting of renal impairment. 1
Primary Mechanism
- GABA antagonism is the central mechanism by which cefepime induces neurotoxicity, with the drug exhibiting concentration-dependent inhibition of this primary inhibitory neurotransmitter in the brain 1
- Cefepime has exceptionally high pro-convulsive activity compared to other beta-lactam antibiotics, with a relative neurotoxic potency of 160 versus penicillin G at 100, making it one of the most neurotoxic agents in its class 2
- The drug's ability to penetrate the blood-brain barrier allows it to reach sufficient concentrations in the CNS to exert these neurotoxic effects 1
Drug Accumulation and Concentration Thresholds
- Cefepime trough concentrations above 22 mg/L or steady-state concentrations above 35 mg/L are associated with neurotoxicity in 50% of patients 2
- Median serum concentrations in patients who developed neurotoxicity were 45 mg/L, while CSF concentrations reached 13 mg/L 1
- Drug accumulation occurs primarily through renal elimination failure, as cefepime is predominantly cleared by the kidneys 3, 4
Critical Risk Factor: Renal Dysfunction
- Renal impairment is the primary risk factor for cefepime-induced neurotoxicity due to drug accumulation, present in 80% of affected patients 1
- Neurotoxicity can occur even when dosing is appropriately adjusted for renal function in 26% of cases, indicating that standard dose adjustments may be insufficient 2
- In one ICU study, 75.3% of patients without neurotoxicity had appropriate dose adjustments versus only 28.6% of those who developed neurotoxicity, yet toxicity still occurred despite proper dosing 5
- Acute kidney injury combined with chronic kidney disease creates particularly high risk, with chronic kidney disease present in 66.7% of neurotoxicity cases versus 35.3% without 5
Clinical Implications of the Mechanism
- The concentration-dependent nature of GABA antagonism explains why symptoms typically resolve within a median of 2 days after drug discontinuation or removal via hemodialysis 1
- The mechanism accounts for the spectrum of neurological manifestations including impaired consciousness (47% of cases), myoclonus (42%), confusion (42%), and seizures including nonconvulsive status epilepticus (25% of those with EEG abnormalities) 1
- Hemodialysis effectively removes cefepime and reverses neurotoxicity by reducing serum concentrations below the neurotoxic threshold 4
Additional Contributing Factors
- Pre-existing brain injury increases susceptibility to cefepime's neurotoxic effects through unclear mechanisms, possibly related to compromised blood-brain barrier integrity 1
- Critical illness itself may alter drug pharmacokinetics and increase CNS vulnerability 5, 6
- The typical 4-day delay from drug initiation to symptom onset suggests cumulative drug accumulation rather than immediate toxicity 1