What is the incidence of cefepime (Fourth-generation cephalosporin) induced encephalopathy?

From the Guidelines

The incidence of cefepime-induced encephalopathy is estimated to be around 26% in patients appropriately exposed to the drug, taking into account their renal function, and up to 48% in patients overexposed. Cefepime-induced encephalopathy is more common in:

• Patients with renal impairment, as it may cause rapid and significant accumulation of cefepime 1
• Patients receiving high doses of cefepime, with trough concentrations above 22 mg/L (when administered by discontinuous infusions) or concentrations at steady state above 35 mg/L (when administered by continuous infusion) associated with neurotoxicity in 50% of patients 1
• Those with pre-existing neurological conditions, as cefepime neurotoxicity has been confirmed in many case series of patients suffering from various neurological disorders such as acute confusional state, encephalopathy, myoclonus, seizures, and status epilepticus 1 To reduce the risk:

1. Adjust cefepime dosing based on renal function, as renal failure is the main risk factor associated with neurological toxicity of beta-lactam antibiotics, including cefepime 1
2. Monitor patients closely for neurological symptoms, especially in high-risk groups, and consider temporarily suspending beta-lactam administration if unexplained neurological manifestations occur 1
3. Consider alternative antibiotics in patients with risk factors, as some molecules such as cefepime have a lower neurotoxicity threshold than other beta-lactam antibiotics 1 Symptoms typically appear within 1-10 days of starting cefepime and can include confusion, disorientation, myoclonus, seizures, and coma, with the condition usually being reversible upon discontinuation of cefepime, with symptoms resolving within 2-7 days. The mechanism is thought to be related to cefepime's ability to cross the blood-brain barrier and antagonize GABA receptors, leading to neuronal hyperexcitability, which is exacerbated in patients with reduced renal clearance of the drug.

From the Research

Incidence of Cefepime-Induced Encephalopathy

• The incidence of cefepime-induced encephalopathy varies across different studies, with reported rates ranging from 1% to 7.5% 2, 3, 4.
• A study published in 2008 found a cumulative incidence of approximately 1% (0.01) in a cohort of 498 patients using cefepime 2.
• Another study published in 2014 reported a cumulative incidence of approximately 4.1% in a cohort of 243 patients with haematological malignancies treated with cefepime 3.
• A study published in 2017 found an incidence of 7.5% in end-stage renal disease patients treated with adjusted-dose cefepime 4.

Risk Factors for Cefepime-Induced Encephalopathy

• Impaired renal function is a significant risk factor for cefepime-induced encephalopathy, with studies showing a higher incidence in patients with reduced glomerular filtration rate (GFR) or creatinine clearance (CLCr) 2, 3, 4.
• Pre-existing central nervous system (CNS) morbidity may also be associated with an increased risk of cefepime-induced encephalopathy in end-stage renal disease patients 4.
• Normal renal function does not entirely eliminate the risk of cefepime-induced encephalopathy, as cases have been reported in patients with normal kidney function 5, 6.

Clinical Features and Outcomes

• The most common clinical manifestations of cefepime-induced encephalopathy include decreased level of consciousness, myoclonus, and altered mental status 3, 6.
• Symptoms of cefepime-induced encephalopathy typically resolve fully after discontinuation of the medication 3, 5, 6.