What is the risk of seizures associated with ertapenem (Invanz) in patients with impaired renal function or a history of seizure disorders?

Ertapenem Seizure Risk

Ertapenem carries a significant risk of seizures and CNS toxicity, particularly in patients with renal dysfunction or pre-existing CNS disorders, with seizures occurring in 0.5-10% of patients depending on risk factors, and you must exercise extreme caution when prescribing this antibiotic to high-risk populations. 1, 2, 3

Risk Magnitude and Incidence

• The FDA label reports seizures occurred in 0.5% of patients during clinical trials, but real-world data suggests much higher rates in high-risk populations 1
• A retrospective study of hemodialysis patients found a 10% incidence of neurotoxicity with standard dosing 2
• A systematic review of 125 cases found an estimated incidence of 1 in 102 courses of ertapenem at a tertiary center 3
• Seizures are the most common manifestation (70% of neurotoxicity cases), followed by altered consciousness/delirium (27%) and hallucinations (17%) 3

High-Risk Patient Populations

Renal Dysfunction

• Patients with compromised renal function are at substantially elevated risk, as ertapenem is renally cleared 1
• In hemodialysis patients (CKD-5D), the approved 0.5g daily dose is associated with frequent neurotoxicity 2
• Even patients with moderate renal impairment (eGFR 30-59 mL/min/1.73 m²) can develop neurotoxicity 4
• Acute kidney injury superimposed on chronic kidney disease further increases risk 4
• 62% of neurotoxicity cases occurred in patients with renal dysfunction 3

CNS Disorders

• Patients with pre-existing CNS disorders (brain lesions, history of seizures) are at highest risk 1
• The FDA label specifically warns that seizures occur "most commonly in patients with CNS disorders and/or compromised renal function" 1
• 42% of neurotoxicity cases had pre-existing CNS conditions 3
• However, seizures can occur even in patients with no prior CNS disease and appropriate dosing for renal function 5

Additional Risk Factors

• Male sex was a significant predictor of seizures (17% incidence vs lower in females, p=0.014) 2
• Dementia increased seizure risk (27% incidence, p=0.012) 2
• Concomitant use of other β-lactams, aminoglycosides, or fluoroquinolones increased risk (19.6%, p=0.042) 2
• Advanced age (mean age 72-74 years in neurotoxicity cases) 2, 3

Timing of Onset

• Neurotoxicity typically develops after a median of 4 days (IQR 3-9 days) of therapy 3
• Seizures can occur as early as day 3 of treatment 5
• The average time to seizure onset in clinical trials was 7 days 1

Critical Drug Interaction: Valproic Acid

• Co-administration of ertapenem with valproic acid or divalproex sodium causes a clinically significant reduction in valproic acid concentrations, dropping levels below therapeutic range and increasing breakthrough seizure risk 1
• Increasing valproic acid dose may not overcome this interaction 1
• The concomitant use of ertapenem and valproic acid/divalproex sodium is generally NOT recommended by the FDA 1
• If ertapenem is absolutely necessary in patients on valproic acid, supplemental anticonvulsant therapy should be considered 1
• Alternative antibiotics should be strongly considered for patients whose seizures are well-controlled on valproic acid 1

Dosing Considerations

• Close adherence to recommended dosage regimens is critical, especially in patients with predisposing factors 1
• Only 15% of neurotoxicity cases received inappropriately high dosing, indicating that even appropriate dosing carries risk 3
• In hemodialysis patients, the standard 0.5g daily dose may still be too high, and alternative strategies (1g loading dose followed by 0.5g post-dialysis for 48-hour intervals or 1g for 72-hour intervals) warrant investigation 2

Management When Neurotoxicity Occurs

• If focal tremors, myoclonus, or seizures occur, immediately evaluate neurologically and place on anticonvulsant therapy if not already instituted 1
• Re-examine the ertapenem dosage to determine whether it should be decreased or discontinued 1
• Discontinuation of ertapenem typically results in rapid resolution—one case showed return to baseline mental status within 24 hours of stopping the drug 4
• Continue anticonvulsant therapy in patients with known seizure disorders 1

Clinical Decision-Making Algorithm

For patients WITH renal dysfunction (CrCl <30 mL/min or on dialysis) OR pre-existing CNS disorders:

• Consider alternative antibiotics as first-line
• If ertapenem is necessary, ensure strict dose adjustment per renal function
• Avoid if patient is on valproic acid
• Monitor closely for early signs of neurotoxicity (days 3-9)

For patients WITHOUT these risk factors:

• Ertapenem can be used with standard monitoring
• Still maintain vigilance as neurotoxicity can occur even in low-risk patients 5

For ALL patients on ertapenem:

• Avoid concomitant nephrotoxic or neurotoxic medications when possible
• Monitor renal function throughout therapy
• Educate patients/families about early neurological symptoms