What is the relationship between Meropenem (a carbapenem antibiotic) and seizures in patients taking antiepileptic (anti-seizure) medications?

From the Guidelines

Meropenem can increase the risk of seizures in patients taking antiepileptic medications, particularly in those with renal impairment or CNS disorders, and close monitoring is essential. The relationship between meropenem and seizures is complex, and the risk is dose-dependent, with higher doses and concentrations associated with a greater risk of neurotoxicity, including seizures 1. Patients with a history of seizures or those on antiepileptic drugs should be closely monitored when receiving meropenem, and dose adjustments may be necessary based on renal function.

Some key points to consider when using meropenem in patients on antiepileptic medications include:

• The seizure risk with meropenem increases in patients with renal impairment, CNS disorders, or when given at high doses 1
• Meropenem can significantly reduce valproate levels by 60-100%, potentially leading to breakthrough seizures, due to its inhibition of valproate's reabsorption from the intestine and increased metabolism
• Blood level monitoring of antiepileptic drugs is recommended during meropenem therapy, with possible dose adjustments or alternative antibiotics like ceftazidime or piperacillin-tazobactam if appropriate for the infection
• If seizures occur during meropenem therapy, discontinuation of the drug should be considered, and appropriate seizure management should be provided

It is essential to note that the main risk factor associated with neurological toxicity of beta-lactam antibiotics, including meropenem, is renal failure, which may cause rapid and significant accumulation of the drug 1. Therefore, careful consideration of the patient's renal function and dose adjustment as needed is crucial to minimize the risk of seizures and other neurotoxic effects.

From the FDA Drug Label

5.3 Seizure Potential Seizures and other adverse CNS experiences have been reported during treatment with meropenem for injection. These experiences have occurred most commonly in patients with CNS disorders (e.g., brain lesions or history of seizures) or with bacterial meningitis and/or compromised renal function During clinical investigations, 2904 immunocompetent adult patients were treated for non-CNS infections with the overall seizure rate being 0. 7% (based on 20 patients with this adverse event). All meropenem-treated patients with seizures had pre-existing contributing factors. Among these are included prior history of seizures or CNS abnormality and concomitant medications with seizure potential Dosage adjustment is recommended in patients with advanced age and/or adult patients with creatinine clearance of 50 mL/min or less Close adherence to the recommended dosage regimens is urged, especially in patients with known factors that predispose to convulsive activity. Continue anti-convulsant therapy in patients with known seizure disorders If focal tremors, myoclonus, or seizures occur, evaluate neurologically, placed on anti-convulsant therapy if not already instituted, and re-examine the dosage of meropenem for injection to determine whether it should be decreased or discontinued.

1. 4 Risk of Breakthrough Seizures Due to Drug Interaction with Valproic Acid The concomitant use of meropenem and valproic acid or divalproex sodium is generally not recommended. Case reports in the literature have shown that co-administration of carbapenems, including meropenem, to patients receiving valproic acid or divalproex sodium results in a reduction in valproic acid concentrations The valproic acid concentrations may drop below the therapeutic range as a result of this interaction, therefore increasing the risk of breakthrough seizures. Increasing the dose of valproic acid or divalproex sodium may not be sufficient to overcome this interaction Consider administration of antibacterial drugs other than carbapenems to treat infections in patients whose seizures are well controlled on valproic acid or divalproex sodium. If administration of meropenem for injection is necessary, consider supplemental anti-convulsant therapy

• Meropenem and Seizures: Meropenem may increase the risk of seizures in patients with a history of seizures or CNS disorders.
• Concomitant Use with Valproic Acid: The concomitant use of meropenem and valproic acid is not recommended due to the risk of reduced valproic acid concentrations and increased risk of breakthrough seizures.
• Recommendations: Continue anti-convulsant therapy in patients with known seizure disorders, and consider supplemental anti-convulsant therapy if meropenem is necessary in patients taking valproic acid or divalproex sodium 2.
• Key Considerations: Dosage adjustment is recommended in patients with advanced age and/or compromised renal function, and close adherence to the recommended dosage regimens is urged, especially in patients with known factors that predispose to convulsive activity 2.

From the Research

Relationship Between Meropenem and Seizures

• The study 3 found that in meropenem-treated patients with meningitis, the incidence of seizures was low and none were drug-related.
• In patients with infections other than meningitis, the incidence of seizures considered by the investigators to be related to meropenem was 0.08% 3.
• Another study 4 reported no adverse events of seizures or allergic reactions related to the study drug in critically ill patients with sepsis.
• A review of clinical outcomes associated with two meropenem dosing strategies found that all studies reported no difference in clinical outcomes, including seizure rates 5.

Meropenem Dosing Strategies

• The alternative dosing regimen of meropenem 500 mg intravenously every 6 hours could be considered a therapeutic option, with no difference in clinical outcomes, including seizure rates, compared to the traditional dosing regimen of 1 g every 8 hours 5.
• Therapeutic drug monitoring (TDM) of meropenem can help maximize clinical outcomes by providing suitable levels of meropenem and guiding the most appropriate dose regimens, which is the main parameter associated with therapeutic success 6.

Patient Populations

• Critically ill patients and those with impaired renal function appear to be the most suitable patients for the application of meropenem TDM, in order to guide therapy 6.
• The study 7 excluded patients with infective endocarditis and central nervous system infection, as well as patients with known meropenem allergy.