Epileptogenic Potential of Carbapenem Agents

Mechanism of Action, Seizure Rates, and Clinical Considerations

April D. Miller, Pharm.D.; Amanda M. Ball, Pharm.D.; P. Brandon Bookstaver, Pharm.D.; Emily K. Dornblaser, Pharm.D.; Charles L. Bennett, M.D., Ph.D.

Disclosures

Pharmacotherapy. 2011;31(4):408-423. 

In This Article

Clinical Considerations

Data on individual agents indicate a low rate of carbapenem-induced seizure activity. With all agents, however, certain clinical considerations are important in selecting antimicrobial agents and dosing in individual patients to minimize neurotoxicity. Although not reported in individual studies, the mechanisms of seizure and individual case reports of carbapenem-induced seizure highlight patient- and drug-specific factors that increase seizure propensity in individual patients. These include increased drug concentrations and neurologic comorbidities such as a history of seizure disorder or underlying CNS pathologic condition (e.g., previous stroke, brain injury, or tumor). Differences in seizure propensity among different agents and drug interactions are discussed in later sections.

Drug Concentrations

Increased concentrations of carbapenem agents are more likely to precipitate seizure activity. This is secondary to the antagonism of the GABA receptor by these agents, whereby increased doses increase this antagonism and increase the risk of seizure. This phenomenon was not observed in clinical studies; however, most studies excluded patients with underlying renal dysfunction. Increased drug concentrations are likely to be seen in patients with renal dysfunction, especially if dosages are not adjusted appropriately and drug accumulation occurs. Monitoring of renal function and periodic dosage adjustments by practitioners can help prevent drug accumulation, seizure activity, and other toxicities. In addition, data on reduced meropenem elimination from the cerebrospinal fluid (CSF) in patients with hydrocephalus warrants consideration.[20] This has not been studied with other agents, but this change in clearance may increase seizure propensity, and dosage adjustments or the use of alternative agents may be appropriate.

Neurologic Comorbidities

Patients in clinical studies who experienced carbapenem-associated seizure activity frequently had underlying neurologic disorders, including a history of seizures, stroke, brain injury, or other anatomic abnormalities. Therefore, these agents should be used with caution in patients with underlying neurologic conditions, and if possible, an alternative therapy should be chosen.

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