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

Management of Carbapenem-associated Seizure

To our knowledge, no human studies examining treatment of carbapenem-induced seizures have been published. Information on their management comes from the proposed mechanisms of neurotoxicity, animal studies, and case reports. Most management experience is with other β-lactam agents; however, mechanistically, management of carbapenem-induced seizures is similar.

Nonpharmacologic Treatment

As with most cases of drug toxicity, identification and discontinuation of the offending agent is the first and most vital step for management of seizure.[4] Because of similar mechanisms of toxicity, other β-lactam agents should be avoided. In managing severe infections, this can present a significant clinical conundrum for practitioners. After resolution of the initial seizure activity, the complexity of the infection may necessitate careful reinitiation of β-lactams at dosages adjusted for renal dysfunction. The carbapenems are removed by hemodialysis, but no case reports or studies validate it as a treatment modality for toxicity.[6,18,72,80] Removal of the agents by hemodialysis may lead to suboptimal drug levels and risk of infectious complications.

Pharmacologic Treatment

As previously described, antagonism of GABA transmission at both GABA and benzodiazepine receptors by carbapenems provides the rationale for pharmacologic treatment of carbapenem-induced seizures. Benzodiazepines are first-line options for management.[16] The selection of agents to manage status epilepticus secondary to carbapenems requires application of the pharmacology of the agents and differs slightly from usual treatment. Immediate treatment with lorazepam or an alternative benzodiazepine should be implemented. For persistent status epilepticus or continued seizure activity, repeated administration of lorazepam, continuous infusions of midazolam, or intermittent doses of long-acting diazepam could be used.

Barbiturates' influence on GABA transmission makes them another option for treatment of carbapenem-induced seizures.[122] Previous literature classifies them as a first-line option for seizure treatment in this setting. Data on their cognitive adverse effects as well as changes in seizure management have decreased the role of barbiturates in the general treatment of seizures. Therefore, the role of these agents remains unclear, but they do remain a feasible treatment option for patients with intractable carbapenem- induced seizures.

Other anticonvulsant agents have either not been studied or are not suitable for the treatment of seizures in this setting. Phenytoin has been considered for carbapenem-induced seizures, but animal data comparing it with benzodiazepines affirmed the efficacy of benzodiazepines in this setting.[122] Its action on sodium channels makes it less useful for influencing the carbapenems' interference with GABA-ergic transmission. Carbamazepine and oxcarbazepine also do not influence GABA transmission and are not likely to be helpful in management. The interaction between valproic acid and carbapenems leads to grossly subtherapeutic valproic acid levels.[123]

Thus, valproic acid cannot be used in this setting. Although data are unavailable, propofol's GABA agonist activity may make it an option for patients who are refractory or intolerant to benzodiazepines or barbiturates. Levetiracetam has gained recent attention as an option for treating status epilepticus. Data do not exist on its efficacy in treating carbapenem-induced seizures, and its precise mechanism is unknown. It is believed to have a mixed mechanism of action, with some facilitation of GABA transmission. It could be useful for patients refractory to or unable to tolerate benzodiazepines or barbiturates.

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