Epileptogenic Potential of Carbapenem Agents: Mechanism of Action, Seizure Rates, and Clinical Considerations

Abstract

Antimicrobials are the most frequently implicated class of drugs in drug-induced seizure, with β-lactams being the class of antimicrobials most often implicated. The seizure-inducing potential of the carbapenem subclass may be directly related to their β-lactam ring structure. Data on individual carbapenems and seizure activity are scarce. To evaluate the available evidence on the association between carbapenem agents and seizure activity, we conducted a literature search of the MEDLINE (1966-May 2010), EMBASE (1974-May 2010), and International Pharmaceutical Abstracts (1970-May 2010) databases. Reference citations from the retrieved articles were also reviewed. Mechanistically, seizure propensity of the β-lactams is related to their binding to γ-aminobutyric acid (GABA) receptors. There are numerous reports of seizure activity associated with imipenem-cilastatin, with seizure rates ranging from 3-33%. For meropenem, doripenem, and ertapenem, the seizure rate for each agent is reported as less than 1%. However, as their use increases and expands into new patient populations, the rate of seizures with these agents may increase. High-dose therapy, especially in patients with renal dysfunction, preexisting central nervous system abnormalities, or a seizure history increases the likelihood of seizure activity. Although specific studies have not been conducted, data indicate that carbapenem-associated seizure is best managed with benzodiazepines, followed by other agents that enhance GABA transmission. Due to the drug interaction between carbapenems and valproic acid, resulting in clinically significant declines in valproic acid serum concentrations, the combination should be avoided whenever possible. Clinicians should be vigilant regarding the possibility of carbapenem-induced seizures when selecting and dosing antimicrobial therapy.

Ertapenem-induced Neuropsychiatric Symptoms in an Elderly Patient with Chronic Kidney Disease Resulting to a Prescribing Cascade

“…Seizure as a rare but a major side-effect of carbapenems are widely reported in literature but non-seizure, neurotoxic events have scarce, limited information available. It is estimated that carbapenem-induced seizure is most with imipenemcilastin (3-33%) [1] but the remaining carbapenems (doripenem, meropenem, ertapenem) have a prevalence of less than 1%. On the other hand, non-seizure toxicity has no prevalence estimate due to a trickle of documented reports involving a small population of patients from post-marketing surveillance.…”

“…It can range from seizures to non-seizure toxicity (agitation, hallucination, delirium, etc.) It is estimated that carbapenem-induced seizure is most with imipenem-cilastin (3-33%) [1], but the remaining (doripenem, meropenem, ertapenem) have a prevalence of less than 1%. Seizure as an adverse drug reaction is highly documented.…”

Drugs that lower the seizure threshold

“…2 Correspondingly, they have dose-dependent effects on the seizure threshold. 3,4 However, the CNS penetration of penicillins and cephalosporins is relatively low. 5 As such, most reports of seizures associated with these agents emerge from their use in high doses (often in the treatment of CNS infections) or in renal failure.…”

Oral and Intramuscular Treatment Options for Early Postpartum Endometritis in Low-Resource Settings

“…49,87 However, meropenem may be a better option because the side effect profile for imipenem-cilastatin includes seizures and neurotoxicity, which are less frequently observed with meropenem. 88,89 Meropenem administered intravenously was efficacious in one study; however, thrice-daily dosing may limit the feasibility using these antimicrobials to treat postpartum endometritis in the community.…”