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

Abstract and Introduction

Abstract

Antimicrobials are the most frequently implicated class of drugs in druginduced 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.

Introduction

Seizure activity secondary to antimicrobial agents is widely described in the literature. The first report was described in 1945, secondary to use of intraventricular benzylpenicillin in a 22-month-old infant with meningitis.[1] Since that time, numerous other reports of seizure activity secondary to antimicrobial agents have been published. One surveillance study reported a frequency of antibiotic-associated seizure of 0.3%. This rate was 3 times greater than that seen with any other class of drugs.[2] Other estimates report the rate of antibiotic-induced seizure as high as 2%.[3]

Data on antibiotic-associated seizure come from animal studies, retrospective database studies, and case reports, with β-lactams being the most frequently implicated class of antimicrobials.[1,2,4,5] Similar to other β-lactams, structural and pharmacokinetic properties of the carbapenem subclass influence their propensity to cause seizure activity, including achievement of high concentrations in cerebral tissues.[6]

Phase III trials and postmarketing studies identified a high rate of seizure with imipenemcilastatin, the first widely used carbapenem. Since their introduction, the carbapenems have become a frequently used subclass of antimicrobials to treat a wide variety of infections including meningitis. Although the penetration of carbapenems through the blood-brain barrier enhances their ability to treat central nervous system (CNS) infections, it can also increase their epileptogenic potential. Meropenem, the second most widely used agent of this class in the United States, received significant scrutiny about its epileptogenic potential but appears to have a lower rate of seizure relative to that of imipenemcilastatin. There are also several new or emerging carbapenems, whose epileptogenic potential is not yet widely reported. In addition, carbapenem use can be expected to increase with time as the prevalence of multidrug-resistant gram-negative pathogens rises. Availability of a once-daily option, such as ertapenem, increases utilization in the outpatient setting and as surgical prophylaxis. Clinician awareness of seizure potential is critical to the safe use of these agents. Although no controlled studies have examined carbapenem-associated seizure, the mechanisms for drug-induced seizure, risk factors, and drug interactions have been well described.[7,8]

The purposes of this review are to discuss possible mechanisms associated with carbapenem-induced seizures, highlight patient- and drug-specific characteristics that predispose seizures, review data on seizure activity with currently marketed carbapenems and agents in development, outline available practical considerations for prevention and management, discuss relevant drug interactions, and describe clinical considerations when selecting carbapenem agents.

Throughout this review, standardized terms in accordance with the International League Against Epilepsy or medical terminology are used.[9–11] Seizure and seizure activity are used interchangeably, and in this context are defined as an abnormal electrical discharge in the brain with physical manifestations including convulsions and altered consciousness.[10] Status epilepticus is defined as a single prolonged seizure or series of seizures without full recovery that lasts 30 minutes or more.[11] Epileptogenic is a term used to describe an agent or event that produces seizure activity.[10] When described, terminology pertaining to seizure activity is as reported in the reference source.

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