History of Cerebrovascular Events: A Relative Contraindication to Ertapenem Treatment

TO the Editor—Seizures have been reported to be a rare adverse affect associated with the parenteral β-lactam antimicrobial agent ertapenem [1]. We describe 2 patients treated with ertapenem who developed seizures; each patient's history included an old cerebrovascular accident. Patient 1 was an 85-year-old man who had been admitted to the hospital for treatment of a urinary tract infection. His history included diabetes mellitus, hypertension, chronic renal failure, benign prostatic hypertrophy, and an old cerebrovascular accident. Laboratory values determined at hospital admission included a urea level of 116 mg/dL and a creatinine level of 4 mg/dL. A urinary culture was positive for Klebsiella species. Therapy with ertapenem (500 mg/day) was initiated. On the fourth day of treatment, the patient experienced 3 seizures. A brain CT demonstrated peripheral and central brain atrophy and an old infarction in the left-middle cerebral artery distribution. Antibiotic treatment was modified. Seizures did not recur. Patient 2 was a 71-year-old man who had been admitted for treatment of a urinary tract infection. His history included diabetes mellitus, hypertension, chronic ischemic heart disease, and an old cerebrovascular accident. Laboratory values obtained at hospital admission included a urea level of 95 mg/dL and a creatinine level of 1.95 mg/dL, which normalized the following day. A urinary culture was positive for Escherichia coli. Therapy with ertapenem (500 mg/day) was initiated. On the fifth day of treatment, he experienced 4 seizures, each accompanied by loss of consciousness. A brain CT demonstrated right temporal-parietal and right occipital old infarctions. The antibiotic treatment was modified; seizures recurred the next day and were treated with anti-epileptics, with no recurrence thereafter. The patient recovered and was discharged from the hospital. Infections due to extended-spectrum β-lactamase (ESBL)—producing enterobacteriaceae have increased markedly in recent years. This trend is expected to continue, and in some institutions, it is already increasing exponentially [2]. Antibiotic options for the treatment of ESBL-producing organisms are extremely limited; carbapenems are the treatment of choice for serious infections due to ESBL-producing organisms [3], and seizures have been associated with use of imipenem and meropenem in <1% of patients treated [4]. A safety analysis of meropenem, including data from 46 clinical trials involving hospitalized patients, has shown that the incidence of seizures during treatment exposures in patients with infections other than meningitis was 0.46% for the total number of seizures and 0.08% for drug-related seizures [5]. Calandra et al. [6] reported that the incidence of seizures during treatment with imipenem was as high as 3%. Of 2046 patients enrolled in 5 Phase IIa and 8 Phase IIb/III clinical trials who were treated with 1 g of ertapenem, seizures were rare (0.2%–0.5% of patients); almost all patients who experienced a seizure had an underlying CNS disease or a known seizure disorder [1]. Results of a pooled analysis of adverse event data from trials involving adults with complicated bacterial infection who received ertapenem included headaches in 2.2% and seizures in 0.5% [7]. A Medline search revealed only 1 case in a patient who underwent peritoneal dialysis and who developed refractory seizures after receiving 2 doses of ertapenem [8]. In our hospital, a 1000-bed hospital, 100 patients had received ertapenem in the prior 12 months, including the 2 patients described above who experienced seizures while exposed to the drug. Both patients' histories included a previous cerebrovascular accident. The presence of an underlying CNS disease—an old cerebrovascular accident (thrombotic or embolic), in particular—was the unique risk factor for the development of seizures [6]. Elderly patients in internal medicine wards are currently among the most common sources of colonization with ESBL-producing microorganisms. A substantial number of these patients have had a stroke in the past. Carbapenems appear to be the last resource to treat nosocomial infections caused by ESBL enterobactereacea. Therefore, it is our opinion that prescribing information for ertapenem should list an old cerebrovascular accident specifically as a relative contraindication to drug use. Potential conflicts of interest. All authors: no conflicts.