Is there data showing which carbapenems are safest in patients with a history of seizures?

What is the comparative safety profile of individual carbapenems, specifically meropenem, imipenem, and doripenem, in patients with a history of seizures?

Comment by InpharmD Researcher

The absolute risk of seizures with carbapenems overall appears to be low, with imipenem having the highest propensity. One retrospective study in older adults significantly correlated carbapenem-induced seizure in patients with a history of seizures; however, this study also found imipenem to have the lowest incidence of seizures (Table 1). Available data suggest benzodiazepines as an option for carbapenem-associated seizures.

carbapenem seizure "prior history"

Background

Carbapenems’ known ability to cause seizures may be directly tied to their beta-lactam ring structure, which is similar enough to gamma-aminobutyric acid (GABA) to antagonize central GABA receptors. Individual carbapenems and seizure activity data are sparse. A literature search of the MEDLINE (1966-May 2010), EMBASE (1974-May 2010), and International Pharmaceutical Abstracts (1970-May 2010) databases was conducted to determine the existing evidence on the connection between carbapenem agents and seizure activity. There have been multiple instances of seizures linked to imipenem-cilastatin, with seizure rates ranging from 3 to 33%. The seizure rate for meropenem, doripenem, and ertapenem is stated to be less than 1%. However, as their usage grows and expands into new patient populations, the rate of seizures associated with these drugs may rise. High-dose therapy also increases the chance of seizure activity, especially in patients with renal impairment, prior central nervous system disorders, or a seizure history. Although no particular studies have been undertaken, statistics suggest that benzodiazepines are the most effective treatment for carbapenem-associated seizures, followed by other drugs that improve GABA transmission. Because carbapenems and valproic acid interact, resulting in clinically substantial decreases in valproic acid serum concentrations, the combination should be avoided wherever possible. When selecting and prescribing antibiotic medication, clinicians should be cautious of the likelihood of carbapenem-induced seizures. [1]

A 2014 meta-analysis examined randomized controlled trials (RCTs) comparing carbapenems with each other (27 studies) or with non-carbapenem antibiotics (169 studies) to assess the risk of seizures for carbapenems (imipenem, meropenem, ertapenem, and doripenem). The risk difference (RD) analysis, based on 169 studies, resulted in increased patients with seizures (2 per 1000 persons, 95% confidence interval [CI] 0.001 to 0.004) among carbapenem recipients versus non-carbapenem recipients. In particular, imipenem was the largest contributor to such a difference, as its use was associated with an additional 4 patients per 1000 with seizures, whereas no other carbapenem was associated with an increased risk of seizure. The pooled odds ratio (OR) analysis, based on 43 studies, yielded similar results suggesting a significant increase in the risk of seizures for carbapenems relative to non-carbapenem comparator antibiotics (OR 1.87, 95% CI 1.35 to 2.59). The ORs for risk of seizures from imipenem, meropenem, ertapenem, and doripenem compared with other non-carbapenem antibiotics were 3.50 (95% CI 2.23 to 5.49), 1.04 (95% CI 0.61 to 1.77), 1.32 (95% CI 0.22 to 7.74) and 0.44 (95% CI 0.13 to 1.53), respectively. Among carbapenems themselves, imipenem appeared most epileptogenic, yet no statistically significant difference in head-to-head comparisons with meropenem. Seizure risk with meropenem did not appear to be associated with a prior history of seizures or renal failure requiring dialysis, although most of the meropenem studies excluded patients with a seizure history. The authors suggest the absolute risk of seizures with carbapenems is low overall, though higher than non-carbapenem antibiotics, and the epileptogenicity between imipenem and meropenem was not statistically different. Unfortunately, the use of anti-seizure prophylaxis due to the potential seizure risk of carbapenems was not within the scope of this meta-analysis. Of note, though most meropenem studies excluded patients with a prior seizure history, the risk does not appear to necessarily correlate with a prior seizure history. [2]

Imipenem is administered with cilastatin to inhibit renal antibiotic breakdown, but cilastatin does not reduce the seizure threshold. However, imipenem poses the highest seizure risk of carbapenems, with a risk ranging from 3-33%, significantly higher than doripenem and ertapenem, which have risks below 1%. The epileptogenic potential is partly due to interactions with GABAA and AMPA/NMDA receptor complexes, with structural differences influencing the proconvulsive effects. Meropenem presents fewer proconvulsive effects compared to imipenem. Studies suggest that imipenem, when properly dosed and adjusted for renal function, does not significantly heighten seizure risks. Various factors elevate seizure risks during carbapenem therapy, including renal insufficiency, CNS injuries, cerebrovascular disease, and concomitant use of neurotoxic drugs; renal dysfunction necessitates dose adjustments to avoid accumulation and seizures. It is unknown if patients with a prior history of epilepsy are a risk factor for carbapenem-induced seizure. [3]

Literature Review

A search of the published medical literature revealed 2 studies investigating the researchable question:

What is the comparative safety profile of individual carbapenems, specifically meropenem, imipenem, and doripenem, in patients with a history of seizures?

Level of evidence

C - Multiple studies with limitations or conflicting results Read more→

Please see Tables 1-2 for your response.

Higher rates of carbapenem-related seizures in older hospitalised adults
Design	Retrospective study N= 1345
Objective	To compare the seizure incidence among older adults admitted to an acute tertiary hospital and treated with intravenous imipenem, meropenem, or ertapenem
Study Groups	Imipenem (n= 436) Ertapenem (n= 457) Meropenem (n= 452)
Inclusion Criteria	Patients aged 60 years or older who received at least 1-day duration of intravenous imipenem, ertapenem or meropenem during the period from 20 September 2012 to 20 June 2013
Exclusion Criteria	Inpatient admission notes unavailable for review during the data collection period
Methods	Electronic health records were reviewed from a single center in Singapore for patients aged 60 and above who received imipenem, ertapenem, or meropenem. Seizures were considered carbapenem-related if they occurred within a week of starting the medication.
Duration	20 September 2012 to 20 June 2013
Outcome Measures	Primary: Seizure incidence among older adults treated with carbapenems Secondary: Relationships between seizures and advanced age, CNS comorbidities, renal impairment, and prior history of seizures
Baseline Characteristics		Imipenem (n= 436)	Ertapenem (n= 457)	Meropenem (n= 452)	P-value
	Age, mean years	77.0 ± 9.59	76.0 ± 9.42	79.4 ± 9.63	<0.001
	Female	191 (43.8%)	261 (57.1)	206 (45.6)	<0.001
	History of seizures	9 (2.1%)	14 (3.1%)	42 (9.3%)	<0.001
	Creatinine clearance, mL/min/1.73 m²	61.5 ± 50.7	57.8 ± 49.9	44.0 ± 45.6	<0.001
Results		Imipenem (n= 436)	Ertapenem (n= 457)	Meropenem (n= 452)
	Seizure occurrence	3 (0.7%)	16 (3.5%)	13 (2.9%)
	The strongest predictor of seizures was the presence of multiple types of CNS pathologies. Compared to subjects with no known CNS disease, subjects with more than one type of CNS disorder were 11.6 times more likely to develop seizures (OR 11.61; 95% CI 3.74 to 36.09; P< 0.001). Additionally, subjects with a prior history of seizures were shown to have four times greater risks of seizures (OR 4.02; 95% CI 1.51 to 10.67; P = 0.005).
Adverse Events	Higher rates of seizures were observed in patients receiving ertapenem (3.5%) and meropenem (2.9%) compared to imipenem (0.7%)
Study Author Conclusions	Older adults prescribed imipenem, ertapenem, and meropenem have an overall seizure rate of 2.4%, exceeding previous reports. Physicians should exercise caution when prescribing carbapenems in the elderly, especially those with known epilepsy and multiple intracranial pathologies.
Critique	The study's retrospective design may introduce information bias, and unobserved prescribing preferences could affect the results. Additionally, this information is limited to older adults, where ethnicity also appeared to make a difference (Malays had a higher risk of seizure: OR 3.30; 95% CI 1.24 to 8.83; p< 0.05).

References:
[1] Neo HY, Tan KT, Caroline C, et al. Higher rates of carbapenem-related seizures in older hospitalised adults. Intern Med J. 2020;50(1):123-127. doi:10.1111/imj.14693

Carbapenem associated seizure in a severe melioidosis patient: A case report
Design	Case report
Case presentation	A 67-year-old woman in Malaysia presented to an intensive care unit for impending respiratory failure. Her past medical history included diabetes, hypertension, and chronic renal failure, but she had no history of seizures or any neurological disease. Medications upon admission included gliclazide, metformin, hydrochlorothiazide, and perindopril. The patient was ventilated and sedated upon transfer to intensive care unit; although afebrile, laboratory results discovered elevated white blood cell and neutrophil counts, as well as impaired renal function (CrCl 10-20 mL/min). The patient was diagnosed with right pleural effusion secondary to community-acquired pneumonia. Blood, urine, and pleural fluid cultures were negative. She was initiated on intravenous (IV) cefepime 2 g stat followed by 1 g Q12 hours and IV azithromycin 500 mg once daily. Additionally, she was administered IV midazolam 3 mg/hour, IV morphine 3 mg/hour, IV omeprazole 40 mg Q12 hours, and IV hydrocortisone 100 mg Q8 hours. On day 2, improvement was observed in chest x-ray in pleural effusion, but due to fibrotic changes in the right lung, the patient was administered IV imipenem 1 g stat followed by 500 mg Q12 hours for melioidosis. On day 3, a second dose of imipenem 500 mg was given per Q12 hour regimen. Three hours following this dose, the patient exhibited an episode of myoclonus jerks of both upper and lower limbs, followed by two additional episodes at 2 and 4 hours apart. Diazepam 10 mg was given IV at each seizure episode. Myoclonus jerks lasted between 5 to 30 seconds. Imipenem was then discontinued and IV meropenem 1 g stat followed by 500 mg Q12 hours was initiated. Still, the patient continued to experience a total of 6 additional seizures throughout the day. She also underwent hemodialysis for anuria. Then, IV phenytoin 100 mg was administered Q8 hours at the end of admission day 3 for seizure management. Due to no improvement in patient's infectious condition, meropenem dose was increased to 1 g Q12 hours on day 4. The frequency of seizures increased to a total of 14 on day 4 despite phenytoin treatment. Phenytoin was eventually substituted with IV sodium valproate 750 mg stat followed by 400 mg Q12 hours. On the following day, the patient's seizures finally resolved. Antibiotic coverage with meropenem was completed on admission day 9 and sodium valproate was continued until discharge from intensive care unit on day 11.
Study Author Conclusions	Carbapenem therapy in excessive doses may induce myoclonus jerks in severe melioidosis patients with renal dysfunction. In order to avoid this neurotoxicity, the doses of carbapenems should be adjusted based on the patient’s renal function. Other alternatives with better neurotoxicity profiles such as ceftazidime should be used in this kind of patients.

References:
[1] Basil JH, Chong CP. Carbapenem associated seizure in a severe melioidosis patient: A case report. Eastern Journal of Medicine. 2013;(18):92-96.