Neurotoxicity of Carbapenems
Neurotoxicity of Carbapenems
By Jessica C. Song, MA, PharmD
Carbapenems are a class of ß-lactam antibiotics that offer broad-spectrum therapy for patients with a variety of infections, including skin/skin structure, intra-abdominal, lower respiratory tract, meningitis, urinary tract, and bone/joint infections.1-3 Since their introduction in the 1980s, there have been 3 carbapenems, imipenem/cilastatin (Primaxin IV®), meropenem (Merrem IV®), and ertapenem (Invanz®), approved by the Food and Drug Administration (FDA) for clinical use in the United States.
Soon after its introduction to clinical practice, imipenem/cilastatin was recognized to have a higher propensity to produce seizures compared with other b-lactam antibiotics, with one review of 2516 patients reporting an incidence of 1.5%.4,5 However, subsequent reports showed a lower incidence of seizure, as the risk factors for this complication have been recognized by health care workers.4-5 This article will review the mechanism of seizure provocation by carbapenems; review the incidence of seizures associated with carbapenems; review key risk factors for carbapenem-induced seizures; and provide dosing recommendations for carbapenems in renally impaired patients.
Mechanism of Seizure Provocation by Carbapenems
Carbapenem-induced convulsions appear to arise from interference with the inhibitory transmitter function induced by gamma-aminobutyric acid (GABA), thereby resulting in reduced inhibition of epileptic discharges.4,6 One study showed that the concentration of meropenem required to inhibit 50% of GABA binding was 20-fold higher than that of imipenem.7 Other proposed mechanisms of carbapenem-induced seizure may be related to its action on the a-amino-3-hydroxy-5-methyl-isoxazolepropionate (AMPA) and N-methyl-D-aspartate (NMDA) receptor complexes and the basicity of the amino functional group of the C-2 side chain (imipenem, meropenem, and ertapenem have different side chains attached to C-2). Differences in the C-2 side chain may result in varying binding affinities for GABA receptors in the central nervous system (CNS).8
Key Risk Factors/General Features of Carbapenem-Induced Seizures
The seizure types described for patients treated with carbapenems have varied widely and include tonic-clonic generalized, focal, and grand mal, with tonic-clonic generalized seizure representing the most frequently occurring type. 7-19 The average time of seizure onset for imipenem was 7 days after the start of therapy (range, 1-29 days) in a report by Calandra and associates that evaluated data from phase III dose-ranging studies of imipenem (n = 1754).11 Less information on the time of seizure onset is available for meropenem and ertapenem. Klugman and colleagues found that seizures were most likely to occur 3-4 days after the start of meropenem treatment in children with bacterial meningitis (n = 190).7 Two patients experienced seizures 10 days after the start of ertapenem treatment in trials evaluating the efficacy of this drug for the treatment of community-acquired pneumonia (n = 478).13,14
Calandra et al found that renal insufficiency, Pseudomonas infection, dosages in excess of those recommended by the manufacturer, and CNS lesions (or history of seizures) increased the risk of seizures in patients treated with imipenem.11 However, imipenem-induced seizures can occur in patients receiving appropriate doses (dose adjusted for renal insufficiency), as shown by Eng and associates, who reported 5 cases of imipenem-induced seizures.9 Of note, quinolones, theophylline, metronidazole, ganciclovir, and cyclosporine may lower the threshold for seizures in patients concomitantly treated with imipenem.5 In addition, other pharmacologic agents known to cause seizures (see Table 1) should be used with caution when combined with carbapenems.20-22
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Table 1 |
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Drugs Reported to Cause Seizures |
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| Drug Class | Drug(s) |
| Antivirals | amantadine, rimantadine, acyclovir, ganciclovir, foscarnet |
| Beta-lactams | oxacillin, penicillin, piperacillin/tazobactam, cephalosporins |
| Quinolones | nalidixic acid, ciprofloxacin, levofloxacin, ofloxacin |
| Anticholinesterase agents | organophosphates, physostigmine, neostigmine |
| Antidepressants | amitriptyline, venlafaxine, fluoxetine, fluvoxamine, sertraline, bupropion |
| Antipsychotics | clozapine, chlorpromazine, haloperidol, quetiapine, risperidone, thioridazine |
| Anxiolytics | benzodiazepines (with abrupt withdrawal) |
| Beta-blockers | propranolol |
| Chemotherapy agents | etoposide, ifosfamide, cisplatinum, L-asparaginase, chlorambucil |
| Antimycobacterial agents | isoniazid, cycloserine |
| General anesthetics | ketamine, halothane, althesin, enflurane |
| Narcotic analgesics | fentanyl, meperidine, pentazocine, propoxyphene |
| Miscellaneous agents | baclofen, cimetidine, cocaine, cyclosporine, ergonovine, folic acid, levodopa, metronidazole, oxytocin, prednisone (with hypocalcemia), salicylates (in overdose), theophylline, metolazone, vitamin K oxide, zolpidem |
Incidence of Seizures
The incidences of seizure associated with imipenem, meropenem, and ertapenem use are reported by the manufacturers to be 0.4%, 0.7%, and 0.5%, respectively.1-3 However, Pestotnik and colleagues showed that appropriate dosing of imipenem resulted in a much lower frequency of seizures in a study of 1951 patients than previously reported in the literature. The frequency of seizures in their patients was 0.2%.10 Moreover, safety data from clinical trials of ertapenem published after the prescribing information for this drug became available revealed a seizure incidence of 0.18%.13-19 Table 2 summarizes the key points of the ertapenem studies.
Cunha and associates8 compared the safety data of meropenem with other antibiotics (including imipenem, ceftazidime ± tobramycin or amikacin, cefotaxime + metronidazole, ceftriaxone + amikacin, or clindamycin + gentamicin or tobramycin) from a database of 26 phase III studies. The frequency of seizures was 0.7% for both meropenem and imipenem, compared with a frequency of 0.2% for cephalosporin-treated patients. To date, no clinical trial comparing the incidence of seizures induced by ertapenem with that of imipenem or meropenem has been published.
Carbapenem Dose Adjustment for Renal Impairment
Table 3 summarizes the dose adjustments required for renally impaired patients receiving carbapenems at Santa Clara Valley Medical Center.
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Table 3 |
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SCVMC Guide to Adult Antimicrobial Therapy 2003 |
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| Drug | CrCl > 50 mL/min | CrCl 10-50 mL/min | CrCl < 10 mL/min |
| Imipenema-c | 500 mg IV q.6h. | 500 mg IV q.8-12h | 250-500 mg IV q.12h. |
| Ertapenema,b,d | 1 g IV q.24h. | CrCl < 30 mL/min: 500 mg IV q.24h. | 500 mg IV q.24h. |
| Meropenema,e | 1g IV q.8h. | CrCl 26-50 mL/min: 1g IV q.12h. CrCl 10-25 mL/min: 500 mg IV q.12h. | 500 mg IV q.24h. |
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aMay be removed by hemodialysis, recommend to schedule dose after dialysis bCrCl is normalized to mL/min/1.73 m2 or mL/min/72 kg cSanford Guide (2003) recommends giving imipenem after hemodialysis and the recommended CAPD dose is 125-250 mg IV q 12h dFor patients on hemodialysis: If ertapenem is administered (500 mg IV) at least 6 hours prior to dialysis, no supplementary dose is necessary. However, if ertapenem (500 mg IV) is administered within 6 hours prior to hemodialysis, a supplementary dose of 150 mg is recommended after the dialysis session. No data on patients undergoing peritoneal dialysis or hemofiltration (continuous arteriovenous or venous-venous) is available. eSanford Guide (2003) recommends giving meropenem after hemodialysis and the recommended CAPD dose is 500 mg IV q 24h. |
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Conclusion
In summary, all carbapenems are potentially neurotoxic and may cause seizures. However, seizures have not been a major problem except for situations when dosing exceeds recommended guidelines. Therefore, it is important to individualize carbapenem regimens for patients’ renal function and to use these drugs with caution in patients receiving other drugs known to cause seizures or in patients with a history of CNS disorders or seizures.
Ms. Song is Assisant Professor of Pharmacy Practice, University of the Pacific School of Pharmacy, Stockton, Calif.; Pharmacist Specialist, Santa Clara Valley Medical Center, San Jose, Calif.
References
1. Imipenem and Cilastatin Sodium (Primaxin IV®) prescribing information. Whitehouse Station, NJ: Merck & Co. Inc.; 2001.
2. Meropenem (Merrem IV®) prescribing information. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2001.
3. Ertapenem (Invanz®) prescribing information. Whitehouse Station, NJ: Merck & Co. Inc.; 2001.
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8. Cunha BA. Int J Antimicrob Agents. 1999;11:167-177.
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Carbapenems are a class of ß-lactam antibiotics that offer broad-spectrum therapy for patients with a variety of infections, including skin/skin structure, intra-abdominal, lower respiratory tract, meningitis, urinary tract, and bone/joint infections.Subscribe Now for Access
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