Evidence for the involvement of GABAA receptor blockade in convulsions induced by cephalosporins

Sugimoto, Masahiro; Uchida, Ichirō; Mashimo, Takashi; Yamazaki, Shigeaki; Hatano, Kazuo; Ikeda, Fumiaki; Mochizuki, Yoshitaka; Terai, Takao; Matsuoka, Naoki

doi:10.1016/s0028-3908(03)00188-6

Cited by 168 publications

(125 citation statements)

References 36 publications

Supporting

Mentioning

117

Contrasting

Unclassified

Order By: Relevance

“…3 Renal insufficiency is a well-recognized risk factor for cefepime neurotoxicity 4,5 and it was present in our patient; however, cases of encephalopathy and status epilepticus have been reported in patients with normal renal function. 6,7 Cefepime neurotoxicity is not widely recognized by clinicians.…”

Section: Discussionmentioning

confidence: 50%

Cefepime neurotoxicity can mimic postanoxic coma with myoclonic status epilepticus

Hocker

Rabinstein

2011

Neur Clin Pract

View full text Add to dashboard Cite

A 61-year-old woman admitted for operative treatment of aortic and mitral stenosis and coronary artery bypass grafting developed encephalopathy and abnormal movements postoperatively. The evening after surgery, she was hypoxic and hypotensive. The following day, she was awake and following commands without any obvious focal deficits. Over subsequent days her mental status worsened as she remained in shock. Hypoperfusion of the kidneys and liver resulted in acute tubular necrosis and transaminitis. On postoperative day 2 she was started empirically on cefepime and vancomycin for fever and leukocytosis of unknown origin. Her level of consciousness gradually declined and by the fifth postoperative day she was comatose and had developed repetitive involuntary movements of the face consisting of sudden opening of the eyes and opening and closing of the jaw. The movements of the mouth were forceful enough to damage 2 endotracheal tubes. She also had dystonic-like movements in the lower extremities. The movements had myoclonic features but at times appeared more dystonic and were strongly exacerbated by stimulation, particularly when applied to the feet (video). Dexmedetomidine was used to minimize the movements. When sedation was held the movements increased and her examination otherwise remained unchanged. The patient's eyes were partially open but she did not track light or moving objects. Brainstem reflexes were preserved but she had no motor response to pain in any of the extremities. A noncontrast CT scan of the brain showed no intracranial pathology. An EEG showed no electroencephalographic correlate to the movements. The background was diffusely slow in the range of 1-4 Hz with intermixed and ␤ activity and no reactivity was observed. The following day, the patient's antibiotic regimen was changed from cefepime to piperacillin/tazobactam for additional anaerobic coverage as fever and leukocytosis remained present and no source had been identified. On the sixth postoperative day, she had regained consciousness and could interact with family and examiners. She could answer questions by shaking and nodding her head and could follow commands in all extremities. The abnormal movements were much less prominent and did not require dexmedetomidine to prevent damage to the endotracheal tube; however, the presence of the tube clearly made the movements of the face more frequent. The following day she underwent tracheostomy placement with removal of the endotracheal tube after which the facial movements disappeared.

show abstract

Section: Discussionmentioning

confidence: 50%

Cefepime neurotoxicity can mimic postanoxic coma with myoclonic status epilepticus

Hocker

Rabinstein

2011

Neur Clin Pract

View full text Add to dashboard Cite

show abstract

“…Convulsions induced by ␤-lactam antibiotics are associated with inhibition of GABA receptor binding (13,18). Cefepime also induces convulsions in mice when administered intracerebroventricularly (8). PTZ is a potent proconvulsant that acts as an indirect GABA A antagonist at the picrotoxin binding site of the GABA A complex (13).…”

Section: Discussionmentioning

confidence: 99%

“…administration are likely to be much lower than those following intracerebroventricular administration, and indeed, cefepime concentrations in cerebrospinal fluid are 9% of the corresponding peak plasma drug concentrations (20). The corrected 50% cytotoxic dose (CD 50 ) value (calculated to normalize based on protein binding [29%]) for cefepime-induced convulsions was 51.3 g/ animal for in vivo intracerebroventricular administration (8). Therefore, convulsive liability of antibiotics may be attributable to penetration through the blood-brain barrier, rather than intrinsic central nervous system effects.…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, while most reported mortalities involve patients with renal failure (3)(4)(5), cases of status epilepticus in patients with normal renal function do occur (6,7). Central nervous system toxicity is believed to be the cause of status epilepticus, and animal studies show that the mechanism underlying cefepime-induced status epilepticus involves blockage of gamma-aminobutyric acid A (GABA A ) receptors (8). This study examined the convulsive effects of cefepime using both in vivo intracerebroventricular administration in mice and in vitro models.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Convulsive Liability of Cefepime and Meropenem in Normal and Corneal Kindled Mice

Tanaka

Takechi

Watanabe

et al. 2014

Antimicrob Agents Chemother

View full text Add to dashboard Cite

bWe have reported significantly higher convulsion prevalence in patients treated with cefepime than in those treated with meropenem. Additionally, cefepime-associated convulsions were found only in patients with brain disorders, not renal failure. Here, we compared the convulsive liability of cefepime and meropenem administered intravenously in normal and corneal kindled mice with low seizure thresholds. We used the proconvulsive test in normal mice following pentylenetetrazol (PTZ) injection and electroconvulsive shock at low-stimulus currents and in corneal kindled mice. We also measured electroencephalogram (EEG) activity 1 min after antibiotic injections. Intravenous injection of cefepime and meropenem at 250 or 500 mg/kg of body weight had no effect on PTZ-induced convulsions in normal mice. However, in convulsions induced by electroconvulsive shock at low-stimulus currents, mean seizure stage following cefepime administration at 500 mg/kg was significantly higher than that following saline injection. Additionally, EEG spikes were recorded for mice that were given cefepime (500 mg/kg). In corneal kindled mice following cefepime injection, mean seizure stage was significantly higher than that following meropenem injection. The convulsive liability of cefepime is significantly higher than that of meropenem in normal and corneal kindled mice. In patients with low seizure thresholds, convulsive liability of cefepime may be assumed.

show abstract

“…These findings indirectly suggest that the excess mortality might be due to toxicity. In vitro and in vivo studies have attributed the proconvulsive effect of cephalosporins to the drug-induced suppression of inhibitory neurotransmission via a concentration-dependent modulation of the ␥-amino-butyric acid [(GABA) A ] receptors (24). Cefepime-related neurological toxicity, including encephalopathy, confusion, myoclonia, seizures, or nonconvulsive status epilepticus, has been reported for patients with severe renal dysfunction (2,6,7,13,17,23).…”

mentioning

confidence: 99%

High Cefepime Plasma Concentrations and Neurological Toxicity in Febrile Neutropenic Patients with Mild Impairment of Renal Function

Lamoth

Buclin

Pascual

et al. 2010

Antimicrob Agents Chemother

157

125

View full text Add to dashboard Cite

High-dose cefepime therapy is recommended for febrile neutropenia. Safety issues have been raised in a recent meta-analysis reporting an increased risk of mortality during cefepime therapy. Cefepime-related neurological toxicity has been associated with overdosing due to severe renal dysfunction. This study aimed to investigate the association between cefepime plasma concentrations and neurological toxicity in febrile neutropenic patients. Cefepime trough concentrations (by high-performance liquid chromatography) were retrospectively analyzed for 30 adult febrile neutropenic patients receiving the recommended high-dose regimen (6 g/day for a glomerular filtration rate [GFR] of >50 ml/min). The dose adjustment to renal function was evaluated by the ratio of the cefepime daily dose per 100 ml/min of glomerular filtration. The association between cefepime plasma concentrations and neurological toxicity was assessed on the basis of consistent neurological symptoms and/or signs (by NCI criteria). The median cefepime concentration was 8.7 mg/liter (range, 2.1 to 38 mg/liter) at a median of 4 days (range, 2 to 15 days) after the start of therapy. Neurological toxicity (altered mental status, hallucinations, or myoclonia) was attributed to cefepime in 6/30 (20%) patients (median GFR, 45 ml/min; range, 41 to 65 ml/min) receiving a median dose of 13.2 g/day per 100 ml/min GFR (range, 9.2 to 14.3 g/day per 100 ml/min GFR). Cefepime discontinuation resulted in complete neurological recovery for five patients and improvement for one patient. A multivariate logistic regression model confirmed high cefepime concentrations as an independent predictor of neurological toxicity, with a 50% probability threshold at >22 mg/liter (P ‫؍‬ 0.05). High cefepime plasma concentrations are associated with neurological toxicity in febrile neutropenic patients with mild renal dysfunction. Careful adherence to normalized dosing per 100 ml/min GFR is crucial. Monitoring of plasma concentrations may contribute to preventing neurological toxicity of high-dose therapy for this life-threatening condition.Cefepime, an extended-spectrum cephalosporin, is recommended for the empirical therapy of febrile neutropenia (11). The time during which the antibiotic plasma concentration is higher than the MIC for the causative pathogen is crucial for efficacy under this life-threatening condition (16). High-dose cefepime therapy (6 g/day for a glomerular filtration rate [GFR] of Ͼ50 ml/min) is recommended to achieve coverage of the most frequent bacterial pathogens in febrile neutropenia, including Pseudomonas aeruginosa (9, 26). Despite success rates of up to 60 to 80%, similar to those of other broadspectrum beta-lactams, cefepime therapy has recently been found to be associated with higher mortality rates (29). These findings indirectly suggest that the excess mortality might be due to toxicity. In vitro and in vivo studies have attributed the proconvulsive effect of cephalosporins to the drug-induced suppression of inhibitory neurotransmission via a concen...

show abstract

Evidence for the involvement of GABAA receptor blockade in convulsions induced by cephalosporins

Cited by 168 publications

References 36 publications

Cefepime neurotoxicity can mimic postanoxic coma with myoclonic status epilepticus

Cefepime neurotoxicity can mimic postanoxic coma with myoclonic status epilepticus

Convulsive Liability of Cefepime and Meropenem in Normal and Corneal Kindled Mice

High Cefepime Plasma Concentrations and Neurological Toxicity in Febrile Neutropenic Patients with Mild Impairment of Renal Function

Contact Info

Product

Resources

About