Cefepime Neurotoxicity

Cefepime is a cephalosporin antibiotic typically used when broad spectrum coverage including Pseudomonas aerigonsa is needed. However, it can produce cefepime neurotoxicity with encephalopathy, myoclonus, reversible aphasia, and/or convulsive or subclinical seizures.

Risk factors for cefepime neurotoxicity

Retrospective studies have shown neurotoxicity is most likely when the cefepime dose is insufficiently corrected for renal function, with renal dysfunction (even with renal dosing), older age, and abnormal brain imaging (1).

Pharmacological studies suggest neurotoxicity is likely when the trough serum concentration is greater than 22 mg/L (2). It is not practical to measure cefepime concentrations in most institutions, but pharmacokinetic modeling suggests that even doses as small as 2g daily can produce high serum concentrations when eGFR is less than 20 mil/min.

Effect of renal dysfunction

Cefepime is primarily cleared through the kidneys, with a half life of 2-3 hours with normal renal function (3). Renal dysfunction slows clearance, with an increase in half life to 12-13 hours at a GFR of 30 ml/min. There is slower hepatic metabolism, so even in the absence of renal function cefepime would be cleared with a half life of ~22 hours.

The net effect of renal dysfunction is to increase the trough concentration of cefepime. Using an aggressive dosing regimen (eg. total daily dose of 6 g) in a patient with a GFR of 15 could potentially result in a cefepime concentration 3-5 times the estimated toxic level.

Clinical presentation of cefepime neurotoxicity

A subacute development of altered mental status over the course of 1-3 days is typical. The onset of encephalopathy can be delayed from initiation of cefepime 1-5 days, starting sooner the greater the mismatch between renal function and the cefepime dose.

Findings on exam include disorientation that can progress to aphasia, positive myoclonus in the hands and face (see video from Neurology, below), and in extreme cases seizures (1).

Ref. 4

Pathophysiology of cefepime neurotoxicity

Cefepime has been shown in both animal models and in vitro to inhibit GABA-A receptors. Since GABA is the major inhibitory neurotransmitter in the brain, cefepime removes the normal inhibition necessary for normal brain function and for suppressing seizure activity (5).

Evaluation

Cefepime neurotoxicity produces a metabolic encephalopathy that can be difficult to differentiate from other causes of encephalopathy. Indeed, because cefepime is used frequently in critically ill patients there are often multiple potential causes for encephalopathy in addition to cefepime (6).

In addition to a standard altered mental status work up, it important to get an eeg and brain imaging when cefepime neurotoxicity is suspected.

An EEG will most likely show diffuse slowing, but with progressively more severe encephalopathy can show intermittent triphasic waves, multifocal sharp waves, a combination of frequent (1-2 Hz) triphasic waves and multifocal sharp waves (which is otherwise rare), and eventually patterns consistent with seizures or status epilepticus (7). These patterns are consistent with a diffuse loss of inhibitory tone in the brain.

Cefepime neurotoxicity, especially in a patient with normal renal function, raises the possibility of an underlying brain abnormality or injury. Brain imaging with a CT head, or if the patient is stable with MRI, might show an otherwise unsuspected lesion.

Treatment

When possible, the most important treatment step is to stop cefepime (1,8). Since the half life is less than a day even with no renal function, hemodialysis is typically not needed, although can and has been used.

When seizures are present treatment for seizure activity is appropriate. Benzodiazepines can be considered since they act as GABA-A agonists, counteracting cefepime‘s GABA antagonism (1).

It is not always possible to stop cefepime because of a lack of appropriate alternative antibiotics. In this case supportive care with or without continuous EEG monitoring is the primary intervention.

Prognosis

The acute effects of cefepime neurotoxicity are typically reversible, although they can contribute to the acute decline in critically ill patients.

While cefepime is cleared relatively quickly from serum, improvement in mental status can be delayed for days. The exact reasons for this delay are not known, but likely include slow clearance out of the CSF, especially when organic acids that build up with renal dysfunction inhibit the transporters that clear cefepime.

References

• 1. Appa et al., Characterizing Cefepime Neurotoxicity: A Systematic Review. Open Forum Infect Dis 2017.
  2. Lamoth et al., High Cefepime Plasma Concentrations and Neurological Toxicity in Febrile Neutropenic Patients with Mild Impairment of Renal Function. Antimicrob Agents Chemother. 2010, 54:4360–4367.
  3. Tam, VH. et al. Pharmacokinetics and Pharmacodynamics of Cefepime in Patients with Various Degrees of Renal Function. Antimicrobial Agents and Chemotherapy. 2003, 47:1853–1861.
  4. Sina Khasani. Cefepime-induced jaw myoclonus. Neurology. March 17, 2015; 84 (11) VIDEO NEUROIMAGES. First published March 16, 2015, DOI: https://doi.org/10.1212/WNL.0000000000001365
  5. Sugimoto et al. Evidence for the involvement of GABA(A) receptor blockade in convulsions induced by cephalosporins. Neuropharmacology 2003, 45:304-314.
  6. Fugate et al., Cefepime neurotoxicity in the intensive care unit: a cause of severe, underappreciated encephalopathy. Crit Care. 2013 17:R264.
  7. Bora, I, et al., Nonconvulsive status epilepticus cases arising in connection with cephalosporins. Epilepsy & Behavior Case Reports. 2016, 6:23-27.
  8. Chatellier, D., et al. Cefepime-induced neurotoxicity: an underestimated complication of antibiotherapy in patients with acute renal failure. Intensive Care Med. 2002, 28: 214.