Cefepime-Induced Neurotoxicity

It should come to the surprise to no one that antibiotics tend to be the class of medications most commonly prescribed. From the “z-pack” to “augmentin” and the quinolones, they are a mainstay for outpatient and inpatient medicine. On the inpatient side, it is common to see the combination of vancomycin and piperacillin-tazobactam as an empiric regimen. With the concern of possible nephrotoxicity due to the aforementioned combination (which may not be a real thing, see here), many switch Zosyn to cefepime to achieve pseudomonas coverage. One of the phenomena has been the higher prevalence of encephalopathy associated with cephalosporins, with cefepime being the prime example and the most commonly cited suspect. 

CNS adverse events from beta-lactams are not new. One of the earliest reports came in 1945, where a 22-month old treated with intraventricular penicillin for meningitis developed seizures as a result (1). Since then, many basic science studies have demonstrated the epileptogenic activity of beta-lactams. In one animal study, older cephalosporins tended to have more epileptogenic activity compared to the newer ones, with seizure-activity being dose-dependent (2):

Intraventricular injection of beta-lactam antibiotics into adult Wistar rats found that cefazolin yielded the highest seizure score in a dose-dependent manner (3):

The hypothetical pathological basis for beta-lactams inducing seizures seems to be blockage of GABAergic receptors, which is involved in inhibitory activity within the brain. In a similar study, intracerebral injections of several antibiotics were used to evaluate convulsive activities in mice (4). A binding and functional assay was used to evaluate this, and not surprisingly, all antibiotics yielded convulsive activity in a dose-dependent fashion:

When looking at the most potent antibiotics, cefazolin had the most potency yielding seizures in 50% of the tested animals at the lowest dose. This was correlated with the ability to displace the muscimol from the GABAergic receptors, which was calculated using the inhibitor constant, Ki, which is the concentration at which the antibiotic displaces GABA from its receptors:

In other words, the lower the Ki, the lower the concentration needed to displace GABA from its receptors. Indeed, this same study found that cephalosporins had no effect on NMDA-R binding.

Clinical Data:

What does beta-lactam neurotoxicity look like? When it comes to cefepime, several case reports have noted the sudden onset of acute delirium in those septic patients that get the antibiotic (5). More robust data comes from retrospective data and reviews. A retrospective cohort study involving 319 patients with cefepime-induced neurotoxicity found the most common symptoms included confusion, agitation, hallucinations, and decreased level of consciousness a median of 2 hospital days after starting cefepime (6). In this cohort, cefepime plasma concentrations were correlated with neurotoxicity:

Indeed, those patients who had a trough of under 7.7 had no risk of developing neurotoxicity. 

Multivariate regression analysis found that mean plasma concentration, ICU stay during admission, and hematological malignancies were the most common risk factors for neurotoxicity. Further, higher eGFR was protective against neurotoxicity, with the highest proportion of those with cefepime induced neurotoxicity having an eGFR of <30ml/min/1.73m3.

A review of 37 studies representing 135 patients found that 80% had some degree of renal dysfunction, with symptoms manifesting themselves in a median of 4 days after initiation of therapy (7). 47% of cases had decreased consciousness, myoclonus was found in 42%, confusion in 42%, seizures in 13%, and agitation in 11%. One of the best tables on the topic comes from this review:

Another review of 71 studies and 198 patients had similar findings; 87% of the patients had renal dysfunction, and median onset of symptoms after cefepime start was 5 days (8). The following symptoms were the most  commonly seen:

A retrospective ICU cohort found that patients with cefepime neurotoxicity were more likely to have chronic renal insufficiency and less likely to have appropriate dose reduction of cefepime (9):

Of course, the diagnosis is difficult to make and if cefepime is on board, it would be reasonable to stop it in someone who is encephalopathic all of the sudden. EEG may help, but its non-specific. A review of 8 patients with cefepime-induced encephalopathy evaluated the EEGs of 4 of these (10). Here, diffuse slow-wave activity (delta waves) and triphasic sharp wave activity were noted, which was suggestive of a metabolic toxic disturbance.

A review of 8 patients revealed that symptoms included decreased consciousness, global aphasia, myoclonus, choreoathetosis, confusion, and coma. Of these, 4 patients underwent an EEG which revealed diffuse slow-wave activity (delta) and triphasic sharp wave activity, suggestive metabolic toxic disturbance. Further EEG data comes from a cohort of 11 patients (11). Here, EEG demonstrated severe generalized polymorphic delta slowing in all, symmetrical in 7, and with a hemispheric predominance in 4. 10 patients had triphasic waves. A review of 34 EEGs also revealed triphasic waves as the predominant waveform:

Next time you have a septic patient on cefepime with an AKI and they develop altered mental status, think about stopping the cefepime first.

References:

1. Johnson HC, Walker AE. INTRAVENTRICULAR PENICILLIN: A NOTE OF WARNING. JAMA. 1945;127(4):217–219. doi:10.1001/jama.1945.9286004000100
2. Yu QH, Kitazumi K, Kamei C, Tasaka K. Epileptogenic activity induced by intravenous injection of certain cephalosporins in rats. J Pharmacobiodyn. 1984 Aug;7(8):586-92. doi: 10.1248/bpb1978.7.586. PMID: 6512680.
3. De Sarro A, De Sarro GB, Ascioti C, Nisticó G. Epileptogenic activity of some beta-lactam derivatives: structure-activity relationship. Neuropharmacology. 1989 Apr;28(4):359-65. doi: 10.1016/0028-3908(89)90030-0. PMID: 2747848.
4. Sugimoto M, Uchida I, Mashimo T, Yamazaki S, Hatano K, Ikeda F, Mochizuki Y, Terai T, Matsuoka N. Evidence for the involvement of GABA(A) receptor blockade in convulsions induced by cephalosporins. Neuropharmacology. 2003 Sep;45(3):304-14. doi: 10.1016/s0028-3908(03)00188-6. PMID: 12871648.
5. Saini T, Gaines MN, Sohal A, Li L. Cefepime-Induced Neurotoxicity. Cureus. 2021 Sep 8;13(9):e17831. doi: 10.7759/cureus.17831. PMID: 34660040; PMCID: PMC8502754.
6. Boschung-Pasquier L, Atkinson A, Kastner LK, Banholzer S, Haschke M, Buetti N, Furrer DI, Hauser C, Jent P, Que YA, Furrer H, Babouee Flury B. Cefepime neurotoxicity: thresholds and risk factors. A retrospective cohort study. Clin Microbiol Infect. 2020 Mar;26(3):333-339. doi: 10.1016/j.cmi.2019.06.028. Epub 2019 Jul 5. PMID: 31284030.
7. Payne LE, Gagnon DJ, Riker RR, Seder DB, Glisic EK, Morris JG, Fraser GL. Cefepime-induced neurotoxicity: a systematic review. Crit Care. 2017 Nov 14;21(1):276. doi: 10.1186/s13054-017-1856-1. PMID: 29137682; PMCID: PMC5686900.
8. Appa AA, Jain R, Rakita RM, Hakimian S, Pottinger PS. Characterizing Cefepime Neurotoxicity: A Systematic Review. Open Forum Infect Dis. 2017 Oct 10;4(4):ofx170. doi: 10.1093/ofid/ofx170. PMID: 29071284; PMCID: PMC5639733.
9. Fugate JE, Kalimullah EA, Hocker SE, Clark SL, Wijdicks EF, Rabinstein AA. Cefepime neurotoxicity in the intensive care unit: a cause of severe, underappreciated encephalopathy. Crit Care. 2013 Nov 7;17(6):R264. doi: 10.1186/cc13094. PMID: 24200036; PMCID: PMC4057506.
10. Sonck J, Laureys G, Verbeelen D. The neurotoxicity and safety of treatment with cefepime in patients with renal failure. Nephrol Dial Transplant. 2008 Mar;23(3):966-70. doi: 10.1093/ndt/gfm713. Epub 2008 Jan 5. PMID: 18175786.
11. Triplett JD, Lawn ND, Chan J, Dunne JW. Cephalosporin-related neurotoxicity: Metabolic encephalopathy or non-convulsive status epilepticus? J Clin Neurosci. 2019 Sep;67:163-166. doi: 10.1016/j.jocn.2019.05.035. Epub 2019 Jun 11. PMID: 31201049.