Published: 2 March 2023
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Risk of neurotoxicity with cephalosporins
Published: 2 March 2023
Prescriber Update 44(1): 2–4
March 2023
The topic of cephalosporins and neurotoxicity was recently discussed
at the December 2022 Medicines Adverse Reaction Committee (MARC) meeting.
The MARC considered the risk of neurotoxicity with cephalosporins to be a class effect.
Medsafe is working with the sponsors of cephalosporin products to update the data sheets as per the MARC’s recommendations (see MARC’s remarks in this edition of Prescriber Update).
Neurotoxicity may occur with all cephalosporins
Cephalosporins are broad-spectrum beta-lactam antibiotics used in primary and secondary care to treat a range of infections.1
Cephalosporins are grouped into 5 generations based on their antibacterial properties and their discovery.2 Table 1 outlines the cephalosporins generally available in New Zealand, by generation.
Table 1: Cephalosporins available in New Zealand, by generation
| 1st generation | 2nd generation | 3rd generation | 4th generation | 5th generation |
|---|---|---|---|---|
| Cefazolin Cefalexin |
Cefuroxime Cefaclor |
Cefotaxime Ceftazidime Ceftriaxone |
Cefepime | Ceftaroline fosamil Ceftolozane* |
* Ceftolozane is available in combination with tazobactam.
Source: Medsafe. Data sheets and Consumer Medicine Information. URL: medsafe.govt.nz/Medicines/infoSearch.asp (accessed 9 January 2023).
Case report and case series reviews found that compared with other cephalosporins, cefepime was associated with the most reports of neurotoxicity internationally.3,4 However, neurotoxicity has been reported with all generations of cephalosporins.3,4
Cephalosporin-induced neurotoxicity may present as a range of conditions
Reports of neurotoxicity with cephalosporins are mainly characterised by encephalopathy, myoclonus and/or seizures.3,5
Encephalopathy is a broad term which refers to brain dysfunction. It describes an altered mental state, representing a spectrum of symptoms from confusion to depressed levels of consciousness.6
Seizures associated with cephalosporins may present as either convulsive or non-convulsive.7 A disruption in the neurotransmitter gamma-aminobutyric acid (GABA) function is proposed to be a possible mechanism for such events.8
Symptoms of neurotoxicity have been reported to develop within several days after starting treatment and to resolve following discontinuation.3,7
Renal impairment is a risk factor, especially if doses are not adjusted
Cephalosporins are excreted by the kidneys. In patients with renal impairment, accumulation can occur, especially when doses are not adjusted appropriately, potentially leading to toxic effects.3,7
Additional risk factors for cephalosporin-induced neurotoxicity include older age groups, underlying central nervous system (CNS) disorders and high doses of cephalosporins administered by intravenous injection.3,7
Critically unwell patients may experience increased penetration of cephalosporins into the CNS due to blood-brain barrier disruption, which may increase their susceptibility to neurotoxicity.6,8
Advice for health professionals
Recognition of cephalosporin-induced neurotoxicity may be challenging. Patients receiving antibiotics often have multiple potential causes of neurological conditions.6,8
At the December 2022 meeting, the MARC recommended that health professionals should consider cephalosporin-induced neurotoxicity in patients with the above risk factors and an unexplained, new onset neurological condition.9 In such cases, withdrawal of the medicine may be appropriate.9
New Zealand case reports
As of 31 October 2022, the Centre for Adverse Reactions Monitoring (CARM) had received several reports that potentially describe cephalosporin-induced neurotoxicity, as shown in Table 2.
Adverse reactions reported in these cases included seizure, convulsion, myoclonus, confusion, encephalopathy, agitation, hallucination and delirium.
Table 2: Potential cases of cephalosporin-induced neurotoxicity reported to the Centre for Adverse Reactions Monitoring (CARM), by generation and cephalosporin, as of 31 October 2022
| Generationa | Cephalosporin | No. of reports | CARM IDs |
|---|---|---|---|
| 1st | Cefazolin | 7 | 58339, 77512, 86695, 97392, 105241, 122558, 137985 |
| Cefalexin | 2 | 123136, 136282 | |
| 2nd | Cefuroxime | 6 | 24559, 26025, 26764b, 52754, 57256, 87469 |
| Cefaclor | 3 | 22512, 33509, 50548 | |
| 3rd | Cefotaxime | 2 | 26764,b 105295 |
| Ceftazidime | 2 | 28172, 136000 | |
| Ceftriaxone | 2 | 107950, 110187 | |
| 4th | Cefepime | 2 | 98398, 108616 |
Notes:
- There were no reports for the 5th generation cephalosporins ceftaroline and ceftolozane.
- Report 26764 had cefuroxime and cefotaxime as co-suspect cephalosporins.
Source: Centre for Adverse Reactions Monitoring
More information
See the sponsors’ data sheets and Consumer Medicine Information (CMI) published on the Medsafe website.
References
- Best Practice Advocacy Centre (bpacNZ). 2011. Appropriate use of cephalosporins. Best Practice Journal 41: 22–8. URL: bpac.org.nz/BPJ/2011/december/cephalosporins.aspx (accessed 9 January 2023).
- Bui T and Preuss CV. 2022. Cephalosporins. In: StatPearls [Internet] 6 November 2022. URL: ncbi.nlm.nih.gov/books/NBK551517/ (accessed 27 January 2023).
- Lacroix C, Kheloufi F, Montastruc F, et al. 2019. Serious central nervous system side effects of cephalosporins: A national analysis of serious reports registered in the French Pharmacovigilance Database. Journal of the Neurological Sciences 398: 196–201. DOI: 10.1016/j.jns.2019.01.018 (accessed 12 January 2023).
- Bhattacharyya S, Darby RR, Raibagkar P, et al. 2016. Antibiotic-associated encephalopathy. Neurology 86(10):963–71. DOI: 10.1212/wnl.0000000000002455 (accessed 12 January 2023).
- Triplett JD, Lawn ND, Chan J, et al. 2019. Cephalosporin-related neurotoxicity: Metabolic encephalopathy or non-convulsive status epilepticus? Journal of Clinical Neuroscience 67: 163–6. DOI: 10.1016/j.jocn.2019.05.035 (accessed 12 January 2023).
- Chalela J. 2022. Acute toxic-metabolic encephalopathy in adults. In: UpToDate 16 June 2020. URL: uptodate.com/contents/acute-toxic-metabolic-encephalopathy-in-adults (accessed 12 January 2023).
- Bora I, Demir AB and Uzun P. 2016. Nonconvulsive status epilepticus cases arising in connection with cephalosporins. Epilepsy & Behavior Case Reports 6: 23-7. DOI: 10.1016/j.ebcr.2016.04.005 (accessed 12 January 2023).
- Wanleenuwat P, Suntharampillai N and Iwanowski P. 2020. Antibiotic-induced epileptic seizures: Mechanisms of action and clinical considerations. Seizure 81: 167–74. DOI: 10.1016/j.seizure.2020.08.012 (accessed 12 January 2023).
- Medsafe. 2022. Minutes of the 192nd Medicines Adverse Reaction Committee meeting 23 December 2022. URL: medsafe.govt.nz/profs/adverse/Minutes192.htm (accessed 12 January 2023).
