The incidence of cefepime-induced neurotoxicity (CIN) has been previously underestimated, and there have only been sporadic reports from critical neurological settings. The present study aimed to investigate the potential factors associated with disease development, electroencephalography (EEG) sub-classification, and outcome measures.
The 10-year medical records of patients who underwent EEG between 2007 and 2016 at a tertiary medical center in Taiwan, and developed encephalopathy after cefepime therapy were retrospectively reviewed. Age- and sex-matched controls were included for further analysis. Demographic data, the occurrence of clinical seizures, non-convulsive status epilepticus (NCSE), use of antiepileptic drugs (AEDs), receiving maintenance or urgent hemodialysis, EEG findings, and functional outcomes were analyzed. The Chi-square test and a logistic regression model were applied to survey significant prognostic factors relating to mortality.
A total of 42 CIN patients were identified, including 25 patients from wards and 17 from intensive care units; their mean age was 75.8 ± 11.8 years. Twenty-one patients (50%) had chronic kidney disease, and 18 (43%) had acute kidney injury. Among these patients, 32 (76%) received appropriate cefepime dose adjustment. Three patients had a normal renal function at the time of CIN onset. The logistic regression model suggested that maintenance hemodialysis and longer duration of cefepime use were independently associated with the development of CIN, with odds ratios of 3.8 and 1.2, respectively. NCSE was frequently noted in the CIN patients (64%). Generalized periodic discharge with or without triphasic morphology was the most common EEG pattern (38%), followed by generalized rhythmic delta activity and generalized spike-and-waves. AEDs were administered to 86% of the patients. A total of 17 patients (40%) did not survive to hospital discharge. Adequate cefepime dose adjustment and early cefepime discontinuation led to a better prognosis.
CIN was associated with high mortality and morbidity rates. Neurotoxic symptoms could still occur when the cefepime dose was adjusted, or in patients with normal renal function. Patients with maintenance hemodialysis or a longer duration of cefepime therapy tended to develop CIN. Early recognition of abnormal EEG findings allowed for the withdrawal of the offending agent, resulting in clinical improvements and a better prognosis at discharge.
This is a preview of subscription content, log in to check access.
Buy single article
Instant access to the full article PDF.
Price includes VAT for USA
Subscribe to journal
Immediate online access to all issues from 2019. Subscription will auto renew annually.
This is the net price. Taxes to be calculated in checkout.
Johnson HC, Walker A. Intraventricular penicillin: a note of warning. J Am Med Assoc. 1945;127(4):217–9.
Sugimoto M, Uchida I, Mashimo T, et al. Evidence for the involvement of GABA(A) receptor blockade in convulsions induced by cephalosporins. Neuropharmacology. 2003;45(3):304–14.
Hantson P, Leonard F, Maloteaux JM, Mahieu P. How epileptogenic are the recent antibiotics? Acta Clin Belg. 1999;54(2):80–7.
Plensa E, Gallardo E, Ribera JM, et al. Nonconvulsive status epilepticus associated with cefepime in a patient undergoing autologous stem cell transplantation. Bone Marrow Transplant. 2004;33(1):119–20.
Barbhaiya RH, Knupp CA, Forgue ST, et al. Pharmacokinetics of cefepime in subjects with renal insufficiency. Clin Pharmacol Ther. 1990;48(3):268–76.
Bresson J, Paugam-Burtz C, Josserand J, et al. Cefepime overdosage with neurotoxicity recovered by high-volume haemofiltration. J Antimicrob Chemother. 2008;62(4):849–50.
Smith NL, Freebairn RC, Park MA, et al. Therapeutic drug monitoring when using cefepime in continuous renal replacement therapy: seizures associated with cefepime. Crit Care Resusc. 2012;14(4):312–5.
Chatellier D, Jourdain M, Mangalaboyi J, et al. Cefepime-induced neurotoxicity: an underestimated complication of antibiotherapy in patients with acute renal failure. Intensive Care Med. 2002;28(2):214–7.
Fernandez-Torre JL, Martinez-Martinez M, Gonzalez-Rato J, et al. Cephalosporin-induced nonconvulsive status epilepticus: clinical and electroencephalographic features. Epilepsia. 2005;46(9):1550–2.
Dixit S, Kurle P, Buyan-Dent L, Sheth RD. Status epilepticus associated with cefepime. Neurology. 2000;54(11):2153–5.
Garcés EO, Azambuja MFA, da Silva D, et al. Renal failure is a risk factor for cefepime-induced encephalopathy. J Nephrol. 2008;21(4):526–34.
Fugate JE, Kalimullah EA, Hocker SE, et al. Cefepime neurotoxicity in the intensive care unit: a cause of severe, underappreciated encephalopathy. Crit Care. 2013;17(6):R264.
Khasani S. Cefepime-induced jaw myoclonus. Neurology. 2015;84(11):1183.
Kim A, Kim JE, Paek YM, et al. Cefepime-induced non-convulsive status epilepticus (NCSE). J Epilepsy Res. 2013;3(1):39–41.
Sonck J, Laureys G, Verbeelen D. The neurotoxicity and safety of treatment with cefepime in patients with renal failure. Nephrol Dial Transplant. 2008;23(3):966–70.
Ugai T, Morisaki K, Tsuda K, et al. Cefepime-induced encephalopathy in patients with haematological malignancies: clinical features and risk factors. Scand J Infect Dis. 2014;46(4):272–9.
Alpay H, Altun O, Biyikli NK. Cefepime-induced non-convulsive status epilepticus in a peritoneal dialysis patient. Pediatr Nephrol. 2004;19(4):445–7.
Chang YM. Cefepime-induced nonconvulsive status epilepticus as a cause of confusion in an elderly patient. J Formos Med Assoc. 2015;114(3):290–1.
Landgrave LC, Lock JL, Whitmore JM, Belcher CE. Pediatric cefepime neurotoxicity. Pediatr Neurol. 2012;47(6):458–60.
Lamoth F, Buclin T, Pascual A, et al. High cefepime plasma concentrations and neurological toxicity in febrile neutropenic patients with mild impairment of renal function. Antimicrob Agents Chemother. 2010;54(10):4360–7.
Appa AA, Jain R, Rakita RM, Hakimian S, Pottinger PS. Characterizing cefepime neurotoxicity: a systematic review. Open Forum Infect Dis. 2017;4(4):ofx170.
Payne LE, Gagnon DJ, Riker RR, et al. Cefepime-induced neurotoxicity: a systematic review. Crit Care. 2017;21(1):276.
Naeije G, Lorent S, Vincent JL, Legros B. Continuous epileptiform discharges in patients treated with cefepime or meropenem. Arch Neurol. 2011;68(10):1303–7.
Jallon P, Fankhauser L, Du Pasquier R, et al. Severe but reversible encephalopathy associated with cefepime. Neurophysiol Clin. 2000;30(6):383–6.
Hirsch LJ, LaRoche SM, Gaspard N, et al. American clinical neurophysiology society’s standardized critical care EEG terminology: 2012 version. J Clin Neurophysiol. 2013;30(1):1–27.
Trinka E, Leitinger M. Which EEG patterns in coma are nonconvulsive status epilepticus? Epilepsy Behav. 2015;49:203–22.
Beniczky S, Hirsch LJ, Kaplan PW, et al. Unified EEG terminology and criteria for nonconvulsive status epilepticus. Epilepsia. 2013;54(Suppl 6):28–9.
Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron. 1976;16(1):31–41.
Hocker SE, Britton JW, Mandrekar JN, Wijdicks EF, Rabinstein AA. Predictors of outcome in refractory status epilepticus. JAMA Neurol. 2013;70(1):72–7.
Claassen J. How I treat patients with EEG patterns on the ictal-interictal continuum in the neuro ICU. Neurocrit Care. 2009;11(3):437–44.
Rodriguez V, Rodden MF, LaRoche SM. Ictal-interictal continuum: a proposed treatment algorithm. Clin Neurophysiol. 2016;127(4):2056–64.
Rodriguez Ruiz A, Vlachy J, Lee JW, et al. Association of periodic and rhythmic electroencephalographic patterns with seizures in critically ill patients. JAMA Neurol. 2017;74(2):181–8.
Witsch J, Frey HP, Schmidt JM, et al. Electroencephalographic periodic discharges and frequency-dependent brain tissue hypoxia in acute brain injury. JAMA Neurol. 2017;74(3):301–9.
Yoo JY, Rampal N, Petroff OA, Hirsch LJ, Gaspard N. Brief potentially ictal rhythmic discharges in critically ill adults. JAMA Neurol. 2014;71(4):454–62.
Jirsch J, Hirsch LJ. Nonconvulsive seizures: developing a rational approach to the diagnosis and management in the critically ill population. Clin Neurophysiol. 2007;118(8):1660–70.
Claassen J, Mayer SA, Kowalski RG, Emerson RG, Hirsch LJ. Detection of electrographic seizures with continuous EEG monitoring in critically ill patients. Neurology. 2004;62(10):1743–8.
Foreman B, Claassen J, Abou Khaled K, et al. Generalized periodic discharges in the critically ill: a case-control study of 200 patients. Neurology. 2012;79(19):1951–60.
Passarelli V, da Conceicao MP, Tres ES, Alves-Junior JF, Baldocchi MA. Stimulus-induced rhythmic, periodic, or ictal discharges (SIRPDs) associated with seizures in cefepime neurotoxicity. Arq Neuropsiquiatr. 2014;72(8):643–4.
Shirota Y, Ohtomo R, Hanajima R, et al. Severely abnormal electroencephalogram in two patients who were treated with cefepime. Clin Neurol. 2012;52(5):356–9.
Bragatti JA, Rossato R, Ziomkowski S, Kliemann FAD. Cefepime-induced encephalopathy: clinical and electroencephalographic features in seven patients. Arq Neuropsiquiatr. 2005;63(1):87–92.
Bora I, Demir AB, Uzun P. Nonconvulsive status epilepticus cases arising in connection with cephalosporins. Epilepsy Behav Case Rep. 2016;6:23–7.
Sivaraju A, Gilmore EJ. Understanding and managing the ictal-interictal continuum in neurocritical care. Curr Treat Options Neurol. 2016;18(2):8.
Rubinos C, Reynolds AS, Claassen J. The ictal-interictal continuum: to treat or not to treat (and how)? Neurocrit Care. 2018;29(1):3–8.
Li HT, Wu T, Lin WR, et al. Clinical correlation and prognostic implication of periodic EEG patterns: a cohort study. Epilepsy Res. 2017;131:44–50.
Liu HY, Chou CC, Yen DJ, Yu HY. Varied responses to benzodiazepine treatment in cephalosporin-related generalized periodic discharges. Epileptic Disord. 2016;18(4):399–407.
Lam S, Gomolin IH. Cefepime neurotoxicity: case report, pharmacokinetic considerations, and literature review. Pharmacotherapy. 2006;26(8I):1169–74.
Mani LY, Kissling S, Viceic D, et al. Intermittent hemodialysis treatment in cefepime-induced neurotoxicity: case report, pharmacokinetic modeling, and review of the literature. Hemodial Int. 2015;19(2):333–43.
Martínez-Rodríguez JE, Barriga FJ, Santamaria J, et al. Nonconvulsive status epilepticus associated with cephalosporins in patients with renal failure. Am J Med. 2001;111(2):115–9.
Chapuis TM, Giannoni E, Majcherczyk PA, et al. Prospective monitoring of cefepime in intensive care unit adult patients. Crit Care. 2010;14(2):R51.
Park HM, Noh Y, Yang JW, Shin DH, Lee YB. Cefepime-induced non-convulsive status epilepticus in a patient with normal renal function. J Epilepsy Res. 2016;6(2):97–9.
Johnson E, Hannawi Y, Martinez NC, Ritzl EK. Cefepime-associated SIRPIDs in a patient with normal renal function. Neurohospitalist. 2016;6(4):167–9.
Meillier A, Rahimian D. Cefepime-induced encephalopathy with normal renal function. Oxf Med Case Rep. 2016;2016(6):118–20.
Maganti R, Jolin D, Rishi D, Biswas A. Nonconvulsive status epilepticus due to cefepime in a patient with normal renal function. Epilepsy Behav. 2006;8(1):312–4.
Capparelli FJ, Diaz MF, Hlavnika A, et al. Cefepime- and cefixime-induced encephalopathy in a patient with normal renal function. Neurology. 2005;65(11):1840.
This work was supported by the Chang Gung Memorial Hospital, Taiwan (Grant Nos. CMRPG3F2301, CMRPG3C1121-3 and CMRPG3H0341) and the Ministry of Science and Technology, Taiwan (Grant Nos. NMRPG3E6101-2 and NMRPG3G0231).
Conflict of interest
The authors declare that they have no conflict of interest.
Ethics Approval and Consent to Participate
This retrospective study was conducted according to the regulations of the institutional review board of the Chang Gung Medical Foundation (201801183B0C601). The ethics committees approved the study protocol and waived the need for informed consent because this observational study did not modify the physician’s treatment decisions, and patients’ anonymity was guaranteed.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Electronic supplementary material
Below is the link to the electronic supplementary material.
About this article
Cite this article
Li, H., Lee, C., Wu, T. et al. Clinical, Electroencephalographic Features and Prognostic Factors of Cefepime-Induced Neurotoxicity: A Retrospective Study. Neurocrit Care 31, 329–337 (2019). https://doi.org/10.1007/s12028-019-00682-y
- Cefepime neurotoxicity
- Periodic discharges
- Prognostic factor