Clinical, Electroencephalographic Features and Prognostic Factors of Cefepime-Induced Neurotoxicity: A Retrospective Study

Abstract

Background

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.

Methods

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.

Results

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.

Conclusions

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.

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References

  1. 1.

    Johnson HC, Walker A. Intraventricular penicillin: a note of warning. J Am Med Assoc. 1945;127(4):217–9.

    Google Scholar 

  2. 2.

    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.

    CAS  PubMed  Google Scholar 

  3. 3.

    Hantson P, Leonard F, Maloteaux JM, Mahieu P. How epileptogenic are the recent antibiotics? Acta Clin Belg. 1999;54(2):80–7.

    CAS  PubMed  Google Scholar 

  4. 4.

    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.

    CAS  PubMed  Google Scholar 

  5. 5.

    Barbhaiya RH, Knupp CA, Forgue ST, et al. Pharmacokinetics of cefepime in subjects with renal insufficiency. Clin Pharmacol Ther. 1990;48(3):268–76.

    CAS  PubMed  Google Scholar 

  6. 6.

    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.

    CAS  PubMed  Google Scholar 

  7. 7.

    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.

    PubMed  Google Scholar 

  8. 8.

    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.

    CAS  PubMed  Google Scholar 

  9. 9.

    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.

    PubMed  Google Scholar 

  10. 10.

    Dixit S, Kurle P, Buyan-Dent L, Sheth RD. Status epilepticus associated with cefepime. Neurology. 2000;54(11):2153–5.

    CAS  PubMed  Google Scholar 

  11. 11.

    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.

    PubMed  Google Scholar 

  12. 12.

    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.

    PubMed  PubMed Central  Google Scholar 

  13. 13.

    Khasani S. Cefepime-induced jaw myoclonus. Neurology. 2015;84(11):1183.

    PubMed  Google Scholar 

  14. 14.

    Kim A, Kim JE, Paek YM, et al. Cefepime-induced non-convulsive status epilepticus (NCSE). J Epilepsy Res. 2013;3(1):39–41.

    PubMed  PubMed Central  Google Scholar 

  15. 15.

    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.

    CAS  PubMed  Google Scholar 

  16. 16.

    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.

    CAS  PubMed  Google Scholar 

  17. 17.

    Alpay H, Altun O, Biyikli NK. Cefepime-induced non-convulsive status epilepticus in a peritoneal dialysis patient. Pediatr Nephrol. 2004;19(4):445–7.

    PubMed  Google Scholar 

  18. 18.

    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.

    PubMed  Google Scholar 

  19. 19.

    Landgrave LC, Lock JL, Whitmore JM, Belcher CE. Pediatric cefepime neurotoxicity. Pediatr Neurol. 2012;47(6):458–60.

    PubMed  Google Scholar 

  20. 20.

    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.

    CAS  PubMed  PubMed Central  Google Scholar 

  21. 21.

    Appa AA, Jain R, Rakita RM, Hakimian S, Pottinger PS. Characterizing cefepime neurotoxicity: a systematic review. Open Forum Infect Dis. 2017;4(4):ofx170.

    PubMed  PubMed Central  Google Scholar 

  22. 22.

    Payne LE, Gagnon DJ, Riker RR, et al. Cefepime-induced neurotoxicity: a systematic review. Crit Care. 2017;21(1):276.

    PubMed  PubMed Central  Google Scholar 

  23. 23.

    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.

    PubMed  Google Scholar 

  24. 24.

    Jallon P, Fankhauser L, Du Pasquier R, et al. Severe but reversible encephalopathy associated with cefepime. Neurophysiol Clin. 2000;30(6):383–6.

    CAS  PubMed  Google Scholar 

  25. 25.

    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.

    CAS  PubMed  Google Scholar 

  26. 26.

    Trinka E, Leitinger M. Which EEG patterns in coma are nonconvulsive status epilepticus? Epilepsy Behav. 2015;49:203–22.

    PubMed  Google Scholar 

  27. 27.

    Beniczky S, Hirsch LJ, Kaplan PW, et al. Unified EEG terminology and criteria for nonconvulsive status epilepticus. Epilepsia. 2013;54(Suppl 6):28–9.

    PubMed  Google Scholar 

  28. 28.

    Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron. 1976;16(1):31–41.

    CAS  PubMed  PubMed Central  Google Scholar 

  29. 29.

    Hocker SE, Britton JW, Mandrekar JN, Wijdicks EF, Rabinstein AA. Predictors of outcome in refractory status epilepticus. JAMA Neurol. 2013;70(1):72–7.

    PubMed  Google Scholar 

  30. 30.

    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.

    PubMed  Google Scholar 

  31. 31.

    Rodriguez V, Rodden MF, LaRoche SM. Ictal-interictal continuum: a proposed treatment algorithm. Clin Neurophysiol. 2016;127(4):2056–64.

    PubMed  Google Scholar 

  32. 32.

    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.

    PubMed  Google Scholar 

  33. 33.

    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.

    PubMed  PubMed Central  Google Scholar 

  34. 34.

    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.

    PubMed  Google Scholar 

  35. 35.

    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.

    CAS  PubMed  Google Scholar 

  36. 36.

    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.

    CAS  PubMed  Google Scholar 

  37. 37.

    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.

    PubMed  PubMed Central  Google Scholar 

  38. 38.

    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.

    PubMed  Google Scholar 

  39. 39.

    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.

    Google Scholar 

  40. 40.

    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.

    PubMed  Google Scholar 

  41. 41.

    Bora I, Demir AB, Uzun P. Nonconvulsive status epilepticus cases arising in connection with cephalosporins. Epilepsy Behav Case Rep. 2016;6:23–7.

    PubMed  PubMed Central  Google Scholar 

  42. 42.

    Sivaraju A, Gilmore EJ. Understanding and managing the ictal-interictal continuum in neurocritical care. Curr Treat Options Neurol. 2016;18(2):8.

    PubMed  Google Scholar 

  43. 43.

    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.

    PubMed  Google Scholar 

  44. 44.

    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.

    PubMed  Google Scholar 

  45. 45.

    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.

    PubMed  Google Scholar 

  46. 46.

    Lam S, Gomolin IH. Cefepime neurotoxicity: case report, pharmacokinetic considerations, and literature review. Pharmacotherapy. 2006;26(8I):1169–74.

    PubMed  Google Scholar 

  47. 47.

    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.

    PubMed  Google Scholar 

  48. 48.

    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.

    PubMed  Google Scholar 

  49. 49.

    Chapuis TM, Giannoni E, Majcherczyk PA, et al. Prospective monitoring of cefepime in intensive care unit adult patients. Crit Care. 2010;14(2):R51.

    PubMed  PubMed Central  Google Scholar 

  50. 50.

    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.

    PubMed  Google Scholar 

  51. 51.

    Johnson E, Hannawi Y, Martinez NC, Ritzl EK. Cefepime-associated SIRPIDs in a patient with normal renal function. Neurohospitalist. 2016;6(4):167–9.

    PubMed  Google Scholar 

  52. 52.

    Meillier A, Rahimian D. Cefepime-induced encephalopathy with normal renal function. Oxf Med Case Rep. 2016;2016(6):118–20.

    Google Scholar 

  53. 53.

    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.

    PubMed  Google Scholar 

  54. 54.

    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.

    CAS  PubMed  Google Scholar 

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Funding

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).

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HL contributed to the design, analysis, and interpretation of the data, and drafting of the manuscript for intellectual content. CL contributed to the design and analysis of the data, and revised the manuscript. TW contributed to the design and acquisition of the data. MC, WT, CC, HH, HC, CL, BC, and WL contributed to the interpretation of the data and statistical analysis. SL contributed to the design and conceptualization of the study, the analysis and interpretation of the data, and drafting, revising, and final approval of the manuscript for intellectual content.

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Correspondence to Siew-Na Lim.

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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.

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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

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Keywords

  • Cefepime neurotoxicity
  • Encephalopathy
  • Periodic discharges
  • Prognostic factor
  • Hemodialysis