nnpNeurology, Neuropsychiatry, PsychosomaticsНеврология, нейропсихиатрия, психосоматика2074-27112310-1342"IMA-Press", LLC10.14412/2074-2711-2023-3-76-81nnp-2033Research ArticleCLINICAL OBSERVATIONSКЛИНИЧЕСКИЕ НАБЛЮДЕНИЯCefepime-induced encephalopathyЦефепим-индуцированная энцефалопатияhttps://orcid.org/0000-0002-7437-5214ПушкарьТ. Н.PushkarT. N.

Кафедра нервных болезней лечебного факультета.

127473, Москва, ул. Делегатская, 20, стр. 1

Department of nervous diseases of Medical Faculty.

20, Delegatskaya St., Build. 1, Moscow 127473

https://orcid.org/0000-0001-8321-5864ВласовП. Н.VlasovP. N.

Павел Николаевич Власов - кафедра нервных болезней лечебного факультета.

127473, Москва, ул. Делегатская, 20, стр. 1

Pavel Nikolaevich Vlasov - Department of nervous diseases of Medical Faculty.

20, Delegatskaya St., Build. 1, Moscow 127473

vpn_neuro@mail.ruhttps://orcid.org/0000-0002-2339-8483Белякова-БодинаА. И.Belyakova-BodinaA. I.

125367, Москва, Волоколамское шоссе, 80

80, Volokolamskoye Shosse, Moscow 125367

https://orcid.org/0000-0002-6381-2925БрутянА. Г.BroutianA. G.

125367, Москва, Волоколамское шоссе, 80

80, Volokolamskoye Shosse, Moscow 125367

ФГБОУ ВО «Московский государственный медико-стоматологический университет им. А.И. Евдокимова» Минздрава РоссииРоссияA.I. Evdokimov Moscow State University of Medicine and Dentistry, Ministry of Health of RussiaRussian FederationФГБНУ «Научный центр неврологии»РоссияResearch Center of NeurologyRussian Federation2023040720231537681Copyright © Pushkar T.N., Vlasov P.N., Belyakova-Bodina A.I., Broutian A.G., 20232023Пушкарь Т.Н., Власов П.Н., Белякова-Бодина А.И., Брутян А.Г.Pushkar T.N., Vlasov P.N., Belyakova-Bodina A.I., Broutian A.G.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://nnp.ima-press.net/nnp/article/view/2033

Cefepime is a fourth-generation cephalosporin antibiotic widely used in clinical practice for various organ systems pathology treatment. The article describes the clinical observation of a patient who, 3 days after cefepime administration, had a decrease in the level of consciousness, regarded as encephalopathy. Cefepime-induced neurotoxicity is characterized by toxic encephalopathy, which manifests 2–6 days after the start of the treatment with this drug and disappears 1–3 days after its withdrawal. Electroencephalography (EEG) abnormalities include generalized periodic discharges (GPR) of triphasic morphology or a pattern corresponding to the criteria for non-convulsive status epilepticus (BSES). In our observation, the EEG recorded stimulus-induced GPRs of triphasic morphology with a frequency of 1.5 Hz; a test with intravenous administration of an antiepileptic drug (levetiracetam) was negative. A day after the withdrawal of cefepime, the patient’s level of consciousness returned to the initial level, and on the EEG periodic discharges completely regressed. Thus, cefepime may cause encephalopathy in patients with rhythmic or intermittent EEG activity, especially in the presence of a stimulus-induced component. In some cases, the use of cefepime may develop epileptic seizures and BSES.

Цефепим – цефалоспориновый антибиотик четвертого поколения, широко применяемый в клинической практике при патологии различных систем организма. В статье приведено описание клинического наблюдения пациентки, у которой через 3 дня после назначения цефепима было отмечено снижение уровня сознания, расцененное как энцефалопатия. Цефепим-индуцированная нейротоксичность характеризуется токсической энцефалопатией, которая проявляется через 2–6 дней после начала приема препарата и проходит через 1–3 дня после его отмены. На электроэнцефалограмме (ЭЭГ) при этом регистрируются генерализованные периодические разряды (ГПР) трифазной морфологии или паттерн, соответствующий критериям бессудорожного эпилептического статуса (БСЭС). В приведенном наблюдении на ЭЭГ регистрировались стимул-индуцированные ГПР трифазной морфологии частотой 1,5 Гц; проба с внутривенным введением антиэпилептического препарата (леветирацетам) оказалась отрицательной. Через день после отмены цефепима уровень сознания пациентки возвратился к исходному, а на ЭЭГ полностью регрессировали периодические разряды. Таким образом, цефепим может вызывать энцефалопатию у пациентов с ритмической или периодической активностью на ЭЭГ, особенно при наличии стимул-индуцированного компонента. В ряде случаев при применении цефепима возможно развитие эпилептических приступов и БСЭС.

цефепимэнцефалопатиябессудорожный эпилептический статусэлектроэнцефалографияSIRPIDscefepimeencephalopathynon-convulsive status epilepticuselectroencephalographySIRPIDsИсследование не имело спонсорской поддержки.The investigation has not been sponsoredReferencesHirsch LJ, Fong MWK, Leitinger M, et al. American Clinical Neurophysiology Society’s Standardized Critical Care EEG Terminology: 2021 Version. J Clin Neurophysiol. 2021 Jan 1;38(1):1-29. doi: 10.1097/WNP.0000000000000806Hirsch LJ, Fong MWK, Leitinger M, et al. American Clinical Neurophysiology Society’s Standardized Critical Care EEG Terminology: 2021 Version. J Clin Neurophysiol. 2021 Jan 1;38(1):1-29. doi: 10.1097/WNP.0000000000000806Neu HC. Safety of cefepime: a new extended-spectrum parenteral cephalosporin. Am J Med. 1996 Jun 24;100(6A):68S-75S. doi: 10.1016/s0002-9343(96)00110-6Neu HC. Safety of cefepime: a new extended-spectrum parenteral cephalosporin. Am J Med. 1996 Jun 24;100(6A):68S-75S. doi: 10.1016/s0002-9343(96)00110-6Dakdouki GK, Al-Awar GN. Cefepimeinduced encephalopathy. Int J Infect Dis. 2004 Jan;8(1):59-61. doi: 10.1016/j.ijid.2003.09.003Dakdouki GK, Al-Awar GN. Cefepimeinduced encephalopathy. Int J Infect Dis. 2004 Jan;8(1):59-61. doi: 10.1016/j.ijid.2003.09.003Wong KM, Chan WK, Chan YH, Li CS. Cefepime-related neurotoxicity in a haemodialysis patient. Nephrol Dial Transplant. 1999 Sep;14(9):2265-6. doi: 10.1093/ndt/14.9.2265Wong KM, Chan WK, Chan YH, Li CS. Cefepime-related neurotoxicity in a haemodialysis patient. Nephrol Dial Transplant. 1999 Sep;14(9):2265-6. doi: 10.1093/ndt/14.9.2265Sutter R, Rüegg S, Tschudin-Sutter S. Seizures as adverse events of antibiotic drugs: A systematic review. Neurology. 2015 Oct 13;85(15):1332-41. doi: 10.1212/WNL.0000000000002023Sutter R, Rüegg S, Tschudin-Sutter S. Seizures as adverse events of antibiotic drugs: A systematic review. Neurology. 2015 Oct 13;85(15):1332-41. doi: 10.1212/WNL.0000000000002023Appa AA, Jain R, Rakita RM, et al. Characterizing Cefepime Neurotoxicity: A Systematic Review. Open Forum Infect Dis. 2017 Oct 10;4(4):ofx170. doi: 10.1093/ofid/ofx170Appa AA, Jain R, Rakita RM, et al. Characterizing Cefepime Neurotoxicity: A Systematic Review. Open Forum Infect Dis. 2017 Oct 10;4(4):ofx170. doi: 10.1093/ofid/ofx170Gangireddy VG, Mitchell LC, Coleman T. Cefepime neurotoxicity despite renal adjusted dosing. Scand J Infect Dis. 2011 Oct;43(10):827-9. doi: 10.3109/00365548.2011.581308Gangireddy VG, Mitchell LC, Coleman T. Cefepime neurotoxicity despite renal adjusted dosing. Scand J Infect Dis. 2011 Oct;43(10):827-9. doi: 10.3109/00365548.2011.581308Nakagawa R, Sato K, Uesaka Y, et al. Cefepime-induced encephalopathy in end-stage renal disease patients. J Neurol Sci. 2017 May 15;376:123-8. doi: 10.1016/j.jns.2017.03.018Nakagawa R, Sato K, Uesaka Y, et al. Cefepime-induced encephalopathy in end-stage renal disease patients. J Neurol Sci. 2017 May 15;376:123-8. doi: 10.1016/j.jns.2017.03.018Li HT, Lee CH, Wu T, et al. Clinical, Electroencephalographic Features and Prognostic Factors of Cefepime-Induced Neurotoxicity: A Retrospective Study. Neurocrit Care. 2019 Oct;31(2):329-37. doi: 10.1007/s12028-019-00682-yLi HT, Lee CH, Wu T, et al. Clinical, Electroencephalographic Features and Prognostic Factors of Cefepime-Induced Neurotoxicity: A Retrospective Study. Neurocrit Care. 2019 Oct;31(2):329-37. doi: 10.1007/s12028-019-00682-yMaganti R, Jolin D, Rishi D, Biswas A. Nonconvulsive status epilepticus due to cefepime in a patient with normal renal function. Epilepsy Behav. 2006 Feb;8(1):312-4. doi: 10.1016/j.yebeh.2005.09.010Maganti R, Jolin D, Rishi D, Biswas A. Nonconvulsive status epilepticus due to cefepime in a patient with normal renal function. Epilepsy Behav. 2006 Feb;8(1):312-4. doi: 10.1016/j.yebeh.2005.09.010Thabet F, Al Maghrabi M, Al Barraq A, Tabarki B. Cefepime-induced nonconvulsive status epilepticus: case report and review. Neurocrit Care. 2009;10(3):347-51. doi: 10.1007/s12028-008-9166-8Thabet F, Al Maghrabi M, Al Barraq A, Tabarki B. Cefepime-induced nonconvulsive status epilepticus: case report and review. Neurocrit Care. 2009;10(3):347-51. doi: 10.1007/s12028-008-9166-8Meillier A, Rahimian D. Cefepime-induced encephalopathy with normal renal function. Oxf Med Case Reports. 2016 Jun 1;2016(6):11820. doi: 10.1093/omcr/omw042Meillier A, Rahimian D. Cefepime-induced encephalopathy with normal renal function. Oxf Med Case Reports. 2016 Jun 1;2016(6):11820. doi: 10.1093/omcr/omw042Boschung-Pasquier L, Atkinson A, Kastner LK, et al. Cefepime neurotoxicity: thresholds and risk factors. A retrospective cohort study. Clin Microbiol Infect. 2020 Mar;26(3):333-9. doi: 10.1016/j.cmi.2019.06.028Boschung-Pasquier L, Atkinson A, Kastner LK, et al. Cefepime neurotoxicity: thresholds and risk factors. A retrospective cohort study. Clin Microbiol Infect. 2020 Mar;26(3):333-9. doi: 10.1016/j.cmi.2019.06.028Sugimoto M, Uchida I, Mashimo T, et al. Evidence for the involvement of GABA(A) receptor blockade in convulsions induced by cephalosporins. Neuropharmacology. 2003 Sep;45(3):304-14. doi: 10.1016/s00283908(03)00188-6Sugimoto M, Uchida I, Mashimo T, et al. Evidence for the involvement of GABA(A) receptor blockade in convulsions induced by cephalosporins. Neuropharmacology. 2003 Sep;45(3):304-14. doi: 10.1016/s00283908(03)00188-6De Sarro A, Ammendola D, Zappala M, et al. Relationship between structure and convulsant properties of some beta-lactam antibiotics following intracerebroventricular microinjection in rats. Antimicrob Agents Chemother. 1995 Jan;39(1):232-7. doi: 10.1128/AAC.39.1.232De Sarro A, Ammendola D, Zappala M, et al. Relationship between structure and convulsant properties of some beta-lactam antibiotics following intracerebroventricular microinjection in rats. Antimicrob Agents Chemother. 1995 Jan;39(1):232-7. doi: 10.1128/AAC.39.1.232Lee S-J. Cefepime-induced neurotoxicity. J Neurocrit Care. 2019;12(2):74-84. doi: 10.18700/jnc.190109Lee S-J. Cefepime-induced neurotoxicity. J Neurocrit Care. 2019;12(2):74-84. doi: 10.18700/jnc.190109Fugate JE, Kalimullah EA, Hocker SE, et al. Cefepime neurotoxicity in the intensive care unit: a cause of severe, underappreciated encephalopathy. Crit Care. 2013 Nov 7;17(6):R264. doi: 10.1186/cc13094Fugate JE, Kalimullah EA, Hocker SE, et al. Cefepime neurotoxicity in the intensive care unit: a cause of severe, underappreciated encephalopathy. Crit Care. 2013 Nov 7;17(6):R264. doi: 10.1186/cc13094Zimmermann P, Camenzind D, Beer JH, Tarnutzer AA. Negative myoclonus as the leading symptom in acute cefepime neurotoxicity. BMJ Case Rep. 2021 Apr 8;14(4):e239744. doi: 10.1136/bcr-2020-239744Zimmermann P, Camenzind D, Beer JH, Tarnutzer AA. Negative myoclonus as the leading symptom in acute cefepime neurotoxicity. BMJ Case Rep. 2021 Apr 8;14(4):e239744. doi: 10.1136/bcr-2020-239744Johnson E, Hannawi Y, Martinez NC, Ritzl EK. Cefepime-Associated SIRPIDs in a Patient With Normal Renal Function. Neurohospitalist. 2016 Oct;6(4):167-9. doi: 10.1177/1941874415611180Johnson E, Hannawi Y, Martinez NC, Ritzl EK. Cefepime-Associated SIRPIDs in a Patient With Normal Renal Function. Neurohospitalist. 2016 Oct;6(4):167-9. doi: 10.1177/1941874415611180Passarelli V, da Conceicao MP, Tres ES, et al. Stimulus-induced Rhythmic, Periodic, or Ictal Discharges (SIRPDs) associated with seizures in cefepime neurotoxicity. Arq Neuropsiquiatr. 2014 Aug;72(8):643-4. doi: 10.1590/0004-282x20140094Passarelli V, da Conceicao MP, Tres ES, et al. Stimulus-induced Rhythmic, Periodic, or Ictal Discharges (SIRPDs) associated with seizures in cefepime neurotoxicity. Arq Neuropsiquiatr. 2014 Aug;72(8):643-4. doi: 10.1590/0004-282x20140094Hirsch LJ, Claassen J, Mayer SA, Emerson RG. Stimulus-induced rhythmic, periodic, or ictal discharges (SIRPIDs): a common EEG phenomenon in the critically ill. Epilepsia. 2004 Feb;45(2):109-23. doi: 10.1111/j.0013-9580.2004.38103.xHirsch LJ, Claassen J, Mayer SA, Emerson RG. Stimulus-induced rhythmic, periodic, or ictal discharges (SIRPIDs): a common EEG phenomenon in the critically ill. Epilepsia. 2004 Feb;45(2):109-23. doi: 10.1111/j.0013-9580.2004.38103.xBraksick SA, Burkholder DB, Tsetsou S, et al. Associated Factors and Prognostic Implications of Stimulus-Induced Rhythmic, Periodic, or Ictal Discharges. JAMA Neurol. 2016 May 1;73(5):585-90. doi: 10.1001/jamaneurol.2016.0006Braksick SA, Burkholder DB, Tsetsou S, et al. Associated Factors and Prognostic Implications of Stimulus-Induced Rhythmic, Periodic, or Ictal Discharges. JAMA Neurol. 2016 May 1;73(5):585-90. doi: 10.1001/jamaneurol.2016.0006Rodriguez Ruiz A, Vlachy J, Lee JW, et al; Critical Care EEG Monitoring Research Consortium. Association of Periodic and Rhythmic Electroencephalographic Patterns With Seizures in Critically Ill Patients. JAMA Neurol. 2017 Feb 1;74(2):181-8. doi: 10.1001/jamaneurol.2016.4990Rodriguez Ruiz A, Vlachy J, Lee JW, et al; Critical Care EEG Monitoring Research Consortium. Association of Periodic and Rhythmic Electroencephalographic Patterns With Seizures in Critically Ill Patients. JAMA Neurol. 2017 Feb 1;74(2):181-8. doi: 10.1001/jamaneurol.2016.4990Zeiler SR, Turtzo LC, Kaplan PW. SPECT-negative SIRPIDs argues against treatment as seizures. J Clin Neurophysiol. 2011 Oct;28(5):493-6. doi: 10.1097/WNP.0b013e318231c00aZeiler SR, Turtzo LC, Kaplan PW. SPECT-negative SIRPIDs argues against treatment as seizures. J Clin Neurophysiol. 2011 Oct;28(5):493-6. doi: 10.1097/WNP.0b013e318231c00aSmith CC, Tatum WO, Gupta V, et al. SPECT-negative SIRPIDs: less aggressive neurointensive care? J Clin Neurophysiol. 2014 Jun;31(3):e6-10. doi: 10.1097/WNP.0000000000000090Smith CC, Tatum WO, Gupta V, et al. SPECT-negative SIRPIDs: less aggressive neurointensive care? J Clin Neurophysiol. 2014 Jun;31(3):e6-10. doi: 10.1097/WNP.0000000000000090Johnson EL, Kaplan PW, Ritzl EK. Stimulus-Induced Rhythmic, Periodic, or Ictal Discharges (SIRPIDs). J Clin Neurophysiol. 2018 May;35(3):229-33. doi: 10.1097/WNP.0000000000000434Johnson EL, Kaplan PW, Ritzl EK. Stimulus-Induced Rhythmic, Periodic, or Ictal Discharges (SIRPIDs). J Clin Neurophysiol. 2018 May;35(3):229-33. doi: 10.1097/WNP.0000000000000434Triplett JD, Lawn ND, Chan J, Dunne JW. Cephalosporin-related neurotoxicity: Metabolic encephalopathy or non-convulsive status epilepticus? J Clin Neurosci. 2019 Sep;67:163-6. doi: 10.1016/j.jocn.2019.05.035Triplett JD, Lawn ND, Chan J, Dunne JW. Cephalosporin-related neurotoxicity: Metabolic encephalopathy or non-convulsive status epilepticus? J Clin Neurosci. 2019 Sep;67:163-6. doi: 10.1016/j.jocn.2019.05.035Beniczky S, Hirsch LJ, Kaplan PW, et al. Unified EEG terminology and criteria for nonconvulsive status epilepticus. Epilepsia. 2013 Sep;54 Suppl 6:28-9. doi: 10.1111/epi.12270Beniczky S, Hirsch LJ, Kaplan PW, et al. Unified EEG terminology and criteria for nonconvulsive status epilepticus. Epilepsia. 2013 Sep;54 Suppl 6:28-9. doi: 10.1111/epi.12270Trinka E, Cock H, Hesdorffer D, et al. A definition and classification of status epilepticus – Report of the ILAE Task Force on Classification of Status Epilepticus. Epilepsia. 2015 Oct;56(10):1515-23. doi: 10.1111/epi.13121Trinka E, Cock H, Hesdorffer D, et al. A definition and classification of status epilepticus – Report of the ILAE Task Force on Classification of Status Epilepticus. Epilepsia. 2015 Oct;56(10):1515-23. doi: 10.1111/epi.13121Bora I, Demir AB, Uzun P. Nonconvulsive status epilepticus cases arising in connection with cephalosporins. Epilepsy Behav Case Rep. 2016 May 20;6:23-7. doi: 10.1016/j.ebcr.2016.04.005Bora I, Demir AB, Uzun P. Nonconvulsive status epilepticus cases arising in connection with cephalosporins. Epilepsy Behav Case Rep. 2016 May 20;6:23-7. doi: 10.1016/j.ebcr.2016.04.005Tchapyjnikov D, Luedke MW. CefepimeInduced Encephalopathy and Nonconvulsive Status Epilepticus: Dispelling an Artificial Dichotomy. Neurohospitalist. 2019 Apr;9(2):100-4. doi: 10.1177/1941874418803225Tchapyjnikov D, Luedke MW. CefepimeInduced Encephalopathy and Nonconvulsive Status Epilepticus: Dispelling an Artificial Dichotomy. Neurohospitalist. 2019 Apr;9(2):100-4. doi: 10.1177/1941874418803225Chang YM. Cefepime-induced nonconvulsive status epilepticus as a cause of confusion in an elderly patient. J Formos Med Assoc. 2015 Mar;114(3):290-1. doi: 10.1016/j.jfma.2013.05.002Chang YM. Cefepime-induced nonconvulsive status epilepticus as a cause of confusion in an elderly patient. J Formos Med Assoc. 2015 Mar;114(3):290-1. doi: 10.1016/j.jfma.2013.05.002O’Rourke D, Chen PM, Gaspard N, et al. Response Rates to Anticonvulsant Trials in Patients with Triphasic-Wave EEG Patterns of Uncertain Significance. Neurocrit Care. 2016 Apr;24(2):233-9. doi: 10.1007/s12028-0150151-8O’Rourke D, Chen PM, Gaspard N, et al. Response Rates to Anticonvulsant Trials in Patients with Triphasic-Wave EEG Patterns of Uncertain Significance. Neurocrit Care. 2016 Apr;24(2):233-9. doi: 10.1007/s12028-0150151-8Баранова ЕА, Данилова ТВ, Халитов ИР, Синкин МВ. Бессудорожный эпилептический статус с электрографическим паттерном трифазных волн. Анналы клинической и экспериментальной неврологии. 2020;14(1):97-103. doi: 10.25692/ACEN.2020.1.11Baranova EA, Danilova TV, Khalitov IR, Sinkin MV. Nonconvulsive status epilepticus with triphasic wave son EEG. Annaly klinicheskoy i eksperimental’noy nevrologii = Annals of Clinical and Experimental Neurology. 2020;14(1):98-103. doi: 10.25692/ACEN.2020.1.11 (In Russ.).Payne LE, Gagnon DJ, Riker RR, et al. Cefepime-induced neurotoxicity: a systematic review. Crit Care. 2017 Nov 14;21(1):276. doi: 10.1186/s13054-017-1856-1Payne LE, Gagnon DJ, Riker RR, et al. Cefepime-induced neurotoxicity: a systematic review. Crit Care. 2017 Nov 14;21(1):276. doi: 10.1186/s13054-017-1856-1Mani 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 Apr;19(2):333-43. doi: 10.1111/hdi.12198Mani 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 Apr;19(2):333-43. doi: 10.1111/hdi.12198Suarez-de-la-Rica A, Hernandez-Gancedo C, Lopez-Tofino A, et al. Severe cefepime-induced status epilepticus treated with haemofiltration. Rev Esp Anestesiol Reanim. 2016 Jun-Jul;63(6):353-6. doi: 10.1016/j.redar.2015.08.005Suarez-de-la-Rica A, Hernandez-Gancedo C, Lopez-Tofino A, et al. Severe cefepime-induced status epilepticus treated with haemofiltration. Rev Esp Anestesiol Reanim. 2016 Jun-Jul;63(6):353-6. doi: 10.1016/j.redar.2015.08.005

The authors declare that there are no conflicts of interest present.