Research Article| Volume 398, P196-201, March 15, 2019

Serious central nervous system side effects of cephalosporins: A national analysis of serious reports registered in the French Pharmacovigilance Database

  • C. Lacroix
    Centre Régional de Pharmacovigilance, Service de Pharmacologie Clinique et Pharmacovigilance, APHM, INSERM, Inst Neurosci Syst, Aix Marseille Univ, Marseille, France
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  • F. Kheloufi
    Centre Régional de Pharmacovigilance, Service de Pharmacologie Clinique et Pharmacovigilance, APHM, INSERM, Inst Neurosci Syst, Aix Marseille Univ, Marseille, France
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  • F. Montastruc
    Centre Midi-Pyrénées de Pharmacovigilance, Pharmacoépidémiologie et d'Informations sur le Médicament, Centre Hospitalier Universitaire, Faculté de Médecine, Service de Pharmacologie Médicale et Clinique, Toulouse, France

    Unité clinique de Pharmacologie psychiatrique, Faculté de Médecine, Centre Hospitalier Universitaire, Toulouse, France
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  • Y. Bennis
    Centre Régional de Pharmacovigilance, Centre Hospitalier Universitaire Amiens-Picardie, Amiens, France
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  • V. Pizzoglio
    Centre Régional de Pharmacovigilance, Hospices Civils de Lyon, Lyon, France
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  • J. Micallef
    Corresponding author: Centre Régional de Pharmacovigilance, Hôpital Sainte-Marguerite, 270, Boulevard de Sainte-Marguerite, 13274 Marseille CEDEX 09, France.
    Centre Régional de Pharmacovigilance, Service de Pharmacologie Clinique et Pharmacovigilance, APHM, INSERM, Inst Neurosci Syst, Aix Marseille Univ, Marseille, France
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Published:January 16, 2019DOI:


      • Central nervous system adverse effects provided by cephalosporins are under-suspected and can lead to death.
      • Central nervous system adverse effects can be neurologic and psychiatric.
      • Ceftriaxone is widely represented with several deaths, an awareness should be important for clinicians.



      Among antibiotics, Central Nervous System (CNS) adverse drug reactions (ADRs) are often under-suspected and overlooked. Cephalosporins are an important cause of drug-induced CNS ADRs but the characteristics of such ADR have not been fully explored. We aimed to characterize the profile of cephalosporins serious CNS ADRs.


      We performed an analysis of serious reports recorded in the French Pharmacovigilance database from 1987 to 2017.


      A total of 511 serious ADRs reports was analyzed. Patients had a mean age of 67.1 years and were mainly men (52.5%), with a mean creatinine clearance of 32.9 ml/min. The most involved molecules were cefepime (33.1%), ceftriaxone (29.7%), ceftazidime (19.6%), cefotaxime (9%) and cefazoline (2.9%), mostly administered intravenously (87.3%). A CNS history was observed in 25% of the reports (n = 128). Patients exhibited encephalopathy (30.3%), confusional state (19.4%), convulsion (15.1%), myoclonia (9.4%), status epilepticus (9.2%), coma (6.3%) and hallucination (4.3%). The mean time of onset was 7.7 days and the mean duration was 6 days. Cephalosporin plasma levels were recorded for 153 patients (29.9%) and 107 were above the standards including 62 (57.9%) related to renal impairment. Electroencephalograms were performed in 38.2% (n = 195) of the patients and 81% (n = 158) were abnormal.


      This study characterizes an off-target CNS ADRs of several cephalosporins. Ceftriaxone represented a large part of our reports after cefepime and it would be relevant to warn healthcare professionals. Investigations (EEG, though plasma levels and renal function) can be precious tools for clinicians to make a prompt diagnosis and improve patients' outcomes.


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        • Cock H.R.
        Drug-induced status epilepticus.
        Epilepsy Behav. EB. 2015; 49: 76-82
        • Bhattacharyya S.
        • Darby R.R.
        • Raibagkar P.
        • Gonzalez Castro L.N.
        • Berkowitz A.L.
        Antibiotic-associated encephalopathy.
        Neurology. 2016; 86: 963-971
        • Grill M.F.
        • Maganti R.K.
        Neurotoxic effects associated with antibiotic use: management considerations.
        Br. J. Clin. Pharmacol. 2011; 72: 381-393
        • Meillier A.
        • Rahimian D.
        Cefepime-induced encephalopathy with normal renal function.
        Oxf. Med. Case Rep. 2016; 2016: 118-120
        • 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: 312-314
        • Martínez-Rodríguez J.E.
        • Barriga F.J.
        • Santamaria J.
        • Iranzo A.
        • Pareja J.A.
        • Revilla M.
        • et al.
        Nonconvulsive status epilepticus associated with cephalosporins in patients with renal failure.
        Am. J. Med. 2001; 111: 115-119
        • Bora I.
        • Demir A.B.
        • Uzun P.
        Nonconvulsive status epilepticus cases arising in connection with cephalosporins.
        Epilepsy Behav. Case Rep. 2016; 6: 23-27
        • Payne L.E.
        • Gagnon D.J.
        • Riker R.R.
        • Seder D.B.
        • Glisic E.K.
        • Morris J.G.
        • et al.
        Cefepime-induced neurotoxicity: a systematic review.
        Crit. Care Lond. Engl. 2017; 21: 276
        • Research C for DE and
        Drug Safety and Availability - FDA Drug Safety Communication: Cefepime and risk of seizure in patients not receiving dosage adjustments for kidney impairment [Internet].
        ([cited 2018 Jul 1]. Available from:)
        • Roncon-Albuquerque R.
        • Pires I.
        • Martins R.
        • Real R.
        • Sousa G.
        • von Hafe P.
        Ceftriaxone-induced acute reversible encephalopathy in a patient treated for a urinary tract infection.
        Neth. J. Med. 2009; 67: 72-75
        • Anzellotti F.
        • Ricciardi L.
        • Monaco D.
        • Ciccocioppo F.
        • Borrelli I.
        • Zhuzhuni H.
        • et al.
        Cefixime-induced nonconvulsive status epilepticus.
        Neurol. Sci. 2012; 33: 325-329
        • Choi J.-Y.
        • Seok H.Y.
        • Lee S.-H.
        • Kim B.-J.
        • Park K.-W.
        • Jung K.-Y.
        Epidural adhesiolysis complicated by cefazolin-induced status epilepticus: two cases.
        Clin. Neurol. Neurosurg. 2008; 110: 1041-1043
        • Jackson G.D.
        • Berkovic S.F.
        Ceftazidime encephalopathy: absence status and toxic hallucinations.
        J. Neurol. Neurosurg. Psychiatry. 1992; 55: 333-334
        • De Silva D.A.
        • Pan A.B.S.
        • Lim S.-H.
        Cefepime-induced encephalopathy with triphasic waves in three Asian patients.
        Ann. Acad. Med. Singap. 2007; 36: 450-451
        • Fernández-Torre J.L.
        • Martínez-Martínez M.
        • González-Rato J.
        • Maestro I.
        • Alonso I.
        • Rodrigo E.
        • et al.
        Cephalosporin-induced nonconvulsive status epilepticus: clinical and electroencephalographic features.
        Epilepsia. 2005; 46: 1550-1552
        • Passarelli V.
        • Conceição MPOM da, Trés ES
        • Alves Junior J.F.
        • Baldocchi M.A.
        Stimulus-induced rhythmic, periodic, or ictal discharges (SIRPDs) associated with seizures in cefepime neurotoxicity.
        Arq. Neuropsiquiatr. 2014; 72: 643-644
        • Pro S.
        • Randi F.
        • Pulitano P.
        • Vicenzini E.
        • Mecarelli O.
        Reversible encephalopathy induced by cefoperazone: a case report monitored with EEG.
        Neurol. Sci. 2011; 32: 465-467
        • Vial T.
        Pharmacovigilance française: missions, organisation et perspectives.
        Therapie. 2016; 71: 135-142
        • Abadie D.
        • Essilini A.
        • Fulda V.
        • Gouraud A.
        • Yéléhé-Okouma M.
        • Micallef J.
        • et al.
        Drug-induced panic attacks: Analysis of cases registered in the French Pharmacovigilance Database.
        J. Psychiatr. Res. 2017; 90: 60-66
        • Lafay-Chebassier C.
        • Chavant F.
        • Favrelière S.
        • Pizzoglio V.
        • Pérault-Pochat M.-C.
        Drug-induced depression: a case/non case study in the French Pharmacovigilance Database.
        Therapie. 2015; 70: 425-432
        • Brefel-Courbon C.
        • Gardette V.
        • Ory F.
        • Montastruc J.L.
        Drug-induced myoclonus: a French Pharmacovigilance Database study.
        Neurophysiol. Clin. Neurophysiol. 2006; 36: 333-336
      1. International conference of harmonisation of technical requirements for registration of pharmaceuticals for human use. Post-approval safety data management: definitions and standards for expedited reporting E2D. 2003.

        • Lamoth F.
        • Buclin T.
        • Pascual A.
        • Vora S.
        • Bolay S.
        • Decosterd L.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: 4360-4367
        • Zeller V.
        • Durand F.
        • Kitzis M.-D.
        • Lhotellier L.
        • Ziza J.-M.
        • Mamoudy P.
        • et al.
        Continuous Cefazolin infusion to treat bone and joint infections: clinical efficacy, feasibility, safety, and serum and bone concentrations.
        Antimicrob. Agents Chemother. 2009; 53: 883-887
        • Seguin P.
        • Verdier M.C.
        • Chanavaz C.
        • Engrand C.
        • Laviolle B.
        • Donnio P.-Y.
        • et al.
        Plasma and peritoneal concentration following continuous infusion of cefotaxime in patients with secondary peritonitis.
        J. Antimicrob. Chemother. 2009; 63: 564-567
        • Aubert G.
        • Carricajo A.
        • Coudrot M.
        • Guyomarcʼh S.
        • Auboyer C.
        • Zeni F.
        Prospective determination of serum ceftazidime concentrations in intensive care units.
        Ther. Drug Monit. 2010; 32: 517-519
        • Mattappalil A.
        • Mergenhagen K.A.
        Neurotoxicity with antimicrobials in the elderly: a review.
        Clin. Ther. 2014; 36: 1489-1511.e4
        • Chang Y.-M.
        Cefepime-induced nonconvulsive status epilepticus as a cause of confusion in an elderly patient.
        J. Formos. Med. Assoc. Taiwan Yi Zhi. 2015; 114: 290-291
        • Landgrave L.C.
        • Lock J.L.
        • Whitmore J.M.
        • Belcher C.E.
        Pediatric Cefepime neurotoxicity.
        Pediatr. Neurol. 2012; 47: 458-460
        • Lin C.-J.
        • Chen S.-P.
        • Wang S.-J.
        • Fuh J.-L.
        Cefepime-related encephalopathy in peritoneal dialysis patients.
        J. Chin. Med. Assoc. 2011; 74: 87-90
        • Dakdouki G.K.
        • Al-Awar G.N.
        Cefepime-induced encephalopathy.
        Int. J. Infect. Dis. 2004; 8: 59-61
        • Alpay H.
        • Altun O.
        • Biyikli N.K.
        Cefepime-induced non-convulsive status epilepticus in a peritoneal dialysis patient.
        Pediatr. Nephrol. 2004; 19: 445-447
        • Plensa E.
        • Gallardo E.
        • Ribera J.-M.
        • Batlle M.
        • Oriol A.
        • Costa J.
        Nonconvulsive status epilepticus associated with cefepime in a patient undergoing autologous stem cell transplantation.
        Bone Marrow Transplant. 2004; 33: 119-120
        • Deshayes S.
        • Coquerel A.
        • Verdon R.
        Neurological adverse effects attributable to β-Lactam antibiotics: a literature review.
        Drug Saf. 2017; 40: 1171-1198
        • Chow K.M.
        • Szeto C.C.
        • Hui A.C.-F.
        • Wong T.Y.-H.
        • Li P.K.-T.
        Retrospective review of neurotoxicity induced by cefepime and ceftazidime.
        Pharmacotherapy. 2003; 23: 369-373
        • Penicillin, ceftazidime, and the epilepsies
        Lancet Lond. Engl. 1992; 340: 400-401
        • Sharma N.
        • Gupta A.
        • Batish S.
        Ceftriaxone-induced acute reversible encephalopathy in a patient with enteric fever.
        Indian J. Pharm. 2012; 44: 124
        • Dubin I.
        • Schattner A.
        Iatrogenic coma: ceftriaxone-associated encephalopathy.
        Postgrad. Med. J. 2018; 94: 357-358
        • Safadi S.
        • Mao M.
        • Dillon J.J.
        Ceftriaxone-induced acute encephalopathy in a peritoneal dialysis patient.
        Case Rep. Nephrol. 2014; 2014: 1-4
        • Kim K.B.
        • Kim S.M.
        • Park W.
        • Kim J.S.
        • Kwon S.K.
        • Kim H.-Y.
        Ceftiaxone-induced neurotoxicity: case report, pharmacokinetic considerations, and literature review.
        J. Korean Med. Sci. 2012; 27: 1120
        • Chen Z.
        • He Y.
        • Wang Z.J.
        The beta-lactam antibiotic, ceftriaxone, inhibits the development of opioid-induced hyperalgesia in mice.
        Neurosci. Lett. 2012; 509: 69-71
        • Knackstedt L.A.
        • Melendez R.I.
        • Kalivas P.W.
        Ceftriaxone restores glutamate homeostasis and prevents relapse to cocaine seeking.
        Biol. Psychiatry. 2010; 67: 81-84
        • Sari Y.
        • Smith K.D.
        • Ali P.K.
        • Rebec G.V.
        Upregulation of Glt1 attenuates cue-induced reinstatement of cocaine-seeking behavior in rats.
        J. Neurosci. 2009; 29: 9239-9243
        • Sari Y.
        • Sakai M.
        • Weedman J.M.
        • Rebec G.V.
        • Bell R.L.
        Ceftriaxone, a Beta-lactam antibiotic, reduces ethanol consumption in alcohol-preferring rats.
        Alcohol Alcohol. 2011; 46: 239-246
        • Grill M.F.
        • Maganti R.
        Cephalosporin-induced neurotoxicity: clinical manifestations, potential pathogenic mechanisms, and the role of electroencephalographic monitoring.
        Ann. Pharmacother. 2008; 42: 1843-1850
        • Céfépime: rappel des risques de réactions graves lors du non respect des posologies recommandées notamment en cas de d'insuffisance rénale - Point d'Information - ANSM: Agence nationale de sécurité du médicament et des produits de santé [Internet]
        ([cited 2018 Jul 1]. Available from:)
        • Céfépime (Axepim® et ses génériques): rappel des risques d'effets indésirables neurologiques graves lors du non-respect des posologies recommandées notamment en cas d'insuffisance rénale - Lettre aux professionnels de santé - ANSM: Agence nationale de sécurité du médicament et des produits de santé [Internet]
        ([cited 2018 Jul 1]. Available from)
        • Doussau de Bazignan A.
        • Thiessard F.
        • Miremont-Salamé G.
        • Conri C.
        • Haramburu F.
        Effets indésirables psychiatriques des fluoroquinolones: cas notifiés à la pharmacovigilance française.
        Rev. Méd. Interne. 2006; 27: 448-452
        • Huwyler T.
        • Lenggenhager L.
        • Abbas M.
        • Ing Lorenzini K.
        • Hughes S.
        • Huttner B.
        • et al.
        Cefepime plasma concentrations and clinical toxicity: a retrospective cohort study.
        Clin. Microbiol. Infect. 2017; 23: 454-459