Neurotoxic effects associated with antibiotic use: management considerations.

The clinical manifestations of antibiotic-induced neurotoxic effects, the underlying mechanisms and management strategies have been reviewed. PubMed and OVID searches (January 1960-June 2010) were conducted using search terms such as antibiotics, side effects, neurotoxicity and encephalopathy which yielded approximately 300 articles. All relevant case reports, case series, letters and retrospective reviews describing neurotoxic effects and those discussing mechanisms of neurotoxicity were included. Antibiotic-induced neurotoxic side effects can have a myriad of neurologic presentations. Patients with prior central nervous system (CNS) disease, renal insufficiency and advanced age may be particularly vulnerable. Treatment consists of discontinuation of the offending agent, use of antiepileptic drugs in the case of seizures or status epilepticus and haemodialysis in certain cases. The risk of CNS toxicity may be reduced via dosage adjustments in high risk populations. Awareness of the potential neurotoxic clinical manifestations of various antibiotics and high degree of vigilance in critically ill patients is essential in identifying a potentially serious, though reversible complications of antibiotic therapy particularly with the advent of newer antimicrobial agents.

[1]  J. Mantz,et al.  Cefepime overdosage with neurotoxicity recovered by high-volume haemofiltration. , 2008, The Journal of antimicrobial chemotherapy.

[2]  Sum Lam,et al.  Cefepime Neurotoxicity: Case Report, Pharmacokinetic Considerations, and Literature Review , 2006, Pharmacotherapy.

[3]  A. Pan,et al.  Cefepime-induced encephalopathy with triphasic waves in three Asian patients. , 2007, Annals of the Academy of Medicine, Singapore.

[4]  C. Inderlied,et al.  Imipenem/cilastatin treatment of bacterial meningitis in children , 1991, The Pediatric infectious disease journal.

[5]  R. Perkins.  APNEA WITH INTRAMUSCULAR COLISTIN THERAPY. , 1964, JAMA.

[6]  S. Isaacson,et al.  Ciprofloxacin‐induced complex partial status epilepticus manifesting as an acute confusional state , 1993, Neurology.

[7]  P. Petiot,et al.  Possibly Linezolid-Induced Peripheral and Central Neurotoxicity: Report of Four Cases , 2005, Infection.

[8]  M. Falagas,et al.  Toxicity of polymyxins: a systematic review of the evidence from old and recent studies , 2006, Critical care.

[9]  P. Gal,et al.  Ampicillin-Induced Neurotoxicity in Very-Low-Birth-Weight Neonates , 1998, The Annals of pharmacotherapy.

[10]  P. Abete,et al.  Neurotoxicity induced by Cefepime in a very old hemodialysis patient. , 2003, Clinical nephrology.

[11]  Side Effects of Ofloxacin in Clinical Trials and in Postmarketing Surveillance , 2012, Drugs.

[12]  A. Mert,et al.  Levofloxacin-induced delirium , 2005, Clinical Neurology and Neurosurgery.

[13]  K. Bruch,et al.  Safety of ofloxacin — adverse drug reactions reported during phase-II studies in europe and in Japan , 2005, Infection.

[14]  J. Turnidge,et al.  Subacute Toxicity of Colistin Methanesulfonate in Rats: Comparison of Various Intravenous Dosage Regimens , 2008, Antimicrobial Agents and Chemotherapy.

[15]  S. Esposito,et al.  Comparative Tolerability of Erythromycin and Newer Macrolide Antibacterials in Paediatric Patients , 1999, Drug safety.

[16]  A. Nava-Ocampo,et al.  Antimicrobial therapy and local toxicity of intraventricular administration of vancomycin in a neonate with ventriculitis. , 2006, Therapeutic Drug Monitoring.

[17]  E. Kurzrock,et al.  Adverse reactions of nitrofurantoin, trimethoprim and sulfamethoxazole in children. , 2004, The Journal of urology.

[18]  C. Snyder,et al.  Seizures Associated with Fluoroquinolones , 2001, The Annals of pharmacotherapy.

[19]  Ya-Fang Chen,et al.  Painful neuropathy due to skin denervation after metronidazole-induced neurotoxicity , 2010, Journal of Neurology, Neurosurgery & Psychiatry.

[20]  R. Marcén,et al.  Neurotoxicity due to imipenem/cilastatin in patients on continuous ambulatory peritoneal dialysis. , 1999, Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association.

[21]  J. Kepes,et al.  Neurotoxicity of intrathecal gentamicin: A case report and experimental study , 1978, Annals of neurology.

[22]  Stanley Lu,et al.  Cerebellar ataxia following prolonged use of metronidazole: case report and literature review. , 2008, International journal of infectious diseases : IJID : official publication of the International Society for Infectious Diseases.

[23]  Neng-neng Cheng,et al.  Neurotoxicity and toxicokinetics of norfloxacin in conscious rats. , 2003, Acta Pharmacologica Sinica.

[24]  A. Bischoff,et al.  [Gentamicin neurotoxicity (polyneuropathy--encephalopathy)]. , 1977, Schweizerische medizinische Wochenschrift.

[25]  D. Sharp,et al.  Reversible optic neuropathy due to metronidazole , 2007, Clinical & experimental ophthalmology.

[26]  M. Falagas,et al.  Colistin treatment in patients with ICU-acquired infections caused by multiresistant Gram-negative bacteria: the renaissance of an old antibiotic. , 2005, Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases.

[27]  L. Mandell,et al.  A new respiratory fluoroquinolone, oral gemifloxacin: a safety profile in context. , 2004, International journal of antimicrobial agents.

[28]  G. Matzke,et al.  Pharmacokinetics of cefepime in subjects with renal insufficiency , 1990, Clinical pharmacology and therapeutics.

[29]  R. Couchenour,et al.  Trimethoprim‐Sulfamethoxazole‐Induced Tremor in an Immunocompetent Patient , 1999, Pharmacotherapy.

[30]  G. Turett,et al.  Polymyxin B Nephrotoxicity and Efficacy against Nosocomial Infections Caused by Multiresistant Gram-Negative Bacteria , 2003, Antimicrobial Agents and Chemotherapy.

[31]  R. Maganti,et al.  Cephalosporin-Induced Neurotoxicity: Clinical Manifestations, Potential Pathogenic Mechanisms, and the Role of Electroencephalographic Monitoring , 2008, The Annals of pharmacotherapy.

[32]  Coraggio Mj,et al.  Nitrofurantoin toxicity in children. , 1989 .

[33]  M. Kramer,et al.  Electroencephalographic effects of flucloxacillin in rats. , 1993, Pharmacology & toxicology.

[34]  L. Leibovici,et al.  Empirical antibiotic monotherapy for febrile neutropenia: systematic review and meta-analysis of randomized controlled trials: authors’ response , 2006 .

[35]  H. Meyer‐Rienecker,et al.  [On nitrofurantoin-polyneuropathy]. , 1966, Der Nervenarzt.

[36]  A. Filippelli,et al.  Hospital-based intensive monitoring of antibiotic-induced adverse events in a university hospital. , 2005, Pharmacological research.

[37]  K. Chow,et al.  Mechanisms of antibiotic neurotoxicity in renal failure. , 2004, International Journal of Antimicrobial Agents.

[38]  Thien-Ly Doan,et al.  Neurotoxicity in patients treated with intravenous polymyxin B: Two case reports. , 2009, American journal of health-system pharmacy : AJHP : official journal of the American Society of Health-System Pharmacists.

[39]  J. Ferguson,et al.  Cure of multiresistant Acinetobacter baumannii central nervous system infections with intraventricular or intrathecal colistin: case series and literature review. , 2006, The Journal of antimicrobial chemotherapy.

[40]  C. Kunin,et al.  Binding of polymyxin antibiotics to tissues: the major determinant of distribution and persistence in the body. , 1971, The Journal of infectious diseases.

[41]  Du Da.  Colistin toxicity. Neuromuscular and renal manifestations. Two cases treated by hemodialysis. , 1973 .

[42]  K. Chow,et al.  Neurotoxicity induced by beta-lactam antibiotics: from bench to bedside , 2005, European Journal of Clinical Microbiology and Infectious Diseases.

[43]  T. A. Boliston,et al.  Tobramycin and neuromuscular blockade , 1978, Anaesthesia.

[44]  I. Wirguin,et al.  Cefuroxime‐induced encephalopathy , 1998, Neurology.

[45]  T. Mashimo,et al.  Evidence for the involvement of GABAA receptor blockade in convulsions induced by cephalosporins , 2003, Neuropharmacology.

[46]  D. Loes,et al.  Reversible Magnetic Resonance Imaging Findings in metronidazole-induced Encephalopathy , 1995, Neurology.

[47]  K. Chow,et al.  Retrospective Review of Neurotoxicity Induced by Cefepime and Ceftazidime , 2003, Pharmacotherapy.

[48]  H. Mikawa,et al.  High doses of penicillin decreases [3H]flunitrazepam binding sites in rat neuron primary culture , 1993, Brain and Development.

[49]  J. Calvert,et al.  Potential Neurologic Toxicity Related to Ciprofloxacin , 1990, DICP : the annals of pharmacotherapy.

[50]  D. Fish,et al.  Pharmacokinetics of Cefepime during Continuous Renal Replacement Therapy in Critically Ill Patients , 2001, Antimicrobial Agents and Chemotherapy.

[51]  M. Badia,et al.  Use of colistin in the treatment of multiple-drug-resistant gram-negative infections. , 2005, American journal of health-system pharmacy : AJHP : official journal of the American Society of Health-System Pharmacists.

[52]  D. Reagan,et al.  Association of a Tourette-Like Syndrome with Ofloxacin , 1996, The Annals of pharmacotherapy.

[53]  G. Dakdouki,et al.  Cefepime-induced encephalopathy. , 2004, International journal of infectious diseases : IJID : official publication of the International Society for Infectious Diseases.

[54]  M. Gutnick,et al.  Penicillinase and the convulsant action of penicillin , 1971, Neurology.

[55]  J. Bazan,et al.  Newer beta-lactam antibiotics: doripenem, ceftobiprole, ceftaroline, and cefepime. , 2009, Infectious disease clinics of North America.

[56]  E. Tolosa,et al.  Reversible oral-facial dyskinesia in a patient receiving ciprofloxacin hydrochloride , 1996, Journal of Neurology.

[57]  E. Buszman,et al.  Therapeutic vancomycin monitoring in children with hydrocephalus during treatment of shunt infections. , 2004, Surgical neurology.

[58]  P. Chu,et al.  Neurotoxicity Associated with Standard Doses of Piperacillin in an Elderly Patient with Renal Failure , 2009, Infection.

[59]  G. Logaras,et al.  Neuromuscular blocking activity of aminoglycoside antibiotics. , 1976 .

[60]  W. Hauser,et al.  Seizures in the Critically Ill: The Role of Imipenem , 2001, Epilepsia.

[61]  M. Farré,et al.  Reversible Coma Secondary to Cefepime Neurotoxicity , 2004, The Annals of pharmacotherapy.

[62]  K. Akahane,et al.  Structure-epileptogenicity relationship of quinolones with special reference to their interaction with gamma-aminobutyric acid receptor sites , 1989, Antimicrobial Agents and Chemotherapy.

[63]  P. Skolnick,et al.  Aminoglycoside neurotoxicity involves NMDA receptor activation , 1999, Brain Research.

[64]  M. Falagas,et al.  Combination Therapy with Intravenous Colistin for Management of Infections Due to Multidrug-Resistant Gram-Negative Bacteria in Patients without Cystic Fibrosis , 2005, Antimicrobial Agents and Chemotherapy.

[65]  T. Chan,et al.  Ciprofloxacin-induced oral facial dyskinesia in a patient with normal liver and renal function. , 2000, Hospital Medicine.

[66]  M. Mcquillen,et al.  Myasthenic syndrome associated with antibiotics. , 1968, Transactions of the American Neurological Association.

[67]  A. De Sarro,et al.  Reversible orofacial dyskinesia after ofloxacin treatment , 2004, Movement disorders : official journal of the Movement Disorder Society.

[68]  L. Hobson‐Webb,et al.  Metronidazole: Newly Recognized Cause of Autonomic Neuropathy , 2006, Journal of child neurology.

[69]  D. Paterson,et al.  Use of parenteral colistin for the treatment of serious infection due to antimicrobial-resistant Pseudomonas aeruginosa. , 2003, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[70]  M. Saidinejad,et al.  Transient Psychosis in an Immune-Competent Patient After Oral Trimethoprim-Sulfamethoxazole Administration , 2005, Pediatrics.

[71]  S. Frytak,et al.  Neurologic toxicity associated with high-dose metronidazole therapy. , 1978, Annals of internal medicine.

[72]  D. Bugnon,et al.  Severe neurotoxicity of cefepime in uremic patients. , 2001, Annals of internal medicine.

[73]  L. Bruno-Murtha,et al.  Bell's Palsy Associated with Linezolid Therapy: Case Report and Review of Neuropathic Adverse Events , 2006, Pharmacotherapy.

[74]  M. Athanasiou,et al.  Intravenous colistin in the treatment of sepsis from multiresistant Gram-negative bacilli in critically ill patients , 2003, Critical care.

[75]  J. Fletcher,et al.  Early onset probable linezolid-induced encephalopathy , 2010, Journal of Neurology.

[76]  P. Pianka,et al.  The outcome of pseudotumor cerebri induced by tetracycline therapy , 2004, Acta neurologica Scandinavica.

[77]  O. V. Hein,et al.  Antibiotic-mediated release of tumour necrosis factor alpha and norharman in patients with hospital-acquired pneumonia and septic encephalopathy , 2004, Intensive Care Medicine.

[78]  E. Wolinsky,et al.  Neurotoxic and nephrotoxic effects of colistin in patients with renal disease. , 1962, The New England journal of medicine.

[79]  Cefepime- and cefixime-induced encephalopathy in a patient with normal renal function , 2005 .

[80]  O. Cars,et al.  Neurotoxicity of β-lactam antibiotics: predisposing factors and pathogenesis , 1991 .

[81]  J. L. Fernández-Torre.  Levofloxacin-induced delirium: Diagnostic considerations , 2006, Clinical Neurology and Neurosurgery.

[82]  Cox Ce,et al.  Intravenous sodium colistimethate therapy of urinary-tract infections: pharmacological and bacteriological studies. , 1970 .

[83]  G. Laureys,et al.  The neurotoxicity and safety of treatment with cefepime in patients with renal failure. , 2007, Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association.

[84]  K. Akahane,et al.  Levofloxacin, an optical isomer of ofloxacin, has attenuated epileptogenic activity in mice and inhibitory potency in GABA receptor binding. , 1994, Chemotherapy.

[85]  K. Abe,et al.  Absence of convulsive liability of doripenem, a new carbapenem antibiotic, in comparison with beta-lactam antibiotics. , 2006, Toxicology.

[86]  G. Gogolák,et al.  Neurotoxicity and CSF level of three penicillins. , 1976, Archives internationales de pharmacodynamie et de therapie.

[87]  R. Peces,et al.  Baclofen neurotoxicity in chronic haemodialysis patients with hiccups. , 1998, Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association.

[88]  J. Harvey,et al.  Abnormal movements with the addition of clindamycin to risperidone in a girl with autism. , 2008, Journal of child and adolescent psychopharmacology.

[89]  C. Lafaix,et al.  A rare case of cotrimoxazole-induced eosinophilic aseptic meningitis in an HIV-infected patient. , 1998, Scandinavian journal of infectious diseases.

[90]  James H. Carrigan,et al.  Factors predisposing to seizures in seriously ill infected patients receiving antibiotics: experience with imipenem/cilastatin. , 1988, The American journal of medicine.

[91]  J. Fiekers.  Effects of the aminoglycoside antibiotics, streptomycin and neomycin, on neuromuscular transmission. II. Postsynaptic considerations. , 1983, The Journal of pharmacology and experimental therapeutics.

[92]  C. Lee,et al.  Interaction of Neuromuscular Blocking Effects ofNeomycin and Polymyxin B , 1979, Anesthesiology.

[93]  L. Leibovici,et al.  Empirical antibiotic monotherapy for febrile neutropenia: systematic review and meta-analysis of randomized controlled trials. , 2006, The Journal of antimicrobial chemotherapy.

[94]  G. Jacobs,et al.  Central nervous system Whipple's disease: relapse during therapy with trimethoprim-sulfamethoxazole and remission with cefixime. , 1994, Gastroenterology.

[95]  Paul F. Smith,et al.  Vestibulotoxicity following aminoglycoside antibiotics and its prevention. , 2003, Current opinion in investigational drugs.

[96]  M. Fonder,et al.  Levofloxacin-induced delirium with psychotic features. , 2008, General hospital psychiatry.

[97]  P. Venegas-Francke,et al.  [Bilateral optic neuritis caused by chloramphenicol]. , 2000, Revista de neurologia.

[98]  Benjamin A Lipsky,et al.  Fluoroquinolone toxicity profiles: a review focusing on newer agents. , 1999, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[99]  R. Thomas.  Neurotoxicity of antibacterial therapy. , 1994, Southern medical journal.

[100]  E. Federman,et al.  Adverse effects of sodium colistimethate. Manifestations and specific reaction rates during 317 courses of therapy. , 1970, Annals of internal medicine.

[101]  P. Derambure,et al.  Cefepime-induced neurotoxicity: an underestimated complication of antibiotherapy in patients with acute renal failure , 2002, Intensive Care Medicine.

[102]  Y. Chan,et al.  Cefepime-related neurotoxicity in a haemodialysis patient. , 1999, Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association.

[103]  T. Beattie,et al.  Reversible encephalopathy after intravenous ciprofloxacin therapy , 1995, Pediatric Nephrology.

[104]  G. Sarma,et al.  Acute painful peripheral neuropathy due to metronidazole. , 2005, Neurology India.

[105]  R. Roncon-Albuquerque,et al.  Ceftriaxone-induced acute reversible encephalopathy in a patient treated for a urinary tract infection. , 2009, The Netherlands journal of medicine.

[106]  A. Seto,et al.  Ertapenem-Associated Seizures in a Peritoneal Dialysis Patient , 2005, The Annals of pharmacotherapy.

[107]  S. Hammer,et al.  Combination therapy with polymyxin B for the treatment of multidrug-resistant Gram-negative respiratory tract infections. , 2004, The Journal of antimicrobial chemotherapy.

[108]  W. Macleod.  Case report: severe neurologic reaction to ciprofloxacin. , 2001, Canadian family physician Medecin de famille canadien.

[109]  M. Watari,et al.  Tardive seizure and antibiotics: case reports and review of the literature. , 2008, The journal of ECT.

[110]  A. Ketcham,et al.  Pseudomonas meningitis complicating radical resection for radiorecurrent cancer of the paranasal sinuses: Report of two patients successfully treated with intrathecal polymyxin , 1973, Journal of surgical oncology.

[111]  Frederico Arthur Dahne Kliemann,et al.  Encefalopatia induzida por cefepime: achados clínicos e eletroencefalográficos em sete pacientes , 2005 .

[112]  T. Buclin,et al.  High imipenem blood concentrations associated with toxic encephalopathy in a patient with mild renal dysfunction. , 2009, International journal of antimicrobial agents.

[113]  Shih-Hua Lin,et al.  Piperacillin/tazobactam-induced seizure rapidly reversed by high flux hemodialysis in a patient on peritoneal dialysis. , 2007, The American journal of the medical sciences.

[114]  D. A. Decker,et al.  Respiratory arrest in myasthenia gravis with colistimethate therapy. , 1971, Archives of neurology.

[115]  P. Norman,et al.  The treatment of gram-negative bacillary infections with colistin. The toxicity and efficacy of large doses in forty-eight patients. , 1962, Annals of internal medicine.