Advertisement

Neurotoxicity induced by beta-lactam antibiotics: from bench to bedside

  • K. M. Chow
  • A. C. Hui
  • C. C. Szeto
Review article

Abstract

Central nervous system toxicity following administration of beta-lactam antibiotics, of which penicillin is the prototype, is a potential cause of morbidity and mortality. In recent years, important advances have been made in the pathogenesis of antibiotic-related neurotoxicity. This review focuses on the experimental and clinical aspects of neurotoxicity caused by beta-lactam antibiotics. The purpose is to provide an update on the pathogenesis, mechanism, and clinical manifestations of the neurotoxicity, along with an overview of the relationship between antibiotic structure and convulsive action. In particular, some of the prevailing ideas about pathogenesis are highlighted, including theories of the mechanism of pathogencity. A better understanding of antibiotic-related neurotoxicity, as derived from animal models and human clinical experience, would be of value in facilitating more efficient and safer use of antimicrobial compounds.

Keywords

GABAA Receptor Nonconvulsive Status Epilepticus Thiazolidine Ring GABAA Subunit GABAA Receptor Complex 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

Acknowledgments

This study is supported in part by a Chinese University of Hong Kong research grant, account 6901031.

References

  1. 1.
    Walker AE, Johnson HC, Kollros JJ (1945) Penicillin convulsions: the convulsive effects of penicillin applied to the cerebral cortex of monkey and man. Surg Gynecol Obstet 81:692–701Google Scholar
  2. 2.
    Johnson HC, Walker AE (1945) Intraventricular penicillin. JAMA 27:217–219Google Scholar
  3. 3.
    Walker AE, Johnson HC (1945) Convulsive factor in commercial penicillin. Arch Surg 50:69–73Google Scholar
  4. 4.
    Niedermeyer E (1995) A. Earl Walker: neurosurgeon, neuroscientist, and epileptologist. Epilepsia 36:516–521CrossRefPubMedGoogle Scholar
  5. 5.
    Reuling S, Cramer C (1945) Intrathecal penicillin. JAMA 27:16–18Google Scholar
  6. 6.
    Dumoff-Stanley E, Dawling H, Swett L (1946) The absorption into and distribution of penicillin in the cerebrospinal fluid. J Clin Invest 25:87–93PubMedCrossRefGoogle Scholar
  7. 7.
    Smith H, Lerner PI, Weinstein L (1967) Neurotoxicity and “massive” intravenous therapy with penicillin: a study of possible predisposing factors. Arch Intern Med 120:47–53CrossRefPubMedGoogle Scholar
  8. 8.
    Chow KM, Szeto CC, Hui AC, Wong TY, Li PK (2003) Retrospective review of neurotoxicity induced by cefepime and ceftazidime. Pharmacotherapy 23:369–373CrossRefPubMedGoogle Scholar
  9. 9.
    Anonymous (1992) Penicillin, ceftazidime, and the epilepsies. Lancet 340:400–401CrossRefPubMedGoogle Scholar
  10. 10.
    DeLorey TM, Olsen RW (1992) γ-aminobutyric acidA receptor structure and function. J Biol Chem 267:16747–16750PubMedGoogle Scholar
  11. 11.
    Wallace KL (1997) Antibiotic-induced convulsions. Crit Care Clin 13:741–762CrossRefPubMedGoogle Scholar
  12. 12.
    Barrons RW, Murray KM, Richey RM (1992) Populations at risk for penicillin-induced seizures. Ann Pharmacother 26:26–29PubMedGoogle Scholar
  13. 13.
    Antoniadis A, Müller WE, Wollert U (1980) Inhibition of GABA and benzodiazepine receptor binding by penicillins. Neurosci Lett 18:309–312CrossRefPubMedGoogle Scholar
  14. 14.
    Twyman RE, Green RM, MacDonald RL (1992) Kinetics of open channel block by penicillin of single GABAA receptor channels from mouse spinal cord neurons in culture. J Physiol 445:97–127PubMedGoogle Scholar
  15. 15.
    Fujimoto M, Munakata M, Akaike N (1995) Dual mechanisms of GABAA response inhibition by beta-lactam antibiotics in the pyramidal neurons of the cerebral cortex. Br J Pharmacol 116:3014–3020PubMedGoogle Scholar
  16. 16.
    Antoniadis A, Müller WE, Wollert U (1980) Benzodiazepine receptor interactions may be involved in the neurotoxicity of various penicillin derivatives. Ann Neurol 8:71–73CrossRefPubMedGoogle Scholar
  17. 17.
    Sugimoto M, Fukami S, Kayakiri H, Yamazaki S, Matsuoka N, Uchida I, Mashimo T (2001) The β-lactam antibiotics, penicillin-G and cefoselis have different mechanisms and sites of action at GABAA receptors. Br J Pharmacol 135:427–432CrossRefGoogle Scholar
  18. 18.
    Gurley D, Amin J, Ross PC, Weiss DS, White G (1995) Point mutations in the M2 region of the alpha, beta, or gamma subunit of the GABAA channel that abolish block by picrotoxin. Receptors Channels 3:13–20PubMedGoogle Scholar
  19. 19.
    Lindquist CE, Dalziel JE, Cromer BA, Birnir B (2004) Penicillin blocks human α1β1 and α1β1γ2S GABAA channels that open spontaneously. Eur J Pharmacol 496:23–32CrossRefPubMedGoogle Scholar
  20. 20.
    Hori S, Kurioka S, Matsuda M, Shimada J (1985) Inhibitory effect of cephalosporins on γ-aminobutyric acid receptor binding in rat synaptic membranes. Antimicrob Agents Chemother 27:650–651PubMedGoogle Scholar
  21. 21.
    Sugimoto M, Uchida I, Mashimo T, Yamazaki S, Hatano K, Ikeda F, Mochizuki Y, Terai T, Matsuoka N (2003) Evidence for the involvement of GABAA receptor blockade in convulsions induced by cephalosporins. Neuropharmacology 45:304–314CrossRefPubMedGoogle Scholar
  22. 22.
    Grøndahl TØ, Langmoen IA (1993) Epileptogenic effect of antibiotic drugs. J Neurosurg 78:938–943Google Scholar
  23. 23.
    Gutnick MJ, Prince DA (1971) Penicillinase and the convulsant action of penicillin. Neurology 21:759–764PubMedGoogle Scholar
  24. 24.
    Esplin B, Théorêt E, Seward E, Capek R (1985) Epileptogenic action of penicillin derivatives: structure–activity relationship. Neuropharmacology 24:571–575CrossRefPubMedGoogle Scholar
  25. 25.
    Kamei C, Sunami A, Tasaka K (1983) Epileptogenic activity of cephalosporins in rats and their structure–activity relationship. Epilepsia 24:431–439PubMedCrossRefGoogle Scholar
  26. 26.
    De Sarro A, De Sarro GB, Ascioti C, Nistico G (1989) Epileptogenic activity of some beta-lactam derivatives: structure–activity relationship. Neuropharmacology 28:359–365CrossRefPubMedGoogle Scholar
  27. 27.
    Hantson P, Léonard F, Maloteaux JM, Mahieu P (1999) How epileptogenic are the recent antibiotics? Acta Clin Belg 54:80–87PubMedGoogle Scholar
  28. 28.
    Williams PD, Bennett DB, Comereski CR (1988) Animal model for evaluating the convulsive liability of β-lactam antibiotics. Antimicrob Agents Chemother 32:758–760PubMedGoogle Scholar
  29. 29.
    Schliamser SE, Cars O, Norrby SR (1991) Neurotoxicity of β-lactam antibiotics: predisposing factors and pathogenesis. J Antimicrob Chemother 27:405–425PubMedCrossRefGoogle Scholar
  30. 30.
    Chatellier D, Jourdain M, Mangalaboyi J, Ader F, Chopin C, Derambure P, Fourrier F (2002) Cefepime-induced neurotoxicity: an underestimated complication of antibiotherapy in patients with acute renal failure. Intensive Care Med 28:214–217CrossRefPubMedGoogle Scholar
  31. 31.
    Chow KM, Szeto CC, Hui AC, Li PK (2004) Mechanisms of antibiotic neurotoxicity in renal failure. Int J Antimicrob Agents 23:213–217CrossRefPubMedGoogle Scholar
  32. 32.
    Hantson P, Leonard F, Maloteaux JM, Mahieu P (1999) How epileptogenic are the recent antibiotics? Acta Clin Belg 54:80–87PubMedGoogle Scholar
  33. 33.
    Norrby SR (2000) Neurotoxicity of carbapenem antibiotics: consequences for their use in bacterial meningitis. J Antimicrob Chemother 45:5–7CrossRefPubMedGoogle Scholar
  34. 34.
    Seamans KB, Gloor P, Dobell RA, Wyant JD (1968) Penicillin-induced seizures during cardiopulmonary bypass: a clinical and electroencephalographic study. N Engl J Med 278:861–868PubMedCrossRefGoogle Scholar
  35. 35.
    Snavely SR, Hodges GR (1984) The neurotoxicity of antibacterial agents. Ann Intern Med 101:92–104PubMedGoogle Scholar
  36. 36.
    Martínez-Rodríguez JE, Barriga FJ, Santamaria J, Iranzo A, Pareja JA, Revilla M, dela Rosa CR (2001) Nonconvulsive status epilepticus associated with cephalosporins in patients with renal failure. Am J Med 111:115–119CrossRefPubMedGoogle Scholar
  37. 37.
    Chow KM, Wang AY, Hui CF, Wong TY, Szeto CC, Li PK (2001) Nonconvulsive status epilepticus in peritoneal dialysis. Am J Kidney Dis 38:400–405PubMedGoogle Scholar
  38. 38.
    Bechtel TP, Slaughter RL, Moore TD (1980) Seizures associated with high cerebrospinal fluid concentrations of cefazolin. Am J Hosp Pharm 37:271–273PubMedGoogle Scholar
  39. 39.
    Nagata M, Yasuhara M (2001) Effect of experimental renal failure on the pharmacodynamics of cefoselis-induced seizures in rats. Biol Pharm Bull 24:1049–1052CrossRefPubMedGoogle Scholar
  40. 40.
    Schliamser SE, Bolander H, Kourtopoulos H, Norrby SR (1988) Neurotoxicity of benzylpenicillin: correlation to concentrations in serum, cerebrospinal fluid and brain tissue fluid in rabbits. J Antimicrob Chemother 21:365–372PubMedCrossRefGoogle Scholar
  41. 41.
    Schliamser SE, Bolander H, Broholm KA, Gerdes U, Kourtopoulos H, Norrby SR (1989) Neurotoxicity of benzylpenicillin in experimental renal failure and Enterobacter cloacae meningitis. J Antimicrob Chemother 24:215–225PubMedCrossRefGoogle Scholar
  42. 42.
    Brouns R, De Deyn PP (2004) Neurological complications in renal failure: a review. Clin Neurol Neurosurg 107:1–16CrossRefPubMedGoogle Scholar
  43. 43.
    Calandra G, Lydick E, Carrigan J, Weiss L, Guess H (1988) Factors predisposing to seizures in seriously ill infected patients receiving antibiotics: experience with imipenem/cilastatin. Am J Med 84:911–918CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag 2005

Authors and Affiliations

  1. 1.Department of Medicine & TherapeuticsChinese University of Hong Kong, Prince of Wales HospitalHong Kong SARChina

Personalised recommendations