Skip to main content
PMC home page
Antimicrobial Agents and Chemotherapy logoLink to Antimicrobial Agents and Chemotherapy
. 1995 Jan;39(1):232–237. doi: 10.1128/aac.39.1.232

Relationship between structure and convulsant properties of some beta-lactam antibiotics following intracerebroventricular microinjection in rats.

A De Sarro 1, D Ammendola 1, M Zappala 1, S Grasso 1, G B De Sarro 1
PMCID: PMC162514  PMID: 7695312

Abstract

The epileptogenic activities of several beta-lactam antibiotics were compared following their intracerebroventricular administration in rats. Different convulsant potencies were observed among the various beta-lactam antibiotics tested, but the epileptogenic patterns were similar. The patterns consisted of an initial phase characterized by wet-dog shakes followed by head tremor, nodding, and clonic convulsions. After the largest doses of beta-lactam antibiotics injected, clonus of all four limbs and/or the trunk, rearing, jumping, falling down, escape response, transient tonic-clonic seizures, and sometimes generalized seizures were observed, followed by a postictal period with a fatal outcome. At a dose of 0.033 mumol per rat, cefazolin was the most powerful epileptogenic compound among the drugs tested. It was approximately three times more potent than benzylpenicillin in generating a response and much more potent than other cephalosporins, such as ceftriaxone, cefoperazone, and cefamandole. No epileptogenic signs were observed with equimolar doses of cefotaxime, cefonicid, cefixime, and ceftizoxime in this model. The more convulsant compounds (i.e., cefazolin and ceftezole) are both characterized by the presence of a tetrazole nucleus at position 7 and show a marked chemical similarity to pentylenetetrazole. Imipenem and meropenem, the two carbapenems tested, also showed epileptogenic properties, but imipenem was more potent than meropenem, with a convulsant potency similar to those of ceftezole and benzylpenicillin. In addition, the monobactam aztreonam possessed convulsant properties more potent than those of cefoperazone and cefamandole. This suggest that the beta-lactam ring is a possible determinant of production of epileptogenic activity, with likely contributory factors in the substitutions at the 7-aminocephalosporanic or 6-aminopenicillanic acid that may increase or reduce the epileptogenic properties of the beta-lactam antibiotics. While the structure-activity relationship was also investigated, there seem to be no convincing correlations among the rank order of lipophilicities and the convulsant potencies of the compounds studied. The lack of marked convulsant properties of cefixime, cefonicid, cefuroxime, and cephradine suggests that these antibiotics may interact with a binding site which is different from that by which the beta-lactam antibiotics exert their convulsant effects or may demonstrate a reduced affinity for the relevant site(s).

Full Text

The Full Text of this article is available as a PDF (227.0 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Antoniadis A., Müller W. E., Wollert U. Inhibition of GABA and benzodiazepine receptor binding by penicillins. Neurosci Lett. 1980 Jul;18(3):309–312. doi: 10.1016/0304-3940(80)90302-x. [DOI] [PubMed] [Google Scholar]
  2. Curtis D. R., Game C. J., Johnston G. A., McCulloch R. M., MacLachlan R. M. Convulsive action of penicillin. Brain Res. 1972 Aug 11;43(1):242–245. doi: 10.1016/0006-8993(72)90288-0. [DOI] [PubMed] [Google Scholar]
  3. De Sarro A., De Sarro G. B., Ascioti C., Nisticó G. Epileptogenic activity of some beta-lactam derivatives: structure-activity relationship. Neuropharmacology. 1989 Apr;28(4):359–365. doi: 10.1016/0028-3908(89)90030-0. [DOI] [PubMed] [Google Scholar]
  4. De Sarro G. B., Calò M., Bagetta G., Anfosso R., Marmo E., Nisticò G., Guarino V. Comparative epileptogenic properties of cefazolin and benzylpenicillin after intracaudate microinjection in rats. Zhongguo Yao Li Xue Bao. 1983 Dec;4(4):236–238. [PubMed] [Google Scholar]
  5. Dingledine R., Gjerstad L. Reduced inhibition during epileptiform activity in the in vitro hippocampal slice. J Physiol. 1980 Aug;305:297–313. doi: 10.1113/jphysiol.1980.sp013364. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Drusano G. L. An overview of the pharmacology of imipenem/cilastatin. J Antimicrob Chemother. 1986 Dec;18 (Suppl E):79–92. doi: 10.1093/jac/18.supplement_e.79. [DOI] [PubMed] [Google Scholar]
  7. Duma R. J., Berry A. J., Smith S. M., Baggett J. W., Swabb E. A., Platt T. B. Penetration of aztreonam into cerebrospinal fluid of patients with and without inflamed meninges. Antimicrob Agents Chemother. 1984 Nov;26(5):730–733. doi: 10.1128/aac.26.5.730. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Eng R. H., Munsif A. N., Yangco B. G., Smith S. M., Chmel H. Seizure propensity with imipenem. Arch Intern Med. 1989 Aug;149(8):1881–1883. [PubMed] [Google Scholar]
  9. Gerald M. C., Massey J., Spadaro D. C. Comparative convulsant activity of various penicillins after intracerebral injection in mice. J Pharm Pharmacol. 1973 Feb;25(2):104–108. doi: 10.1111/j.2042-7158.1973.tb10602.x. [DOI] [PubMed] [Google Scholar]
  10. Gloor P., Testa G. Generalized penicillin epilepsy in the cat: effects of intracarotid and intravertebral pentylenetetrazol and amobarbital injections. Electroencephalogr Clin Neurophysiol. 1974 May;36(5):499–515. doi: 10.1016/0013-4694(74)90207-7. [DOI] [PubMed] [Google Scholar]
  11. Gu J. W., Neu H. C. In vitro activity of Ro 23-9424, a dual-action cephalosporin, compared with activities of other antibiotics. Antimicrob Agents Chemother. 1990 Feb;34(2):189–195. doi: 10.1128/aac.34.2.189. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Gutnick M. J., Van Duijn H., Citri N. Relative convulsant potencies of structural analogues of penicillin. Brain Res. 1976 Sep 10;114(1):139–143. doi: 10.1016/0006-8993(76)91015-5. [DOI] [PubMed] [Google Scholar]
  13. Hori S., Kurioka S., Matsuda M., Shimada J. Inhibitory effect of cephalosporins on gamma-aminobutyric acid receptor binding in rat synaptic membranes. Antimicrob Agents Chemother. 1985 Apr;27(4):650–651. doi: 10.1128/aac.27.4.650. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Kamei C., Sunami A., Tasaka K. Epileptogenic activity of cephalosporins in rats and their structure-activity relationship. Epilepsia. 1983 Aug;24(4):431–439. doi: 10.1111/j.1528-1157.1983.tb04913.x. [DOI] [PubMed] [Google Scholar]
  15. Nisticò G., De Sarro G. B., Naccari F., Musolino R., Rotiroti D., Gallitto G., Di Perri R. Cefazolin: a valid model of experimental epilepsy? Monogr Neural Sci. 1980;5:14–19. doi: 10.1159/000387477. [DOI] [PubMed] [Google Scholar]
  16. Patel J. B., Giles R. E. Meropenem: evidence of lack of proconvulsive tendency in mice. J Antimicrob Chemother. 1989 Sep;24 (Suppl A):307–309. doi: 10.1093/jac/24.suppl_a.307. [DOI] [PubMed] [Google Scholar]
  17. Raichle M. E., Kutt H., Louis S., McDowell F. Neurotoxicity of intravenously administered penicillin G. Arch Neurol. 1971 Sep;25(3):232–239. doi: 10.1001/archneur.1971.00490030058006. [DOI] [PubMed] [Google Scholar]
  18. Rotiroti D., de Sarro G. B., Musolino R., Nisticò G. A new model of experimental epilepsy: the cefazolin-induced epilepsy. Prog Clin Biol Res. 1983;124:129–144. [PubMed] [Google Scholar]
  19. Semel J. D., Allen N. Seizures in patients simultaneously receiving theophylline and imipenem or ciprofloxacin or metronidazole. South Med J. 1991 Apr;84(4):465–468. doi: 10.1097/00007611-199104000-00013. [DOI] [PubMed] [Google Scholar]
  20. Van Hartesveldt C., Petit T. L., Isaacson R. L. Epileptogenic effects of several penicillins and penicillin-related compounds in rat neocortex. Epilepsia. 1975 Sep;16(3):449–455. doi: 10.1111/j.1528-1157.1975.tb06072.x. [DOI] [PubMed] [Google Scholar]
  21. Williams P. D., Bennett D. B., Comereski C. R. Animal model for evaluating the convulsive liability of beta-lactam antibiotics. Antimicrob Agents Chemother. 1988 May;32(5):758–760. doi: 10.1128/aac.32.5.758. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. de Boer T., Stoof J. C., van Duyn H. Effect of penicillin on transmitter release from rat cortical tissue. Brain Res. 1980 Jun 16;192(1):296–300. doi: 10.1016/0006-8993(80)91033-1. [DOI] [PubMed] [Google Scholar]
  23. van Gelder N. M., Siatitsas I., Ménini C., Gloor P. Feline generalized penicillin epilepsy: changes of glutamic acid and taurine parallel the progressive increase in excitability of the cortex. Epilepsia. 1983 Apr;24(2):200–213. doi: 10.1111/j.1528-1157.1983.tb04880.x. [DOI] [PubMed] [Google Scholar]

Articles from Antimicrobial Agents and Chemotherapy are provided here courtesy of American Society for Microbiology (ASM)

RESOURCES