Chapter 29 : Central Nervous System Toxicity

MyBook is a cheap paperback edition of the original book and will be sold at uniform, low price.

Preview this chapter:
Zoom in

Central Nervous System Toxicity, Page 1 of 2

| /docserver/preview/fulltext/10.1128/9781555817817/9781555812317_Chap29-1.gif /docserver/preview/fulltext/10.1128/9781555817817/9781555812317_Chap29-2.gif


Central nervous system (CNS) reactions have been well known to occur sporadically with all nonfluorinated and fluorinated quinolone antibacterial agents. Studies using positron emission tomography have shown that fleroxacin is rapidly and equally distributed to the various parts of the brain and that lomefloxacin or ciprofloxacin do not affect cerebral blood flow or oxygen or glucose metabolism. Impaired excretory organ function, resulting in slower elimination of quinolones, may result in increased risks of accumulation of the drugs and subsequent CNS toxicity. Quinolones with a pyrrolidinyl side chain, like tosufloxacin and clinafloxacin, have intermediate binding, and those with alkylated side chains, such as temafloxacin and sparfloxacin, have low affinity. Interaction between ciprofloxacin and methadone has been described in one patient who developed confusion, sedation, and respiratory depression. Although serious reactions, seizures, and mental alterations occur, they are very rare. Risk factors for such reactions are high doses (including overdosing as a result of altered excretion, e.g., due to renal or hepatic failure or advanced age), previous epilepsy, and, probably, interactions with nonsteroidal anti-inflammatory drugs (NSAIDs) or theophylline.

Citation: Norby S. 2003. Central Nervous System Toxicity, p 461-465. In Hooper D, Rubinstein E (ed), Quinolone Antimicrobial Agents, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555817817.ch29
Highlighted Text: Show | Hide
Loading full text...

Full text loading...


1. Akahane, K.,, M. Sekiguchi,, T. Une,, and Y. Usada. 1989. Structure-epileptogenicity relationship of quinolones with special reference to their interaction with gamma-amino butyric acid receptor sites. Antimicrob. Agents Chemother. 33:17041708.
2. Akahane, K.,, Y. Tsutomi,, Y. Kimura,, and Y. Kitano. 1994. Levofloxacin, an optical isomer of ofloxacin, has attenuated epileptogenic activity in mice and inhibitory potency in GABA receptor binding capacity. Chemotherapy 40:412417.
3. Akahane, K.,, S. Ohkawara,, M. Nomura,, and M. Kato. 1996. Effects of bile duct ligation and unilateral nephrectomy on brain concentrations and convulsant potential of the quinolone antibacterial agent levofloxacin in rats. Fund. Appl. Toxicol. 29:280286.
4. Anderson, E. E.,, B. Anderson, Jr.,, and B. S. Nashold. 1971. Childhood complications of nalidixic acid. JAMA 216:10231024.
5. Ball, P.,, L. Mandell,, Y. Niki,, and G. Tillotson. 1999. Comparative tolerability of the newer fluoroquinolone antibacterials. Drug Safety 21:407421.
6. Bednarczyk, E. M.,, J. A. Green,, A. D. Nelson,, G. P. Leisure,, D. Little,, L. P. Adler,, M. S. Berridge,, E. A. Panacek,, and F. D. Miraldi. 1992. Comparative assessment of the effect of lomefloxacin, ciprofloxacin, and placebo on cerebral blood flow, and glucose and oxygen metabolism in healthy subjects by positron emission tomography. Pharmacotherapy 12:370375.
7. Bonis, L. O.,, and B. Sundstrom. 1967. Intracranial hypertension in a child during treatment with nalidixic acid. Br. Med. J. 2:744745.
8. Bowie, W. R.,, V. Willetts,, and P. J. Jeweson. 1989. Adverse reactions in a dose-ranging study with a new long-acting fluoroquinolone, fleroxacin. Antimicrob. Agents Chemother. 33:17781782.
9. Cahal, D. A. 1965. Reactions to nalidixic acid. Br. Med. J. 2:590.
10. Christ, W. 1990. Central nervous system toxicity of quinolones: human and animal findings. J. Antimicrob. Chemother. 26(Suppl. B):219225.
11. Davey, P. G.,, M. Charter,, S. Kelly,, T. R., K, Varma,, I Jacobson,, A. Freeman,, E. Precious,, and J. Lambert. 1994. Ciprofloxacin and sparfloxacin penetration into human brain tissue and their activity as antagonists of GABAA receptor of rat vagus nerve. Antimicrob. Agents Chemother. 38:3561362.
12. De Sarro, A.,, V. Cecchetti,, V. Fravolini,, F. Naccari,, O. Tabarini,, and G. De Sarro. 1999. Effects of novel 6-desfluoroquinolones and classic quinolones on pentyleneterazoleinduced seizures in mice. Antimicrob. Agents Chemother. 43:17291736.
13. Domagala, J. M. 1994. Structure-activity and structure-sideeffects relationships for the quinolone antibacterials. J. Antimicrob. Chemother. 33:685706.
14. Fan-Harvard, P.,, V. Sanchorawala,, J . Oh,, E. M. Moser,, and S. P. Smith. 1994. Concurrent use of foscarnet and ciprofloxacin may increase the propensity for seizures. Ann. Pharmacother. 28:869872.
15. Finegold, S. M.,, L. G. Miller,, D. Psnick,, D. K. Patterson,, and A. Davis. 1967. Nalidixic acid: clinical and laboratory studies. Antimicrob. Agents. Chemother. 1966:189197.
16. Fischman, A. J.,, E. Livni,, J . Babich,, N. M. Alpert,, Y.-Y. Liu,, E. Thom,, R. Cleeland,, B. L. Prosser,, J. A. Correia,, H. W. Strauss,, and R. H. Rubin. 1993. Pharmacokinetics of [18F] fleroxacin in healthy human subjects studied by using positron emission tomography. Antimicrob. Agents Chemother. 37:21442152.
17. Fisher, O. D. 1967. Nalidixic acid and intracranial hypertension. Br. Med. J. 2:744745.
18. Gonzales, J. P.,, and I. M. Henwood. Pefloxacin: a review of its antibacterial activity, pharmacokinetic properties and therapeutic use. Drugs 37:6628668.
19. Herrlin, K.,, M. Segerdahl,, L. L. Gustafsson,, and L. Kalso. 2000. Methadone, ciprofloxacin, and adverse drug reactions. Lancet 356:20692070.
20. Hon, S.,, J. Shimada,, A. Saito,, M. Matsuda,, and T. Miyahara. 1989. Comparison of the inhibitory effects of new quinolones on γ-aminobutyric acid receptor binding in the presence of antiinflammatory drugs. Rev. Infect. Dis. 11(Suppl. 5):S1397S1398.
21. Islam, M. A.,, and P. A. Davis. 1965. Convulsion, hyperglycaemia, and glycosuria from overdose of nalidixic acid. JAMA 192:11001101.
22. Karki, S. D.,, D. W. Bentley,, and M. Raghavan. 1990. Seizure with ciprofloxacin and theophylline combined therapy. DICP 24:595596.
23. Kawakami, J.,, K. Ohashi,, K. Tamamoto,, Y. Sawada,, and T. Iga. 1997. Effect of acute renal failure on neurotoxicity of enoxacin in rats. Biol. Pharm. Bull. 20:931934.
24. Kremer, L.,, M. Walton,, and E. N. Wardle. 1967. Nalidixic acid and intracranial hypertension. Br. Med. J. 4:488.
25. Kucers, A.,, and N. McK,. Bennett. 1975. Nalidixic and oxolinic acids, p. 479489. In A. Kucers,, and N. M. Bennett (ed.), The Use of Antibiotics, 2nd ed. Wlliam Heinemann Medical Books Ltd., London, United Kingdom.
26. Lipsky, B. A.,, and C. A. Baker. 1999. Fluoroquinolone toxicity profiles: a review focusing on newer agents. Clin. Infect. Dis. 28:352364.
27. Lode, H. 1999. Potential interactions of the extended-spectrum fluoroquinolones with the CNS. Drug Safety 21:123135.
28. Lor, E.,, and Y. Q. Liu. 1994. Neurologic sequelae associated with foscarnet therapy. Ann. Pharmacother. 28:10351037.
29. Matsuo, H.,, M. Ryu,, A. Nagata,, T. Uchida,, J.-I. Kawakami,, K. Yamamoto,, T. Iga,, and Y. Sawada. 1998. Neurotoxicodynamics of the interaction between ciprofloxacin and foscarnet in mice. Antimicrob. Agents Chemother. 42:691694.
30. Matuschka, P. R.,, and R. S. Vissing. 1995. Clinafloxacintheophylline drug interactions. Ann. Pharmacother. 29: 378380.
31. Melvani, S.,, and B. R. Speed. 2000. Alatrofloxacin-induced seizures during slow intravenous infusion. Ann. Pharmacother. 34:10171019.
32. Mizuno, J .,, S. Dugimoto,, A. Kaneko,, T. Tsutsui,, N. Zushi,, and K. Machida. 2001. Convulsions following the combination of single preoperative oral administration of enoxacin and single postoperative intravenous administration of flurbiprofen axetil. Masui 50:425428.
33. Murata, M.,, I. Tamai,, H. Kato,, O. Nagata,, H. Kato,, and A. Tsuji. 1999. Efflux transport of a new quinolone antibacterial agent, HSR-903, across the blood-brain barrier. J. Pharmacol. Exp. Ther. 290:5157.
34. Naora, K.,, N. Ichikawa,, H. Hirano,, and K. Iwamoto. 1999. Distribution of ciprofloxacin into the central nervous system in rats with acute renal or hepatic failure. J. Pharm. Pharmacol. 51:609616.
35. Nau, R.,, T. Schmidt,, K. Kaye,, J. L. Froula,, and M. G. Tauber. 1995. Quinolone antibiotics in therapy of experimental pneumococcal meningitis in rabbits. Antimicrob. Agents Chemother. 39:593597.
36. Olsen, R. W. 1981. GABA-benzodiazepine-barbiturate receptor interactions. J. Neurochem. 37:113.
37. Ooie, T.,, H. Suzuki,, T. Terasaki,, and Y. Sugiayma. 1996. Characterization of the transport properties of a quinolone antibiotic, fleroxacin, in rat choroid plexus. Pharm. Res. 13:523527.
38. Ostergaard, C.,, T. K. Sorensen,, J.D. Knudsen,, and N. Frimodt-Muller. 1998. Evaluation of moxifloxacin, a new 8-methoxyquinolone, for treatment of meningitis caused by a penicillin-resistant pneumococcus in rabbits. Antimicrob. Agents Chemother. 42:17061712.
39. Sanchez, R. M.,, C. Wang,, G. Gardner,, L. Orlando,, D. L. Tauck,, P. A. Rosenber,, E. Aizenman,, and F. E. Jensen. 2000. Novel role for the NMDA receptor redox modulatory site in the pathophysiology of seizures. J. Neurosci. 20:24092417.
40. Schlienger, R. G.,, C. Wyser,, R. Ritz,, and W. E. Haefeli. 1996. Clinico-pharmacological case (4). Epileptic seizure as an unwanted drug effect on theophylline poisoning. Schweiz. Rundsch. Med. Prax. 85:14071412.
41. Schmuck, G.,, A. Schurmann,, and G. Schluter. 1998. Determination of the excitatory potencies of fluoroquinolones in the central nervous system by and in vitro model. Antimicrob. Agents Chemother. 42:18311836.
42. Semel, J. D.,, and N. Allen. 1991. Seizures in patients simultaneously receiving theophylline and imipenem or ciprofloxacin or metronidazole. South. Med. J. 84:465468.
43. Smirnov, A.,, A. Wellmer,, J . Gerber,, K. Maier,, S. Henne,, and R. Nau. 2000. Gemifloxacin is effective in experimental pneumococcal meningitis. Antimicrob. Agents Chemother. 44:767770.
44. Stahlmann, R.,, and H. Lode. 1999. Toxicity of quinolones. Drugs 58(Suppl. 2):3742.
45. Teng, R.,, S. C. Harris,, D. E. Nix,, J. J. Schentag,, G. Foulds,, and T. E. Liston. 1995. Pharmacokinetics and safety of trovafloxacin (CP-99,219), a new quinolone antibiotic, following administration of single oral doses to healthy male volunteers. J. Antimicrob. Chemother. 36:385394.
46. Thomson, A. H.,, G. D. Thomson,, M. Hepburn,, and B. Whiting. 1987. A clinically significant interaction between ciprofloxacin and theophylline. Eur. J. Clin. Pharmacol. 33:435436.
47. Tsuji, A.,, H. Sato,, Y. Kume,, J. Tamai,, E. Okezaki,, O. Nagata,, and H. Kato. 1988. Inhibitory effects of quinolone antibacterial agents on gamma-aminobutyric acid binding to receptor sites in rat brain membranes. Antimicrob. Agents Chemother. 32:190194.
48. Tsutomi, Y.,, K. Matsubayashi, and K, Akahane. 1994. Quantitation of GABAA receptor inhibition required for quinolone-induced convulsions in mice. J. Antimicrob. Chemother. 34:737746.
49. Williams, P. D.,, and D. R. Helton. 1991. The preconvulsive activity of quinolone antibiotics in an animal model. Toxicol. Lett. 52:2328.


Generic image for table
Table 1

In vitro binding of quinolones to GABA A receptors with or without anti-inflammatory drugs (10⁻⁴ M)

Citation: Norby S. 2003. Central Nervous System Toxicity, p 461-465. In Hooper D, Rubinstein E (ed), Quinolone Antimicrobial Agents, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555817817.ch29
Generic image for table
Table 2

Potentiation of the CNS toxicity of quinolone antibiotics

Citation: Norby S. 2003. Central Nervous System Toxicity, p 461-465. In Hooper D, Rubinstein E (ed), Quinolone Antimicrobial Agents, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555817817.ch29

This is a required field
Please enter a valid email address
Please check the format of the address you have entered.
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error