Enoxacin

Enoxacin[note 1] is an oral broad-spectrum fluoroquinolone antibacterial agent used in the treatment of urinary tract infections and gonorrhea. Insomnia is a common adverse effect.[1][2] It is no longer available in the United States.

Enoxacin
Clinical data
AHFS/Drugs.comMonograph
MedlinePlusa601013
Routes of
administration		Oral
ATC code
Identifiers
IUPAC name
  • 1-ethyl-6-fluoro-4-oxo-7-(piperazin-1-yl)-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
Chemical and physical data
FormulaC15H17FN4O3
Molar mass320.324 g·mol−1
3D model (JSmol)
Melting point220 to 224 °C (428 to 435 °F)
SMILES
  • Fc1c(nc2c(c1)C(=O)C(\C(=O)O)=C/N2CC)N3CCNCC3
InChI
  • InChI=1S/C15H17FN4O3/c1-2-19-8-10(15(22)23)12(21)9-7-11(16)14(18-13(9)19)20-5-3-17-4-6-20/h7-8,17H,2-6H2,1H3,(H,22,23) Y
  • Key:IDYZIJYBMGIQMJ-UHFFFAOYSA-N Y
  (verify)

It has been shown recently that it may have cancer inhibiting effect.[3]

Mechanism of action

Quinolones and fluoroquinolones are bactericidal drugs, eradicating bacteria by interfering with DNA replication. Like other fluoroquinolones, enoxacin functions by inhibiting bacterial DNA gyrase and topoisomerase IV. The inhibition of these enzymes prevents bacterial DNA replication, transcription, repair and recombination.[4][5] Recently, it was shown that Enoxacin inhibits the expression of the microRNA mir-34-5p, leading to an increase in the lifespan of the nematode C. elegans.[6] Enoxacin is active against many Gram-positive bacteria.[note 2] The quinolone is also active against Gram-negative bacteria[note 3][7][8]

Pharmacokinetics

After oral administration enoxacin is rapidly and well absorbed from the gastrointestinal tract. The antibiotic is widely distributed throughout the body and in the different biological tissues. Tissue concentrations often exceed serum concentrations. The binding of enoxacin to serum proteins is 35 to 40%. The serum elimination half-life, in subjects with normal renal function, is approximately 6 hours. Approximately 60% of an orally administered dose is excreted in the urine as unchanged drug within 24 hours.[9][10] A small amount of a dose of drug administered is excreted in the bile.[11] High concentrations of the fluoroquinolone are reached in the urinary tract and this fact ensures an antibacterial effect continued over time, particularly in this district.

Medical uses

Enoxacin can be used to treat a wide variety of infections, particularly gastroenteritis including infectious diarrhea, respiratory tract infections, gonorrhea[12] and urinary tract infections.[13][14]

Adverse effects

Enoxacin, like other fluoroquinolones, is known to trigger seizures or lower the seizure threshold.[15] The compound should not be administered to patients with epilepsy or a personal history of previous convulsive attacks as may promote the onset of these disorders.[16]

Contraindications

Enoxacin is contraindicated in subjects with a history of hypersensitivity to the substance or any other member of the quinolone class, or any component of the medicine. Enoxacin, like other fluoroquinolones, can cause degenerative changes in weightbearing joints of young animals. The compound should only be used in children when the expected benefits are outweigh the risks.[17][18]

Interactions
  • Fenbufen: co-administration with some quinolones, including enoxacin may increase the risk of seizures. For this reason, concomitant administration of fenbufen and the quinolone should be avoided, as a precaution.[19][20][21][22]
  • Theophylline: in patients treated concurrently with theophylline and enoxacin, concentrations of the methylxanthine in plasma arise due to a reduced metabolic clearance of theophylline.[23][24][25][26]
  • Ranitidine, sucralfate, antacids containing magnesium or aluminum, supplements containing calcium, iron, or zinc: co-administration with these substances can lead to therapeutic failure of the antibiotic due to decreased absorption by the intestinal tract. For example, magnesium or aluminum antacids turn enoxacin into insoluble salts that are not readily absorbed by the gastroenteric tract.[27][28][29]

Notes
  1. Enoxacin is sold under the following trade names: Almitil, Bactidan, Bactidron, Comprecin, Enoksetin, Enoxen, Enroxil, Enoxin, Enoxor, Flumark, Penetrex, Gyramid, Vinone.
  2. Examples of Gram-positive bacteria include: Staphylococcus aureus, Staphylococcus epidermidis, Clostridium perfringens.
  3. Gram-negative bacteria include: Acinetobacter, Citrobacter, Campylobacter, Escherichia coli, Haemophilus influenzae, Klebsiella pneumoniae, Moraxella catarrhalis, Serratia marcescens, Pseudomonas aeruginosa, Proteus mirabilis, Proteus vulgaris, Salmonella, Shigella flexneri.

References
  1. Rafalsky, V.; Andreeva, I.; Rjabkova, E.; Rafalsky, Vladimir V (2006). Rafalsky, Vladimir V (ed.). "Quinolones for uncomplicated acute cystitis in women". Cochrane Database Syst Rev. 3 (3): CD003597. doi:10.1002/14651858.CD003597.pub2. PMC 7003573. PMID 16856014.
  2. Mogabgab, WJ. (Dec 1991). "Recent developments in the treatment of sexually transmitted diseases". Am J Med. 91 (6A): 140S–144S. doi:10.1016/0002-9343(91)90327-T. PMID 1767802.
  3. Melo, S.; Villanueva, A.; Moutinho, C.; Davalos, V.; Spizzo, R.; Ivan, C.; Rossi, S.; Setien, F.; Casanovas, O.; Simo-Riudalbas, L.; Carmona, J.; Carrere, J.; Vidal, A.; Aytes, A.; Puertas, S.; Ropero, S.; Kalluri, R.; Croce, C. M.; Calin, G. A.; Esteller, M. (2011). "Small molecule enoxacin is a cancer-specific growth inhibitor that acts by enhancing TAR RNA-binding protein 2-mediated microRNA processing". Proceedings of the National Academy of Sciences. 108 (11): 4394–4399. Bibcode:2011PNAS..108.4394M. doi:10.1073/pnas.1014720108. PMC 3060242. PMID 21368194.
  4. Yoshida H, Nakamura M, Bogaki M, Ito H, Kojima T, Hattori H, Nakamura S (April 1993). "Mechanism of action of quinolones against Escherichia coli DNA gyrase". Antimicrob. Agents Chemother. 37 (4): 839–45. doi:10.1128/aac.37.4.839. PMC 187778. PMID 8388200.
  5. Wolfson JS, Hooper DC (October 1985). "The fluoroquinolones: structures, mechanisms of action and resistance, and spectra of activity in vitro". Antimicrob. Agents Chemother. 28 (4): 581–6. doi:10.1128/aac.28.4.581. PMC 180310. PMID 3000292.
  6. Pinto, Silas; Sato, Vitor N.; De-Souza, Evandro A.; Ferraz, Rafael C.; Camara, Henrique; Pinca, Ana Paula F.; Mazzotti, Diego R.; Lovci, Michael T.; Tonon, Guilherme; Lopes-Ramos, Camila M.; Parmigiani, Raphael B.; Wurtele, Martin; Massirer, Katlin B.; Mori, Marcelo A. (September 2018). "Enoxacin extends lifespan of C. elegans by inhibiting miR-34-5p and promoting mitohormesis". Redox Biology. 18: 84–92. doi:10.1016/j.redox.2018.06.006. PMC 6037660. PMID 29986212.
  7. Chin NX, Neu HC (November 1983). "In vitro activity of enoxacin, a quinolone carboxylic acid, compared with those of norfloxacin, new beta-lactams, aminoglycosides, and trimethoprim". Antimicrob. Agents Chemother. 24 (5): 754–63. doi:10.1128/aac.24.5.754. PMC 185938. PMID 6229216.
  8. Wise R, Andrews JM, Danks G (March 1984). "In-vitro activity of enoxacin (CL-919), a new quinoline derivative, compared with that of other antimicrobial agents". J. Antimicrob. Chemother. 13 (3): 237–44. doi:10.1093/jac/13.3.237. PMID 6586712.
  9. Wise R, Lockley R, Dent J, Webberly M (July 1984). "Pharmacokinetics and tissue penetration of enoxacin". Antimicrob. Agents Chemother. 26 (1): 17–9. doi:10.1128/aac.26.1.17. PMC 179907. PMID 6591851.
  10. Wise R, Lister D, McNulty CA, Griggs D, Andrews JM (1986). "The comparative pharmacokinetics and tissue penetration of four quinolones including intravenously administered enoxacin". Infection. 14 Suppl 3: S196–202. doi:10.1007/bf01667843. PMID 3463542. S2CID 21959049.
  11. Flowerdew, A., E. Walker, and S. J. Karran. "Evaluation of biliary pharmacokinetics of oral enoxacin, a new quinolone antibiotic." 14th International Congress of Chemotherapy, Kyoto. 1985.
  12. van der Willigen AH, van der Hoek JC, Wagenvoort JH, van Vliet HJ, van Klingeren B, Schalla WO, Knapp JS, van Joost T, Michel MF, Stolz E (April 1987). "Comparative double-blind study of 200- and 400-mg enoxacin given orally in the treatment of acute uncomplicated urethral gonorrhea in males". Antimicrob. Agents Chemother. 31 (4): 535–8. doi:10.1128/aac.31.4.535. PMC 174773. PMID 3111354.
  13. Huttunen M, Kunnas K, Saloranta P (February 1988). "Enoxacin treatment of urinary tract infections in elderly patients". J. Antimicrob. Chemother. 21 Suppl B: 105–11. doi:10.1093/jac/21.suppl_b.105. PMID 3162900.
  14. Backhouse CI, Matthews JA (June 1989). "Single-dose enoxacin compared with 3-day treatment for urinary tract infection". Antimicrob. Agents Chemother. 33 (6): 877–80. doi:10.1128/aac.33.6.877. PMC 284249. PMID 2764538.
  15. De Sarro A, Zappalá M, Chimirri A, Grasso S, De Sarro GB (July 1993). "Quinolones potentiate cefazolin-induced seizures in DBA/2 mice". Antimicrob. Agents Chemother. 37 (7): 1497–503. doi:10.1128/aac.37.7.1497. PMC 188001. PMID 8395790.
  16. Simpson KJ, Brodie MJ (July 1985). "Convulsions related to enoxacin". Lancet. 2 (8447): 161. doi:10.1016/s0140-6736(85)90270-3. PMID 2862357. S2CID 45528661.
  17. Chalumeau M, Tonnelier S, D'Athis P, Tréluyer JM, Gendrel D, Bréart G, Pons G (June 2003). "Fluoroquinolone safety in pediatric patients: a prospective, multicenter, comparative cohort study in France". Pediatrics. 111 (6 Pt 1): e714–9. doi:10.1542/peds.111.6.e714. PMID 12777590. Retrieved 2014-09-24.
  18. Committee on Infectious Diseases (September 2006). "The use of systemic fluoroquinolones". Pediatrics. 118 (3): 1287–92. doi:10.1542/peds.2006-1722. PMID 16951028. Retrieved 2014-09-24.
  19. Morita H, Maemura K, Sakai Y, Kaneda Y (May 1988). "[A case of convulsion, loss of consciousness and subsequent acute renal failure caused by enoxacin and fenbufen]". Nippon Naika Gakkai Zasshi (in Japanese). 77 (5): 744–5. doi:10.2169/naika.77.744. PMID 3216153.
  20. Hara Y, Ally A, Suzuki T, Murayama S (October 1992). "[Effects of drugs on the convulsions induced by the combination of a new quinolone antimicrobial, enoxacin, and a nonsteroidal anti-inflammatory drug, fenbufen, in mice]". Nippon Yakurigaku Zasshi (in Japanese). 100 (4): 301–5. doi:10.1254/fpj.100.301. PMID 1446880.
  21. Masukawa T, Nakanishi K, Natsuki R (April 1998). "Role of nitric oxide in the convulsions following the coadministration of enoxacin with fenbufen in mice". Jpn. J. Pharmacol. 76 (4): 425–9. doi:10.1254/jjp.76.425. PMID 9623721.
  22. Masukawa T, Nakanishi K (February 1997). "Circadian variation in enoxacin-induced convulsions in mice coadministered with fenbufen". Jpn. J. Pharmacol. 73 (2): 175–7. doi:10.1254/jjp.73.175. PMID 9074952.
  23. Wijnands WJ, van Herwaarden CL, Vree TB (July 1984). "Enoxacin raises plasma theophylline concentrations". Lancet. 2 (8394): 108–9. doi:10.1016/s0140-6736(84)90283-6. PMID 6145999. S2CID 22217064.
  24. Niki Y, Soejima R, Kawane H, Sumi M, Umeki S (October 1987). "New synthetic quinolone antibacterial agents and serum concentration of theophylline". Chest. 92 (4): 663–9. doi:10.1378/chest.92.4.663. PMID 3477409. Archived from the original on 2014-09-25. Retrieved 2014-09-25.
  25. Mizuki Y, Fujiwara I, Yamaguchi T, Sekine Y (August 1996). "Structure-related inhibitory effect of antimicrobial enoxacin and derivatives on theophylline metabolism by rat liver microsomes". Antimicrob. Agents Chemother. 40 (8): 1875–80. doi:10.1128/AAC.40.8.1875. PMC 163433. PMID 8843297.
  26. Sano M, Kawakatsu K, Ohkita C, Yamamoto I, Takeyama M, Yamashina H, Goto M (1988). "Effects of enoxacin, ofloxacin and norfloxacin on theophylline disposition in humans". Eur. J. Clin. Pharmacol. 35 (2): 161–5. doi:10.1007/bf00609246. PMID 3191935. S2CID 1513011.
  27. Grasela TH, Schentag JJ, Sedman AJ, Wilton JH, Thomas DJ, Schultz RW, Lebsack ME, Kinkel AW (May 1989). "Inhibition of enoxacin absorption by antacids or ranitidine". Antimicrob. Agents Chemother. 33 (5): 615–7. doi:10.1128/aac.33.5.615. PMC 172500. PMID 2751276.
  28. Nix DE, Lebsack ME, Chapelsky M, Sedman AJ, Busch J, Norman A (April 1993). "Effect of oral antacids on disposition of intravenous enoxacin". Antimicrob. Agents Chemother. 37 (4): 775–7. doi:10.1128/aac.37.4.775. PMC 187758. PMID 8494374.
  29. Misiak PM, Eldon MA, Toothaker RD, Sedman AJ (January 1993). "Effects of oral cimetidine or ranitidine on the pharmacokinetics of intravenous enoxacin". J Clin Pharmacol. 33 (1): 53–6. doi:10.1002/j.1552-4604.1993.tb03903.x. PMID 8429114. S2CID 35219055.

Further reading
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