Octenidine dihydrochloride

Octenidine dihydrochloride is a cationic surfactant, with a gemini-surfactant structure, derived from 4-aminopyridine. It is active against Gram-positive and Gram-negative bacteria. Since 1987, it has been used primarily in Europe as an antiseptic prior to medical procedures, including on neonates.

Octenidine dihydrochloride^[1]

Names
IUPAC name 1,1′-(Decane-1,10-diyl)bis(N-octylpyridin-4(1H)-imine)—hydrogen chloride (1/2)
Other names N,N′-(decane-1,10-diyldi-1(4H)-pyridyl-4-ylidene)bis(octylammonium) dichloride
Identifiers
CAS Number	70775-75-6 Y Octenidine: 71251-02-0 Y
3D model (JSmol)	Interactive image
ChEBI	CHEBI:478961
ChEMBL	ChEMBL36342
ChemSpider	46370
ECHA InfoCard	100.068.035
EC Number	274-861-8
PubChem CID	198481
UNII	U84956NU4B Y Octenidine: OZE0372S5A Y
CompTox Dashboard (EPA)	DTXSID90221025
InChI InChI=1S/C36H62N4.2ClH/c1-3-5-7-9-15-19-27-37-35-23-31-39(32-24-35)29-21-17-13-11-12-14-18-22-30-40-33-25-36(26-34-40)38-28-20-16-10-8-6-4-2;;/h23-26,31-34H,3-22,27-30H2,1-2H3;2*1H Key: SMGTYJPMKXNQFY-UHFFFAOYSA-N InChI=1/C36H62N4.2ClH/c1-3-5-7-9-15-19-27-37-35-23-31-39(32-24-35)29-21-17-13-11-12-14-18-22-30-40-33-25-36(26-34-40)38-28-20-16-10-8-6-4-2;;/h23-26,31-34H,3-22,27-30H2,1-2H3;2*1H
SMILES CCCCCCCCN=C1C=CN(C=C1)CCCCCCCCCCN2C=CC(=NCCCCCCCC)C=C2.Cl.Cl
Properties
Chemical formula	C36H64Cl2N4
Molar mass	623.84 g·mol−1
Pharmacology
ATC code	R02AA21 (WHO) A01AB24 (WHO), QA01AB24 (WHO), combination codes: D08AJ57 (WHO), G01AX66 (WHO)
Legal status	EU: Rx-only[2]
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa). Infobox references

Medical uses

Since 1987, octenidine has been used in Europe as an antiseptic, in concentrations of 0.1 to 2.0%.^{[citation needed]} It is a substitute for chlorhexidine, with respect to its slow action and concerns about the carcinogenic impurity 4-chloroaniline.^{[citation needed]} Octenidine preparations are less expensive than chlorhexidine and no resistance had been observed as of 2007.^[3] They may contain the antiseptic phenoxyethanol.^[4] It is not listed in the Annex V of authorized preservatives of the European Cosmetic Regulation 1223/2009.

Efficacy

Octenidine dihydrochloride is active against Gram-positive and Gram-negative bacteria.^[5]

In vitro suspension tests with 5 minute exposure time have shown that octenidine requires lower effective concentrations than chlorhexidine to kill common bacteria like Staphylococcus aureus, Escherichia coli, Proteus mirabilis and the yeast Candida albicans.^[6]

Comparison between octenidine and chlorhexidine determined by the suspension test after 5 minutes of exposure.

	Effective concentration, %
	Octenidine dihydrochloride	Chlorhexidine digluconate
Staphylococcus aureus	0.025	>0.2
Escherichia coli	0.025	0.1
Proteus mirabilis	0.025	>0.2
Candida albicans	0.01	0.025
Pseudomonas aeruginosa	0.025	>0.2

An observational study of using octenidine on the skin of patients in 17 intensive care units in Berlin in 2014 showed decreasing nosocomial infection rates.^[7]

In a survey of German neonatal intensive-care units octenidine without phenoxyethanol and octenidine were the most common skin antiseptics used for intensive-care procedures. Skin complications included blistering, necrosis and scarring, which has not been previously reported in this population.^[4]

In a 2016 study of pediatric cancer patients with long-term central venous access devices using octenidine/isopropanol for the disinfection of catheter hubs and 3-way stopcocks as part of a bundled intervention, the risk of bloodstream infections decreased.^[8]

Safety

Octenidine is absorbed neither through the skin, nor through mucous membranes, nor via wounds and does not pass the placental barrier. However, cation-active compounds cause local irritation and are extremely poisonous when administered parenterally.^[6]

In a 2016 in vitro study of mouth rinses on gingival fibroblasts and epithelial cells octenidine showed a less cytotoxic effect, especially on epithelial cells, compared to chlorhexidine after 15 min.^[9] Wound irrigation with octenidine has caused severe complications in dogs,^[10] aseptic necrosis and chronic inflammation in penetrating hand wounds in humans.^[11][12]

Synthesis

The secondary amine (3) is formed by reaction of octan-1-amine (1) and 4-bromopyridine (2). Treatment of this with 1,10-dichlorodecane (4) yields octenidine as its dihydrochloride salt.^[13][14][15]

References

1. EC no. 274-861-8, ECHA
2. "List of nationally authorised medicinal products - Active substance: octenidine" (PDF). www.ema.europa.eu.
3. Al-Doori, Z.; Goroncy-Bermes, P.; Gemmell, C. G.; Morrison, D. (June 2007). "Low-level exposure of MRSA to octenidine dihydrochloride does not select for resistance". The Journal of Antimicrobial Chemotherapy. 59 (6): 1280–1281. doi:10.1093/jac/dkm092. ISSN 0305-7453. PMID 17439976.
4. C.D. Biermann; A. Kribs; B. Roth; I. Tantcheva-Poor (2016). "Use and Cutaneous Side Effects of Skin Antiseptics in Extremely Low Birth Weight Infants - A Retrospective Survey of the German NICUs". Klinische Pädiatrie. 228 (4): 208–12. doi:10.1055/s-0042-104122. PMID 27362412. S2CID 5099338.
5. Sedlock, D M; Bailey, D M (December 1985). "Microbicidal activity of octenidine hydrochloride, a new alkanediylbis[pyridine] germicidal agent". Antimicrobial Agents and Chemotherapy. 28 (6): 786–790. doi:10.1128/AAC.28.6.786. ISSN 0066-4804. PMC 180329. PMID 3909955.
6. Hans-P. Harke (2007), "Disinfectants", Ullmann's Encyclopedia of Industrial Chemistry (7th ed.), Wiley, pp. 1–17, doi:10.1002/14356007.a08_551, ISBN 978-3-527-30673-2
7. Gastmeier P, Kämpf K, Behnke M, Geffers C, Schwab F (2016). "An observational study of the universal use of octenidine to decrease nosocomial bloodstream infections and MDR organisms". Journal of Antimicrobial Chemotherapy. 71 (9): 2569–76. doi:10.1093/jac/dkw170. PMID 27234462.
8. Furtwängler, Rhoikos; Laux, Carolin; Graf, Norbert; Simon, Arne (2015). "Impact of a modified Broviac maintenance care bundle on bloodstream infections in paediatric cancer patients". GMS Hygiene and Infection Control. 10: Doc15. doi:10.3205/dgkh000258. PMC 4657435. PMID 26605135.
9. Schmidt, J.; Zyba, V.; Jung, K.; Rinke, S.; Haak, R.; Mausberg, R. F.; Ziebolz, D. (2016). "Cytotoxic effects of octenidine mouth rinse on human fibroblasts and epithelial cells – an in vitro study". Drug and Chemical Toxicology. 39 (3): 322–330. doi:10.3109/01480545.2015.1121274. PMID 26654138. S2CID 19546288.
10. Kaiser, S.; Kramer, M.; Thiel, C. (2015). "Severe complications after non-intended usage of octenidine dihydrochloride. A case series with four dogs". Tierärztliche Praxis. Ausgabe K, Kleintiere/Heimtiere. 43 (5): 291–298. doi:10.15654/TPK-150029. PMID 26353826. S2CID 80926611.
11. Lachapelle, JM. (2014). "A comparison of the irritant and allergenic properties of antiseptics". European Journal of Dermatology. 24 (1): 3–9. doi:10.1684/ejd.2013.2198. PMID 24492204.
12. Franz, T.; Vögelin, E. (2012). "Aseptic tissue necrosis and chronic inflammation after irrigation of penetrating hand wounds using Octenisept®". The Journal of Hand Surgery, European Volume. 37 (1): 61–64. doi:10.1177/1753193411414353. PMID 21816890. S2CID 29175202.
13. US patent 4206215, Denis M. Bailey, "Antimicrobial bis-[4-(substituted-amino)-1-pyridinium]alkanes", issued 1980-06-03, assigned to Sterling Drug Inc
14. Bailey, Denis M.; DeGrazia, C. George; Hoff, Stephanie J.; Schulenberg, Patsy L.; O'Connor, John R.; Paris, Donald A.; Slee, Andrew McKenzie (1984). "Bispyridinamines: a new class of topical antimicrobial agents as inhibitors of dental plaque". Journal of Medicinal Chemistry. 27 (11): 1457–1464. doi:10.1021/jm00377a014. ISSN 0022-2623. PMID 6492075.
15. "Octenidine". Pharmaceutical Substances. Thieme. Retrieved 2024-07-21.