Original Paper

Skin Pharmacol Physiol 2010;23:244–258 Received: August 21, 2009

Accepted after revision: February 24, 2010
DOI: 10.1159/000314699
Published online: May 18, 2010

Octenidine Dihydrochloride, a Modern

Antiseptic for Skin, Mucous Membranes
and Wounds
N.-O. Hübner a J. Siebert b A. Kramer a 
     

a
  Institute of Hygiene and Environmental Medicine, Ernst Moritz Arndt University Greifswald, Greifswald, and
b
  Schülke & Mayr GmbH, Norderstedt, Germany

Key Words reduce the risk of colonization or transmission of patho-

Octenidine dihydrochloride ⴢ Skin antisepsis ⴢ Mucous gens, and thus the risk of infection, or to treat infections.
membrane antisepsis ⴢ Wound antisepsis ⴢ In the last few decades, new promising substances
Antimicrobial efficacy ⴢ Local tolerance ⴢ Toxicity ⴢ have been evaluated in clinical use. To choose the right
Safety ⴢ Contraindications antiseptic, the therapist needs overall data about efficacy,
mode of action, interactions, toxicology, safety, clinical
applications and contraindications. This article is meant
Abstract as a guideline for clinicians and studies octenidine dihy-
Octenidine dihydrochloride (octenidine) was introduced for drochloride (octenidine) as an antiseptic to be used on
skin, mucous membrane and wound antisepsis more than skin, mucosa and wounds based on the current literature
20 years ago. Until now, a wealth of knowledge has been and unpublished original data as well.
gained, including in vitro and animal studies on efficacy, tol-
erance, safety and clinical experience both from case reports
and prospective controlled trials. Nowadays, octenidine is an Areas of Application
established antiseptic in a large field of applications and rep-
resents an alternative to older substances such as chlorhexi- Antisepsis
dine, polyvidone-iodine or triclosan. The review is based on
the current literature and unpublished original data as well. Octenidine, approved as a medicinal substance in sev-
Copyright © 2010 S. Karger AG, Basel eral European countries [1], is used for skin antisepsis in
combination with aliphatic alcohols, e.g. propan-1-ol and
propan-2-ol, or with detergents such as antiseptic soap,
Introduction and for antisepsis on wounds and mucosa either as a sin-
gle substance, as an approved combination of octenidine
While antibiotics encounter a dramatic increase in re- and phenoxyethanol as aqueous solution (OPE) or either
sistance which limits their therapeutic use, antiseptics
with unspecific modes of action are highly unlikely to
produce resistant pathogens. They are topically used to Jörg Siebert is a remunerated employee of Schülke & Mayr GmbH.
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© 2010 S. Karger AG, Basel Nils-Olaf Hübner, MD

1660–5527/10/0235–0244$26.00/0 Institute of Hygiene and Environmental Medicine
University of Edinburgh

Fax +41 61 306 12 34 Ernst Moritz Arndt University Greifswald

E-Mail [email protected] Accessible online at: Walther-Rathenau-Strasse 49a, DE–17489 Greifswald (Germany)
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www.karger.com www.karger.com/spp Tel. +49 38 3451 5546, Fax +49 38 3451 5541, E-Mail nhuebner @ uni-greifswald.de
in combination with aliphatic alcohols or glycerol and ucts were shown to be effective for whole-body cleansing
detergents without phenoxyethanol [2]. in cases of MRSA colonization [21, 22]. Sloot et al. [23]
reported redness in 4 out of 28 patients who were washed
Prophylactic and Therapeutic Use on Skin with a diluted preparation based on octenidine for 5 days.
Antisepsis Prior to Skin-Penetrating Procedures It remains unclear whether this was caused by octeni-
For skin antisepsis prior to skin-penetrating proce- dine, the detergent or the frequent washing itself and con-
dures (e.g. insertion of arterial or venous catheters, punc- trasts with results for tolerance of highly fragile skin of
tures, surgical procedures), fixed combinations of octeni- neonates [7]. Using octenidine as an antiseptic liquid
dine with aliphatic alcohols are available. The idea be- soap, a mouth rinsing solution and as a nasal cream in a
hind these combinations is to add a sustained antimi- total of 107 nurses resulted in a successful decolonization
crobial effect to the otherwise fast and broad, but only in 98.1% of the cases. In 68% of the cases, decolonization
immediate antimicrobial action of alcohols. Applying was achieved already in the first cycle [24]. These results
skin antisepsis prior to the insertion of a central or pe- underline the high effectiveness of a regime based on oc-
ripheral venous catheter using a combination of 0.1% oc- tenidine-containing antiseptic preparations as part of an
tenidine with 30% propan-1-ol and 45% propan-2-ol was overall decolonization concept.
significantly more effective than the combination of 74%
ethanol with 10% propan-2-ol for 24 h [3]. No adverse ef- Acne Therapy
fects of octenidine were reported. In a prospective observational study with 30 patients,
For skin antisepsis of neonates, it is extremely impor- OPE applied once or twice daily for 6 weeks has proven
tant to choose a safe antiseptic. In this case, the OPE for- to be a cost-effective alternative in treating mild to mod-
mulation is superior to polyvidone (PVP)-iodine, which erate inflammatory acne lesions and may allow reduced
is contraindicated due to iodine absorption, and to pure prescriptions of anti-acne antibiotics causing bacterial re-
alcohol-based formulas, which can cause erosions in pre- sistance [25].
term infants [4, 5] and are absorbed, too [6]. Unlike alco-
hol-based antiseptics, OPE does not cause skin damage Nail Infections
in premature infants born before the 27th week of gesta- Fifteen patients were treated topically by soaking the
tion [7]. In contrast to chlorhexidine [8] and triclosan [9], affected nails twice a day for 10 min in OPE for 6 weeks,
octenidine is not absorbed, but phenoxyethanol is ab- concluding that OPE seems to represent an interesting,
sorbed through the skin, metabolized to phenoxyacetic well-tolerated, safe and efficacious therapeutic choice for
acid and excreted in the urine [7]. Due to this potential the treatment of Pseudomonas nail infection [26].
risk and though adverse effects have not been reported
with the OPE formulation yet, the actual recommenda- Skin Tolerance
tion for neonatal skin antisepsis in Germany is the use of Adverse effects of octenidine on intact skin were as-
octenidine without phenoxyethanol in the formulation sessed using New Zealand white rabbits. A 2% octenidine
[10]. The manufacturer of octenidine provides the raw solution was applied 4 times on day 1 and twice daily on
material to clinical pharmacies on request to produce a days 2–6 on the healthy skin of the animals. Toxic effects
final product. were compared to groups treated with a solution contain-
ing 4% propan-2-ol or water, respectively. Treatment with
Eradication of Microbial Colonization octenidine led to no overt behavioural changes or adverse
Eradication of unwanted colonization with potential effects, which corresponds to results in an open field and
pathogens is a typical antiseptic indication. The eradica- labyrinth test, whereas chlorhexidine induced changes of
tion of micro-organisms which are resistant to antibiotics behaviour [27]. Some animals in the test group showed
and colonize the skin, like methicillin-resistant Staphylo- ‘minimal’ and ‘slight’ erythema similar to the controls.
coccus aureus (MRSA), is particularly important. For this Used in severely immunocompromised patients for
purpose, a liquid soap containing octenidine, used like a the care of central venous catheter insertion sites, octeni-
shampoo or a shower gel, is available. This is of particular dine was highly effective with good skin tolerability [28].
interest, because resistances to the topical antibiotic mu-
pirocine are increasing worldwide [11–13] and the effi- Prophylactic and Therapeutic Use on Mucosa
cacy of chlorhexidine-based formulas has been repeat- For prophylactic use on intact mucosa, octenidine is
edly doubted recently [14–20]. Octenidine-based prod- most often used as OPE or as single substance. OPE is ap-
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Octenidine Dihydrochloride for Skin, Skin Pharmacol Physiol 2010;23:244–258 245

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proved by the Federal Institute for Medicinal Products daily for 30 days, similar results were obtained when a
and Medical Devices of Germany for repeated, short- 1:4 dilution of a 1.1% octenidine saccharine-containing
term antiseptic treatment of mucous membranes and ad- gel was administered twice daily or 4 times daily (high-
jacent skin prior to diagnostic and surgical procedures in dose group) on the upper jaw exterior gum, the upper jaw
the anogenital region (vagina, vulva, glans penis), in the palate, the lower jaw exterior gum and the lower jaw sub-
oral cavity and for wound treatment. lingual area of beagle dogs [internal data of Schülke &
Mayr GmbH, Norderstedt, Germany].
Genitalia The good tolerability and favourable effect of an oc-
The efficacy of OPE on male genitalia (e.g. used prior tenidine mouth rinse was confirmed in a prospective
to catheterization of the bladder) was shown to be supe- clinical trial with soft-tissue assessment, gingivitis,
rior to chlorhexidine [29, 30]. While PVP-iodine was in- plaque and dental stain as primary endpoints [42]. Adult
ferior in the immediate effect, OPE had a good residual volunteers (n = 451) were stratified in 2 balanced groups
effect and was better tolerated [19, 29, 31–35]. In a pro- according to gender, plaque and gingivitis scores. Both
spective, multicentre, randomized, case-control study groups received dental prophylaxis with dentifrice, tooth-
(n = 491), octenidine was a suitable alternative to clotrim- brushes and mouth rinse either containing 0.1% octeni-
azole in the treatment of acute vaginal candidosis [36]. In dine or placebo. They were given instructions to rinse
the treatment of bacterial vaginosis, OPE spray was as ef- with their assigned product for 30 s twice each day. Ex-
fective as the standard therapy with metronidazole (n = amination after 6 and 12 weeks showed no differences in
450) [37]. Patients stated that OPE was more comfortable, the oral soft-tissue condition but the group rinsing with
easier to apply, and side effects were less common [25]. 0.1% octenidine had significantly less plaque (39%), gin-
givitis (50%) and bleeding sites (60%). The test group had
Oral Cavity significantly higher stain formation and experienced lon-
There are many indications to use an antiseptic solu- ger prophylaxis times to remove the stain compared to
tion to reduce the bacterial load in the human oral cavity control, too [42].
(e.g. prior to operations, for plaque reduction, in venti- Recently, a mouth rinse containing octenidine with-
lated patients and to eradicate a colonization with MRSA) out phenoxyethanol was introduced, which was superior
[1]. OPE as well as octenidine alone were significantly su- to OPE in terms of taste and local tolerability [44]. This
perior to other current oral cavity antiseptics [38–40]. mouth rinse is especially meant for daily mouth hygiene
OPE showed expressed antimicrobial action in the re- in e.g. intensive-care patients and for decontamination of
gime of anti-inflammatory therapy of parodontal diseas- MRSA.
es [41].
In in vitro models, the plaque inhibition was more ef- Prophylactic and Therapeutic Use on Wounds
ficient than with chlorhexidine. For plaque accumula- Octenidine is used either as single substance or as OPE
tion, degrees of gingivitis and bleeding, howbeit associ- to prevent or treat microbial infection or colonization, re-
ated with staining, octenidine was superior to placebo spectively. In a prospective clinical study on patients with
[42, 43]. Octenidine could inhibit the adhesion of Can- advanced cancer and neoplastic ulcers after 3 weeks of
dida spp. to human buccal epithelia, too [43]. Its broad- treatment with OPE, common wound pathogens such as
spectrum efficacy, including Gram-positive as well as S. aureus, Staphylococcus epidermidis and Proteus mirabi-
Gram-negative organisms and yeast, makes octenidine lis, which were cultured prior to the treatment, were suc-
well applicable for mouth antisepsis in ventilated patients cessfully eradicated and improvements in the clinical con-
and patients receiving inhalation glucocorticoid therapy. dition of the ulcers, characterized by a reduction in necro-
This indication has to be evaluated in randomized con- sis, exudate, erythema and oedema, were recorded [45].
trolled trials.
Wound Tolerability
Tolerance The irritation threshold of OPE, assessed in the hen
Beagle dogs treated with an anti-dental-plaque formu- egg test on chorio-allantoic membrane, was found to be
lation containing placebo, 0.025 and 0.1% octenidine up 10–100 times lower than that of the combination of poly-
to 3 times daily for 1 month showed no drug-related ef- hexanide with macrogol [46].
fects including macroscopic or microscopic tissue chang- OPE was shown to be equal to Ringer solution with re-
es. Compared to placebo that was administered 4 times gard to wound healing of superficial wounds in pigs using
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 includes the eradication from the nose [55–58]. Mupiro-
cine is still the most widely used local antibiotic for erad-
2Cl–
C8H17 NH N+ (CH2)10 +N NH C8H17 ication, but resistance against mupirocine is increasing
and alternatives are urgently needed [11–13]. A patent
claims the invention of semisolid preparations contain-
ing octenidine [59]. For an octenidine ointment to be
2Cl– used in the nose, there is limited data available describing
C8H17 +NH N (CH2)10 N +NH C8H17
the efficiency of this therapy. While octenidine ointment
is advised by some experts [24, 60], at least in cases of mu-
C 36H 62N4 · 2HCl pirocine resistance, it cannot be recommended as a full
Mr: 623.8
substitute for intranasal mupirocine at the moment.

Argumentative Scolicidal Therapy

Fig. 1. Chemical structure of octenidine dihydrochloride. Octenidine has a fast and strong scolicidal efficacy [61,
62] and could be used as a scolicidal agent both periop-
eratively and for the puncture, aspiration, injection and
re-aspiration method.
a double-blind, randomized, stratified, controlled, paral-
lel-group study design [47]. In a double-blinded, random-
ized, controlled clinical study on chronic wounds, OPE Antimicrobial Impregnation
significantly improved the granulation over a 4-week ob-
servation period compared to Ringer solution [48]. This As octenidine was shown to be effective against bio-
good tolerability could be confirmed in a multicentre ran- film-forming organisms [63–65], its use for impregnation
domized double-blinded study on skin donor sites [49]. of implants and textiles appears promising, as it could be
In contrast to alcohols and polyhexanide, octenidine demonstrated for poly-L-lactide-coated titanium plate
did not alter the capillary microcirculation in the mouse osteosynthesis, impregnated with octenidine and triclo-
ear model [50]. san, on local infection resistance [66]. First experiences
with coated surgical sutures showed superior efficacy
Other Fields of Application against S. aureus but inferior biocompatibility in com-
Peritoneum parison to triclosan-coated sutures [44]. Octenidine is
The use of antiseptic solutions to prevent intra-ab- only suitable for antimicrobial coatings of tracheotomy
dominal infections is controversial, because they can tubes to a limited extent unless methods are developed to
cause an enhanced inflammatory response but may also allow sustained attachment or incorporation to the tub-
prevent microbial infection. The knowledge of the use of ing [67]. Various studies and patents claim methods to
octenidine-containing solutions for the irrigation of the coat or incorporate materials with antimicrobial impreg-
peritoneum is limited and conflictive. In in vitro tests, no nation with octenidine and other antiseptics as active
stimulation of tumour necrosis factor ␣ was detectable agents [68–70]. Initial studies with modified silica coat-
[51]. Case reports indicate that irrigation with OPE in ings, containing embedded octenidine on textiles, showed
concentrations of 0.1–0.025% can cause chemical perito- a convincing long-term effect against fungi [71].
nitis and ascites [52, 53]. On the other hand, irrigation
with octenidine can prevent the formation of peritoneal
adhesions in rats in a concentration of 0.01%, while rats Chemicophysical Characteristics
treated with 0.05% octenidine died [54]. This seems to
imply a dose-dependent effect. Further studies are need- Octenidine dihydrochloride [CAS No. 70775-75-6;
ed to rate the possible role of octenidine for peritoneal N,Nⴕ-(1,10-decanediyldi-1[4H]-pyridinyl-4-ylidene)-bis-
irrigation. (1-octanamine) dihydrochloride] is a cationic, surface-
active substance (see formula, fig. 1). Octenidine express-
Nose ly differs from quaternary ammonium compounds such
The nares are the most important source of S. aureus. as benzalkonium chloride and from guanidines such as
Therefore, a successful eradication of MRSA inevitably chlorhexidine because the amide and ester structures are
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Octenidine Dihydrochloride for Skin, Skin Pharmacol Physiol 2010;23:244–258 247

Mucous Membranes and Wounds
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 Table 1. Interaction of octenidine and chlorhexidine digluconate, incorporated in agar, with antibiotics, placed
in the form of commercial antibiotic paper discs on the agar surface after diffusion time of 18 h [80]

Test organism Octenidine Chlorhexidine digluconate

Müller- isosensitest blood agar Müller- isosensitest blood agar
Hinton agar agar Hinton agar agar

Imipenem
Enterococcus faecalis + + + 0 0 +
Enterococcus faecium + + + – 0 +
Pseudomonas aeruginosa + + + 0 0 –
Escherichia coli 0 + + – – 0
Piperacillin + tazobactam
Enterococcus faecalis + + + + – 0
Enterococcus faecium + 0 + 0 – +
Pseudomonas aeruginosa 0 + + – – +
Escherichia coli 0 + – 0 0 –

+ = Synergism; 0 = no interaction; – = antagonism.

not part of the molecule. Therefore, 4-chloraniline, the used together with PVP-iodine-based antiseptics, be-
toxicologically critical part of the chlorhexidine mole- cause octenidine can release iodine radicals from the
cule, cannot be liberated. Octenidine is stable in the pH PVP complex, resulting in a tissue irritation as well as
range from 1.6 to 12.2, under the influence of light, and strong brown to violet discolouration in the border areas.
can be steam sterilized up to 130 ° C in aqueous solutions.
    The assessment of interactions seems to be important
It can be stored at room temperature [72]. The molecular for antibiotics, because combined use of antiseptics and
weight is approximately 624 Da. It has 2 non-interacting antibiotics in wound infections constitutes a clinical
cation-active centres in its molecule, which are separated practice. While antibiotics are administered orally or in-
by a long aliphatic hydrocarbon chain. It therefore binds travenously, they are intended to act on the spot. First
readily onto negatively charged surfaces, such as micro- results from in vitro studies indicate that the combina-
bial cell envelopes and eukaryotic cell membranes. Pre- tion of octenidine with systemic antibiotics could not
liminary results imply a particularly strong adherence to only be additive but even synergistic [79]. In contrast to
lipid bacterial cell membrane components (e.g. cardio- chlorhexidine, octenidine showed synergistic interac-
lipin) explaining the high antimicrobial efficacy without tions with antibiotics or was without interference (ta-
adversely affecting human epithelial or wound tissue ble 1). Further studies are necessary to evaluate the effect
[73]. Analogously to other cationic antiseptics like of combined use of systemic and local antimicrobial ther-
chlorhexidine and polyhexanide, salts of fatty acid glyc- apy.
erol phosphates in the cell membrane are assumed to be
the main binding partners [74]. Interaction with enzy-
matic systems and polysaccharides in the cell wall of mi- Antimicrobial Efficacy and Resistance
cro-organisms [14, 75] and induction of leakages in the
cytoplasmic membrane [76] were described. This was Spectrum of Activity
shown for yeast mitochondrial membranes, too [77].
Due to its unspecific, strong absorption and interac-
tion with cell wall and cell membrane structures, octeni-
Interactions dine has a broad antimicrobial spectrum against Gram-
positive and Gram-negative bacteria including MRSA [1],
Octenidine shows synergism with phenoxyethanol, plaque-forming bacteria such as Actinomyces and Strep-
hence OPE is readily available and widely used [78]. As tococcus spp. [81], Chlamydia, Mycoplasma [82; Kirchhoff
our own laboratory test showed, octenidine should not be as well as Schmitz and Wellmann cited in 83] and fungi
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Table 2. Concentrations (mg/l) leading to an average reduction of burden (table 2) and after 30 min in the presence of 10%
≥3.8 (C. albicans) or ≥4.8 log steps (S. aureus, P. aeruginosa) with- fetal bovine serum (table 3), the effectiveness of octeni-
in 1 min in tests according to DIN EN 1,040 and 1,275 [88]
dine exceeded those of the other antiseptic agents [88].
Active agent S. aureus P. aeruginosas C. albicans Results from the suspension test with octenidine after 5,
15, 60 and 1,000 min contact time revealed a fast micro-
Octenidine 10 50 25 bicidal effect against different pathogens including S. epi-
PVP-iodine 250 250 500 dermidis, S. aureus, P. mirabilis, Streptococcus pyogenes,
Polyhexanide 250 500 5,000 K. pneumoniae, E. coli, P. aeruguinosa and C. albicans in
Chlorhexidine 2,000 3,000 3,000
Triclosan 250 20,000 10,000 concentrations 5- to 20-fold lower compared to chlorhex-
idine [72, 85, 94]. This was confirmed in the quantitative
suspension test [86]. Presence of albumin, blood (tested
up to 10%) and mucin did not reduce the efficacy, but
high levels of free cardiolipin or of chondroitin sulphate
Table 3. Concentrations (mg/l) leading to a 3 log10 reduction with-
in 30 min in fetal bovine serum [95]
could abolish or diminish the microbicidal activity of oc-
tenidine [73].
Active agent S. aureus E. coli In an infected dentine block model with Enterococcus
faecalis, OPE gel (1:1) decreased viable bacteria signifi-
OPE 17.5 22.5 cantly from 57.2 to 5.7% after 10 min contact time. After
Benzalkonium chloride 80 100 7 days, only 1 of 10 samples showed a positive bacterial
Chlorhexidine digluconate 85 100
Polyhexanide 100 90 culture [96].
Cetylpyridinium chloride 80 125 Octenidine acts as a limited virucidal ingredient. Con-
Triclosan 250 500 centrations of 0.1% are highly effective against f2- and
PVP-iodine 7,000 7,000 MS2-coliphages (66 log) within 5 min but lack efficacy
Silver nitrate >10,000 >10,000 against PhiX174-phages. This implies a virucidal effect
Silver(I) sulphadiazine >10,000 >10,000
against enveloped viruses as shown for hepatitis B and
herpes simplex viruses, but no efficacy against hydro-
philic, non-enveloped viruses such as adenoviruses [94,
97].
[84, 85]. Octenidine is superior to chlorhexidine and alex- While 0.1 and 0.001% of octenidine are scolicidal
idine as an inhibitor of plaque-forming enzymes of Strep- within 15 and 30 min [61], octenidine has no sporicidal
tococcus mutans [84]. and no protozoocidal effect.

Efficacy
The antimicrobial efficacy in vitro is about 3–10 times Inactivation of Biofilms
higher than that of chlorhexidine with minimal inhibi-
tory concentrations for S. aureus and Escherichia coli of Octenidine was shown to be highly effective against
1.0 ␮g/ml, for Klebsiella pneumoniae and P. mirabilis of biofilms induced by species isolated from catheter-relat-
2.0 ␮g/ml, for Pseudomonas aeruginosa of 3.9 ␮g/ml and ed and orthopaedic implant infections as well as by labo-
for different Candida strains of 1.5 and 3.0 ␮g/ml [1, 76, ratory strains of S. epidermidis and P. aeruginosa, respec-
79, 86–88]. This was confirmed on skin and wounds [83] tively [63–65].
and for plaque reduction in animal studies [89, 90]. The Regarding Streptococcus sanguis biofilms grown on
residual effect of octenidine is remarkable [91, 92]. Besides hydroxyapatite discs, chlorhexidine was superior to PVP-
the direct antimycotic effect, octenidine induced changes iodine and octenidine [98]. In another biofilm model
in the lipid and sterol contents of Candida albicans and is simulating the plaque-reducing and biofilm-clearing ac-
binding to human buccal epithelial cells in vitro [76, 93]. tivity, OPE performed equally to chlorhexidine and hex-
The minimal microbicidal concentrations after 5 min etidine [99]. Octenidine was shown to be more effective
contact time are 250 ␮g/ml octenidine for S. aureus, E. against biofilms on medical implants compared to genta-
coli, P. mirabilis and P. aeruginosa and 100 ␮g/ml for C. micin, too [63].
albicans and are thus much lower than those of chlorhex- Octenidine rapidly killed planktonic cells and bio-
idine [88, 94]. After contact time of 1 min without bio- films of Listeria monocytogenes and was equally effective
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in killing L. monocytogenes biofilms on polystyrene and rats 24 and 48 h after dosing (oral), respectively. The total
stainless-steel matrices even in the presence of organic radioactivity in the carcass accounted for 0.21%, and all
matter [100]. other tissues contained !0.05% of the applied dose, so the
absorbed amounts are ^6%. Most of the applied sub-
stance was excreted in the faeces [internal data of Schülke
Residual (Long-Lasting) Effect & Mayr].
These results were endorsed in vitro with artificially
Because octenidine binds readily to negatively charged perfused, freshly prepared human placenta. While with-
surfaces and is not percutaneously absorbed, at least a in 2 min octenidine was above the limits of detection
part of the applied substance remains on the site of ap- (2 ppm) in the venous eluate on the maternal side, no oc-
plication and thus exerts a sustained antimicrobial effect tenidine was detectable in the venous eluate on the foetal
[92]. side during the observation period of 60 min [105].
Because octenidine is only approved and used topi-
cally and is virtually not absorbed, no systemic effects are
Resistance to be expected. Therefore, no further pharmacokinetic
studies or studies on behalf of the metabolism have been
Microbial resistances were not detectable or inducible conducted.
in vitro and are not to be expected on account of the
mechanism of action [101–103].
Cytotoxicity

Further Biological Effects In vitro results from cell culture and explants show
that the cytotoxicity of octenidine is comparable to
Octenidine was shown to significantly improve phago- chlorhexidine and is thus considerably greater than that
cytosis by neutrophils in human blood in vitro by inter- of PVP-iodine [106]. Erythrocytes and granulocytes in-
action with the bacterial cell wall [104]. cubated with OPE in concentrations up to 0.05% for 30
In a whole-blood model without and with addition of min showed no metabolic disturbances [107].
lipopolysaccharide, no stimulation of tumour necrosis To rate the relevance of the cytotoxic effect for an an-
factor ␣ was detectable. Without the addition of lipopoly- tiseptic, its cytotoxicity has to be evaluated against its an-
saccharide, no release of platelet-derived growth factor timicrobial effect. The so-called biocompatibility index is
AB was detectable, but with addition of lipopolysaccha- obtained from the quotients determined under identical
ride dose-dependent stimulation could be detected [51]. test conditions of 50% inhibitory concentrations in cell
culture and the concentration that achieves a bacterial
reduction of 3 log10 steps in the quantitative suspension
Toxicology test after 30 min of contact time. A biocompatibility in-
dex 11 is achieved only by polyhexanide and octenidine,
Most of the toxicological data were recorded during meaning that these substances are more toxic (i.e. effec-
the eighties and nineties of the last century to prove the tive) to the test micro-organisms than to murine fibro-
safety of octenidine for its medicinal use. The data were blasts [95].
collected according to the then used quality criteria for It has been shown that octenidine binds readily to mu-
conducting toxicological tests and were previously unre- rine fibroblasts, human epithelial cells and primary kera-
leased. References are given for all other data. tinocytes. Once bound, it cannot be removed easily (e.g.
by washing) but builds stable combinations with cell sur-
faces. The cytotoxic effect of octenidine is greatly reduced
Absorption, Metabolism and Excretion in these complexes, but surprisingly, the antiseptic effi-
cacy remains unchanged and is not affected by 10% fetal
Octenidine is virtually not absorbed via the skin or bovine serum [73, 95]. While this phenomenon needs
mucous membranes. After topical application in mice, further investigation, it might explain the differences
using 14C-octenidine, no radioactivity was detectable in from in vitro findings with relatively high cytotoxicity
serum at any time. Identical results were obtained with (comparable to chlorhexidine) and favourable clinical re-
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Table 4. Single-dose toxicity of octenidine dihydrochloride

Species Application Doses Gender Maximum Approximate Noteworthy findings

mg/kg b.w. n per group non-lethal dose lethal dose
mg/kg mg/kg

Mice p.o. 125–1,000 both sexes 1,000 – No mortalities and no clinical signs within 7 days
1:1 (10)
Sprague- p.o., 1% 500–3,160 male (10) 7 days: 500 LD50 (7 days): 800 Matted fur, dyspnoea, ataxia, partial to complete
Dawley aqueous 14 days: 1/10 absence of motor activity, brown exudates around eyes
albino tragacanth deaths in and nose, loose stools in the two highest-dose groups;
rats 500-mg group dead animals: congested lungs, pitted areas of the
glandular portion of the stomach, adhesion of the
stomach to the liver (12/35 animals), also observed in 3
surviving animals
i.v., distilled 5, 8, 12.6 male (10) 7 days: 5 LD50 (7 days): 10 Ataxia, partial decrease in motor activity followed by
water pH 7.0 jerky leg movements, dyspnoea, loss of righting reflex
(high- and middle-dose groups); dead animals: no
gross tissue changes; survivors: n = 3: necrotic tail
New p.o. (stomach 80, 250, 800 male/female 250 – Within 8 days initial loss in body weight in the two
Zealand tube), (4/2) lower-dose groups, anorexia in the high-dose group; 2
white suspended rabbits of the 800-mg group died on days 4 and 7;
rabbits in 1% gum inactivity, nasal discharge, dyspnoea, loose or black
tragacanth stools were recorded; gross pathology revealed areas of
hyperaemia in the stomach mucosa

Internal data of Schülke & Mayr GmbH. b.w. = Body weight; p.o. = per os; LD50 = 50% lethal dose; i.v. = intravenous;

sults. The formation of stable complexes with cells might The oral repeat-dose toxicity (table 5) was assessed in
have a favourable effect on tolerability, because only the different species; the chronic toxicity was assessed in
top cell layer is exposed to the active substance, working Charles River CD albino and Charles River COBS-CD
as an antibacterial shield to the deeper regeneration tis- rats of both sexes (table  5) [internal data of Schülke &
sue. The sustained release of octenidine from these com- Mayr].
plexes maintains low, non-cytotoxic but antimicrobial
concentrations in the wound.
Chronic Dermal Toxicity

Oral Single-Dose and Repeat-Dose Toxicity To assess chronic dermal toxicity, 2.5 ml of skin cleans-
er in the final concentration of 0.5%, which corresponds
Single oral doses of octenidine (table  4) up to 1,000 to 0.125% octenidine, were applied to the back of rabbits
mg/kg in mice resulted in no mortality during the obser- once daily over a period of 6 months. Two control groups
vation period of 7 days. Male rats were used to estimate were treated with a 1:4 dilution of the vehicle solution and
50% lethal doses (LD50) within 7 days after administra- distilled water. In none of the assessed parameters (food
tion of octenidine (once via stomach tube in doses up to consumption, body mass, erythema, weekly measured
3,160 mg/kg). LD50 was calculated to be 800 mg/kg (range skin thickness at the application site, haematology, blood
650–970 mg/kg) [internal data of Schülke & Mayr]. analyses, organ mass, gross and microscopic pathology)
Similar results were obtained with rabbits treated with were drug-related effects found [internal data of Schülke
single oral doses of 80.0, 250 and 800 mg/kg octenidine, & Mayr].
observed for 8 days [internal data of Schülke & Mayr]. In contrast to chlorhexidine, no neurotoxic reactions
For male rats, the LD50 after single intravenous ad- were seen in rats in the labyrinth test with dermal appli-
ministration of octenidine within 7 days of observation cation of 0.5 ml twice daily over 90 days [27].
was calculated to be 10.0 mg/kg (range 8.2–12.5 mg/kg)
[internal data of Schülke & Mayr].
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Table 5. Repeat-dose toxicity of octenidine dihydrochloride (controls:vehicle)

Species/ Application Application Doses Males/ NOAEL Noteworthy findings

strain (n) per day females
and duration n per group

Charles p.o. (gavage), dissolved 1/day 0.5, 2, 12/12 Except 0.5 mg/kg, respiratory distress at some time during
River in distilled water 13 weeks 4 mg/kg treatment; food consumption dose-dependently reduced;
CD-1 mice marked gaseous distension and decreases in metabolic effi-
ciency caused by antiseptic inducing changes in endogenous
flora; 4 mg/kg: increased incidences of inflammatory changes
involving lung parenchyma and pleura, particularly among fe-
male mice
p.o. (diet) 1/day 32, 64, 128, 20/20 32 mg/kg 3 mice died due to drug-related reasons; with increased daily
13 weeks 256 mg/kg dose body weight in male mice was reduced with reduced food
utilization; only 3 males of the high-dose group showed signs
of slight distension of the abdomen; no further symptoms were
observed
Charles p.o., stomach tube, 1/day 10, 50, 10/10 10 mg/kg: distension in some animals on day 5; 50.0 mg/kg:
River CD 1% gum tragacanth 14 days 250 mg/kg abdominal distension in all males and several females; 250 mg/
albino rats kg: 12/20 drug-related deaths; distended abdomen, respiratory
depression, dyspnoea, rales and bloody exudates around eyes
and nares preceding death; animals that died showed loss of
body weight; haematology, blood and urine analysis unre-
markable, gross observation: deficient body fat, distension of
the caecum, small accessory organs, spleens and thymi, con-
gestion of lungs and kidneys in rats that died; no microscopic
drug effects
p.o., stomach tube, 1/day 5, 10, 15/15 20 ml/kg 20 mg/kg: food consumption was slightly reduced in both sex-
aqueous solution con- 5 weeks 20 mg/kg es, growth rate was slightly depressed in males, but slightly
taining 16% ethanol increased in females; no further drug-related observations
(commercial anti-
plaque mouthwash)
Charles p.o. (intubation), 1/day 2, 8, 28/28 In the low-, mid- and high-dose groups, n = 4, n = 15 and n =
River dissolved in distilled 12 months 32 mg/kg 30 animals died prematurely; most dead animals showed oe-
COBS-CD water dematous haemorrhagic alveolitis; tissue changes were in-
rats duced by incidental introduction of test substance into the
lungs
New On intact dorsal skin, Day 1: 2.25 ml 3/3 No drug- Mild skin reactions at the application site were observed in al-
Zealand aqueous solution con- 4/day related most all animals of all groups due to the mechanical lathering
white taining 4% propan-2- days 2–6: effects of the skin after application
rabbits ol (commercial surgi- 2/day observed
cal scrub formulation,
2%), 5 min contact
time
On intact dorsal skin 1/day on 0.125%, 3/3 0.5% Nasal discharge in all groups was not attributable to test med-
(10 ! 15 cm), com- weekdays 0.5% ication; slight to moderate erythema was observed occasion-
mercial skin cleanser 6 months ally in animals receiving test medication and vehicle, but no
preparation, aqueous dose relationship or increase in incidence during the course of
solution containing the study; no systemic effects; clinical chemistry analyses, gross
6% (vol/vol) propan- and microscopic findings revealed no drug-related pathology;
2-ol, 2.5 ml per appli- test substances were washed from skin once weekly; total ex-
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Table 5 (continued)

Species/ Application Application Doses Males/ NOAEL Noteworthy findings

strain (n) per day females
and duration n per group

Beagle Topically, oral cavity, 3/day on 0.025%, 3/3 No drug- Food consumptions, body weight changes, heart and respira-
dogs aqueous solution con- weekdays, 0.1% related tory rates, body temperature, ophthalmoscopic findings, elec-
taining 16% ethanol, 2/day on effects trocardiograms, haematology, blood and urine analysis nor-
2 ml per application weekends observed mal in all animals; no gross or microscopic tissue changes
4 weeks
Topically, oral cavity, 4/day on 0.275% 3/3
1.1% octenidine sac- weekdays,
charine dentifrice gel: 2/day on
total daily application weekends
volume 8 ml 30 days
p.o., stomach tube, 1/day 1, 6, 3/3 1 and No animal died; 18.0 mg/kg: postmedication emesis in 5/6
1% gum tragacanth 5 weeks 18 mg/kg 6 mg/kg: dogs with incidences ranging from occasional to frequent,
no drug- loose stools appeared infrequently; food consumption, body
related weight changes, heart and respiratory rates, body temperature,
symp- ophthalmoscopic findings, electrocardiograms, haematology,
toms blood and urine analysis normal in all animals; no gross or
microscopic tissue changes
p.o., dissolved in 1/day 2, 8 mg/kg 4/4 2 mg/kg: 2 dogs died with marked changes of the lung and in-
distilled water 12 months tensive haematic suffusions in interstitial tissue of pancreas; 18
mg/kg: emesis, salivation, anorexia, 5 dogs died; examinations
revealed oesophagitis and changes in lung and heart

Internal data of Schülke & Mayr GmbH. NOAEL = No observable adverse effect level; p.o. = per os.

Genotoxicity and Carcinogenicity in rabbits treated with octenidine orally prior to mating,
no adverse effects on spermatogenesis or oogenesis, fertil-
Neither the Ames test, using Salmonella typhimurium ity and reproductive parameters, course of pregnancy, par-
strains TA 98, TA 100, TA 1,535, TA 1,537 and TA 1,538, turition and lactation were observed. No embryotoxic or
nor tests with mouse lymphoma cells, CHO cell cultures, teratogenetic effects were recorded. Neither survival rate,
human lymphocytes and in vivo tests using Charles Riv- postnatal development nor suckling of progeny was influ-
er CD-1 mice that were treated with octenidine via oral enced by octenidine [internal data of Schülke & Mayr].
gavage suggested any mutagenic or genotoxic potential of
octenidine [internal data of Schülke & Mayr].
Octenidine did not show any carcinogenic potential in Local Tolerance
CD-1 (ICR) albino mice treated topically with octenidine
on the naked backs 3 days a week for 18 months. Charles Applied locally either as solution or as soaked test pad,
River CD Sprague-Dawley rats treated with octenidine octenidine did not show any photosensitization or de-
once daily in doses up to 8 mg/kg by oral gavage for 104 layed contact sensitization (table 6).
weeks (males) and 106 weeks (females) did not show any
carcinogenic effect but confirmed results from other stud-
ies about the chronic toxicity, especially possible respira- Adverse Effects and Contraindications
tory tract irritations [internal data of Schülke & Mayr].
Octenidine should not be used for joint irrigation, be-
cause even a concentration of 0.005% octenidine is toxic
Reproductive and Developmental Toxicity for cartilage [108].
After irrigation of deep penetrating stab wounds in
Octenidine showed neither reproductive nor develop- children’s hands under pressure with OPE, severe and
mental toxicity in rats and rabbits. In COBS CD rats and long-lasting oedematous reactions with tissue damage
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Table 6. Dermal tolerance of octenidine dihydrochloride in guinea pig Hartley strain

Application Doses Gender Noteworthy findings

n per group

Photosensitizing potential 0.05 ml of 2% skin cleanser solution Male/female (5/5) Octenidine, either as skin cleanser solution or as
(Vinson and Borselli); topically, (containing 6% propan-2-ol); skin aqueous solution, as well as CHX and ethanol, as neg-
clipped cervical neck; o.d., cleanser vehicle; 2% aqueous solution; ative control, were without skin-irritating, i.e. photo-
5 days (induction) followed by 4% CHX (commercial brand); 2% TCSA sensitizing, effects during the induction and challenge
UV radiation (15 min), washing (ethanolic solution); ethanol (absolute) phases, with the exception of 1 guinea pig treated with
of application sites prior to next octenidine aqueous solution showing an erythema
dosing 9 days after last dosing: score of 1 on the third challenge day; the positive con-
challenge with TCSA o.d., trol (TCSA) showed expected erythema scores; no be-
3 days (naive site) havioural changes
Delayed contact sensitization 0.4 ml 2% skin cleanser solution Male/female (5/5) Like ethanol and vehicle control, octenidine did not
potential (Buehler); topically (containing 6% isopropyl alcohol); skin result in any irritation or delayed contact sensitiza-
(pad), clipped thoracolumbar cleanser vehicle; 0.1% DNCB (ethanolic tion during induction (24 h after dosing) and during
region 6 h once a week for solution); ethanol (absolute); the challenge phase (24 and 48 h after dosing, both
3 weeks (induction); application sites);
challenge: 14 days after last only challenge (non-induced naive Male/female (2/2) DNCB as positive control induced erythema at appli-
application, on 2 naive sites of controls): 0.4 ml 2% skin cleanser solu- cation site (mean erythema scores of 2.0 and 2.1); with
the back tion (containing 6% isopropyl alcohol); exception of animals treated with vehicle control, in
skin cleanser vehicle; 0.1% DNCB all groups loose stools in 1 or more animals; no deaths
(ethanolic solution) occurred

o.d. = Once daily; UV = ultraviolet; CHX = chlorhexidine gluconate; TCSA = tetrachlorosalicylanilide; DNCB = 1-chloro-2,4-dinitrobenzene.

occurred presumably due to the slow absorption of oc- strain isolates so far, but a wealth of clinical knowledge
tenidine from the surrounding tissue [109]. As a conse- has been gained, which is backed by in vitro and animal
quence, octenidine is contraindicated for pressure irriga- studies on safety, tolerability and efficacy.
tion of stab wounds or wound cavities if not ensuring free Octenidine binds readily on negatively charged sur-
outflow and drain-off. faces of microbial cell envelopes, disrupts microcellular
Octenidine is not approved for peritoneal irrigation, metabolism and thus inactivates Gram-positive and
and preparations based on octenidine in combination Gram-negative bacteria, yeasts, dermatophytes, envel-
with phenoxyethanol should not be used for irrigations oped viruses and echinococcal cysts. The minimal in-
of the bladder nor on the tympanic membrane as long as hibitory concentrations against common pathogens are
these indications have not been investigated. in the same range as those of well-known antibiotics and
antimycotics, but while the anti-infective activity of these
substances is limited to a restricted spectrum of organ-
Ecotoxicology isms and may cause resistances, octenidine works well
against the whole spectrum of micro-organisms.
In the OECD closed bottle test, octenidine was readily In contrast to antibiotics, octenidine is only suitable
biodegradable after 5 days, i.e. the substance presents no for topical use. It is approved as medicinal substance for
risk for the environment [110]. skin, mucous membrane and wound antisepsis. On a first
glance, this seems to be an obvious drawback to systemi-
cally available antibiotics, but actually, it is not. While
Discussion local therapy with antibiotics often leads to microbial re-
sistance, intolerability, toxic side effects and sensitization,
Antiseptics, as the older siblings of antibiotics, have a octenidine is well tolerated and does not induce resis-
wide variety of indications. Due to their unspecific mode tance. In comparison to systemic antibiotics, a high con-
of action, they are less likely to induce any resistances, if centration can be easily achieved at the site of action by
ever. Regarding octenidine, which was introduced as an- local application. First results of local interaction with an-
tiseptic more than 20 years ago, no resistance has been tibiotics point to a synergistic effect at least with some
induced experimentally or described in clinical or wild- substances, but this needs further investigation.
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 Because octenidine is virtually not absorbed through In view of its local and systemic safety, there are no
the skin, mucous membranes or from wounds, toxic side restrictions for octenidine as an additive in hand disin-
effects or systemic interactions are not to be expected. fectants, skin antiseptics and wash preparations. Result-
Results from toxicological studies on different species ing from its efficacy and antimicrobial spectrum, octeni-
prove the low toxicity. The LD50 after oral exposure to dine for dermal use is superior to the other currently used
OPE was calculated to be 40–50 ml/kg, which would antiseptic substances for prophylactic antisepsis. Partic-
mean that even a full bottle (250 ml) would be unlikely to ularly for the eradication of MRSA in cases of coloniza-
kill a 2-year-old, normally developed child, if swallowed tion or infection, the efficacy of chlorhexidine, which is
[111]. still the most widely used substance, has been repeatedly
The LD50 in rats after intravenous application of OPE doubted recently [15–20].
was found to be approximately 10 mg/kg (applied over 7 Formulated with suitable galenic bases and substanc-
days). Therefore, even an accidental injection of a small es, octenidine might in future become a promising agent
dose is unlikely to cause any harm in man. The toxicity for therapeutic indications in dermatology.
of octenidine alone is much lower still with an LD50 of 800 On mucous membranes, octenidine is superior to
mg/kg orally in rats, and lower as for example the toxic- PVP-iodine, polyhexanide and chlorhexidine, and must
ity of chlorhexidine digluconate (635 mg/kg) [106]. be regarded as an agent of choice. Antiseptic efficacy is
The toxic effects found in tests with animals were achieved within 30 s, while polyhexanide requires 1–25
changes in the lungs, emesis, loose stools, salivation and min, depending on the pathogen.
anorexia as well as body weight and unspecific neuro- Octenidine is contraindicated for pressure irrigation
logical symptoms such as ataxia and reduced motor ac- of stab wounds, must not be used for joint irrigation and
tivity. The cause of the changes in the lungs is unclear but should not be used for peritoneal lavage, irrigation of the
could be explained by an incidental and misplaced appli- bladder or the tympanic membrane as long as safety and
cation of the test substance by the gavage through the efficacy for these indications have not been investigated.
trachea into the lung tissue. Further studies are needed to
explain the toxic effects in the lungs, especially because
octenidine mouth rinses are used in patients with re- Conclusion
duced consciousness. The gastro-intestinal symptoms
are attributable to a markedly altered flora in the gut. Introduced more than 20 years ago, octenidine is an
Octenidine is well tolerated on the skin, mucous mem- established antiseptic to be used on the skin, mucous
branes and wounds. Only in rare cases is a slight, tempo- membranes and wounds prophylactically as well as ther-
ral discomfort on the application site described for OPE. apeutically in a growing field of applications and could
The biocompatibility index, that means the ratio of fi- replace classical antiseptics like chlorhexidine, PVP-io-
broblast cytotoxicity to E. coli or S. aureus toxicity, was dine or triclosan. It is easy and safe to handle, chemically
distinct: 11 only for octenidine and polyhexanide, fol- stable, not inflammable, without resistance development
lowed with indices !1 for chlorhexidine, PVP-iodine, tri- and low toxicity to man and the environment alike. Its
closan and silver compounds [95]. This is in concordance popularity among therapists and wound care specialists
with favourable clinical experience and results from clin- is based on the good clinical results, easy and pain-free
ical and animal studies, where octenidine is well tolerated application and local tolerance. Beside readily available
and leads to improved wound healing compared to con- combinations with phenoxyethanol, mouth rinses and
trol [1, 28, 45, 47–49, 51]. vaginal applications, semi-fluid preparations and dress-
While liquid preparations of octenidine are estab- ings are described. While well described by in vitro, in
lished for the use on skin, mucosa and wounds, data for vivo and clinical studies, further research of octenidine
other indications are still not satisfactory (clinical studies is still worth to be conducted. Especially the interaction
for intranasal use have not been published so far, and re- with tissue components, interaction with other anti-in-
sults on the peritoneum are controversial). Gels, oint- fective substances and new fields of application such as
ments and occlusive wound dressing with octenidine are for example the nose, eye and peritoneum are still open
described but awaiting clinical evaluation. In the future, fields of investigation.
a liposomal formulation of octenidine could extend the
practical importance even further because of its broad
therapeutic range [112].
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