Original Paper
Skin Pharmacol Physiol 2010;23:244–258
DOI: 10.1159/000314699
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
Octenidine dihydrochloride ⴢ Skin antisepsis ⴢ Mucous
membrane antisepsis ⴢ Wound antisepsis ⴢ
Antimicrobial efficacy ⴢ Local tolerance ⴢ Toxicity ⴢ
Safety ⴢ Contraindications
Abstract
Octenidine dihydrochloride (octenidine) was introduced for
skin, mucous membrane and wound antisepsis more than
20 years ago. Until now, a wealth of knowledge has been
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
established antiseptic in a large field of applications and rep-
resents an alternative to older substances such as chlorhexi-
dine, polyvidone-iodine or triclosan. The review is based on
the current literature and unpublished original data as well.
Copyright © 2010 S. Karger AG, Basel
Introduction
While antibiotics encounter a dramatic increase in re-
sistance which limits their therapeutic use, antiseptics
with unspecific modes of action are highly unlikely to
produce resistant pathogens. They are topically used to
© 2010 S. Karger AG, Basel
1660–5527/10/0235–0244$26.00/0
Fax +41 61 306 12 34
E-Mail karger@karger.ch Accessible online at:
www.karger.com www.karger.com/spp
Received: August 21, 2009
Accepted after revision: February 24, 2010
Published online: May 18, 2010
reduce the risk of colonization or transmission of patho-
gens, and thus the risk of infection, or to treat infections.
In the last few decades, new promising substances
have been evaluated in clinical use. To choose the right
antiseptic, the therapist needs overall data about efficacy,
mode of action, interactions, toxicology, safety, clinical
applications and contraindications. This article is meant
as a guideline for clinicians and studies octenidine dihy-
drochloride (octenidine) as an antiseptic to be used on
skin, mucosa and wounds based on the current literature
and unpublished original data as well.
Areas of Application
Antisepsis
Octenidine, approved as a medicinal substance in sev-
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,
and for antisepsis on wounds and mucosa either as a sin-
gle substance, as an approved combination of octenidine
and phenoxyethanol as aqueous solution (OPE) or either
Jörg Siebert is a remunerated employee of Schülke & Mayr GmbH.
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Nils-Olaf Hübner, MD
Institute of Hygiene and Environmental Medicine
University of Edinburgh
Ernst Moritz Arndt University Greifswald
Walther-Rathenau-Strasse 49a, DE–17489 Greifswald (Germany)
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Tel. +49 38 3451 5546, Fax +49 38 3451 5541, E-Mail nhuebner @ uni-greifswald.de
in combination with aliphatic alcohols or glycerol and
detergents without phenoxyethanol [2].
Prophylactic and Therapeutic Use on Skin
Antisepsis Prior to Skin-Penetrating Procedures
For skin antisepsis prior to skin-penetrating proce-
dures (e.g. insertion of arterial or venous catheters, punc-
tures, surgical procedures), fixed combinations of octeni-
dine with aliphatic alcohols are available. The idea be-
hind these combinations is to add a sustained antimi-
crobial effect to the otherwise fast and broad, but only
immediate antimicrobial action of alcohols. Applying
skin antisepsis prior to the insertion of a central or pe-
ripheral venous catheter using a combination of 0.1% oc-
tenidine with 30% propan-1-ol and 45% propan-2-ol was
significantly more effective than the combination of 74%
ethanol with 10% propan-2-ol for 24 h [3]. No adverse ef-
fects of octenidine were reported.
For skin antisepsis of neonates, it is extremely impor-
tant to choose a safe antiseptic. In this case, the OPE for-
mulation is superior to polyvidone (PVP)-iodine, which
is contraindicated due to iodine absorption, and to pure
alcohol-based formulas, which can cause erosions in pre-
term infants [4, 5] and are absorbed, too [6]. Unlike alco-
hol-based antiseptics, OPE does not cause skin damage
in premature infants born before the 27th week of gesta-
tion [7]. In contrast to chlorhexidine [8] and triclosan [9],
octenidine is not absorbed, but phenoxyethanol is ab-
sorbed through the skin, metabolized to phenoxyacetic
acid and excreted in the urine [7]. Due to this potential
risk and though adverse effects have not been reported
with the OPE formulation yet, the actual recommenda-
tion for neonatal skin antisepsis in Germany is the use of
octenidine without phenoxyethanol in the formulation
[10]. The manufacturer of octenidine provides the raw
material to clinical pharmacies on request to produce a
final product.
Eradication of Microbial Colonization
Eradication of unwanted colonization with potential
pathogens is a typical antiseptic indication. The eradica-
tion of micro-organisms which are resistant to antibiotics
and colonize the skin, like methicillin-resistant Staphylo-
coccus aureus (MRSA), is particularly important. For this
purpose, a liquid soap containing octenidine, used like a
shampoo or a shower gel, is available. This is of particular
interest, because resistances to the topical antibiotic mu-
pirocine are increasing worldwide [11–13] and the effi-
cacy of chlorhexidine-based formulas has been repeat-
edly doubted recently [14–20]. Octenidine-based prod-
Octenidine Dihydrochloride for Skin,
Mucous Membranes and Wounds
ucts were shown to be effective for whole-body cleansing
in cases of MRSA colonization [21, 22]. Sloot et al. [23]
reported redness in 4 out of 28 patients who were washed
with a diluted preparation based on octenidine for 5 days.
It remains unclear whether this was caused by octeni-
dine, the detergent or the frequent washing itself and con-
trasts with results for tolerance of highly fragile skin of
neonates [7]. Using octenidine as an antiseptic liquid
soap, a mouth rinsing solution and as a nasal cream in a
total of 107 nurses resulted in a successful decolonization
in 98.1% of the cases. In 68% of the cases, decolonization
was achieved already in the first cycle [24]. These results
underline the high effectiveness of a regime based on oc-
tenidine-containing antiseptic preparations as part of an
overall decolonization concept.
Acne Therapy
In a prospective observational study with 30 patients,
OPE applied once or twice daily for 6 weeks has proven
to be a cost-effective alternative in treating mild to mod-
erate inflammatory acne lesions and may allow reduced
prescriptions of anti-acne antibiotics causing bacterial re-
sistance [25].
Nail Infections
Fifteen patients were treated topically by soaking the
affected nails twice a day for 10 min in OPE for 6 weeks,
concluding that OPE seems to represent an interesting,
well-tolerated, safe and efficacious therapeutic choice for
the treatment of Pseudomonas nail infection [26].
Skin Tolerance
Adverse effects of octenidine on intact skin were as-
sessed using New Zealand white rabbits. A 2% octenidine
solution was applied 4 times on day 1 and twice daily on
days 2–6 on the healthy skin of the animals. Toxic effects
were compared to groups treated with a solution contain-
ing 4% propan-2-ol or water, respectively. Treatment with
octenidine led to no overt behavioural changes or adverse
effects, which corresponds to results in an open field and
labyrinth test, whereas chlorhexidine induced changes of
behaviour [27]. Some animals in the test group showed
‘minimal’ and ‘slight’ erythema similar to the controls.
Used in severely immunocompromised patients for
the care of central venous catheter insertion sites, octeni-
dine was highly effective with good skin tolerability [28].
Prophylactic and Therapeutic Use on Mucosa
For prophylactic use on intact mucosa, octenidine is
most often used as OPE or as single substance. OPE is ap-
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Skin Pharmacol Physiol 2010;23:244–258 245
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proved by the Federal Institute for Medicinal Products
and Medical Devices of Germany for repeated, short-
term antiseptic treatment of mucous membranes and ad-
jacent skin prior to diagnostic and surgical procedures in
the anogenital region (vagina, vulva, glans penis), in the
oral cavity and for wound treatment.
Genitalia
The efficacy of OPE on male genitalia (e.g. used prior
to catheterization of the bladder) was shown to be supe-
rior to chlorhexidine [29, 30]. While PVP-iodine was in-
ferior in the immediate effect, OPE had a good residual
effect and was better tolerated [19, 29, 31–35]. In a pro-
spective, multicentre, randomized, case-control study
(n = 491), octenidine was a suitable alternative to clotrim-
azole in the treatment of acute vaginal candidosis [36]. In
the treatment of bacterial vaginosis, OPE spray was as ef-
fective as the standard therapy with metronidazole (n =
450) [37]. Patients stated that OPE was more comfortable,
easier to apply, and side effects were less common [25].
Oral Cavity
There are many indications to use an antiseptic solu-
tion to reduce the bacterial load in the human oral cavity
(e.g. prior to operations, for plaque reduction, in venti-
lated patients and to eradicate a colonization with MRSA)
[1]. OPE as well as octenidine alone were significantly su-
perior to other current oral cavity antiseptics [38–40].
OPE showed expressed antimicrobial action in the re-
gime of anti-inflammatory therapy of parodontal diseas-
es [41].
In in vitro models, the plaque inhibition was more ef-
ficient than with chlorhexidine. For plaque accumula-
tion, degrees of gingivitis and bleeding, howbeit associ-
ated with staining, octenidine was superior to placebo
[42, 43]. Octenidine could inhibit the adhesion of Can-
dida spp. to human buccal epithelia, too [43]. Its broad-
spectrum efficacy, including Gram-positive as well as
Gram-negative organisms and yeast, makes octenidine
well applicable for mouth antisepsis in ventilated patients
and patients receiving inhalation glucocorticoid therapy.
This indication has to be evaluated in randomized con-
trolled trials.
Tolerance
Beagle dogs treated with an anti-dental-plaque formu-
lation containing placebo, 0.025 and 0.1% octenidine up
to 3 times daily for 1 month showed no drug-related ef-
fects including macroscopic or microscopic tissue chang-
es. Compared to placebo that was administered 4 times
246 Skin Pharmacol Physiol 2010;23:244–258
daily for 30 days, similar results were obtained when a
1:4 dilution of a 1.1% octenidine saccharine-containing
gel was administered twice daily or 4 times daily (high-
dose group) on the upper jaw exterior gum, the upper jaw
palate, the lower jaw exterior gum and the lower jaw sub-
lingual area of beagle dogs [internal data of Schülke &
Mayr GmbH, Norderstedt, Germany].
The good tolerability and favourable effect of an oc-
tenidine mouth rinse was confirmed in a prospective
clinical trial with soft-tissue assessment, gingivitis,
plaque and dental stain as primary endpoints [42]. Adult
volunteers (n = 451) were stratified in 2 balanced groups
according to gender, plaque and gingivitis scores. Both
groups received dental prophylaxis with dentifrice, tooth-
brushes and mouth rinse either containing 0.1% octeni-
dine or placebo. They were given instructions to rinse
with their assigned product for 30 s twice each day. Ex-
amination after 6 and 12 weeks showed no differences in
the oral soft-tissue condition but the group rinsing with
0.1% octenidine had significantly less plaque (39%), gin-
givitis (50%) and bleeding sites (60%). The test group had
significantly higher stain formation and experienced lon-
ger prophylaxis times to remove the stain compared to
control, too [42].
Recently, a mouth rinse containing octenidine with-
out phenoxyethanol was introduced, which was superior
to OPE in terms of taste and local tolerability [44]. This
mouth rinse is especially meant for daily mouth hygiene
in e.g. intensive-care patients and for decontamination of
MRSA.
Prophylactic and Therapeutic Use on Wounds
Octenidine is used either as single substance or as OPE
to prevent or treat microbial infection or colonization, re-
spectively. In a prospective clinical study on patients with
advanced cancer and neoplastic ulcers after 3 weeks of
treatment with OPE, common wound pathogens such as
S. aureus, Staphylococcus epidermidis and Proteus mirabi-
lis, which were cultured prior to the treatment, were suc-
cessfully eradicated and improvements in the clinical con-
dition of the ulcers, characterized by a reduction in necro-
sis, exudate, erythema and oedema, were recorded [45].
Wound Tolerability
The irritation threshold of OPE, assessed in the hen
egg test on chorio-allantoic membrane, was found to be
10–100 times lower than that of the combination of poly-
hexanide with macrogol [46].
OPE was shown to be equal to Ringer solution with re-
gard to wound healing of superficial wounds in pigs using
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2Cl–
C8H17 NH N+ (CH2)10 +N NH C8H17
2Cl–
C8H17 +NH N (CH2)10 N +NH C8H17
C 36H 62N4 · 2HCl
Mr: 623.8
Fig. 1. Chemical structure of octenidine dihydrochloride.
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
significantly improved the granulation over a 4-week ob-
servation period compared to Ringer solution [48]. This
good tolerability could be confirmed in a multicentre ran-
domized double-blinded study on skin donor sites [49].
In contrast to alcohols and polyhexanide, octenidine
did not alter the capillary microcirculation in the mouse
ear model [50].
Other Fields of Application
Peritoneum
The use of antiseptic solutions to prevent intra-ab-
dominal infections is controversial, because they can
cause an enhanced inflammatory response but may also
prevent microbial infection. The knowledge of the use of
octenidine-containing solutions for the irrigation of the
peritoneum is limited and conflictive. In in vitro tests, no
stimulation of tumour necrosis factor ␣ was detectable
[51]. Case reports indicate that irrigation with OPE in
concentrations of 0.1–0.025% can cause chemical perito-
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
treated with 0.05% octenidine died [54]. This seems to
imply a dose-dependent effect. Further studies are need-
ed to rate the possible role of octenidine for peritoneal
irrigation.
Nose
The nares are the most important source of S. aureus.
Therefore, a successful eradication of MRSA inevitably
Octenidine Dihydrochloride for Skin,
Mucous Membranes and Wounds
includes the eradication from the nose [55–58]. Mupiro-
cine is still the most widely used local antibiotic for erad-
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
used in the nose, there is limited data available describing
the efficiency of this therapy. While octenidine ointment
is advised by some experts [24, 60], at least in cases of mu-
pirocine resistance, it cannot be recommended as a full
substitute for intranasal mupirocine at the moment.
Argumentative Scolicidal Therapy
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.
Antimicrobial Impregnation
As octenidine was shown to be effective against bio-
film-forming organisms [63–65], its use for impregnation
of implants and textiles appears promising, as it could be
demonstrated for poly-L-lactide-coated titanium plate
osteosynthesis, impregnated with octenidine and triclo-
san, on local infection resistance [66]. First experiences
with coated surgical sutures showed superior efficacy
against S. aureus but inferior biocompatibility in com-
parison to triclosan-coated sutures [44]. Octenidine is
only suitable for antimicrobial coatings of tracheotomy
tubes to a limited extent unless methods are developed to
allow sustained attachment or incorporation to the tub-
ing [67]. Various studies and patents claim methods to
coat or incorporate materials with antimicrobial impreg-
nation with octenidine and other antiseptics as active
agents [68–70]. Initial studies with modified silica coat-
ings, containing embedded octenidine on textiles, showed
a convincing long-term effect against fungi [71].
Chemicophysical Characteristics
Octenidine dihydrochloride [CAS No. 70775-75-6;
N,Nⴕ-(1,10-decanediyldi-1[4H]-pyridinyl-4-ylidene)-bis-
(1-octanamine) dihydrochloride] is a cationic, surface-
active substance (see formula, fig. 1). Octenidine express-
ly differs from quaternary ammonium compounds such
as benzalkonium chloride and from guanidines such as
chlorhexidine because the amide and ester structures are
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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
toxicologically critical part of the chlorhexidine mole-
cule, cannot be liberated. Octenidine is stable in the pH
range from 1.6 to 12.2, under the influence of light, and
can be steam sterilized up to 130 ° C in aqueous solutions.
   
It can be stored at room temperature [72]. The molecular
weight is approximately 624 Da. It has 2 non-interacting
cation-active centres in its molecule, which are separated
by a long aliphatic hydrocarbon chain. It therefore binds
readily onto negatively charged surfaces, such as micro-
bial cell envelopes and eukaryotic cell membranes. Pre-
liminary results imply a particularly strong adherence to
lipid bacterial cell membrane components (e.g. cardio-
lipin) explaining the high antimicrobial efficacy without
adversely affecting human epithelial or wound tissue
[73]. Analogously to other cationic antiseptics like
chlorhexidine and polyhexanide, salts of fatty acid glyc-
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-
cro-organisms [14, 75] and induction of leakages in the
cytoplasmic membrane [76] were described. This was
shown for yeast mitochondrial membranes, too [77].
Interactions
Octenidine shows synergism with phenoxyethanol,
hence OPE is readily available and widely used [78]. As
our own laboratory test showed, octenidine should not be
used together with PVP-iodine-based antiseptics, be-
cause octenidine can release iodine radicals from the
PVP complex, resulting in a tissue irritation as well as
strong brown to violet discolouration in the border areas.
The assessment of interactions seems to be important
for antibiotics, because combined use of antiseptics and
antibiotics in wound infections constitutes a clinical
practice. While antibiotics are administered orally or in-
travenously, they are intended to act on the spot. First
results from in vitro studies indicate that the combina-
tion of octenidine with systemic antibiotics could not
only be additive but even synergistic [79]. In contrast to
chlorhexidine, octenidine showed synergistic interac-
tions with antibiotics or was without interference (ta-
ble 1). Further studies are necessary to evaluate the effect
of combined use of systemic and local antimicrobial ther-
apy.
Antimicrobial Efficacy and Resistance
Spectrum of Activity
Due to its unspecific, strong absorption and interac-
tion with cell wall and cell membrane structures, octeni-
dine has a broad antimicrobial spectrum against Gram-
positive and Gram-negative bacteria including MRSA [1],
plaque-forming bacteria such as Actinomyces and Strep-
tococcus spp. [81], Chlamydia, Mycoplasma [82; Kirchhoff
as well as Schmitz and Wellmann cited in 83] and fungi
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248 Skin Pharmacol Physiol 2010;23:244–258 Hübner /Siebert /Kramer

     
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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
higher than that of chlorhexidine with minimal inhibi-
tory concentrations for S. aureus and Escherichia coli of
1.0 ␮g/ml, for Klebsiella pneumoniae and P. mirabilis of
2.0 ␮g/ml, for Pseudomonas aeruginosa of 3.9 ␮g/ml and
for different Candida strains of 1.5 and 3.0 ␮g/ml [1, 76,
79, 86–88]. This was confirmed on skin and wounds [83]
and for plaque reduction in animal studies [89, 90]. The
residual effect of octenidine is remarkable [91, 92]. Besides
the direct antimycotic effect, octenidine induced changes
in the lipid and sterol contents of Candida albicans and is
binding to human buccal epithelial cells in vitro [76, 93].
The minimal microbicidal concentrations after 5 min
contact time are 250 ␮g/ml octenidine for S. aureus, E.
coli, P. mirabilis and P. aeruginosa and 100 ␮g/ml for C.
albicans and are thus much lower than those of chlorhex-
idine [88, 94]. After contact time of 1 min without bio-
Inactivation of Biofilms
Octenidine was shown to be highly effective against
biofilms induced by species isolated from catheter-relat-
ed and orthopaedic implant infections as well as by labo-
ratory strains of S. epidermidis and P. aeruginosa, respec-
tively [63–65].
Regarding Streptococcus sanguis biofilms grown on
hydroxyapatite discs, chlorhexidine was superior to PVP-
iodine and octenidine [98]. In another biofilm model
simulating the plaque-reducing and biofilm-clearing ac-
tivity, OPE performed equally to chlorhexidine and hex-
etidine [99]. Octenidine was shown to be more effective
against biofilms on medical implants compared to genta-
micin, too [63].
Octenidine rapidly killed planktonic cells and bio-
films of Listeria monocytogenes and was equally effective
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Mucous Membranes and Wounds
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in killing L. monocytogenes biofilms on polystyrene and
stainless-steel matrices even in the presence of organic
matter [100].
Residual (Long-Lasting) Effect
Because octenidine binds readily to negatively charged
surfaces and is not percutaneously absorbed, at least a
part of the applied substance remains on the site of ap-
plication and thus exerts a sustained antimicrobial effect
[92].
Resistance
Microbial resistances were not detectable or inducible
in vitro and are not to be expected on account of the
mechanism of action [101–103].
Further Biological Effects
Octenidine was shown to significantly improve phago-
cytosis by neutrophils in human blood in vitro by inter-
action with the bacterial cell wall [104].
In a whole-blood model without and with addition of
lipopolysaccharide, no stimulation of tumour necrosis
factor ␣ was detectable. Without the addition of lipopoly-
saccharide, no release of platelet-derived growth factor
AB was detectable, but with addition of lipopolysaccha-
ride dose-dependent stimulation could be detected [51].
Toxicology
Most of the toxicological data were recorded during
the eighties and nineties of the last century to prove the
safety of octenidine for its medicinal use. The data were
collected according to the then used quality criteria for
conducting toxicological tests and were previously unre-
leased. References are given for all other data.
Absorption, Metabolism and Excretion
Octenidine is virtually not absorbed via the skin or
mucous membranes. After topical application in mice,
using 14C-octenidine, no radioactivity was detectable in
serum at any time. Identical results were obtained with
250 Skin Pharmacol Physiol 2010;23:244–258
rats 24 and 48 h after dosing (oral), respectively. The total
radioactivity in the carcass accounted for 0.21%, and all
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
& Mayr].
These results were endorsed in vitro with artificially
perfused, freshly prepared human placenta. While with-
in 2 min octenidine was above the limits of detection
(2 ppm) in the venous eluate on the maternal side, no oc-
tenidine was detectable in the venous eluate on the foetal
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
to be expected. Therefore, no further pharmacokinetic
studies or studies on behalf of the metabolism have been
conducted.
Cytotoxicity
In vitro results from cell culture and explants show
that the cytotoxicity of octenidine is comparable to
chlorhexidine and is thus considerably greater than that
of PVP-iodine [106]. Erythrocytes and granulocytes in-
cubated with OPE in concentrations up to 0.05% for 30
min showed no metabolic disturbances [107].
To rate the relevance of the cytotoxic effect for an an-
tiseptic, its cytotoxicity has to be evaluated against its an-
timicrobial effect. The so-called biocompatibility index is
obtained from the quotients determined under identical
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
test after 30 min of contact time. A biocompatibility in-
dex 11 is achieved only by polyhexanide and octenidine,
meaning that these substances are more toxic (i.e. effec-
tive) to the test micro-organisms than to murine fibro-
blasts [95].
It has been shown that octenidine binds readily to mu-
rine fibroblasts, human epithelial cells and primary kera-
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
in these complexes, but surprisingly, the antiseptic effi-
cacy remains unchanged and is not affected by 10% fetal
bovine serum [73, 95]. While this phenomenon needs
further investigation, it might explain the differences
from in vitro findings with relatively high cytotoxicity
(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
have a favourable effect on tolerability, because only the
top cell layer is exposed to the active substance, working
as an antibacterial shield to the deeper regeneration tis-
sue. The sustained release of octenidine from these com-
plexes maintains low, non-cytotoxic but antimicrobial
concentrations in the wound.
The oral repeat-dose toxicity (table 5) was assessed in
different species; the chronic toxicity was assessed in
Charles River CD albino and Charles River COBS-CD
rats of both sexes (table  5) [internal data of Schülke &
Mayr].
Chronic Dermal Toxicity

Oral Single-Dose and Repeat-Dose Toxicity
Single oral doses of octenidine (table  4) up to 1,000
mg/kg in mice resulted in no mortality during the obser-
vation period of 7 days. Male rats were used to estimate
50% lethal doses (LD50) within 7 days after administra-
tion of octenidine (once via stomach tube in doses up to
3,160 mg/kg). LD50 was calculated to be 800 mg/kg (range
650–970 mg/kg) [internal data of Schülke & Mayr].
Similar results were obtained with rabbits treated with
single oral doses of 80.0, 250 and 800 mg/kg octenidine,
observed for 8 days [internal data of Schülke & Mayr].
For male rats, the LD50 after single intravenous ad-
ministration of octenidine within 7 days of observation
was calculated to be 10.0 mg/kg (range 8.2–12.5 mg/kg)
[internal data of Schülke & Mayr].
To assess chronic dermal toxicity, 2.5 ml of skin cleans-
er in the final concentration of 0.5%, which corresponds
to 0.125% octenidine, were applied to the back of rabbits
once daily over a period of 6 months. Two control groups
were treated with a 1:4 dilution of the vehicle solution and
distilled water. In none of the assessed parameters (food
consumption, body mass, erythema, weekly measured
skin thickness at the application site, haematology, blood
analyses, organ mass, gross and microscopic pathology)
were drug-related effects found [internal data of Schülke
& Mayr].
In contrast to chlorhexidine, no neurotoxic reactions
were seen in rats in the labyrinth test with dermal appli-
cation of 0.5 ml twice daily over 90 days [27].
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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
Neither the Ames test, using Salmonella typhimurium
strains TA 98, TA 100, TA 1,535, TA 1,537 and TA 1,538,
nor tests with mouse lymphoma cells, CHO cell cultures,
human lymphocytes and in vivo tests using Charles Riv-
er CD-1 mice that were treated with octenidine via oral
gavage suggested any mutagenic or genotoxic potential of
octenidine [internal data of Schülke & Mayr].
Octenidine did not show any carcinogenic potential in
CD-1 (ICR) albino mice treated topically with octenidine
on the naked backs 3 days a week for 18 months. Charles
River CD Sprague-Dawley rats treated with octenidine
once daily in doses up to 8 mg/kg by oral gavage for 104
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-
tory tract irritations [internal data of Schülke & Mayr].
Reproductive and Developmental Toxicity
Octenidine showed neither reproductive nor develop-
mental toxicity in rats and rabbits. In COBS CD rats and
in rabbits treated with octenidine orally prior to mating,
no adverse effects on spermatogenesis or oogenesis, fertil-
ity and reproductive parameters, course of pregnancy, par-
turition and lactation were observed. No embryotoxic or
teratogenetic effects were recorded. Neither survival rate,
postnatal development nor suckling of progeny was influ-
enced by octenidine [internal data of Schülke & Mayr].
Local Tolerance
Applied locally either as solution or as soaked test pad,
octenidine did not show any photosensitization or de-
layed contact sensitization (table 6).
Adverse Effects and Contraindications
Octenidine should not be used for joint irrigation, be-
cause even a concentration of 0.005% octenidine is toxic
for cartilage [108].
After irrigation of deep penetrating stab wounds in
children’s hands under pressure with OPE, severe 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
(Vinson and Borselli); topically,
clipped cervical neck; o.d.,
5 days (induction) followed by
UV radiation (15 min), washing
of application sites prior to next
dosing 9 days after last dosing:
challenge with TCSA o.d.,
3 days (naive site)
Delayed contact sensitization
potential (Buehler); topically
(pad), clipped thoracolumbar
region 6 h once a week for
3 weeks (induction);
challenge: 14 days after last
application, on 2 naive sites of
the back
0.05 ml of 2% skin cleanser solution
(containing 6% propan-2-ol); skin
cleanser vehicle; 2% aqueous solution;
4% CHX (commercial brand); 2% TCSA
(ethanolic solution); ethanol (absolute)
0.4 ml 2% skin cleanser solution
(containing 6% isopropyl alcohol); skin
cleanser vehicle; 0.1% DNCB (ethanolic
solution); ethanol (absolute);
only challenge (non-induced naive
controls): 0.4 ml 2% skin cleanser solu-
tion (containing 6% isopropyl alcohol);
skin cleanser vehicle; 0.1% DNCB
(ethanolic solution)
Male/female (5/5) Octenidine, either as skin cleanser solution or as
aqueous solution, as well as CHX and ethanol, as neg-
ative control, were without skin-irritating, i.e. photo-
sensitizing, effects during the induction and challenge
phases, with the exception of 1 guinea pig treated with
octenidine aqueous solution showing an erythema
score of 1 on the third challenge day; the positive con-
trol (TCSA) showed expected erythema scores; no be-
havioural changes
Male/female (5/5) Like ethanol and vehicle control, octenidine did not
result in any irritation or delayed contact sensitiza-
tion during induction (24 h after dosing) and during
the challenge phase (24 and 48 h after dosing, both
application sites);
Male/female (2/2) DNCB as positive control induced erythema at appli-
cation site (mean erythema scores of 2.0 and 2.1); with
exception of animals treated with vehicle control, in
all groups loose stools in 1 or more animals; no deaths
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-
tenidine from the surrounding tissue [109]. As a conse-
quence, octenidine is contraindicated for pressure irriga-
tion of stab wounds or wound cavities if not ensuring free
outflow and drain-off.
Octenidine is not approved for peritoneal irrigation,
and preparations based on octenidine in combination
with phenoxyethanol should not be used for irrigations
of the bladder nor on the tympanic membrane as long as
these indications have not been investigated.
Ecotoxicology
In the OECD closed bottle test, octenidine was readily
biodegradable after 5 days, i.e. the substance presents no
risk for the environment [110].
Discussion
Antiseptics, as the older siblings of antibiotics, have a
wide variety of indications. Due to their unspecific mode
of action, they are less likely to induce any resistances, if
ever. Regarding octenidine, which was introduced as an-
tiseptic more than 20 years ago, no resistance has been
induced experimentally or described in clinical or wild-
strain isolates so far, but a wealth of clinical knowledge
has been gained, which is backed by in vitro and animal
studies on safety, tolerability and efficacy.
Octenidine binds readily on negatively charged sur-
faces of microbial cell envelopes, disrupts microcellular
metabolism and thus inactivates Gram-positive and
Gram-negative bacteria, yeasts, dermatophytes, envel-
oped viruses and echinococcal cysts. The minimal in-
hibitory concentrations against common pathogens are
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-
isms and may cause resistances, octenidine works well
against the whole spectrum of micro-organisms.
In contrast to antibiotics, octenidine is only suitable
for topical use. It is approved as medicinal substance for
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
local therapy with antibiotics often leads to microbial re-
sistance, intolerability, toxic side effects and sensitization,
octenidine is well tolerated and does not induce resis-
tance. In comparison to systemic antibiotics, a high con-
centration can be easily achieved at the site of action by
local application. First results of local interaction with an-
tibiotics point to a synergistic effect at least with some
substances, but this needs further investigation.
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 Because octenidine is virtually not absorbed through
the skin, mucous membranes or from wounds, toxic side
effects or systemic interactions are not to be expected.
Results from toxicological studies on different species
prove the low toxicity. The LD50 after oral exposure to
OPE was calculated to be 40–50 ml/kg, which would
mean that even a full bottle (250 ml) would be unlikely to
kill a 2-year-old, normally developed child, if swallowed
[111].
The LD50 in rats after intravenous application of OPE
was found to be approximately 10 mg/kg (applied over 7
days). Therefore, even an accidental injection of a small
dose is unlikely to cause any harm in man. The toxicity
of octenidine alone is much lower still with an LD50 of 800
mg/kg orally in rats, and lower as for example the toxic-
ity of chlorhexidine digluconate (635 mg/kg) [106].
The toxic effects found in tests with animals were
changes in the lungs, emesis, loose stools, salivation and
anorexia as well as body weight and unspecific neuro-
logical symptoms such as ataxia and reduced motor ac-
tivity. The cause of the changes in the lungs is unclear but
could be explained by an incidental and misplaced appli-
cation of the test substance by the gavage through the
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-
duced consciousness. The gastro-intestinal symptoms
are attributable to a markedly altered flora in the gut.
Octenidine is well tolerated on the skin, mucous mem-
branes and wounds. Only in rare cases is a slight, tempo-
ral discomfort on the application site described for OPE.
The biocompatibility index, that means the ratio of fi-
broblast cytotoxicity to E. coli or S. aureus toxicity, was
distinct: 11 only for octenidine and polyhexanide, fol-
lowed with indices !1 for chlorhexidine, PVP-iodine, tri-
closan and silver compounds [95]. This is in concordance
with favourable clinical experience and results from clin-
ical and animal studies, where octenidine is well tolerated
and leads to improved wound healing compared to con-
trol [1, 28, 45, 47–49, 51].
While liquid preparations of octenidine are estab-
lished for the use on skin, mucosa and wounds, data for
other indications are still not satisfactory (clinical studies
for intranasal use have not been published so far, and re-
sults on the peritoneum are controversial). Gels, oint-
ments and occlusive wound dressing with octenidine are
described but awaiting clinical evaluation. In the future,
a liposomal formulation of octenidine could extend the
practical importance even further because of its broad
therapeutic range [112].
Octenidine Dihydrochloride for Skin,
Mucous Membranes and Wounds
In view of its local and systemic safety, there are no
restrictions for octenidine as an additive in hand disin-
fectants, skin antiseptics and wash preparations. Result-
ing from its efficacy and antimicrobial spectrum, octeni-
dine for dermal use is superior to the other currently used
antiseptic substances for prophylactic antisepsis. Partic-
ularly for the eradication of MRSA in cases of coloniza-
tion or infection, the efficacy of chlorhexidine, which is
still the most widely used substance, has been repeatedly
doubted recently [15–20].
Formulated with suitable galenic bases and substanc-
es, octenidine might in future become a promising agent
for therapeutic indications in dermatology.
On mucous membranes, octenidine is superior to
PVP-iodine, polyhexanide and chlorhexidine, and must
be regarded as an agent of choice. Antiseptic efficacy is
achieved within 30 s, while polyhexanide requires 1–25
min, depending on the pathogen.
Octenidine is contraindicated for pressure irrigation
of stab wounds, must not be used for joint irrigation and
should not be used for peritoneal lavage, irrigation of the
bladder or the tympanic membrane as long as safety and
efficacy for these indications have not been investigated.
Conclusion
Introduced more than 20 years ago, octenidine is an
established antiseptic to be used on the skin, mucous
membranes and wounds prophylactically as well as ther-
apeutically in a growing field of applications and could
replace classical antiseptics like chlorhexidine, PVP-io-
dine or triclosan. It is easy and safe to handle, chemically
stable, not inflammable, without resistance development
and low toxicity to man and the environment alike. Its
popularity among therapists and wound care specialists
is based on the good clinical results, easy and pain-free
application and local tolerance. Beside readily available
combinations with phenoxyethanol, mouth rinses and
vaginal applications, semi-fluid preparations and dress-
ings are described. While well described by in vitro, in
vivo and clinical studies, further research of octenidine
is still worth to be conducted. Especially the interaction
with tissue components, interaction with other anti-in-
fective substances and new fields of application such as
for example the nose, eye and peritoneum are still open
fields of investigation.
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