Journal Identification = EJD Article Identification = 2198 Date: March 14, 2014 Time: 12:1 pm Review article Eur J Dermatol 2014; 24(1): 3-9 Jean-Marie LACHAPELLE A comparison of the irritant and allergenic Department of Dermatology properties of antiseptics Catholic University of Louvain Cliniques Universitaires Saint-Luc 10, Avenue Hippocrate Over recent years, interest in the use of antiseptics has been reinforced B-1200 Brussels Belgium as these molecules are not concerned by the problem of bacterial resis- tance. Whereas the in vitro efficacy of antiseptics has been well-studied, Reprints: J.-M. Lachapelle much less is known regarding their irritant and allergenic properties. <[email protected]> This review provides an update on the comparative irritant and aller- genic properties of commonly-used antiseptics in medicine nowadays. All antiseptics have irritant properties, especially when they are mis- used. Povidone-iodine has an excellent profile in terms of allergenicity. Allergic contact dermatitis is uncommon but is often misdiagnosed by practitioners, who confuse allergy and irritation. Chlorhexidine has been incriminated in some cases of allergic contact dermatitis; it is considered a relatively weak allergen, although it may rarely cause immunological contact urticaria and even life-threatening anaphylaxis. Octenidine is considered a safe and efficient antiseptic when used for superficial skin infections, however, aseptic tissue necrosis and chronic inflammation have been reported following irrigation of penetrating hand wounds. Polihexanide is an uncommon contact allergen as regards irritant and/or allergic contact dermatitis but cases of anaphylaxis have been reported. Considering the data available comparing the irritant and allergenic prop- erties of major antiseptics currently in use, it should be acknowledged that all antiseptics may induce cutaneous side-effects. The present article reviews the most recent safety data that can guide consumers’ choice. Key words: adaptive immunity, chlorhexidine, hexamidinediisethion- ate, innate immunity, octenidine, polyhexanide, povidone-iodine, Article accepted on 7/29/2013 quaternary ammonium compounds, silver dressings, triclosan or many years, topical antibiotics have been con- to topical antibiotics and this leads to a reinforced interest sidered the treatment of choice of superficial skin in antiseptics, which are not concerned by the problem of F bacterial infections and/or infected wounds. bacterial resistance. More recently, Staphylococcus aureus has become a major Antiseptics are well studied regarding in vitro efficacy but health problem worldwide. Multi-drug resistant strains are less regarding irritancy and allergenic properties. There- endemic in hospitals (MRSA). Moreover, there is now fore, this article is exclusively focused on the comparative a rapid emergence of community-associated methicillin- irritant and allergenic properties of the most important anti- resistant S. aureus (CA-MRSA). The resistance of these septics used nowadays. strains to antibiotics has been emphasized. Neomycin and bacitracin, known for their allergenic properties, are less used in Europe, in contrast to the United States and/or African countries. Irritant and allergic contact dermatitis: Two topical antibiotics are frequently used in European countries : sodium fusidate (Fucidin®) and mupirocine a new perspective (Bactroban®). Resistance to sodium fusidate has been doc- umented [1] and its allergenic properties identified. In this A new approach to common side effects consecutive study, a clear link between prescription of the antibiotic to applied chemicals onto the skin is now developing. and an increase in bacterial resistance was demonstrated. Classically, in previous years, the two main side effects, The use of mupirocine (exceptionally allergenic) is lim- irritation and contact allergy, were considered entirely ited to well-defined indications, such as nasal carriage of separate entities. Times have changed, due to a better under- S. aureus, but resistance has been indicated [2]. But the most standing of the processes involved in the two types of doi:10.1684/ejd.2013.2198 important message is the increased resistance of S. aureus reaction. EJD, vol. 24, n◦ 1, January-February 2014 3 To cite this article: Lachapelle JM. A comparison of the irritant and allergenic properties of antiseptics. Eur J Dermatol 2014; 24(1): 3-9 doi:10.1684/ejd.2013.2198 Journal Identification = EJD Article Identification = 2198 Date: March 14, 2014 Time: 12:1 pm Irritant contact dermatitis is the prototype of innate immu- than others. Dermatochemistry can, to some extent, explain nity. The pathways of inflammatory cascades include a these discrepancies [8]. Mercury compounds are out of vast repertoire of cells, as well as different cytokines and course. chemokines. Activation of innate immunity is necessary for the devel- opment of allergic contact dermatitis (ACD). The latter is therefore linked with the activation of T effector lym- The comparative irritant properties of phocytes, specifically sensitized to allergens (adaptive antiseptics immunity). This view has been clearly demonstrated [3-5]. In other words, most chemicals in direct contact with the skin are potentially irritant; their irritancy is related, not only There are several reports on the cytotoxicity of antisep- to their chemical nature, but also to several environmen- tics but it is important to compare them under identical tal factors : concentration, vehicle, occlusion, temperature test conditions. The cytotoxicity of PVP-I, chlorhexidine or altered skin (mechanical trauma, ulcerations, eczema- digluconate (Chex), octenidine dihydrochloride (Oct) and tous lesions, etc.). These considerations apply directly to polyhexamethyl enebiguanide (polihexanide, PHMD) was antiseptics, which share irritant and, rarely, allergenic prop- compared on CHO-K1 cells. PVP-I was more than 20 times erties. better tolerated by L929 cells than Chex, Oct and PHMD The practical implication of the new concept for the clin- [9]. ician is : if the patch test remains the “gold standard” for Another investigation analyzing the stratum corneum toler- diagnosing allergic contact dermatitis, it has to be inter- ance of PVP-I 10%, PVP-I 7.5% and chlorhexidine showed preted more cautiously, in particular in cases of weak that PVP-I 10% is less aggressive to the stratum corneum (questionable : ± ?) reactions, to avoid a misinterpretation than PVP-I 7.5% and chlorhexidine [10]. In a comparison of the conclusion (irritation versus allergy). Its pertinence between PVP-I, benzalkonium chloride, chlorhexidine glu- has to be reinforced by additional tests, such as the open test, conate and alkyldiaminoethylglycine hydrochloride, PVP-I semi-open test [6] and ROAT test [7]. More sophisticated had a weaker skin irritancy versus the other antiseptics [11]. laboratory investigations have been developed [3, 5]. They Recently, seventeen burn wound dressings, ointments and represent the only scientific way to differentiate irritant creams showed that the most cytotoxic products included from allergic contact reactions, by unquestionably trap- those containing silver or chlorhexidine [12]. ping the antigen-specific T lymphocytes in relation to a All these studies are in vitro studies and need to be defined allergen. But at the present time, these techniques confirmed clinically. An in vivo comparison of leg are inaccessible to the clinician. ulcers treated by PVP-I, silver sulfadiazine and chlorhex- idine indicated that the densities in microvessels and dendrocytes (no dendrocytoclasis) were higher in PVP-I- assigned lesions than those receiving silver sulfadiazine Antiseptics and disinfectants or chlorhexidine digluconate, resulting in better wound healing with PVP-I compared to the other antimicro- The terms “antiseptics” and “disinfectants” are often bials [13, 14]. 70% ethanol, Softasept®, Octenisept® used as synonyms in the current literature, even in (octenidine) and Lavasept® (polihexanide) were com- well-documented textbooks of dermatology. In fact, the pared, octenidine had the least impact on microcirculatory definitions are quite important : parameters [15]. A study assessing the tissue compati- Antiseptics are substances that inhibit the growth and bilities of Dibromol® (bromchlorophene, isopropyl alco- development of microorganisms (without necessarily hol, sodium 3.5-dibromo-4-hydroxybenzenesulphonate), killing them) in living tissues. Their indications are varied, Kodan® (propanol), Jodobac® (PVP-I), Octenisept® such as the cleansing of preoperative skin, the cleansing ® of acute and chronic wounds and also in the treatment of (octenidine), 0.2% Lavasept (polihexanide) hydrogen per- superficial skin infections. oxide, 0.5% chlorhexidine digluconate and 60% 2-propanol Disinfectants refer, by definition, to substances designed found that the most severe tissue toxicity was induced by 0.5% chlorhexidine digluconate and by propanol. Irritation to destroy pathogens in the environment (e.g. on work sur- ® ® faces or operating materials). They are very diversified, values were determined for Dibromol , Octenisept and with different chemical structures. Classical examples are: 60% 2-propanol but moderate vascular injuries were caused bleach (chlorinated water, “eau de Javel”), formaldehyde, by PVP-I. Lavasept® and hydrogen peroxide showed no glutaraldehyde, glyoxal and quaternary ammonium com- tissue toxicity [16]. pounds. It is noteworthy that the latter are used both