Antimicrobials
are widely used as preservatives to prevent microbial spoilage of preparations
(due to micro-organisms being inadvertently introduced during their manufacture
or use), as antiseptics to destroy or inhibit micro-organisms on living tissue
(the intention is to limit or prevent the harmful effects of infection), and as
disinfectants on inanimate objects and materials, the skin, and other membranes
and in bodily cavities to destroy micro-organisms. Some compounds are used for both preservation and disinfection,
such as alcohol, quaternary ammonium compounds, thiomersal, and chlorocresol
(1).
Preservatives
are used in many products of concern to dermatology, such as topical
pharmaceuticals (medications) and cosmetics and many household, industrial
(where they are called biocides), and other products, like paper, napkins, and
shoes (2).
Antimicrobials
can cause irritant reactions, contact-allergic and photo-allergic reactions, as
well as contact urticaria (3).
In
addition to adverse skin reactions in patients who use topical preparations
containing preservatives, antiseptic agents, or disinfectants, antimicrobials
may also be responsible for occupational dermatitis in medical personnel and
other professionals involved in the control or prevention of infection. This article discusses the antimicrobial
allergens we have encountered over the last 12 years i.e. 1985-1997. Allergic reactions to antibiotics will not
be covered here.
Preservatives
are the second most important sensitizing agents in cosmetics (e.g. 4). They often consist of mixtures to enhance
the antimicrobial spectrum. In a recent
study (5), we found that, although the methyl(chloro)isothiazolinone mixture
ranks first, its frequency almost halved in the 1991-1996 period relative to
the 1985-1990 period (4). Indeed, this
preservative was commonly used in the 1980s and was then a frequent cause of
cosmetic contact allergy. Since then,
it has been generally replaced by preservatives that had already been on the
market previously, such as formaldehyde (for which the frequency of reactions
has almost doubled in recent years) and its releasers, such as quaternium-15,
diazolidinylurea, imidazolidinylurea, hydantoine and bromo-nitropropanediol as
well as a new preservative mixture containing methyldibromoglutaronitrile and
phenoxyethanol. This last preservative
(also called Euxyl K400), which we have been routinely testing since April
1992, has now become an increasingly important allergen, the principal allergenic
culprits being methyldibromoglutaronitrile or dibromodicyanobutane (6). Of course, the spectrum of the different
preservatives found to be allergens may differ from country to country (e.g. 7,
8). Other cosmetic preservatives
identified are chloroacetamide (a strong allergen even in minute
concentrations), triclosan (mainly in deodorants), bradophen (a quaternary
compound in one of the "udder creams" that are used to treat irritant
hand dermatitis), captan (in hairdressing products), farnesol (in antiperspirants,
cross-reacts with balsam of Peru), and bromonitrodioxane.
Contact
sensitivity to preservatives such as parabens, which are often used in
cosmetics may be primarily induced by topical pharmaceutical products, which
are likely to facilitate the development of contact allergy because they are
applied to eczematous or otherwise damaged skin.
The
other preservatives identified in pharmaceutical products as allergens are
thiomersal, for which most of the positive reactions encountered are irrelevant
(e.g. 9), benzylalcohol (also used in perfumes), benzoic and sorbic acid,
chlorocresol, benzalkonium chloride, and chlorbutol (both often used in eye
drops).
The
antimicrobials used as antiseptics are mainly thiomersal and other mercurials
(e.g. merbromine), cetrimide, chloramine, nitrofurazone, quinoline derivatives
(clioquinol, chlorquinaldolhol), chlorhexidine, alcohol, hexamidine,
chloroxylenol, isopropanol, and sodium hypochlorite. Some of these substances may also produce severe contact urticaria
reactions, such as chloramine (e.g. 10) and chlorhexidine (e.g. 11).
One
should not forget, however, that certain antiseptic medications (as well as
disinfectants) may also sensitize through other ingredients present in the
formulation; nonoxynols (45 positive reactions!) are non-ionic surfactants
present in iodine-PVP solutions, and certain chlorhexidine and hexamidine
preparations and are the typical examples in this regard (12). In addition, lauramine oxide, an aliphatic
amine present in a surgical scrub, caused 8 cases of professional hand
dermatitis inmedical personnel.
Some
of these antiseptics are also disinfectants, such as alcohol, isopropanol,
quaternary ammoniumcompounds, chlorocresol, chloroxylenol, and formaldehyde.
Formaldehyde,
together with glyoxal and particularly glutaraldehyde, causes occupational
contact dermatitis (also airborne) in health care personnel (including
dentists). Dodicin or
dodecyldi(aminoethyl)glycine is mainly used for surface disinfection and has
been found to be the cause of allergic contact eczema in a swimming teacher.
The
antimicrobial allergens found in industrial products (often called biocides)
such as soluble oils, water-based paints, and glues are formaldehyde,
isothiazolinone derivatives, benzotriazole, chloroacetamide, and
methylolchloroacetamide. TheBiobans
were found to be specific causes of professional dermatitis due to metalworking
fluids, while formaldehyde is used more often in household products.
Thiocyanomethylbenzothiazole
is used to preserve leather. Reactions
to it were found in patients with shoe dermatitis. In all of the cases except six, cross-sensitivity was found with
other mercaptobenzothiazoles. Thus it
is difficult to determine whether it primarily sensitizes as a preservative
agent or as a rubber additive in glues or rubber materials for shoes.
A
wide variety of antimicrobials may be responsible for adverse skin reactions,
including irritancy, allergic and photo-allergic contact eczema, and contact
urticaria. This article discusses
allergic contact eczema due to their presence in topical pharmaceuticals,
cosmetics, and household, industrial, and other products. In some cases, they may cause occupational
dermatitis, particularly in health-care workers.
1.
Martindale, The Extra Pharmacopoeia. The Pharmaceutical Press, 30th edition,
London, 1993, pp. 781 and1132.
2.
Rycroft RJG, Menne T, Frosch PJ (eds.). Textbook of Contact Dermatitis, 2nd edition,
Berlin, Springer-Verlag, 1995.
3.
de Groot AC, Weyland JW, Nater JP. Unwanted effects of cosmetics and drugs used
in dermatology. Amsterdam, Elsevier,
1994.
4.
Dooms-Goossens A, Kerre S, Drieghe J, Bossuyt
L, Degreef H. Cosmetic products and
their allegens. Eur. J. Dermatol. 1992,
2:465-468.
5.
Goossens A, Merckx L. L'allergie de contact aux cosmétiques. In: Progrès en dermato-allergologie. Marseille, M‚ discript, 1997, pp. 89-95.
6.
Jagtman B, van Geest T, van der Kley J. Methyldibromoglutaronitrile is an important
contact allergen in the Netherlands.
Contact Dermatitis 1996, 34:118-120.
7.
Perrenoud D, Birchner A, Hunziker T. Frequency of sensitisation to 13 common
preservatives in Switzerland. Contact
Dermatitis 1994, 30:276-279.
8.
Jacobs M-C, White IR, Rycroft RJG. Patch testing with preservatives at St.
John's from 1982-1993. Contact
Dermatitis 1995, 33:247-254.
9.
Müller H.
All these positive tests to thiomersal.
Contact Dermatitis 1994, 31:209-213.
10. Dooms-Goossens A, Gevers B, Mertens A, Vanderheyden D. Allergic contact urticaria due to
chloramine. Contact Dermatitis 1983,
9:319-320.
11. Okano M, Nomura H, Hata S, Okada N, Sato K, Kitano Y, Tashiro H,
Yoshimoto Y, Hama P. Anaphylactic
symptoms due to chlorhexidine gluconate.
Arch. Dermatol. 1989, 125:50-52.
12. Dooms-Goossens A, Gidi de Alam A, Degreef H. Contact sensitivity to nonoxynals: a cause of intolerance to
antiseptic preparations. In: Frosch A,
Dooms-Goossens A, Lachapelle J-M, Rycroft RJG, Scheper RJ (eds.). Current Topics in Contact Dermatitis. Springer-Verlag, Berlin, 1983.
13. Flyvholm M-A. Identification of
formaldehyde releasers and occurrence of formaldehyde and formaldehyde
releasers in registered chemical products.
Am. J. of Ind. Med. 1993, 24:533-552.