Department of Internal Medicine, Westlake Hospital, Melrose Park, IL.
Address correspondence and reprint requests to Radhika Sreedhar, MD, MS, Department of Internal Medicine, Westlake Hospital, 1225 West Lake St, Melrose Park, IL 60160. E-mail: email@example.com.
Cellulitis is a common entity in a community hospital setting. It is imperative to consider alternative diagnosis in the setting of an atypical presentation. This case highlights the importance of taking a meticulous history in the evaluation of patients presenting with a picture of cellulitis.
A 28-year-old woman presented to the emergency department with swelling of right cheek (Fig. 1). The patient initially noted a papule at the angle of mouth on the right side. She scratched the papule that subsequently grew bigger and spread to involve the right cheek. There was no history of intravenous drug use, insect bite, recent travel, or pets at home. The patient reported allergy to penicillin in form of hives. She was prescribed oral trimethoprim/sulfamethoxazole that she took for 1 week. Despite antibiotic treatment, the erythema persisted. She had no fever or chills during this period. She was diagnosed to have facial cellulitis and was admitted to the medical floor for administration of vancomycin.
The patient was afebrile and nontoxic. Local examination revealed a diffuse swelling involving lower half of the right cheek. Areas of excoriation and crusting were present in the center. It was erythematous, warm, and tender to touch. She had no leukocytosis. There was no significant improvement in the affected area, despite administration of intravenous vancomycin. On further questioning, the patient gave a history of repeated application of neomycin ointment over the affected area. Vancomycin was discontinued, and the patient responded to topical corticosteroids.
This case highlights the importance of recognizing allergic contact dermatitis (ACD) caused by neomycin. Neomycin is an aminoglycoside produced by Streptomyces fradiae. It binds to the 30S subunit of the bacterial ribosome to inhibit protein synthesis.1 Several topical preparations of neomycin are available including ointments, creams, and eye and ear drops.
Allergic contact dermatitis represents a delayed-type hypersensitivity to small molecular weight chemicals that act as haptens.2 The incidence of ACD based on the National Health and Nutrition Examination Survey is 13.6 cases/1000 patients per year.3 Neomycin contact allergy has been estimated to be relatively common, with a prevalence of approximately 1%.4 According to a German study, the 1 year incidence of contact dermatitis to neomycin was 29 persons/100,000 in the general population.5 The frequency of allergy to topical neomycin was 5 times more common than that to topical clioquinol and 10 times more common than that to topical fusidic acid.6 Topical antibiotics, such as neomycin and bacitracin, induce more ACD than any other class of medicines.7
The risk of contact dermatitis with neomycin is higher among patients with leg stasis dermatitis and atopic dermatitis. Otitis media is a specific risk factor when neomycin is used. Fifty-six percent of patients with chronic otorrhea had positive patch tests, the most frequent offenders being neomycin and framycetin.8 The incidence of ACD increases with age9 and with the number of additional positive reactions to other standard series allergens. Abrasions and cuts are much less at risk to develop ACD.
An intact cellular immune system is required for the development of ACD. The interaction between antigen and the T lymphocyte component of the cellular immune system is mediated by antigen-presenting epidermal cells and is divided into 2 sequential phases.
In the initial sensitization phase, the antigen penetrates stratum corneum and binds to the surface of the Langerhans cells. The Langerhans cells leave the epidermal compartment, carrying the antigen to regional lymph nodes. In the regional lymph nodes, the antigen is presented by Langerhans cells to T lymphocytes, followed by clonal expansion of T lymphocytes that recognize the specific antigen. Antigen-specific T lymphocytes circulate back to the epidermis.
In the elicitation phase, antigen-specific T lymphocytes are reexposed to the antigen by Langerhans cells. They are activated, release cytokines, and recruit other inflammatory cells, resulting in a dermatitis.10 The initial sensitization takes 10 to 14 days to produce a reaction, whereas reexposure takes hours to several days.
It is important to recognize that patients with ACD to neomycin can cross-react in decreasing order of frequency with the following: neomycin, framycetin, gentamycin, kanamycin, paromomycin, spectinomycin, and tobramycin, when they are used topically or systemically. The patients should be cautioned about the cross-reactivity, and these antibiotics should be avoided if possible.
In the acute stage, patients present with erythema, edema, and vesicle formation. The appearance of a rash with straight edges, sharply defined areas, and skip areas are clues to ACD. The vesicles may coalesce to form bullae or rupture, resulting in oozing of clear liquid. This is often followed by crusting, scaling, and, in the chronic phase, lichenification.7
If not treated, ACD resolves over 3 or 4 weeks with avoidance of allergen. With repeated exposure, the ACD may become widespread and may evolve into exfoliative erythroderma.10 Regardless of the type of rash, the presence of pruritus is almost invariable in ACD. The absence of fever and leukocytosis is a valuable clue to the noninfectious nature of this process.10 History of exposure to the offending antigen is the key to diagnosis of contact allergy and should be actively sought.
The large areas of redness and edema make ACD a mimic of cellulitis. The presence of vesicles should make one suspect herpes simplex and varicella-zoster infections. The crusting and oozing lesions can often be mistaken for impetigo.10
The epicutaneous patch test is considered the gold standard for diagnosing ACD. The classic ACD eruption appears within 2 to 3 days of sufficient allergen contact. A 96-hour interval may be optimal for interpreting patch tests of allergens known to induce late-phase reactions, such as neomycin.7 It must be recognized that the patch test only indicates sensitivity, not the cause of the rash. It is history that nails the diagnosis.
The cornerstone of treatment of ACD is identification of the allergen and avoidance of the same. Glucocorticoids stop the proliferation of lymphocytes and decrease the production of cytokines. These properties make them the ideal agents for the treatment of ACD.
Topical glucocorticoids are adequate for dermatitis involving less than 10% of the skin surface. Lower potency steroids are preferred for the intertrigenous areas, whereas higher potency steroids are reserved for the trunk and extremities.7 The commonly used low-potency steroids include desonide 0.05% and hydrocortisone 1%. The moderate potency steroids include triamcinolone 0.1% and mometasone furoate 0.1%.11 A glucocorticoid ointment of moderate potency is applied 2 times a day for 2 or 3 weeks.
If the dermatitis involves more than 10% of the skin surface, prednisone 1 or 2 mg/kg per day, as a single morning dose for 7 to 10 days, with the dose tapered over an additional 7 to 10 days, is recommended in conjunction with topical glucocorticoid therapy.7
There is ongoing research regarding the role of calcineurin inhibitors in the setting of ACD. These agents are cell selective inhibitors of inflammatory cytokines in T cells. The medications belonging to this class include tacrolimus, pimecrolimus, and cyclosporine.12 These agents can be used in areas like the face where steroids are contraindicated.
Tacrolimus is a macrolactam that prevents the transcription of messenger RNA for inflammatory cytokines in helper T cells.13 In a double-blind comparison study on patients with nickel allergy, tacrolimus was found to be more effective than placebo in ameliorating the symptoms of ACD.13 In a study done by Pacor et al,14 tacrolimus ointment 0.1% seemed to be effective and safe in the treatment of nickel-induced steroid-resistant ACD.
Pimecrolimus is a cell-selective cytokine inhibitor that has shown promise in the treatment of inflammatory skin conditions when applied topically.15 Preliminary studies showed a clear trend toward symptom resolution in patients with ACD using pimecrolimus.16
This case highlights the importance of obtaining a careful history and recognizing drug reaction caused by neomycin in the form of ACD. It is important to keep ACD in mind when patients using topical antibiotics present with persistent erythema, edema, rash, and pruritus in the absence of fever and leukocytosis.
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14. Pacor ML, Di Lorenzo G, Martinelli N, et al. Tacrolimus ointment in nickel sulphate-induced steroid-resistant allergic contact dermatitis. Allergy Asthma Proc. 2006;27(6):527-531.
15. Eichenfield LF, Lucky AW, Boguniewicz M, et al. Safety and efficacy of pimecrolimus (ASM 981) cream 1% in the treatment of mild and moderate atopic dermatitis in children and adolescents. J Am Acad Dermatol. 2002;46:495-504.
16. Bhardwaj SS, Jaimes JP, Liu A, et al. A double-blind randomized placebo-controlled pilot study comparing topical immunomodulating agents and corticosteroids for treatment of experimentally induced nickel contact dermatitis. Dermatitis. 2007;18(1):26-31.
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