Q:

11/4/2013
I have a 15YO female with CF, history of very frequent CF exacerbations who last admission developed ecchymotic circular macules of lower extremties and lower abdomen that were biopsied and found to be fixed drug eruption vs. erythema multiforme. She had also had burning of her lips at the time of the rash. She had been on several days of Zosyn and levoquinolone which were both stopped at the same time with improvement of symptoms, given benadryl prn but no steroids was required. She returns with CF exacerbation, given the fear of EM, she is being treated with an alternative antibiotic regimen with improvement (avoiding all beta lactams and quinolones). However, given that she has frequent CF exacerbations probably will need antibiotics in the future, would you electively try to challenge her to a different beta lactam or quinolone in the background that she may have had EM? And if you did the challenge, how gradual would you do it?

A:

Thank you for your inquiry.

The question you posed is certainly salient, but unfortunately, has no definitive answer. There are two forms of challenges one can use to confirm a diagnosis of a fixed drug eruption. There is the oral, systemic challenge, and the patch test challenge. Oral challenge is considered contraindicated, of course, in erythema multiforme. Thus, at first glance the question would be, does your patient have erythema multiforme or fixed drug eruption. However, in your patient, the fixed drug eruption, at least according to your description, was generalized, and oral challenge is contraindicated in a patient with generalized fixed drug eruption just as it is in a patient with erythema multiforme (1). Thus, in general, one would be very reluctant to pursue an oral challenge in your patient regardless of the diagnosis.

In addition, one cannot predict in a fixed drug eruption whether or not the reaction was drug or class specific. Clearly, crossreactivity to related drugs has been demonstrated in patients with fixed drug eruptions by challenge studies (2). Thus, there is no assurance that one would not produce a reaction when employing compounds of the same class.

Thus, in summary, I would be very reluctant to perform a systemic oral challenge in your patient. However, since you asked about the technique employed, should you ever decide for any reason to perform an oral challenge, there are published protocols that I might mention. Usually one would wait two to four weeks after resolution of the symptoms, and then begin a graded challenge. A protocol can be seen in Reference Number 3 below (3). In addition, in Reference Number 1, a brief description of a protocol is mentioned. In this instance, the starting dose is 1/10th of the therapeutic dose, and doses are increased every 12 to 24 hours until the therapeutic dose is reached or a reaction occurs. Flare-ups can occur quickly (within 30 minutes) or as late as 8 hours.

The other alternative you have as a provocation test is the patch test. There is no standardized universally accepted method or dose, but there are many reports of provocative patch testing to identify the culprit in fixed drug eruptions. Patch testing is of course considered safer. The drug is diluted in water to a 10 to 20% concentration, mixed with petrolatum, and then applied to the area previously exhibiting a lesion. Positive tests usually occur within 24 to 48 hours. However, the exact sensitivity and specificity of patch testing has not been established in large numbers of patients.

Finally, Reference Number 1 is a superb resource, and much of what I have mentioned is taken directly from this source. And you might find the additional references copied below helpful as well.

Thank you again for your inquiry and we hope this response is helpful to you.

References:
Shiohara T, M.D., Ph.D. in UpToDate: Fixed drug eruption chapter; updated February 21, 2013.
Tham SN, et al. Archives of Dermatology 1996; 132(9):1134-1135.
Miah MA, et al. Mymensingh Med J 2008, July; 17(2 Supplement):S1-S5.

Additional References:
Curr Opin Allergy Clin Immunol. 2009 Aug;9(4):316-21. doi: 10.1097/ACI.0b013e32832cda4c.
Fixed drug eruption: pathogenesis and diagnostic tests.
Shiohara T.
Source
Department of Dermatology, Kyorin University School of Medicine, 6-20-2 Shinkawa, Mitaka, Tokyo 181-8611
Abstract
Purpose of Review: Fixed drug eruption is a simplified disease model for elucidating the mechanism(s) of how skin inflammation is induced by skin-resident T cells. In this review, we focus on how the presence of intraepidermal CD8+T cells resident in the fixed drug eruption lesions can provide exciting new clues to our understanding of pathomechanisms of inflammatory skin diseases.
Recent Findings: Intraepidermal CD8+T cells with an effector-memory phenotype resident in fixed drug eruption lesions have a major contributing role in the development of localized tissue damage. Activation of these CD8+T cells is sufficient for triggering the lesion, however, but not sufficient to cause extensive tissue damage observed in the fully evolved lesions; additional recruitment of CD4+ and CD8+T cells to a specific tissue site would also contribute to the late stage of lesion development. The influx of regulatory T cells into the epidermis observed in fully evolved lesions would serve to limit harmful immune reactions. Consistent with this, positive patch test reactions are only observed at the site of previous lesions harboring significant numbers of intraepidermal CD8+T cells.
Summary: Intraepidermal CD8+T cells may represent double-edged swords of the skin immune system with protective and destructive capacity.

J Drugs Dermatol. 2012 Feb;11(2):244-6.
Multifocal, fixed-drug eruption masquerading as recurrent erythema multiforme.
Elm MK, Murchland MR.
Source
Dermatology Service, San Antonio Military Medical Center, San Antonio, TX, USA. Abstract
Fixed drug eruptions often have a characteristic appearance, which, when correlated with the clinical history, can be easily identified. However, multifocal fixed drug eruptions, especially the non-pigmenting variety, can present a diagnostic challenge, especially in the absence of a complete medication history. We present such a case, in which the patient was taking two over-the-counter medications, both of which contain uncommon causes of multifocal fixed drug eruptions.

Clin Exp Dermatol. 1990 Sep;15(5):387-8.
Multifocal fixed drug eruption mimicking erythema multiforme.
Sowden JM, Smith AG.
Source
Department of Dermatology, North Staffordshire Hospital Centre, Stoke-on-Trent, UK.
Abstract
A 38-year-old woman presented with a widespread bullous eruption that recurred during menstruation. Skin biopsy suggested erythema multiforme. As she was receiving synthetic progesterones for dysmenorrhoea the diagnosis of an auto-immune progesterone dermatitis was considered. However, subsequent investigations confirmed the diagnosis to be a fixed drug eruption to mefenamic acid taken for dysmenorrhoea.

Curr Allergy Asthma Rep. 2009 Jan;9(1):71-7.
Fixed drug eruption: a prototypic disorder mediated by effector memory T cells.
Mizukawa Y, Shiohara T.
Source
Department of Dermatology, Kyorin University School of Medicine, Mitaka, Tokyo
Abstract
Effector memory T cells are uniquely specialized to mediate protective immunity. However, their excessive activation may result in the development of organ-specific inflammatory diseases, which have not been extensively studied. Fixed drug eruption (FDE), a localized variant of drug-induced dermatoses characterized by relapse in the same location, is a prototypic disorder mediated by excessive activation of effector memory T cells, which are resident in the lesional epidermis. A variety of clinical and pathologic features uniquely observed in FDE lesions can be explained by the presence of CD8(+) intraepidermal T cells with the effector memory phenotype in the FDE lesion. This review focuses on how these T cells are generated, retained in the epidermis, and activated to cause epidermal damage.

Sincerely,
Phil Lieberman, M.D.

AAAAI - American Academy of Allergy Asthma & Immunology