Fixed Drug Eruptions

Updated: Aug 12, 2019
  • Author: David F Butler, MD; Chief Editor: Dirk M Elston, MD  more...
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Overview

Background

The term fixed drug eruption (FDE) describes the development of one or more annular or oval erythematous patches as a result of systemic exposure to a drug; these reactions normally resolve with hyperpigmentation and may recur at the same site with reexposure to the drug. Repeated exposure to the offending drug may cause new lesions to develop in addition to "lighting up" the older hyperpigmented lesions.

Adverse reactions to medications are common and often manifest as a cutaneous eruption. Drug-induced cutaneous disorders frequently display a characteristic clinical morphology such as morbilliform exanthem, urticaria, hypersensitivity syndrome, pseudolymphoma, photosensitivity, pigmentary changes, acute generalized exanthematous pustulosis, lichenoid dermatitis, vasculitis, Stevens-Johnson syndrome, or fixed drug eruption.

Several variants of fixed drug eruption have been described, based on their clinical features and the distribution of the lesions. [1, 2, 3, 4, 5, 6, 7] These include the following:

  • Pigmenting fixed drug eruption

  • Generalized or multiple fixed drug eruption

  • Linear fixed drug eruption

  • Wandering fixed drug eruption

  • Nonpigmenting fixed drug eruption

  • Bullous fixed drug eruption

  • Eczematous fixed drug eruption

  • Urticarial fixed drug eruption

  • Erythema dyschromicum perstans–like fixed drug eruption

  • Vulvitis

  • Oral

  • Psoriasiform

  • Cellulitislike eruption [8]

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Pathophysiology

Although the exact mechanism is unknown, recent research suggests a cell-mediated process that initiates both the active and quiescent lesions. The process may involve an antibody-dependent, cell-mediated cytotoxic response. [9] CD8+ effector/memory T cells play an important role in reactivation of lesions with re-exposure to the offending drug. [10, 11]

The offending drug is thought to function as a hapten that preferentially binds to basal keratinocytes, leading to an inflammatory response. [12] Through liberation of cytokines such as tumor necrosis factor-alpha, keratinocytes may locally up-regulate expression of the intercellular adhesion molecule-1 (ICAM1). [13] The up-regulated ICAM1 has been shown to help T cells (CD4 and CD8) migrate to the site of an insult. [14, 15]

The newly arriving and residential CD8 cells likely perpetuate tissue damage by their production of the inflammatory cytokines interferon-gamma and tumor necrosis factor-alpha. CD8 cells isolated from active lesions have also been shown to express alpha E beta 7, a ligand for E-cadherin, which may further contribute to the lymphocyte’s ability to localize to the epidermis. Other cell surface molecules, such as CLA/alpha4beta1/CD4a, that bind E-selectin/vascular cellular adhesion molecule-2/ICAM1 help to further attract CD8 cells to the area. [9]

Changes in cell surface markers allow vascular endothelium to select CD4 cells for migration into active lesions. These regulatory CD4 cells likely produce interleukin 10, which has been shown to help suppress immune function, resulting in a resting lesion. [9] As the inflammatory response dissipates, interleukin 15 expression from keratinocytes is thought to help ensure the survival of CD8 cells, helping them fulfill their effector memory phenotypes. Thus, when reexposure to the drug occurs, a more rapid response develops in the exact location of any prior lesions. [9]

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Etiology

The major categories of causative agents of fixed drug eruption include antibiotics, antiepileptics, nonsteroidal anti-inflammatory agents, sildenafil, and phenothiazines, although numerous other agents and certain foods such as cashews and licorice have also been reported as causative agents. Ingestion of the causative agent may occur via any route, including oral, rectal, or intravenous. [16, 17]

Certain classes of drugs with cross-reactions within a class have been reported to elicit a fixed drug eruption with quinolones [18] and with nonsteroidal anti-inflammatory agents. [19] In some patients, the reaction may be to a dye rather than the active ingredient. [20] Fixed drug eruption may rarely be related to foods, including residual antibiotics in meat products and quinine contained in tonic water. [21, 22]

While fixed drug eruptions are uncommon with general anesthesia, propofol has been implicated in causing a drug eruption on the penis. [23]

The most common cause is trimethoprim-sulfamethoxazole. [3, 24] Other substances implicated to cause fixed drug eruptions are as follows [1, 12, 16, 25, 5, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36] :

Table. Substances Implicated in Fixed Drug Eruptions (Open Table in a new window)

Acetaminophen

Acyclovir

Allopurinol

Allylisopropyl-acetylurea

Amide local anesthetics

Amlexanox

Amoxicillin

Anticonvulsants

Articaine

Aspirin

Atenolol

Barbiturates

Botulinum toxin

Carbamazepine

Cashew nut

Ceftriaxone

Celecoxib

Cetirizine

Chloral hydrate

Chlordiazepoxide

Chlorhexidine

Chlormezanone

Chlorphenesin carbonate

Citicoline

Clarithromycin

Clioquinol

Clopidogrel

Codeine

Colchicines

Cyclizine

Cyproterone acetate

Dextromethorphan

Dimenhydrinate

Diphenhydramine

Dipyrone

Docetaxel

Eperisone hydrochloride

Erythromycin

Ethenzamide

Feprazone

Finasteride

Flecainide

Fluconazole

Fluoroquinolones

Foscarnet

Gabapentin

Griseofulvin

Hydroxyzine

Ibuprofen

Interferon

Iodinated radiography contrast media

Iomeprol

Kakkon

Ketoconazole

Lactose

Lamotrigine

Lentils

Liquorice

Lomeprol

Lopamidoln

Loratadine

Lormetazepam

Magnesium trisilicate

Mefenamic acid

Melatonin

Methaqualone

Metramizole

Metronidazole

Metaform

Minocycline

Multivitamins

Naproxen

Nimesulide

Omeprazole

Ondansetron

Opium alkaloids

Oxyphenbutazone

Paclitaxel

Pamabrom

Papaverine

Para-aminosalicylic acid

Penicillins

Phenazone

Phenolphthalein

Phenylbutazone

Phenylephrine

Phenylpropanolamine

Phenytoin

Pipemidic acid

Piroxicam

Procarbazine

Prochlorperazine

Pseudoephedrine

Quinine

Rifampin

Scopolia

Sodium benzoate

Strawberries

Sulfamethoxazole

Tartrazine

Terbinafine

Tetracyclines

Theophylline

Thiacetazone

Ticlopidine

Tinidazole

Tolfenamic acid

Tosufloxacin

Tranexamic acid

Trimethoprim

Tropisetron

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Epidemiology

Frequency

United States

The prevalence of drug eruptions has been reported to range from 2-5% for inpatients and greater than 1% for outpatients. [37] Fixed drug eruptions may account for as much as 16-21% of all cutaneous drug eruptions. The actual frequency may be higher than current estimates, owing to the availability of a variety of over-the-counter medications and nutritional supplements that are known to elicit fixed drug eruptions.

International

The international prevalence is variable but is likely similar to that in the United States. Most studies report fixed drug eruptions to be the second or third most common skin manifestation of adverse drug events. [38]

Race

Fixed drug eruptions have no known racial predilection. A genetic susceptibility to developing a fixed drug eruption with an increased incidence of HLA-B22 is possible. [39, 40]

Sex

One large study of 450 patients revealed a male-to-female ratio of 1:1.1 for fixed drug eruptions. [1]

Age

Fixed drug eruptions have been reported in patients as young as 1.5 years and as old as 87 years. The mean age at presentation is 30.4 years in males and 31.3 years in females. [1]

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Prognosis

The prognosis is very good, and an uneventful recovery should be expected. No deaths due to fixed drug eruption have been reported. Residual hyperpigmentation is very common, but this is less likely with the nonpigmenting variant.

Widespread lesions may initially mimic toxic epidermal necrolysis, but they have a benign clinical course. [41] Again, localized hyperpigmentation is a common complication, but pain, infection, and, rarely, hypopigmentation, also may occur. [1]

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Patient Education

Patients should be counseled on medication avoidance and possible cross-reactions of similar medications. Patients should notify their physicians of all drug allergies they have experienced.

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