eMedicine Specialties > Dermatology > Allergy & Immunology

Fixed Drug Eruptions

Author: David F Butler, MD, Professor of Dermatology, Texas A&M University College of Medicine; Director, Division of Dermatology, Scott and White Clinic; Director Dermatology Residency Training Program, Scott and White Clinic
Coauthor(s): Jordan R Ilse, MD, Staff Physician, Scott and White Internal Medicine Residency Program, Temple, Texas
Contributor Information and Disclosures

Updated: Nov 15, 2007

Introduction

Background

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 (FDE). The term 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. 

Several variants of FDE have been described, based on their clinical features and the distribution of the lesions.^1,2,3 These include the following:

• Pigmenting FDE
• Generalized or multiple FDE
• Linear FDE
• Wandering FDE
• Nonpigmenting FDE
• Bullous FDE
• Eczematous FDE
• Urticarial FDE
• Erythema dyschromicum perstans–like FDE

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.⁴

The offending drug is thought to function as a hapten that preferentially binds to basal keratinocytes, leading to an inflammatory response.⁵ Through liberation of cytokines such as tumor necrosis factor-alpha, keratinocytes may locally up-regulate expression of the intercellular adhesion molecule-1 (ICAM1).⁶ The up-regulated ICAM1 has been shown to help T cells (CD4 and CD8) migrate to the site of an insult.^7,8 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.⁴  

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.⁴ 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.⁴

Frequency

United States

The prevalence of drug eruptions has been reported to range from 2-5% for inpatients and greater than 1% for outpatients.⁹ FDEs 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 FDEs.

International

The international prevalence is variable but is likely similar to that in the United States. Most studies report FDEs to be the second or third most common skin manifestation of adverse drug events.¹⁰  

Mortality/Morbidity

No deaths have been attributed to FDEs. Widespread lesions may initially mimic toxic epidermal necrolysis, but they have a benign clinical course.¹¹ Localized hyperpigmentation is a common complication, but pain, infection, and, rarely, hypopigmentation, also may occur.¹  

Race

FDEs have no known racial predilection. A genetic susceptibility to developing an FDE with an increased incidence of HLA-B22 is possible.^12,13

Sex

One large study of 450 patients revealed a male-to-female ratio of 1:1.1.¹

Age

FDEs 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

Clinical

History

The initial eruption is often solitary and located on the sacral region, hip, proximal extremity, lip/perioral region, or genitalia. With the initial FDE attack, a delay of up to 2 weeks may occur from the initial exposure to the drug to the development of the skin lesion.¹⁴ Skin lesions develop over a period of hours but require days to become necrotic. Lesions may persist from days to weeks and then fade slowly to residual oval hyperpigmented patches.

Subsequent reexposure to the medication results in a reactivation of the site, with inflammation occurring within 30 minutes to 16 hours.¹⁵ The reactivation of old lesions also may be associated with the development of new lesions at other sites.

Patients may not be cognizant that a drug, nutritional supplement, or over-the-counter medication triggered the skin problem. They may be convinced that an insect, particularly a spider, may be the culprit. A careful history is required to elicit the fact that a drug has been taken and is temporally related to the onset of the eruption. Medications taken episodically, such as pain relievers, antibiotics, or laxatives, are often to blame. When able to be identified, patients often report ingestion of one the following types of medications¹⁶ :

• Analgesics
• Muscle relaxants
• Sedatives
• Anticonvulsants
• Antibiotics

Physical

The most common clinical manifestation is the pigmenting FDE, which usually manifests as round or oval, sharply demarcated erythematous/edematous plaques located on the lip, hip, sacrum, or genitalia.²  These erythematous patches or plaques gradually fade with residual hyperpigmentation (see Media Files 1-5). The center of the patch may blister or become necrotic. Other less common variants may manifest as lesions resembling erythema multiforme, toxic epidermal necrolysis, eczema, urticaria, a linear pattern following Blaschko lines, bullous lesions, a migrating eruption, or a nonpigmenting form with no postinflammatory hyperpigmentation.³

Initially, a single lesion or a few lesions develop, but, with reexposure, additional lesions occur. The vast majority of patients present with 1-30 lesions, ranging in size of 0.5-5 cm, but reports of lesions greater than 10 cm have been published. Lesions may be generalized. The most common reported site is the lips, and these may be seen in up to half of all cases.¹

Medications may also follow a site-specific eruption pattern. For example, trimethoprim-sulfamethoxazole (Bactrim) has been shown to favor the genital region (especially in males) and naproxen and the oxicams involve the lips.²

Resting/inactive lesions tend to appear as round or oval, gray, hyperpigmented macules. 

Upon reexposure, the resting hyperpigmented macules activate, developing a violaceous center encircled by concentric rings of erythema. Re-administration of the medication poses the risk of increased pigmentation, size, and number of lesions.
 
Individuals with darker pigmentation may develop postinflammatory hypopigmented macules once the lesions have resolved.⁵

Causes

The major categories of causative agents of FDE include antibiotics, antiepileptics, nonsteroidal anti-inflammatory agents, and phenothiazines, although numerous other agents and certain foods have also been reported as causative agents. Ingestion of the causative agent may occur via any route, including oral, rectal, or intravenous.¹⁶
 
The most common cause is trimethoprim-sulfamethoxazole.³  Other substances implicated to cause FDEs are as follows^1,5,16 :

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