American Journal of Clinical Dermatology

https://doi.org/10.1007/s40257-020-00505-3

REVIEW ARTICLE

Fixed Drug Eruptions: An Update, Emphasizing the Potentially Lethal

Generalized Bullous Fixed Drug Eruption
Shreya Patel1 · Ann M. John2 · Marc Zachary Handler1 · Robert A. Schwartz1 

© Springer Nature Switzerland AG 2020

Abstract
A fixed drug eruption (FDE) is a relatively common reaction associated with more than 100 medications. It is defined
as a same-site recurrence with exposure to a particular medication. The primary approach and treatment for all types of
FDEs are to identify and remove the causative agent, often accomplished by a thorough history of medication and other
chemical exposures, and possibly prior episodes. The most common category of FDE, localized FDE, whether bullous or
non-bullous, is self-limited. Although one can confirm the causative agent using oral challenge testing, it is not recom-
mended due to the risk of severe exacerbation or possible generalization; patch testing is now preferred. Bullous FDE
may resemble erythema multiforme. Treatment of localized FDE includes medication removal, patient counseling, and
symptomatic relief. Failure to remove the causative agent in localized FDE can lead to recurrence, which is associated
with increased inflammation, hyperpigmentation, and risk of a potentially lethal generalized bullous FDE (GBFDE),
which may resemble Stevens–Johnson syndrome (SJS) or toxic epidermal necrolysis (TEN). Distinguishing GBFDE
from SJS and TEN is salient and will be stressed: GBFDE has more rapid onset in 1–24 h rather than in weeks, less or no
mucosal involvement, less or no systemic involvement, and a tendency for a more favorable prognosis; however, recent
experience suggests it may be just as life-threatening. This review will provide a comprehensive update and approach to
diagnosis and management.

1 Introduction
Key Points 
A fixed drug eruption (FDE) is often a clinically striking aller-
A fixed drug eruption (FDE) is a common drug eruption gic phenomenon characterized by an erythematous or viola-
with distinctive morphology and etiology that ranges ceous circular patch, plaque, or bullae with a somewhat dusky-
from antibiotics to cryptic exposure such as to quinine in grey center denoted for same-site recurrence after re-exposure
a gin and tonic. to a specific drug, often with more involved sites with each
Generalized bullous FDE may resemble SJS/TEN and recurrence [1–3]. FDE is a delayed type IV hypersensitivity
may prove to be as deadly. reaction [4, 5]. First described by Bourns [6] in England in
1889, the term FDE was coined by the Frenchman Brocq [7] as
an “éruption érythémato-pigmentée fixe” in 1894 to describe
a reaction to antipyrine [7, 8]. Categorization of FDE is based
on its clinical morphology, the major types being localized

1
* Robert A. Schwartz Dermatology, Rutgers New Jersey Medical School, 185
[email protected] South Orange Avenue, Medical Science Building H‑576,
Newark, NJ 07103‑2757, USA
Shreya Patel
2
[email protected] Dermatology, Robert Wood Johnson University Hospital,
One World’s Fair Drive, Suite 2400, Somerset, NJ 08873,
Ann M. John
USA
[email protected]
Marc Zachary Handler
[email protected]

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 S. Patel et al.

pigmenting, localized bullous, mucosal, non-pigmenting, gen- [18–20]. In the later stages, recruited CD8+ T cells, CD4+
eralized, and generalized bullous. The localized pigmenting T cells, and neutrophils cause damage to melanocytes and
type of FDE is the most common type and is a self-limited keratinocytes [19]. Damage to the melanocytes leads to mel-
reaction [9, 10]. Recognition and management of the rare gen- anin leakage into the dermis [9]. This injury is controlled
eralized bullous FDE (GBFDE) is a clinical conundrum that by the activation of FoxP3+ regulatory T cells within 24 h,
may have life-threatening consequences. Lyell [10] has pro- which abate the activation mediated by both central memory
claimed that his original description of four patients with toxic and resident memory CD8+ T cells [19, 21]. Patients who
epidermal necrolysis (TEN) contains two patients who actually develop an FDE may have reduced amounts of FoxP3+ reg-
had GBFDE. Difficulty in distinguishing GBFDE from TEN ulatory T cells in the lesional periphery [21, 22].
has long been a problem [3]. We concur that GBFDE is quite After discontinuation of the drug, the basal layer of the
unusual, has no precise incidence figures available, and is often epidermis starts to regenerate and the inflammatory cells
misdiagnosed and rarely documented. begin undergoing apoptosis [2]. During regeneration, the
dermal macrophages undergo phagocytosis of the leaked
2 Epidemiology melanin and remain at the site, leading to the observed
residual hyperpigmentation [9]. The basal layer keratino-
Drug-induced skin reactions occur in 2–5% of hospitalized cytes release interleukin (IL)-15 during regeneration, which
patients and 1% of outpatients [11]. FDE is a relatively com- leads to the formation of resident memory CD8+ T cells [23,
mon cutaneous drug reaction, representing up to 14–22% 24]. The resident memory CD8+ T cells are implicated in
of patients, second only to morbilliform reactions [4, 9, 12, the same-site recurrence of FDE [23, 25]. Resident memory
13]. In one survey, GBFDE affected mainly older patients CD8+ T cells have shown swift reactivation and release of
(median age 78 years, range 68–84 years) [3], in whom this interferon-γ upon drug provocation in vivo [21]. In addi-
diagnosis and other special types of FDE may be missed tion, CD3+ CD8+ T cells with markers similar to resident
[14]. In one small Indian survey, FDE was most common memory CD8+ T cells are documented in the epidermis
among patients aged 21–30 years and affected both sexes of latent FDE lesions [21]. These resident memory T cells
equally, the most common offenders being antimicrobials have been implicated in other recurrent same-site conditions,
and non-steroidal anti-inflammatory drugs (NSAIDs), with including psoriasis and cutaneous T-cell lymphoma [24].
fluoroquinolones and nitroimidazole most closely linked
[15]. In a study of 450 Pakistani FDE patients, 69% of
patients had the condition for at least 1 year before diagnosis 4 Genetics
[16]. Orally administered drugs are the most common cause
of an FDE [2], with topical and intravaginal medications Multiple types of drug hypersensitivity reactions, including
being less likely [17]. FDE, have been associated with specific human leukocyte
An FDE can occur after exposure to ultraviolet in the A or antigens (HLAs) [26]. These HLA genes produce major
B range (UVA/UVB) or to food instead of a drug [8]. Some- histocompatibility complex (MHC) molecules. In FDE,
times referred to as a fixed food eruption, it is probably best CD8+ T cells play a critical inflammatory role by recogniz-
viewed as a type of FDE. The distinction can be challenging, ing certain drugs in association with specific MHC class I
as exemplified by quinine, an antimalarial compound found molecules found on keratinocytes [27]. MHC class I mol-
in tonic water; quinine can produce FDE in people drinking ecules are derived from HLA-A, HLA-B, and HLA-C genes
tonic water by itself or in a gin and tonic [44]. Other foods, in humans. There are several examples of HLA-A or HLA-B
including kiwifruit, peanuts, cashew nuts, and asparagus, associated with FDE, including HLA-B22 with feprazone-
may rarely produce an FDE; however, sometimes foods may induced FDE, and HLA-A30 with trimethoprim-sulfameth-
contain antibiotics or other drugs that can cause an FDE. oxazole-induced FDE [22, 27].

3 Pathogenesis 5 Clinical Presentation

The immunological reaction at the FDE site has been exten- FDE is first evident as a red or violaceous circular plaque
sively studied, with its pathological changes being well with a dusky-grey center [28]. The eruption may be solitary,
described [9]. During the first 8 h, the basal layer of the a localized cluster, or diffuse. In one study, 16% of patients
epidermis is damaged by exposure to the offending agent had a single plaque, 36% had two to five plaques, and 47%
[2]. Resident epidermal memory CD8+ T-cell activation had more than five plaques on initial presentation [16]. FDE
by medication antigens plays a key role as these CD8+ T can appear at any skin site but targets areas with thin skin,
cells release early cytotoxic mediators such as interferon-γ such as the lip mucosa, genitals, and perianal sites [22].
Fixed Drug Eruptions: An Update, Emphasizing the Potentially Lethal Generalized Bullous Fixed Drug Eruption

Areas of prior cutaneous trauma such as burns, bites and rare and, when evident, rather mild; (3) patients usually do
healed herpes simplex virus (HSV) infection are favored tar- not feel sick or have fever, and are generally in much better
gets [21]. FDEs occur up to 1 week after the first drug expo- overall health than those with SJS/TEN; (4) most patients
sure, and, for subsequent exposures, between 30 min and 8 h report a history of a similar, often local reaction.
afterwards [29]. FDE is usually asymptomatic, but may be
painful or pruritic [30]. It usually resolves a few weeks after 5.1 Histology
stopping the medication, but the post-inflammatory hyper-
pigmentation can last up to a few months afterwards (Fig. 1) FDE demonstrates changes in the epidermis and upper
[28]. GBFDE tends to be first evident as widespread well- dermis [8, 31]. Histological changes include a vacuolar
demarcated, dusky-red or heavily pigmented oval patches, interface dermatitis, hydropic degeneration of the basal epi-
some polycyclic, with non-tense blisters and erosions. Typi- dermal layer, spongiosis, a normal keratin layer, scattered
cal clinical features that may aid in differentiating GBFDE individual keratinocyte necrosis, a perivascular lymphocytic
from Stevens–Johnson syndrome/TEN are as follows: (1) and eosinophilic infiltrate, and pigmentary incontinence [31,
blistering usually affects only a small percentage of body 32]. FDE has overlapping pathologic features with erythema
surface area, and between the large blisters there are siz- multiforme, SJS, and TEN, although FDE tends to show
able areas of intact skin; (2) erosive mucosal involvement is increased inflammation and many more dermal melano-
phages, as will be detailed shortly in discussing GBFDE.

5.2 Common Medications

Over 100 medications can cause FDE, with many com-

mon substances being implicated (Tables 1, 2) [33]. FDE
is most commonly seen with trimethoprim-sulfamethoxa-
zole, nitroimidazoles such as metronidazole and tinidazole,
fluoroquinolones such as levofloxacin and ciprofloxacin,
and NSAIDs [28, 33]. Other causative antibiotics include
tetracyclines, amoxicillin, and rifampin [1, 30, 34]. Other
analgesics include acetaminophen, salicylates, piroxicam,
and mefenamic acid [1, 9]. Oral contraceptives, phenol-
phthalein-containing laxatives, barbiturates, and other sul-
fonamides are frequently involved [1, 33, 35]. In Singapore,
NSAIDs caused half of the cases, with etoricoxib alone the
most implicated [36]. Substances such as tartrazine in food
additives and cold medication and quinine in alcoholic bev-
erages, such as gin and tonic, may be overlooked, but should
Fig. 1  Fixed drug eruption with distinctive post-inflammatory hyper- be considered [9]. Influenza vaccine may rarely be etiologic
pigmentation
[28].
There are cases of cross-reactivity between drugs of
similar structure [2]. Tetracyclines and trimethoprim-sul-
Table 1  Common causes of fixed drug eruptions
famethoxazole most commonly show cross-sensitivity [1,
Exposure type Causative substance 36]. Awareness of cross-reactivity is important in FDE as
Analgesics/NSAIDS Acetaminophen, salicylates,
patients should be made aware of which medications may
piroxicam, mefenamic acid potentiate a recurrence [37].
Antibiotics Trimethoprim-sulfamethoxazole,
metronidazole, tetracyclines,
ciprofloxacin, levofloxacin, 6 Diagnosis
amoxicillin, rifampin, tinidazole
Tonic water Quinine
It is imperative to review the patient’s medications and his-
Contraception Oral contraceptives
tory of consumed drugs [2]. Ingested drugs that are over-
Additives/colorants Tartrazine
the-counter, herbal, and only occasionally taken should
Laxatives Phenolphthalein
be included. The etiology can be difficult to elucidate in
Sedatives Barbiturates
patients with multiple medications and a first-time episode
NSAIDs non-steroidal anti-inflammatory drugs [37].
 S. Patel et al.

Table 2  Common medications by type of fixed drug eruption Biopsy is indicated in patients with an unclear diagnosis
or associated systemic symptoms such as fever, malaise, or
Type of fixed drug eruption Common medications
arthralgias, and is also indicated in the special subtypes of
Localized Trimethoprim-sulfamethoxazole generalized FDE, GBFDE, and mucosal FDE.
and NSAIDs
Oral mucosal Naproxen and trimethoprim-
sulfamethoxazole 6.1 Differential Diagnosis
Female genital mucosal NSAIDs
Male genital mucosal Tetracyclines and trimethoprim- FDE resembles erythema multiforme, both clinically and
sulfamethoxazole
histopathologically [2]; however, FDE tends to be more
Non-pigmenting Pseudoephedrine
localized, appears as oval-shaped patches, and does not
Generalized bullous Antibiotics (metronidazole,
trimethoprim-sulfamethoxazole, contain the characteristic edematous halo associated with
rifampicin) and analgesics erythema multiforme or target lesions. Histopathologi-
(ibuprofen) cally, erythema multiforme, SJS, TEN, and FDE share
NSAIDs non-steroidal anti-inflammatory drugs
similar epidermal changes; however, localized pigmenting
FDE shows greater psoriasiform epidermal hyperplasia,
more spongiosis, and prominent melanophage involve-
FDE can sometimes be confirmed using oral challenge or ment [43]. Localized contact dermatitis, phytophoderma-
patch testing [29]. Oral challenge has been the gold standard titis, and lichen planus can also resemble erythematous
of diagnosis but is now usually contraindicated due to the plaques of FDE [2, 45]. HSV can be mistaken for FDE,
risk of widespread FDE or GBFDE [5, 38–40]. The oral especially when mucosal membranes are involved or a
challenge test involves orally administering subtherapeutic reaction occurs at the site of a prior HSV lesion.
doses of the suspected drug and assessing for a reaction [2].
One-tenth of the dose, at least 2 weeks after the last recur-
rence, has been the standard recommendation [9]. In a large 7 Special Subtypes
study of 450 Pakistani cases, common adverse effects associ-
ated with the oral challenge test included pruritus, fever, and Mucosal FDEs target the oral and genital mucosa. Unlike
generalized urticaria [16]. classical FDE, mucosal FDE commonly has bullous or
Patch testing is the best confirmation method and is erosive lesions without residual hyperpigmentation [38].
methodologically easier and safer than oral challenge [2]. Mucosal FDEs usually do have associated cutaneous find-
Patch testing is conducted on a hyperpigmented site in ings. Oral mucosal lesions may occur on the tongue and
an area of previous FDE, utilizing normal skin as a con- hard palate. Naproxen and trimethoprim-sulfamethoxazole
trol. However, the sensitivity of patch testing depends on are the most commonly implicated medications [2]. The
the reactivity of resident memory CD8+ T cells and drug differential of isolated oral FDE includes herpes simplex
permeability through the skin [37]. Patch testing is inef- labialis, pemphigus vulgaris, aphthous stomatitis, and
fective in patients without visible lesions as it relies on Behçet’s disease [27, 28]. Male genital FDE most com-
the resident memory CD8+ T cells that lie primarily in monly affects the glans penis, likely caused by tetracy-
the hyperpigmented epidermis. Patch testing is a sensi- clines or trimethoprim-sulfamethoxazole [35, 36], while
tive marker for NSAIDs, but not for antibiotics [2], and the vulva is affected in female patients, with NSAIDs
is therefore not considered a reliable testing method [37]. being the commonly linked [2].
Patch testing should be performed a few weeks after the The non-pigmenting FDE (NPFDE) is a rare subtype, typ-
lesions resolve to avoid a false negative result due to a ically caused by pseudoephedrine [36, 40]. NPFDE presents
refractory period. similarly to localized pigmenting FDE; however, NPFDE
An uncommon method of FDE confirmation is per- does not have residual hyperpigmentation after resolution
formed using the lymphocyte transformation test (LTT), due to the lack of hydropic degeneration and pigment incon-
which aims to measure a sensitized T-cell reaction in tinence [40]. NPFDE also tends to have more symmetrical,
response to the in vitro addition of the drug [41]. LTT is well-circumscribed lesions than localized pigmenting FDE.
primarily used in confirming drug hypersensitivity reac- Generalized FDE is similar to localized pigmenting
tions, where it has a sensitivity of 60–70%. LTT has not FDE but presents with multiple bilateral cutaneous mac-
been shown to be an effective confirmatory test for FDE; ules. Generalized FDE spares the mucosa and typically
however, selected reports have shown potential for LTT, occurs on the trunk and extremities.
as it has been diagnostic in specific cases of FDE caused
by allopurinol or fluconazole [41, 42].
Fixed Drug Eruptions: An Update, Emphasizing the Potentially Lethal Generalized Bullous Fixed Drug Eruption

7.1 Generalized Bullous Fixed Drug Eruption

Recurrent FDE is associated with an increased amount of

inflammation and hyperpigmentation with each occurrence
[33, 46, 47]. Recurrence increases the risk for GBFDE, a
rare reaction with cutaneous bullae and vesicles (Fig. 2)
[5, 33]. Despite the generally accepted idea that GBFDE
has little, if any, systemic involvement and a substan-
tially better prognosis than SJS or TEN, GBFDE is still
potentially life-threatening, as documented in a recent
study with a surprisingly high 22% mortality rate among
elderly patients (13 of 58 died) [3]. One tends to see well-
demarcated red-brown patches with overlying bullae on a
background of diffuse hyperpigmentation. This mortality
rate was only slightly lower with GBFDE than for those Fig. 2  Generalized bullous fixed drug eruption, a rare reaction with
with SJS/TEN despite GBFDE having much less or no cutaneous bullae and vesicles
mucosal and visceral involvement (Table 3). These two
groups did not differ in other preselected criteria for sever-
regulatory T cells, and fewer intraepidermal CD56-posi-
ity. GBFDE is defined by the involvement of at least three
tive cells.
of six separated body areas, including the head and neck,
trunk, upper limbs, lower limbs, and genital area [8, 48].
Since most cases of GBFDE involve < 10% of the skin,
it commonly resembles SJS [5]. GBFDE is suggested
8 Treatment
when a patient presents with a history of similar previous
The primary treatment of FDE is removal of the causative
episodes, an onset of 30 min to 1 day after drug inges-
drug, the identification of which can at times be challeng-
tion, and lack or minimal mucosal involvement [5, 33, 34].
ing [56]. Patients should be counseled to avoid the drug
SJS/TEN usually occurs 1–4 weeks after drug ingestion
and be offered a list of cross-reacting medications. Medi-
and almost always involves the mucous membranes; SJS/
cal management is symptomatic to relieve pruritus or pain
TEN patients may have more severe systemic symptoms
[11]. For cutaneous pruritus, medium or high-dose topical
such as fevers and chills without a history of prior similar
corticosteroids or oral ­H1 antihistamines may be employed
episodes [5].
[10]. Mild oral lesions can usually be managed with vis-
An evaluation of a skin biopsy specimen is the pre-
cous lidocaine, topical corticosteroids, or calcium carbon-
ferred confirmation method (Table 4). GBFDE may also
ate. For those with severe oral involvement, hospitaliza-
clinically resemble staphylococcal scalded skin syndrome,
tion and feeding support may be required. In patients with
pseudoporphyria, and vancomycin-induced linear immu-
erosive genital FDE, zinc oxide paste may be provided to
noglobulin (Ig) A bullous dermatosis [48–54], but these
reduce irritation and the risk of infection.
disorders are separable histologically. GBFDE shows
The primary treatment for generalized and GBFDE is
increased inflammation with eosinophils, fewer necrotic
removal of the causative drug, along with supportive care.
keratinocytes, and more melanin-containing dermal mac-
Moderate-dose oral corticosteroids have not been shown
rophages compared with SJS/TEN [8, 48]. Nevertheless,
to be effective but are often administered [49]. Identifica-
GBFDE may have full-thickness epidermal necrosis,
tion of GBFDE affects the level of patient management,
which histologically strongly resembles and may be almost
with those mislabeled as SJS/TEN more likely to receive
indistinguishable from SJS and TEN [3, 33, 34, 47]. In that
a higher level of care [33]. Use of cyclosporine has been
case, potentially valuable distinctions may be serum gran-
advocated based on favorable responses in a few patients
ulysin levels and the number of intraepidermal granuly-
[57, 58]. Relative to SJS/TEN, GBFDE has been consid-
sin-expressing cells, which were found to be much lower
ered to have a better prognosis and has the potential to
than in SJS/TEN [8]. Granulysin, a lipid-binding protein,
be managed without hospitalization in mild cases [33].
induces apoptosis in a mechanism involving caspases and
However, with mortality at 22% among elderly patients in
other pathways, and may be elevated sera from patients
one series [5], we believe that intensive care and possible
with SJS/TEN [55]. Rapid immunochromatographic test-
admission to a burns unit should be considered in severe
ing for serum granulysin may be useful for the predic-
cases.
tion of SJS and TEN. Furthermore, GBFDE is associated
with more dermal CD4-positive cells, including Foxp31
 S. Patel et al.

Table 3  Generalized bullous fixed drug eruption versus Stevens–Johnson syndrome/toxic epidermal necrolysis overlapping characteristics

Overlapping characteristics GBFDE SJS/TEN

Onset 1–24 h 1–4 weeks

Mucosal involvement Little or none Major mucosal component
Hyperpigmentation Hyperpigmentation marked/diffuse Little or no hyperpigmentation
Adjacent skin normal Adjacent skin affected
Systemic involvement Little or none Major involvement
Mortality Lower mortality Higher mortality
Serum granulysin Low levels Higher levels

GBFDE generalized bullous fixed drug eruption, SJS Stevens–Johnson syndrome, TEN toxic epidermal necrolysis

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