23
Dermatologic Drug
Reactions and Common
Skin Conditions
Rebecca M. Law and David T.S. Law
KEY CONCEPTS
1 The skin is the largest organ of the human body. It performs
many vital functions such as (a) protecting the body
against injury, physical agents, and ultraviolet radiation;
(b) regulating body temperature; (c) preventing dehydration,
thus helping to maintain fluid balance; (d) acting as a sense
organ; and (e) acting as an outpost for immune surveillance.
Skin also has a role in vitamin D production and absorption.
2 Age-related factors affect the epidermis and dermis.
Pediatric skin is thinner and better hydrated, which enhances
topical drug absorption and potential drug toxicities. Elderly
skin is drier, thinner, and more friable, which may predispose
to external insults.
3 Patients presenting with a skin condition should be
interviewed thoroughly regarding signs and symptoms,
urgency, other subjective complaints, and medication
history. The skin eruption should be carefully assessed
to help distinguish between a disease condition and a
drug-induced skin reaction.
4 Drug-induced skin reactions can be irritant or allergic in nature.
5 Allergic drug reactions can be classified into exanthematous,
urticarial, blistering, and pustular eruptions. Exanthematous
reactions include maculopapular rashes and drug
hypersensitivity syndrome. Urticarial reactions include urticaria,
angioedema, and serum sickness-like reactions. Blistering
reactions include fixed drug eruptions, Stevens-Johnson’s
syndrome, and toxic epidermal necrolysis. Pustular eruptions
include acneiform drug reactions and acute generalized
exanthematous pustulosis. Other drug-induced skin reactions
include hyperpigmentation and photosensitivity.
6 Not all skin reactions are drug induced.
7 Contact dermatitis is a common skin disorder caused either
by an irritant or an allergic sensitizer.
8 The first goals of therapy in the management of contact
dermatitis involve identification, withdrawal, and avoidance
of the offending agent. A thorough history, including work
history, must be carefully reviewed for potential contactants.
9 Other goals of therapy for contact dermatitis include
providing symptomatic relief, implementing preventative
measures, and providing coping strategies and other
information for patients and caregivers.
10 Diaper dermatitis is most often seen in infants, although the
condition may also be seen in older adults who wear diapers
for incontinence. Management includes frequent diaper
changes, air drying, gentle cleansing, and using barriers.
11 Skin cancers include squamous cell carcinoma, basal cell
carcinoma, and malignant melanoma.
Copyright © 2014 McGraw-Hill Education. All rights reserved.
e|CHAPTER
INTRODUCTION
1. 1 Skin is an essential part of the body. Although it is not
commonly thought of as such, skin is an organ. In fact, it
is the human body’s largest organ, with an average surface
area of about 1.8 m2.1 The organ system that includes the
skin is known as the integumentary system.
2. The human skin consists of an outer epidermis and an inner
dermis. The epidermis primarily provides protection from
the environment and performs a critical barrier function—
keeping in water and other vital substances and keeping out
foreign elements. The dermis is a connective tissue layer
that primarily provides resiliency and support for various
skin structures and appendages such as sweat glands, seba-
ceous glands, hair, and nails.
3. Because the skin surface is such a visible part of the
body, changes that are slow or subtle often go unnoticed.
Slowly enlarging and evolving moles or dry skin condi-
tions can go undetected even though such changes can be
life threatening in some cases (e.g., malignancy). Health
professionals who have direct contact with patients should
be able to distinguish between common self-treatable skin
lesions and common skin lesions that must be seen and
treated professionally, such as melanoma and squamous
cell carcinoma.
4. Skin infections and infestations are not covered in this
chapter but are discussed in Chapter 88. Acne, psoriasis, and
atopic dermatitis are discussed in Chapters 77 to 79.
STRUCTURE AND
FUNCTIONS OF THE SKIN
The integumentary system comprises the epidermis and dermis.
The epidermis, which is derived from ectoderm, is further divided
into four layers: stratum basale (basal layer), stratum spinosum
(prickle cell layer), stratum granulosum (granular layer), and stra-
tum corneum (horny layer). The stratum corneum is the outermost
layer of skin and primarily is responsible for the barrier function.
The epidermis is thick on the palms and soles and thin on other
parts of the body, with some variations. For example, the palms
and soles contain sweat glands but lack sebaceous glands, which
are found almost everywhere else in the skin, with the highest
concentration on the face and trunk areas. Sebaceous glands and
small hair follicles together form pilosebaceous units, which orig-
inate in the dermis and have follicular ducts extending through the
epidermis to the skin surface. Sebaceous glands produce sebum,
347
348
a lipid-like substance.1 (Increased production by sebaceous glands
is partially responsible for acne.2)
Skin cells are called keratinocytes. They produce keratin, a
protein network that gives epithelial cells resilience to mechani-
cal stress. Keratinocytes begin at the stratum basale as box-shaped
basal cells. As the cells mature, they migrate toward the skin surface,
elongating and flattening as they divide and differentiate, ending as
corneocytes in the stratum corneum. Corneocytes are flattened kera-
tinocytes containing keratin tonofibrils (filaments composed of ker-
SECTION
atin and keratohyalin granules). They are often termed dead because
they do not contain nuclei and are not capable of mitosis. Each cell
covers a much larger surface area as a corneocyte compared with
its basal origin. Overlapping corneocytes provide for the skin bar-
rier.1 (Note that abnormal keratinocyte activity accounts for some
2 skin diseases. For example, psoriasis is associated with increased
keratinocyte cell turnover, and acne is partially caused by increased
keratin production.2)
Organ-Specific Function Tests and Drug-Induced Diseases
Melanocytes are pigment-producing cells in the stratum
basale. They produce melanin, a yellow–brown/black pigment.
Melanin granules are spread out into a protective layer in the stra-
tum corneum, reducing ultraviolet (UV) penetration into the skin.
UV radiation causes human skin to increase both melanin produc-
tion and keratinocyte proliferation as a protective effort.1
The skin surface is normally covered with a hydrolipid film
composed of sweat, oils (sebaceous lipids and free fatty acids),
corneocytes, protein decomposition products, and transepidermal
water. Some of these are natural moisturizing factors that help the
skin retain water. Thus, the hydrolipid film is a permeability barrier
that keeps the skin supple.1
Because of the presence of lactic acid and various amino acids
from sweat, free fatty acids from sebum, and amino acids from shed-
ding corneocytes, human skin is normally acidic, generally with
a pH of 5.5 to 6. Bacteria thrive in an alkaline environment. As a
result, the skin also functions as a protective acid mantle against
invasion by pathogenic bacteria and fungi.1
The dermis, which is derived from mesoderm, is a much thicker
layer that contains nerve endings and blood vessels. It is made up
of collagen and elastin, which provide support for various skin
structures and appendages. Eccrine (sweat) glands, hair follicles,
sebaceous glands, and arrector pili muscles originate in the dermis.
Subcutaneous tissue (adipose tissue with nerves and blood vessels)
lies beneath the dermis.1
Skin is also involved in regulating body temperature, prevent-
ing dehydration, acting as a sense organ, and playing a role in vita-
min D production and absorption.
Age-Related Changes and Other
Skin-Related Considerations
2 Age-related changes in the structure and functions of the epider-
mis and dermis are important.
In general, pediatric skin contains more water and is thin-
ner, allowing for enhanced topical drug absorption in both the
rate and amount of drug absorbed. This increases the potential
for drug toxicities. Increased topical absorption and toxicity have
been reported with the use of rubbing alcohol, boric acid powders,
and hexachlorophene emulsions and soaps in infants and young
children. Even drugs that are not normally used topically may be
systemically absorbed. For example, a theophylline gel (17 mg
spread over an area 2 cm in diameter) applied to the abdomens
of premature infants produced therapeutic serum theophylline
concentrations.3
Well-hydrated, unbroken skin provides maximal protection
against microbial invaders. Aged skin tends to be drier, thinner,
and more friable, which increases susceptibility to external insults.
Copyright © 2014 McGraw-Hill Education. All rights reserved.
In addition, the healing time after skin injury may be prolonged in
aged skin. UV radiation is associated with accelerated skin aging
and skin cancers (e.g., malignant melanoma, basal cell carcinoma).
Skin should be constantly protected from UV damage by the use
of sunscreens that block both UVA and UVB, with a sun protec-
tion factor (SPF) of at least 15, preferably 30 or higher. Sunscreens
should be applied 20 minutes before sun exposure and reapplied
after sweating or swimming.
It should not be surprising that skin health is related to over-
all health. Exercise and adequate sleep along with maintaining
a healthy, well-balanced diet are key factors. Ample daily fluid
intake and regular use of moisturizers are important for skin
hydration. Malnourishment can cause a patient to become immu-
nocompromised, which may adversely affect the ability of the
skin to act as a barrier. Nutritional deficiencies can cause skin
problems, including dry skin. Specific food allergies can cause
skin reactions (e.g., rashes, hives). Patients with atopic dermatitis
often have multiple food sensitivities and allergies, resulting in
hives and skin rashes and/or systemic manifestations. For skin
cleansing, soapless cleansers may be preferable to soap because
they may cause less skin irritation. Repeated and frequent expo-
sure to soap or other cleansers that cause cumulative irritation
(e.g., with surfactants and emulsifiers) can result in irritant con-
tact dermatitis.
PATIENT ASSESSMENT
When patients present with dermatologic disorders, a standard
approach to assessment should be used. This is especially impor-
tant for pharmacists who must decide whether to recommend non-
prescription therapies or refer patients to medical practitioners, and
to nurse practitioners and physician assistants, who must evaluate
symptoms and decide whether a supervising physician or derma-
tologist should be involved.
Patient History: Questions to Ask
3 With all skin conditions, including possible drug-induced reac-
tions, a comprehensive patient history is important. These include
questioning and physically assessing the patient to obtain the fol-
lowing information:
1. Signs and Symptoms
a. Onset. When did the lesions first appear? It is important
to distinguish between an acute and a chronic condition.
b. Progression. Are the lesions improving or worsening or
spreading? If lesions are worsening, how quickly are the
lesions becoming more severe or widespread?
c. Timeframe. Did the occurrence of skin lesions correlate
temporally with the use of any medications? This may
help to distinguish between a drug-induced condition and
a disease-related condition.
d. Location(s) and description of the lesions. Specific
details about where the lesions occur and what they
look like will help to identify the type of skin condi-
tion. For example, plaque psoriasis is usually diagnosed
in this manner and not through laboratory means. How-
ever, for conditions such as skin cancers,4 a skin biopsy
may be needed to establish a definitive histopathologic
diagnosis.
e. Presenting symptoms. Is there pruritus? Are the lesions
painful? Pruritus is a common symptom for various skin
conditions (e.g., atopic dermatitis, allergic and irritant
contact dermatitis, psoriasis, bullous pemphigoid, lichen
planus, pityriasis rosea) as well as systemic conditions

(e.g., chronic renal failure, hepatobiliary diseases, malig-
nancy, parasitosis) and drug reactions.5
f. Previous occurrence. Has the patient presented with sim-
ilar lesions before? If so, that may be extremely helpful
in establishing a diagnosis and deciding on a course of
treatment.
2. Urgency
349
be categorized as macules (eFig. 23-1), papules (eFig. 23-2),
nodules (eFig. 23-3), blisters (eFig. 23-4), or plaque and lichenifi-
cation (eFig. 23-5).
However, some skin conditions may cause more than one
type of lesion. For example, patients with acne vulgaris may pres-
ent with macules, papules, nodules, or a combination of these.
Another example is psoriasis—the most common type is plaque

e|CHAPTER  
a. Severity, area, and extent of skin involvement. If a large psoriasis noted by discrete, well-defined plaques; however, there
area of the body is involved or if signs of severe dis- are other types of psoriasis such as guttate or erythrodermic with
ease such as skin sloughing or hives (and in some cases,
if the face is involved) are present, more urgent treatment
may be  required, and an immediate referral to a physi-
cian would be appropriate if the patient was first seen by
another health professional such as a pharmacist. In some
cases, a dermatology consult or an emergency hospital
admission would be needed.
23
b. Signs of a systemic or generalized reaction or disease

Dermatologic Drug R
condition. Is there a fever? If there is any indication that
the patient has a systemic disease condition, whether
drug induced or disease related, and particularly if the
patient is febrile, this generally indicates a more urgent
situation requiring immediate medical attention. For
example, erythrodermic psoriasis is distinguishable from
plaque psoriasis and would require immediate medical
care. (See Chap. 78 for details about psoriasis.)

­ eactions and Common Skin Conditions

3. Medication History
a. Is the patient using any medication that could poten-
tially cause the observed skin condition? Temporal cor-
relation with medication use is important in evaluating
for  a  potential drug-induced skin reaction. Although A
possible, drug-induced skin reactions do not generally
begin after the offending agent has already been discon-
tinued. However, for some medications it is possible for
the patient to have used the offending drug for months to
years before a skin reaction occurs.
b. If the patient had presented with similar skin lesions
previously, was the patient taking the same or similar
medication(s) at that time? If so, did the skin lesions
improve after drug discontinuation?
4. Differential Diagnosis
a. Is this a disease-related problem, a drug-induced prob-
lem, or a food allergy? What other possible diseases
or conditions might present in this manner? It is not
possible to provide a thorough discussion about dif-
ferential diagnoses of skin lesions in this chapter. The
reader should be aware that there are differential diag-
noses for each type of skin lesion. For example, besides
drugs (e.g., antimalarials, cyclophosphamide, clofazi-
mine, busulfan, 5-fluorouracil), other causes of hyper-
pigmentation include Wilson’s disease, malabsorption
syndromes, lymphomas, porphyria cutanea tarda, neu-
B
rofibromatosis, Albright’s syndrome, physical trauma,
and others.6 Besides drugs (e.g., aspirin, nonsteroidal
antiinflammatory drugs [NSAIDs], penicillins, sulfon- eFIGURE 23-1  Macules are circumscribed, flat lesions of any
amides, opiates), other causes of urticaria include infec- shape or size that differ from surrounding skin because of
tion (viral, bacterial, fungal, parasitic), insect stings, their color. A. Macules may be the result of hyperpigmentation
foods and food additives, cold, pressure, dermatogra- (a), hypopigmentation, dermal pigmentation (b), vascular
phism, cholinergic stimulation (exercise, hot shower, abnormalities, capillary dilation (erythema) (c), or purpura (d).
emotional stress), hereditary C1 inhibitor deficiency, B. The clinical appearance of a drug reaction that has produced
and others.7 an eruption consisting of multiple, well-defined red macules of
varying size that blanch upon pressure (diascopy) and are thus
a result of inflammatory vasodilation. (Reprinted with permission from
Lesion Assessment Stewart MI, Bernhard JD, Cropley TG, Fitzpatrick TB. The structure of skin lesions and
As discussed briefly in the following section, the appearance of fundamentals of diagnosis. In: Freedberg IM, Eisen AZ, Wolff K, et al., eds. Fitzpatrick’s
skin lesions can give some clues as to their causes. Lesions may Dermatology in General Medicine, 6th ed. New York: McGraw-Hill, 2003:18.)

Copyright © 2014 McGraw-Hill Education. All rights reserved.

350
SECTION
  

2
A
Organ-Specific Function Tests and Drug-Induced Diseases

eFIGURE 23-2  Papules are small, solid, elevated lesions that are
usually less than 1 cm in diameter. The major portion of a papule
projects above the plane of the surrounding skin. A. Papules
may result, for example, from metabolic deposits in the
dermis (a), from localized dermal cellular infiltrates (b), and
from localized hyperplasia of cellular elements in the dermis
and epidermis (c). Papules with scaling are referred to as
papulosquamous lesions, as in psoriasis (see Chap. 78). B. Clinical
examples of papules. The examples are two well-defined and
dome-shaped papules of firm consistency and brownish color,
which are dermal melanocytic nevi. C. Multiple, well-defined
and coalescing papules of varying size are seen. Their violaceous
color, glistening surface, and flat tops are characteristic of lichen
planus. (Reprinted with permission from Stewart MI, Bernhard JD, Cropley TG,
Fitzpatrick TB. The structure of skin lesions and fundamentals of diagnosis. In: Freedberg
IM, Eisen AZ, Wolff K, et al., eds. Fitzpatrick’s Dermatology in General Medicine, 6th ed.
New York: McGraw-Hill, 2003:18.)
C
eFIGURE 23-3  Nodules are palpable, solid, round, or ellipsoidal
lesions. Depth of involvement or substantive palpability, rather
than diameter, differentiates a nodule from a papule. A. Nodules
may extend into the dermis or subcutaneous tissue (a) or be
located in the epidermis (b). B. A well-defined, firm nodule with
a smooth and glistening surface through which telangiectasia
(dilated capillaries) can be seen; there is central crusting
indicating tissue breakdown and thus incipient ulceration
(nodular basal cell carcinoma). C. Multiple nodules of varying size
can be seen (melanoma metastases). (Reprinted with permission from
Stewart MI, Bernhard JD, Cropley TG, Fitzpatrick TB. The structure of skin lesions and
fundamentals of diagnosis. In: Freedberg IM, Eisen AZ, Wolff K, et al., eds. Fitzpatrick’s
Dermatology in General Medicine, 6th ed. New York: McGraw-Hill, 2003:18.)

Copyright © 2014 McGraw-Hill Education. All rights reserved.

 351

e|CHAPTER  
A B 23

Dermatologic Drug R
eFIGURE 23-4  Vesicles and bullae are the technical terms for blisters. Whereas vesicles are circumscribed lesions that contain fluids,
bullae are vesicles that are larger than 0.5 cm in diameter. A. Whereas subcorneal vesicles (a) result from fluid accumulation just below
the stratum corneum, spongiotic vesicles (b) result from intercellular edema. B. Multiple translucent subcorneal vesicles are extremely
fragile, collapse easily, and thus lead to crusting (arrows). These lesions are staphylococcal impetigo. (Reprinted with permission from Stewart MI,
Bernhard JD, Cropley TG, Fitzpatrick TB. The structure of skin lesions and fundamentals of diagnosis. In: Freedberg IM, Eisen AZ, Wolff K, et al., eds. Fitzpatrick’s Dermatology in General
Medicine, 6th ed. New York: McGraw-Hill, 2003:18.)

­ eactions and Common Skin Conditions

A

eFIGURE 23-5  A. Plaque is a mesa-like elevation that occupies

a relatively large surface area relative to its height above the skin
surface. B. Well-defined, reddish, scaling plaques can coalesce
to cover large areas of the back and buttocks, with some
regression in the center as is common in psoriasis (see Chap. 78).
C. Lichenification, a thickening of the skin and accentuation of
skin, can result from repeated rubbing. It develops frequently
in patients with atopy and occurs in eczematous dermatitis
and other conditions associated with pruritus. Lesions of
lichenification are not as well defined as most plaques and
often show signs of scratching, such as excoriations and crusts.
(Reprinted with permission from Stewart MI, Bernhard JD, Cropley TG, Fitzpatrick TB.
The structure of skin lesions and fundamentals of diagnosis. In: Freedberg IM, Eisen AZ,
Wolff K, et al., eds. Fitzpatrick’s Dermatology in General Medicine, 6th ed. New York:
McGraw-Hill, 2003:18, and Garg Amit, Levin Nikki A, Bernhard Jeffrey D. Structure of
Skin Lesions and Fundamentals of Clinical Diagnosis. In: Wolff K, Goldsmith LA, Katz

B SI, Gilchrest B, Paller AS, Leffell DJ, eds. Fitzpatrick’s Dermatology in General Medicine,
7th ed. http://www.accessmedicine.com/content.aspx?aID=2965385).

Copyright © 2014 McGraw-Hill Education. All rights reserved.

352
varying lesions. Wheals developing as a result of a drug reaction
may present as papules or plaques. In contrast, some skin condi-
tions present with a characteristic lesion. For example, lichenifica-
tion is a thickening of the skin usually caused by chronic rubbing
or scratching and can be seen in patients with chronic pruritus or
atopic dermatitis.
Drug-Induced Skin Reactions
4 Drug-induced skin reactions can be irritant or allergic in origin.
SECTION
Irritant reactions are localized. Examples include chemical
vaginitis, such as those resulting from vaginal douches, spermicides,
and imidazoles; and vesication, produced by drug extravasation, as
with agents such as anthracyclines.
Allergic reactions depend on inducing an immune response
2 from the host; thus, the reaction may be systemic rather than limited
to skin manifestations.
5 Allergic drug reactions can be classified as exanthematous,
Organ-Specific Function Tests and Drug-Induced Diseases
urticarial, blistering, or pustular eruptions (eFig. 23-6).8 Skin reac-
tions accompanied by fever are generally more serious systemic
disorders. These may be life threatening in some cases, although
afebrile skin reactions are not always minor (e.g., urticaria,
angioedema).
Maculopapular skin reaction is an afebrile exanthematous
eruption that is considered the most commonly encountered aller-
gic skin reaction. Signs and symptoms of a maculopapular skin
rash include erythematous macules and papules that may be pru-
ritic. No fever, blisters, or pustules are present. The lesions usually
begin within 7 to 10 days after starting the offending medication
and generally resolve within 7 to 14 days after drug discontinu-
ation. However, in a previously sensitized patient, the onset may
be earlier (within 2–3 days). The lesions may spread and become
confluent. Usual drug culprits include penicillins, cephalosporins,
sulfonamides, and some anticonvulsant medications.
Drug hypersensitivity syndrome is an exanthematous eruption
accompanied by fever, lymphadenopathy, and multiorgan involve-
ment (including the kidneys, liver, lung, bone marrow, heart, and
brain). Signs and symptoms usually begin 1 to 4 weeks after
starting the offending drug, and the reaction may be fatal if not
promptly treated.
Types of cutaneous drug eruptions
Exanthematous Urticarial
Fever Fever
No Yes No Yes
Simple Hypersensitivity Urticaria/ Serum
maculopapular syndrome angioedema sickness-like
eruption reaction
eFIGURE 23-6  Types of cutaneous drug eruptions. (SJS, Stevens-Johnson’s syndrome; TEN, toxic epidermal necrolysis; AGEP, acute
generalized exanthematous pustulosis.) (Adapted from Knowles S. Drug-induced skin reactions. In: Patient Self-Care (PSC). Ontario, Canada: Canadian Pharmacists
Association, 2002.)
Copyright © 2014 McGraw-Hill Education. All rights reserved.
This condition is also known as drug reaction with eosinophilia
and systemic symptoms. It is commonly referred to by the acronym
DRESS.
Usual drug culprits include allopurinol, sulfonamides, some
anticonvulsants (barbiturates, phenytoin, carbamazepine, lamotrig-
ine), and dapsone. For patients taking allopurinol, several factors
increase the risk of serious skin reactions: renal impairment, hyper-
tension, and use of thiazide diuretics or excessive allopurinol doses
(i.e., not dose adjusted for renal impairment).9,10
Urticaria and angioedema are simple eruptions that are caused
by drugs in about 5% to 10% of cases. Other causes include foods
(likely the most significant offenders) and physical factors such as
cold or pressure, infections, and exposure to latex. The condition
may also be idiopathic.
Urticaria has been called the cutaneous manifestation of
anaphylaxis. It is an IgE-related (type 1) allergic reaction that
may be the first symptom of an emerging anaphylactic reaction.
It is characterized by hives, extremely pruritic red raised wheals;
angioedema; and mucous membrane swelling. These symptoms
typically occur within minutes (anaphylactic) to hours (anaphy-
lactoid) (eFig. 23-7). Individual lesions typically last less than
24 hours, but new lesions may continually develop. Offending
drugs include penicillins and related antibiotics, aspirin, sulfon-
amides, x-ray contrast media, opiates, and others. Latex allergy
is linked to the natural rubber latex (NRL) proteins, which bind
with human IgE and result in contact urticaria, asthma, and ana-
phylaxis.11 Aside from latex gloves and medical products, other
sources of NRL proteins include rubber insoles of shoes, bal-
loons, inflatable mattresses, and poinsettia plants.
Serum sickness–like reactions are complex urticarial eruptions
presenting with fever, rash (usually urticarial), and arthralgias, usu-
ally within 1 to 3 weeks after starting the offending drug. This is
not a true serum sickness, and the patient does not have immune
complex formation, vasculitis, or renal lesions.8
Fixed drug eruptions are simple eruptions presenting as pru-
ritic, red, raised lesions that may blister. Symptoms can include
burning or stinging. Lesions may evolve into plaques.8 These so-
called “fixed” drug eruptions recur in the same area each time the
offending drug is given. Lesions appear within minutes to days and
Blistering Pustular
Fever Fever
No Yes No Yes
Fixed drug SJS, TEN Acneiform AGEP
eruption
 353

e|CHAPTER  
23

Dermatologic Drug R
A B C

eFIGURE 23-7  A. Wheals are rounded or flat-topped papules or plaques that are characteristically evanescent, disappearing within
hours. An eruption consisting of wheals is termed urticaria and usually itches. B. Wheals may be tiny papules 3 to 4 mm in diameter, as
in cholinergic urticaria. C. Alternatively, wheals may present as large, coalescing plaques, as in allergic reactions to penicillin or other
drugs or alimentary allergens. (Reprinted with permission from Stewart MI, Bernhard JD, Cropley TG, Fitzpatrick TB. The structure of skin lesions and fundamentals of
diagnosis. In: Freedberg IM, Eisen AZ, Wolff K, et al., eds. Fitzpatrick’s Dermatology in General Medicine, 6th ed. New York: McGraw-Hill, 2003:18.)

­ eactions and Common Skin Conditions

disappear within days, leaving hyperpigmented skin for months
(eFig. 23-8). Usual drug culprits include tetracyclines, barbitu-
rates, sulfonamides, codeine, phenolphthalein, acetaminophen, and
NSAIDs.
Stevens-Johnson’s syndrome (SJS) and toxic epidermal necrol-
ysis (TEN) are complex blistering eruptions that, together with ery-
thema multiforme (EM), are known as acute bullous disorders. They
are histologically similar and have been considered part of an “EM
spectrum of diseases.”12 EM may be considered a dermatologic dis-
order not associated with a drug reaction, whereas SJS and TEN are
immune complex or cell-mediated allergic responses to offending
agents, including drugs.12,13 Because of their histologic similarity,
SJS and TEN have been considered either distinct disorders or pro-
gressions of the same disorder based on the percentage of skin area
involved, and these two entities are often discussed together.12
SJS and TEN are rare, severe, and life-threatening condi-
tions with an acute onset (within 7–14 days of drug exposure).
Patients present with generalized tender or painful bullous forma-
tion with accompanying systemic signs and symptoms, including
fever, headache, and respiratory symptoms, that rapidly deteriorate.
Lesions show rapid confluence and spread, resulting in extensive
epidermal detachment and sloughing.12 This may result in marked
loss of fluids; drop in blood pressure; electrolyte imbalances; and
secondary infections, including Staphylococcus epidermidis and
­methicillin-resistant Staphylococcus aureus (MRSA). Usual drug
culprits include sulfonamides, penicillins, some anticonvulsants
(hydantoins, carbamazepine, barbiturates, lamotrigine), NSAIDs,
and allopurinol. In children, a pooled analysis using data from two
multicenter international case–control studies confirmed the follow-
ing drug risk factors for SJS and TEN: antiinfective sulfonamides,
phenobarbital, carbamazepine, and lamotrigine. In addition, acet-
aminophen use is suspected to increase the risk.13 However, cases eFIGURE 23-8  Hyperpigmentation. This patient exhibits a
in children only represented 10% of the population in both studies striking amiodarone-induced, slate-gray pigmentation of the face.
because the incidence of SJS and TEN increases with age.13 The blue color (ceruloderma) is caused by deposition of a brown
Acneiform drug reactions are simple pustular eruptions pigment in the dermis contained in macrophages and endothelial
caused by medications that induce acne (whiteheads or black- cells. (Reprinted with permission from Ortonne J-P, Bahadoran P, Fitzpatrick TB, et al.
heads). The onset is usually about 1 to 3 weeks. Common drug Hypomelanoses and hypermelanoses. In: Freedberg IM, Eisen AZ, Wolff K, et al., eds.
culprits include corticosteroids, androgenic hormones, some Fitzpatrick’s Dermatology in General Medicine, 6th ed. New York: McGraw-Hill, 2003:876.)

Copyright © 2014 McGraw-Hill Education. All rights reserved.

354
anticonvulsants, isoniazid, and lithium. Topical acne treatments
can be used to manage symptoms if the offending drug cannot be
discontinued or replaced.
Acute generalized exanthematous pustulosis (AGEP) is a com-
plex pustular eruption characterized by acute onset (within days
after starting the offending drug), fever, diffuse erythema, and many
pustules. About 50% of patients have other cutaneous lesions, and
25% may have mucosal erosions. Generalized desquamation occurs
2 weeks later.8 Usual drug culprits include β-lactam antibiotics,
SECTION
macrolides, and calcium channel blockers.
Other Drug-Induced Skin Reactions  Hyperpigmentation of
the skin (eFig. 23-8) may be related to increased melanin (e.g.,
hydantoins), direct deposition (e.g., silver, mercury, tetracyclines,
2 antimalarials), or other mechanisms (some cytotoxic drugs, such as
5-fluorouracil, may cause banding on nails or tracking along veins).
Photosensitivity reactions (eFig. 23-9) may be phototoxic or
photoallergic. Drugs that induce phototoxic reactions absorb UVA
Organ-Specific Function Tests and Drug-Induced Diseases
light, resulting in skin damage. Severity tends to be proportional
to the drug dose. Usual drug culprits include amiodarone, tetracy-
clines, sulfonamides, psoralens, and coal tar.
Drug-induced photoallergic reactions result from UVA trans-
formation of medications into allergens. In this syndrome, skin
damage may occasionally spread beyond sun-exposed skin. These
reactions require sensitization to the offending drug and are not dose
related. Usual drug culprits include sulfonamides, sulfonylureas,
thiazides, NSAIDs, chloroquine, and carbamazepine.
Management and Prevention of a Drug-Induced Skin
­Reaction  6 The first rule of thumb in managing skin reactions
is to remember that not all are drug induced. In clinical practice,
a diagnosis of drug-induced skin reaction is often a diagnosis of
exclusion (i.e., the diagnosis is reached after other possible diag-
noses have been ruled out). Potential foods and other causes have
to be thoroughly investigated, and a detailed patient interview is
important, as discussed earlier. Consistent with the assessment for
any adverse drug reaction, the likelihood of a drug-induced skin
reaction should be categorized as probable, possible, or not prob-
able (unlikely). It may not be possible to categorize a drug-induced
eFIGURE 23-9  Photosensitivity. Severe solar damage of the
face revealing both telangiectasias and actinic keratoses at
different stages in development, including flat, pink macules
and hyperkeratotic papules. (Reprinted with permission from Duncan KO,
Leffell DJ. Epithelial precancerous lesions. In: Freedberg IM, Eisen AZ, Wolff K, et al.,
eds. Fitzpatrick’s Dermatology in General Medicine, 6th ed. New York: McGraw-Hill,
2003:722.)
Copyright © 2014 McGraw-Hill Education. All rights reserved.
skin reaction as definite because this requires rechallenge with the
potentially offending agent, and this should not be done with most
reactions. Reactions are often unpredictable adverse drug reac-
tions unrelated to the normal pharmacologic effects of the drug.
Fortunately, unpredictable adverse drug reactions (e.g., allergic,
idiosyncratic, carcinogenic) usually affect only a small percentage
of patients.
If a drug-induced skin reaction is suspected, the most impor-
tant treatment in nearly all cases is discontinuing the suspected
drug as quickly as possible and avoiding the use of potential cross-­
sensitizers. In most instances, that is the only specific treatment
required. In severe cases, a short course of systemic corticosteroids
may be needed. In a few instances, it may be possible to continue the
offending drug and “treat through” the reaction8 (e.g., ampicillin-
associated maculopapular skin rash).
The next step is to control symptoms associated with the drug
reaction (e.g., pruritus). Furthermore, any signs or symptoms of a
systemic or generalized reaction may require additional supportive
therapies specific to the severity and type of signs and symptoms
seen. For high fevers, an antipyretic such as acetaminophen is more
appropriate than aspirin or an NSAID because these may exacerbate
skin lesions for some reactions. Depending on the type of skin reac-
tion, the affected skin condition may take days to weeks or months
to resolve.
For patients with life-threatening SJS or TEN, supportive mea-
sures such as maintenance of adequate blood pressure and fluid and
electrolyte balance, use of broad-spectrum antibiotics and vanco-
mycin for secondary infections, and IV immunoglobulin (IVIG)
may all be appropriate. IVIG has been shown to halt disease pro-
gression and enhance recovery for SJS or TEN.12 The use of cor-
ticosteroids for SJS or TEN is somewhat controversial; although
they may curb disease progression, they may also increase the risk
of infection and thus contribute to increased mortality.12 If used,
relatively high initial doses followed by rapid tapering as soon as
disease progression halts is indicated.12 Refer to the Drug-Induced
Skin Reactions case in the Pharmacotherapy Casebook to further
explore management.
Patient education should be provided. Advice to the patient
should include information about the suspected drug and poten-
tial drugs to avoid in the future and which drugs may be used.
Potential cross-sensitizers should be identified. For patients with
photosensitivity reactions, information should be provided about
preventive measures such as the use of sunscreens and sun avoid-
ance (eFig. 23-9). For patients with severe reactions (e.g., anaphy-
laxis), information about MedicAlert programs may be appropriate.
Genetic predisposition has not been established for most drug-
induced reactions, but for severe reactions such as SJS or TEN or
hypersensitivity syndromes, the risk may be higher in first-degree
relatives of affected patients.
COMMON SKIN DISORDERS
Contact Dermatitis
7 Contact dermatitis is defined as an inflammation of the skin
caused by irritants or allergic sensitizers.14 It describes and includes
all skin reactions resulting from direct contact of the skin or mucous
membranes with an exogenous agent, which may be a “foreign”
molecule such as a drug or chemical, UV light, or temperature.14
The skin or mucous membranes may react nonimmunologi-
cally or immunologically to an exogenous agent, resulting in either
an irritant or allergic skin reaction as described earlier. However, the
distinction between an allergic contact dermatitis (ACD) and irritant
contact dermatitis (ICD) has become increasingly blurred14; ICD is
often a diagnosis of exclusion, as in cases when patch test results for
ACD are negative.14

Furthermore, an exogenous dermatitis can be superimposed on
an endogenous skin eruption such as acne.14 Irritant effects may be
considerably enhanced by occlusion. Contact dermatitis must also
be distinguished from atopic dermatitis and other dermatologic con-
ditions such as dyshidrotic dermatitis, lichen simplex dermatitis,
acne rosacea, and other conditions. (See Chap. 79 for a discussion
on atopic dermatitis.)
355
localized, but for ACD, it may extend beyond the borders of the
exposed area of contact, and the reaction may rarely become sys-
temic (e.g., latex allergy).
ICD is generally a multifactorial response involving contact
with a substance that chemically abrades, irritates, or otherwise
damages the skin; cellular damage in ICD occurs via T cells (acti-
vated by irritant or innate mechanisms) releasing proinflammatory

e|CHAPTER  
Contact dermatitis is a common skin problem for which cytokines.14 ACD is the clinical manifestation of contact hypersen-
5.7 million physician visits are made per year.14 Almost any of the sitivity;15 skin allergens tend to be low-molecular-weight molecules
more than 85,000 chemicals in the world environment may be a skin (haptens) that become immunogenic after conjugation with skin
irritant, and more than 3,700 substances have been identified as con-
tact allergens.14 Although all age groups may be affected, ACD is
rare in the first years of life (<10 years), but the rate of occurrence in
older children may exceed that in adults.14
The prevalences of ACD to individual allergens is similar in
children and adults; allergens include nickel, fragrances, Toxicoden-
23
dron (formerly known as Rhus), and rubber chemicals.14 There may

Dermatologic Drug R
be a slight female preponderance, presumably caused by exposure
to specific contactants in jewelry and cosmetics.14
The clinical presentation of contact dermatitis is that of an
eczematous inflammation with erythema, vesicles, papules, crust-
ing, fissuring, or scaling (eFigs. 23-10 and 23-11). The area may
itch, burn, or sting and may be extremely pruritic. The severity may
range from a mild, short-lived condition to a severe and persistent
condition but is rarely life threatening.14 The gross and histologic

­ eactions and Common Skin Conditions

appearances of ICD and ACD are often similar and may be difficult
to distinguish.14 However, the rash or lesion for ICD is frequently

eFIGURE 23-11  A. This patient has allergic chronic dermatitis

eFIGURE 23-10  Acute dermatitis caused by poison ivy. Note
the linear arrangement of lesions typical of phytodermatitis
acquired by inadvertent contact with the plant. The severe
vesiculobullous reaction is typical for urushiol, an oily poisonous
irritant found in Toxicodendron spp. (Reprinted with permission from Belsito
DV. Allergic contact dermatitis. In: Freedberg IM, et al., eds. Fitzpatrick’s Dermatology in
General Medicine, 6th ed. New York: McGraw-Hill, 2003:1167.)
involving the dorsal aspects of the hands and the distal forearms
but with minimal involvement of the palms. In this case, contact
dermatitis is secondary to use of thiuram present in rubber
gloves prescribed for treatment of an irritant hand dermatitis.
B. This patient, a florist, has allergic contact dermatitis as a
consequence of exposure to tuliposide A, the allergen in Peruvian
lilies (Alstroemeria spp.). Note the more prominent involvement
of the palms of the dominant hand. (Reprinted with permission from Belsito
DV. Allergic contact dermatitis. In: Freedberg IM, et al., eds. Fitzpatrick’s Dermatology in
General Medicine, 6th ed. New York: McGraw-Hill, 2003:1167.)

Copyright © 2014 McGraw-Hill Education. All rights reserved.

356
proteins, resulting in a complex series of interactions that involve
antigen-presenting Langerhans or other dendritic cells or CD4+ and
CD8+ T cells,14 including interleukin-17–producing TH17 cells.15
Because ACD is immunologically mediated, the patient may
have tolerated exposure to the offending agent for some time, mak-
ing it more difficult to pinpoint the culprit. Furthermore, the reaction
may continue to develop for some time after the offending agent is
removed.
8 The first goal of therapy in the management of contact
SECTION
dermatitis involves identifying, withdrawal, and avoidance of the
offending agent. A thorough history, including work history, must
be carefully reviewed for potential contactants. Nonwork activities
such as hobbies (e.g., painting, gardening, camping, fishing) may
be additional potential sources of exposure. Patch testing is the gold
2 standard for identifying a contact allergen,14 but it is impractical to
test an unlimited number of allergens.
Standard panels of allergens have been designed and validated
Organ-Specific Function Tests and Drug-Induced Diseases
by collaborative research dermatologic societies; however, these
may account for only 25% to 30% of the most relevant contact aller-
gens.14 Many patients need additional testing, Customized patch
tests may be needed, depending on the patient’s exposure history.14
The most common causes of occupational contact dermati-
tis are chromium (leather exposure); rubber and rubber additives
(gloves); nickel (work tools and metal working); food ingredients,
including intact proteins (for food processing workers); fertilizers
and pesticides (for farmers); and handwashing (disinfectants, irri-
tants in soaps).14
The most common cause of plant dermatitis is Toxicodendron
(Rhus) dermatitis. This genus includes poison ivy, poison oak, and
poison sumac. These plants contain the offender urushiol oil, one of
several oleoresins that are sensitizers and irritants. Urushiol oil is
also found in mango skin, cashew nut oil, ginkgo (female) leaves,
Japanese lacquer, and Indian marking ink.14
Cosmetics and personal hygiene products, such as hair condi-
tioners and shampoos, nail polishes and hardeners, mascara, foun-
dations, antiperspirants and deodorants, and toothpastes, may all
contain potential causes of contact dermatitis. The most important
classes are fragrances, preservatives, formulation excipients, glues,
and sunblocks;14 fragrances are among the most common causes of
contact dermatitis in the United States.14
9 The second goal of therapy in contact dermatitis is to pro-
vide symptomatic relief while decreasing skin lesions. The affected
skin may require supportive treatment such as the use of cold com-
presses to sooth and cleanse the skin or topical corticosteroids to
help resolve the inflammatory process. Compresses are applied to
wet or oozing lesions, removed, remoistened, and reapplied every
few minutes for a 20- to 30-minute period. Calamine lotion or
Burow solution (aluminum acetate) may be soothing.
Topical corticosteroids are considered the mainstay of treat-
ment, and patients with ACD respond better than those with ICD.
Generally, higher potency corticosteroids are used initially, switch-
ing to medium- or lower-potency corticosteroids as the condition
improves.14 Refer to the Topical Corticosteroid Potency Chart in
Chapter 78 (Table 78-2) for specific examples.
Other treatments may be effective. Tacrolimus ointment has
been shown to be effective for nickel-induced ACD in a small ran-
domized placebo-controlled clinical trial.16 Oatmeal baths and oral
first-generation antihistamines may provide relief for excessive itch-
ing. If the affected areas are already dry or hardened (e.g., licheni-
fication), wet dressings applied as soaks (without removal for up to
20–30 minutes) will soften and hydrate the skin (these should not be
used for acute exudating lesions because the skin area may become
macerated, further damaging its barrier function).
The third goal of contact dermatitis therapy is to implement
preventive measures. Prevention involves both primary and second-
ary measures.
Copyright © 2014 McGraw-Hill Education. All rights reserved.
Primary prevention may be done in the workplace by initiating
surveillance programs and educating workers about proper skin care
and chemical exposure.
Secondary prevention involves the use of moisturizers to
prevent dryness and fissuring of the skin. The efficacy of barrier
creams is controversial.14 The damaged skin may need to be pro-
tected against secondary infections, at least until the acute stage
subsides. Debris, produced by oozing, scaling, or crusting, should
not be allowed to accumulate. Rarely, some workers may have per-
sistent dermatitis despite removal of offenders, and a small number
of workers change jobs because of severe recalcitrant occupational
contact dermatitis.14
A final goal of therapy is to provide patient and caregiver infor-
mation and support, helping them to develop coping strategies for
contact dermatitis, as required.
Diaper Dermatitis
10 Diaper dermatitis, more commonly known as diaper rash,
is most often seen in infants, although the condition may also be
seen in older adults who wear diapers for incontinence. It is an
acute inflammatory dermatitis affecting the buttocks, genital, and
perineum regions that are covered by a diaper. The rash is erythema-
tous, and severe rashes may have vesicles or oozing erosions. The
rash may be infected by Candida species and present with confluent
red plaques, papules, and pustules.
Management of diaper dermatitis includes frequent diaper
changes, air drying (removing the diaper for as long as practical),
gentle cleansing (preferably with nonsoap cleansers and lukewarm
water), and the use of barriers. Commercial diaper wipes containing
fragrance or alcohol should be avoided. Zinc oxide has astringent
and absorbent properties and provides an effective barrier. Petrola-
tum also provides a water-impermeable barrier but has no absorbent
ability and may trap moisture.
Patients with candidal (yeast) diaper rash should be treated
with a topical antifungal agent which is then covered by a barrier
product. Imidazoles are the treatment of choice for this type of
diaper rash. After the rash subsides, the antifungal agent should be
stopped and the barrier product continued to prevent recurrence.
In severe inflammatory diaper rashes, a very low-potency topi-
cal corticosteroid (hydrocortisone 0.5% to 1%) may be used for
short periods of 1 to 2 weeks.
Skin Cancers
Actinic keratoses are precursors to the development of skin cancers.
UV radiation (with UVA a greater risk than UVB) may induce abnor-
mal keratinocyte changes. These present as actinic keratoses. These
lesions can develop into squamous cell or basal cell carcinomas.
Actinic keratoses are most often found in elderly fair-skinned
patients and on chronically sun-exposed areas, such as hands, fore-
arms, head, and neck.
11 Skin cancers include squamous cell carcinoma, basal cell
carcinoma, and malignant melanoma.
Squamous cell carcinoma (SCC) is a skin cancer most com-
monly seen in older patients (eFig. 23-12). Risk factors include
fair complexion, prolonged sun exposure, UV radiation (including
PUVA used for treatment of psoriasis), and long-term immunosup-
pression (including the use of biologic response modifiers for treat-
ment of conditions such as psoriasis). Most SCCs present as firm,
flesh-colored, or erythematous papules or plaques. Treatment is pri-
marily via surgical excision.
Basal cell carcinoma (BCC) is a very common skin disor-
der (eFig. 23-13). BCC most commonly presents as a pigmented
nodule on the head and neck. Treatment may vary based on his-
tology and may involve surgical excision as well as the use of
 357

e|CHAPTER  
A

23

Dermatologic Drug R
­ eactions and Common Skin Conditions
eFIGURE 23-12  Squamous cell carcinoma. This case of
squamous cell carcinoma must be differentiated in diagnosis
from chondrodermatitis nodularis helicis, which, unlike
carcinoma, is painful. (Reprinted with permission from Grossman D, Leffell DJ.
Squamous cell carcinoma. In: Freedberg IM, Eisen AZ, Wolff K, et al., eds. Fitzpatrick’s
Dermatology in General Medicine, 6th ed. New York: McGraw-Hill, 2003:738.)

topical agents such as imiquimod, or antineoplastic agents such

as 5-fluorouracil. eFIGURE 23-13  Basal cell carcinoma. A. Basal cell carcinoma,
Malignant melanoma, unless detected early and excised, often nodular type. B. An ulcerated nodular basal cell carcinoma.
produces systemic metastases. Its incidence has increased over the (Reprinted with permission from Carucci JA, Leffell DJ. Basal cell carcinoma. In:
past few decades, with an estimated one in 65 Americans developing Freedberg IM, Eisen AZ, Wolff K, et al., eds. Fitzpatrick’s Dermatology in General
melanoma during their lifetimes.17 Medicine, 6th ed. New York: McGraw-Hill, 2003:749.)
A changing mole is often a harbinger of melanoma. These are
detected by skin examination; dermatologists often have melanoma
clinics for this purpose. Moles are examined for asymmetry, irregu-
lar borders, variegated colors, and size (eFig. 23-14). Full-body skin

A B

eFIGURE 23-14  Melanomas. These two superficial spreading melanomas illustrate the ABCDs of melanoma. A, asymmetry. The lesions
are not symmetrical and often have irregular borders. B, Border. Note the highly irregular, uneven, and notched border. C, Color. The
color is variegated with different shades of brown, black, and tan. D, Diameter. The diameter is usually (but not always) more than 6 mm
in melanomas. (Reprinted with permission from Langley RGB, Barnhill RL, Mihm MC Jr, et al. Neoplasms: Cutaneous melanoma. In: Freedberg IM, Eisen AZ, Wolff K, et al., eds.
Fitzpatrick’s Dermatology in General Medicine, 6th ed. New York: McGraw-Hill, 2003:925.)

Copyright © 2014 McGraw-Hill Education. All rights reserved.

358
examinations are important in screening for melanoma because it
can occur anywhere on the skin.17
Other risk factors include prolonged sun exposure and the abil-
ity to tan, family history, and drug treatments such as PUVA (pso-
ralen plus UVA) or biologic response modifiers used for psoriasis.
Suspicious pigmented lesions should be fully excised as soon
as possible rather than biopsied; malignant melanomas are best
diagnosed and microstaged with an excisional biopsy of the entire
lesion.18 Delayed diagnosis of malignant melanoma directly affects
SECTION
patient survival adversely.17 Treatment may also include systemic
antineoplastic therapy, such as temozolomide or dacarbazine for
metastatic melanoma.
2 CONCLUSIONS
This chapter provided coverage about the skin and associated age-
related changes, lesion assessment and recognition, drug-induced
Organ-Specific Function Tests and Drug-Induced Diseases
skin reactions, contact dermatitis, diaper dermatitis, and briefly dis-
cussed common skin cancers. Other common skin disorders are cov-
ered in the following three chapters, including acne (see Chap. 77),
psoriasis (see Chap. 78), and atopic dermatitis (see Chap. 79). Skin
and soft tissue infections (see Chap. 88) and parasitic diseases (see
Chap. 93) are detailed later in this text.
ABBREVIATIONS
ACD allergic contact dermatitis
AGEP acute generalized exanthematous pustulosis
BCC basal cell carcinoma
EM erythema multiforme
ICD irritant contact dermatitis
IVIG IV immunoglobulin
MRSA methicillin-resistant Staphylococcus aureus
NRL natural rubber latex
NSAID nonsteroidal antiinflammatory agent
PUVA Psoralens + ultraviolet A light
SCC squamous cell carcinoma
SJS Stevens-Johnson’s syndrome
SPF a sun protection factor
TEN toxic epidermal necrolysis
UV ultraviolet
UVA ultraviolet A
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