Step 2 CK · Dermatology

Cutaneous Drug Reactions

Name: Cutaneous Drug Reactions
Creator: Veli Bakalov, MD

Telling a benign rash from the one that peels the skin off

Dermatology·Drug Reactions & Blistering Disease·5 min read·9 high-yield points·Reviewed by Veli Bakalov, MD @HemeOncBuddy

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Latency names the reaction: urticaria and anaphylaxis in minutes to hours (type I), AGEP in 1–2 days, morbilliform in 4–14 days, SJS/TEN in 1–3 weeks, DRESS in 2–8 weeks (longest).
Morbilliform eruption is the most common drug rash: symmetric trunk macules and papules with no mucosal or systemic involvement (penicillins, sulfonamides, allopurinol, anticonvulsants); stop the drug, give antihistamines.
Red flags (mucosal involvement, skin pain, blisters with a positive Nikolsky sign, facial edema, fever, lymphadenopathy, eosinophilia, organ dysfunction) mean stop the drug and admit.
SJS/TEN is full-thickness epidermal necrosis: SJS under 10% BSA, overlap 10–30%, TEN over 30%; fever prodrome, painful dusky skin, at least two mucosal sites, Nikolsky positive.
SJS/TEN culprits: sulfonamides, lamotrigine, carbamazepine, phenytoin, allopurinol, nevirapine, oxicam NSAIDs (Mycoplasma in children now counts as a separate entity, MIRM); HLA-B*15:02 with carbamazepine, HLA-B*58:01 with allopurinol.
SJS/TEN care: stop the drug immediately, burn-unit or ICU support, early ophthalmology; TEN mortality approaches 30%, predicted by SCORTEN (age >40, HR >120, cancer, BSA >10%, BUN >28, bicarbonate <20, glucose >252).
DRESS: 2–8 weeks after anticonvulsants, allopurinol, sulfonamides, or vancomycin; fever, rash, facial edema, lymphadenopathy, eosinophilia, hepatitis, HHV-6 reactivation; stop the drug and give systemic steroids.
Fixed drug eruption recurs at the SAME site with each exposure and leaves hyperpigmentation; erythema multiforme (acral target lesions) usually follows HSV, not drugs.
Anaphylaxis: IM epinephrine 1:1000 into the anterolateral thigh first; antihistamines and steroids are only adjuncts.

Approach to a drug rash: timing, mechanism, and red flags

Ask when the drug was started. Latency after the first dose is the best single clue to the reaction type. IgE-mediated (type I) reactions appear within minutes to hours. The delayed eruptions (morbilliform, SJS/TEN, DRESS, and fixed drug eruption) are T-cell-mediated (type IV) and take days to weeks.

Drug reactions by latency

Reaction	Onset after drug	Mechanism	Hallmark
Urticaria, angioedema, anaphylaxis	Minutes to hours	Type I (IgE)	Wheals, airway swelling, bronchospasm, hypotension
AGEP	1–2 days	T-cell, neutrophil-rich	Sterile pustules in folds, fever, neutrophilia
Morbilliform	4–14 days	Type IV	Symmetric trunk macules and papules; no mucosal disease
SJS/TEN	1–3 weeks	Type IV (cytotoxic T cells)	Painful dusky skin, mucosal erosions, Nikolsky sign
DRESS	2–8 weeks (longest)	Type IV; HHV-6 reactivation	Facial edema, eosinophilia, hepatitis
Fixed drug eruption	Within hours of each re-exposure	Type IV	One dusky plaque, same site every time

Red flags of a severe reaction. Any of these means stop the drug and admit:

Mucosal involvement (mouth, eyes, genitals)
Skin pain or tenderness out of proportion to the rash
Blisters or detachment with a positive Nikolsky sign
Facial edema, fever, or lymphadenopathy
Eosinophilia or organ dysfunction (transaminitis, rising creatinine)

Isolated trunk macules without any red flag suggest a benign morbilliform eruption.

Benign and localized eruptions

Morbilliform (exanthematous) eruption. The most common drug reaction: symmetric erythematous macules and papules that start on the trunk about 4–14 days after the drug, without mucosal or systemic involvement. Culprits include penicillins, sulfonamides, allopurinol, and anticonvulsants. It is a type IV reaction; stop the drug and give antihistamines for itch.

Aminopenicillins (ampicillin, amoxicillin) given during infectious mononucleosis commonly provoke a morbilliform rash.

Fixed drug eruption. A solitary, well-demarcated, round, dusky or violaceous plaque that recurs at exactly the same site with each exposure and heals with postinflammatory hyperpigmentation. Favored sites are the lips, hands, and genitals. Culprits: sulfonamides (such as trimethoprim-sulfamethoxazole), NSAIDs, tetracyclines, and acetaminophen.

Acute generalized exanthematous pustulosis (AGEP). Erupts within 1–2 days of a drug (aminopenicillins, macrolides, hydroxychloroquine) as dozens of small, sterile, non-follicular pustules on erythematous skin, starting on the face and skin folds, with fever and neutrophilia. It resolves quickly once the drug is stopped.

Stevens-Johnson syndrome and toxic epidermal necrolysis

One spectrum of full-thickness epidermal necrosis, graded by the body surface area (BSA) that detaches.

<10%BSA detached: SJS

10–30%SJS/TEN overlap

>30%BSA detached: TEN

Presentation. A febrile prodrome precedes painful dusky or targetoid skin, erosions of at least two mucosal sites, and a positive Nikolsky sign: lateral pressure shears off the epidermis, indicating full-thickness detachment.

Culprits. Sulfonamides, anticonvulsants (lamotrigine, carbamazepine, phenytoin), allopurinol, nevirapine, and oxicam NSAIDs. In children, Mycoplasma pneumoniae causes Mycoplasma-induced rash and mucositis (MIRM), formerly grouped with SJS: mucosa-predominant, sparse skin lesions, and a better prognosis than drug-induced SJS. Lamotrigine risk rises with rapid dose escalation and with concurrent valproate.

HLA-B*15:02 predisposes to carbamazepine SJS/TEN in patients of Asian ancestry (screen before prescribing), and HLA-B*58:01 predisposes to allopurinol reactions.

Stop the culprit drug immediatelyThe single most important step; never rechallenge.
Treat like a burnBurn unit or ICU: fluids, electrolytes, wound care, and infection surveillance.
Ophthalmology earlyOcular involvement can scar and threaten vision.
AdjunctsIVIG, cyclosporine, and steroids remain controversial.

Managing SJS/TEN

Prognosis. Mortality in TEN approaches 30%, and sepsis is the leading cause of death. SCORTEN assigns 1 point for each of seven criteria; a higher score predicts higher mortality:

Age over 40, heart rate over 120, malignancy
Detached BSA over 10%
BUN over 28 mg/dL, bicarbonate under 20, glucose over 252 mg/dL

Erythema multiforme versus SJS/TEN

Feature	Erythema multiforme	SJS/TEN
Main trigger	Infection: herpes simplex first, Mycoplasma second; rarely drugs	Drugs (Mycoplasma mucositis in children is now classified as MIRM)
Lesions	Target (iris) lesions with three zones	Dusky, targetoid lesions that blister and slough
Distribution	Hands and extensors, spreading centrally	Widespread
Mucosa	Only in EM major	At least two sites, severe
Detachment	Little or none	Nikolsky positive
Course	Self-limited; acyclovir suppression for recurrent HSV-driven EM	Life-threatening; burn-unit care

Staphylococcal scalded skin syndrome also sheds skin but affects young children, spares the mucosa, and splits high in the epidermis (exfoliative toxin against desmoglein-1); it is treated with antistaphylococcal antibiotics, not burn-unit drug withdrawal.

DRESS

Drug reaction with eosinophilia and systemic symptoms appears 2–8 weeks after the drug, the longest latency of any eruption. Expect fever, a morbilliform rash, facial edema, lymphadenopathy, eosinophilia, and internal organ injury, with hepatitis the most common. Culprits: anticonvulsants (phenytoin, carbamazepine), allopurinol, sulfonamides, and vancomycin.

Treatment. Stop the drug and give systemic steroids, tapered slowly because DRESS tends to flare as steroids are withdrawn.

The long 2–8 week latency and HHV-6 reactivation distinguish DRESS from other eruptions. Fever, facial swelling, eosinophilia, and transaminitis 3 weeks after starting phenytoin is DRESS until proven otherwise.

Immediate reactions: urticaria, angioedema, and anaphylaxis

Type I (IgE-mediated). Acute urticaria, angioedema, and anaphylaxis occur within minutes to hours of exposure; penicillins, foods, and insect stings are classic triggers.

IM epinephrine first1:1000 (1 mg/mL) into the anterolateral thigh for airway compromise, hypotension, or bronchospasm; repeat every 5–15 minutes if needed.
SupportAirway, oxygen, and IV fluids for hypotension.
AdjunctsAntihistamines and steroids, which never replace epinephrine.

Anaphylaxis

Antihistamines, steroids, or albuterol alone are wrong answers for anaphylaxis. Discharge with an epinephrine autoinjector and document the allergy.