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Drug Eruptions and Reactions

By

Julia Benedetti

, MD, Harvard Medical School

Last full review/revision Jul 2020| Content last modified Jul 2020
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Drugs can cause multiple skin eruptions and reactions. The most serious of these are discussed elsewhere in THE MANUAL and include Stevens-Johnson syndrome and toxic epidermal necrolysis, hypersensitivity syndrome, serum sickness, exfoliative dermatitis, angioedema, anaphylaxis, and drug-induced vasculitis.

Symptoms and Signs

Symptoms and signs vary based on the cause and the specific reaction (see Table: Types of Drug Reactions and Typical Causative Agents).

Table
icon

Types of Drug Reactions and Typical Causative Agents

Type of Reaction

Description and Comments

Typical Causative Agents

Acneiform eruptions

Resemble acne but lack comedones and usually begin suddenly

Corticosteroids, epidermal growth factor receptor (EGFR) and mitogen-activated protein kinase (MEK) inhibitors, iodides, bromides, hydantoins, androgenic steroids, lithium, isoniazid, phenytoin, phenobarbital, vitamins B2, B6, and B12

Acute generalized exanthematous pustulosis

Rapidly appearing and spreading pustular eruption

Most commonly antibiotics, including macrolides and penicillins

Blistering eruptions

Appear with widespread vesicles and bullae

Pemphigus: Penicillin, penicillamine, and other thiol compounds

Bullous pemphigoid: Penicillamine and furosemide (most common)

Cutaneous necrosis

Appears as demarcated, painful, erythematous or hemorrhagic lesions progressing to hemorrhagic bullae and full-thickness skin necrosis with eschar formation

Warfarin, heparin, barbiturates, epinephrine, norepinephrine, vasopressin, levamisole (contaminant in street preparations of cocaine)

Drug-induced lupus

Appears as lupus-like syndrome, although often without the rash

Procainamide, minocycline, hydralazine, anti-tumor necrosis factor (TNF) drugs, penicillamine, isoniazid, quinidine, interferon, methyldopa, chlorpromazine, practolol

Drug reaction with eosinophilia and systemic symptoms or drug hypersensitivity syndrome

Manifests as fever, facial edema, and rash 2–6 weeks after first dose of a drug

Patients may have elevated eosinophils, atypical lymphocytes, hepatitis, pneumonitis, lymphadenopathy, and myocarditis

Thyroiditis can be a sequela

Antiseizure drugs, allopurinol, sulfonamides, minocycline, vancomycin

Flagellate dermatitis

Linear erythematous wheals

Bleomycin

Characterized by tender red nodules, predominantly in the pretibial region, but occasionally involving the arms or other areas

Sulfonamides, oral contraceptives, penicillin, bromides, iodides

Exfoliative dermatitis/erythroderma

Characterized by redness and scaling of the entire skin surface

May be fatal

Penicillin, sulfonamides, beta-lactams, hydantoins, allopurinol, barbiturates, carbamazepine, phenobarbital

Fixed drug eruptions

Appear as frequently isolated, well-circumscribed, circinate or ovoid dusky red or purple lesions on the skin or mucous membranes (especially of the genitals) and reappear at the same sites each time the drug is taken

Antibiotics, NSAIDs, acetaminophen, barbiturates, antimalarials, antiseizure drugs

Lichenoid or lichen planus–like eruptions

Appear as angular papules that coalesce into scaly plaques

Angiotensin-converting enzyme inhibitors, beta-blockers, methyldopa, quinidine, thiazides, penicillamine, quinacrine

Morbilliform or maculopapular eruptions (exanthems)

Most common hypersensitivity drug reaction

Mildly pruritic, typically appearing 3 to 7 days after start of the drug

Almost any drug (especially barbiturates, analgesics, sulfonamides, ampicillin, and other antibiotics)

Mucocutaneous eruptions

Vary from a few small oral vesicles or urticaria–like skin lesions to painful oral ulcers with widespread bullous skin lesions (see Erythema Multiforme and Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis)

Penicillin, barbiturates, sulfonamides (including derivatives used to treat hypertension and diabetes)

Palpable purpura

Nonblanching purpuric papules most commonly on the lower extremities

Antibiotics (eg, sulfonamides and beta-lactams, hydralazine, propylthiouracil, phenytoin, allopurinol)

Phototoxic reactions: Occur after direct damage of the tissue by exposure to the sunlight and drug and occur shortly after exposure and can look like a burn, including blistering; eruptions limited to sun-exposed skin

Photoallergic reactions: Cell-mediated, can occur later, often with skin changes similar to those of eczema, and can spread to nonexposed skin

Drugs that can cause phototoxic or photoallergic reactions: NSAIDs, chlorpromazine, phenothiazines, and sulfonamides

Drugs that tend to cause only phototoxic reactions: Antibiotics (eg, tetracyclines, fluoroquinolones)

Serum sickness–type drug reaction

A type III immune complex reaction

Acute urticaria and angioedema more common than morbilliform or scarlatiniform eruptions

Possibly polyarthritis, myalgias, polysynovitis, fever, and neuritis

Penicillin, insulin, foreign proteins

Characterized by focal areas of dusky red lesions, skin pain, and epidermal detachment of < 10% of BSA in SJS and > 30% of BSA in TEN*

Skin and mucosa are involved; lips can develop hemorrhagic crusts and ulcerations

Severe forms resemble staphylococcal scalded skin syndrome, a staphylococcal toxin–mediated disorder that occurs in infants, young children, and immunosuppressed patients

May be fatal

Antiseizure drugs, NSAIDs, penicillin, sulfonamides, antiretroviral drugs

Common

Classically but not always IgE-mediated

Easily recognized by typical well-defined edematous wheals

May be accompanied by angioedema or other manifestations of anaphylaxis

Occasionally the first sign of impending serum sickness, with fever, joint pain, and other systemic symptoms developing within days

NSAIDs can worsen urticaria, and urticaria can be a sign of many other drug reactions

* When epidermal detachment occurs on 10 to 30% of BSA, the term SJS/TEN overlap is used.

BSA = body surface area; NSAIDs = nonsteroidal anti-inflammatory drugs.

Diagnosis

  • Clinical evaluation and drug exposure history

  • Sometimes skin biopsy

A detailed history is often required for diagnosis, including recent use of over-the-counter drugs. Because the reaction may not occur until several days or even weeks after first exposure to the drug, it is important to consider all new drugs and not only the one that has been most recently started.

No laboratory tests reliably aid diagnosis, although biopsy of affected skin is often suggestive.

Sensitivity can be definitively established only by rechallenge with the drug, which may be hazardous and unethical in patients who have had severe reactions. Occassionally, patch testing can be helpful in patients with fixed drug eruptions.

Treatment

  • Discontinuation of offending drug

  • Sometimes antihistamines and corticosteroids

Most drug reactions resolve when drugs are stopped and require no further therapy. Whenever possible, chemically unrelated compounds should be substituted for suspect drugs. If no substitute drug is available and if the reaction is a mild one, it might be necessary to continue the treatment under careful watch despite the reaction.

Pruritus and urticaria can be controlled with oral antihistamines and topical corticosteroids. For IgE-mediated reactions (eg, urticaria), desensitization can be considered when there is critical need for a drug.

If anaphylaxis occurs, treatment is with aqueous epinephrine (1:1000) 0.2 mL subcutaneously or IM, parenteral antihistamines, and with the slower-acting but more persistent soluble hydrocortisone 100 mg IV, which may be followed by an oral corticosteroid for a short period.

Key Points

  • Because drugs can cause a wide variety of reactions, drugs should be considered as causes of almost any unexplained skin reaction.

  • Base the diagnosis primarily on clinical criteria, including a detailed history of prescription and over-the-counter drugs.

  • Stop the suspected offending drug and treat symptoms as needed.

Drugs Mentioned In This Article

Drug Name Select Trade
No US brand name
LEVOPHED
CORTEF, SOLU-CORTEF
CUPRIMINE
TYLENOL
TEGRETOL
ZYLOPRIM
MINOCIN
ADRENALIN
VASOSTRICT
LASIX
VANCOCIN
No brand name
DILANTIN
LANIAZID
COUMADIN
PANHEPRIN
LITHOBID
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