Drug eruptions can mimic almost any inflammatory dermatosis. Maculopapular, urticarial, morbilliform , papulosquamous, pustular, and bullous morphologies may be encountered. Adverse drug reactions also can cause pruritus or dysesthesia unaccompanied by rash.

Drug-induced reaction should be considered in the differential diagnosis of any symmetric cutaneous eruption with sudden onset in a patient who takes medications. Certain classes of systemic medications, such as antimicrobial agents, nonsteroidal anti-inflammatory drugs (NSAIDs), cytokines, chemotherapeutic agents, and psychotropic agents, are associated with a high rate of cutaneous reactions. Prompt identification and withdrawal of the offending agent may help limit toxic effects associated with the drug. Often, the decision whether to discontinue a potentially vital drug presents a dilemma. This article provides an overview of the clinical recognition, epidemiology, pathophysiology, and management of cutaneous drug eruptions.

Nonallergic drug eruptions are more common than allergic-type eruptions and may be classified according to the following:

Allergic-type drug reactions may be classified under the 4 types of immunologic reactions proposed by Coombs and Gell and include the following:

Allergic drug reactions are seen in only a small set of sensitized individuals. Antibodies can be demonstrated in fewer than 5% of cutaneous drug eruptions. Allergic reactions are not dose dependent. They usually begin 7-20 days after administration of a medication has begun. Blood or tissue eosinophilia may be present. When chemically related medicines are administered, allergic reactions may recur because of cross-reactivity.

Insulin and other proteins are associated with type I reactions and may be immunoglobulin E mediated. Penicillin, cephalosporins, sulfonamides, and rifampin are known to cause type II reactions. Quinine, salicylates, chlorpromazine, and sulfonamides can cause type III reactions. Type IV reactions, the most common allergic eruptions, often are encountered in contact hypersensitivity to topical medications such as neomycin.

Frequency:

Morbidity: Most eruptions are mild and self-limited, resolving after the offending agent is discontinued. Severe potentially life-threatening eruptions occur in approximately 1 in 1000 hospital patients. Mortality rates for Stevens-Johnson syndrome (SJS) generally are below 5%.

The mortality rate associated with TEN is high, approaching 20-30%. Sepsis is the primary direct cause of death.

Women have a 35% higher incidence of adverse cutaneous reactions to drugs than men and a 15- to 20-fold greater risk of anaphylactic reaction to radiocontrast media.

Causes:

Amoxicillin - 5.1%, Trimethoprim sulfamethoxazole - 4.7%, Ampicillin - 4.2%, Semisynthetic penicillin - 2.9%, Blood (whole human) - 2.8%, Penicillin G - 1.6%, Cephalosporins - 1.3%, Quinidine - 1.2%, Gentamicin sulfate - 1.0%, Packed red blood cells - 0.8%, Mercurial diuretics - 0.9%, Heparin - 0.7%.

Sulfasalazine - 20%, Trimethoprim-sulfamethoxazole - 14.9%, Dapsone - 3.1%, Aminopenicillins - 9.3%, Penicillins - 3.8%, Anticonvulsants - 3.4%, Penicillinase-resistant penicillins - 2.9%, Cephalosporins - 2.7%, Quinolones - 2.1%, Ketoconazole - 2.0%, Clindamycin - 1.8%, Primaquine - 1.8%, Tetracycline - 1.2%, Pentamidine - 1.0%, NSAIDs - 0.9% ,Erythromycin - 0.6%, Zidovudine - 0.3%

Allopurinol ,Anticonvulsants, Nonsteroidal anti-inflammatory drugs, Sulfa drugs, Bumetanide, Captopril, Furosemide, Penicillamine, Piroxicam, Thiazide diuretics.

Acneiform - Amoxapine, corticosteroids, halogens, haloperidol, hormones, isoniazid, lithium, phenytoin, and trazodone

Acute generalized exanthematous pustulosis - Beta-lactam antibiotics, macrolides, and mercury. Less commonly associated drugs: Acetaminophen, allopurinol, bufexamac, buphenine, carbamazepine, carbutamide, chloramphenicol, cotrimoxazole, clobazam, cyclins (eg, tetracycline), diltiazem, furosemide, hydroxychloroquine, imipenem, isoniazid, nadoxolol, nifedipine, phenytoin, pipemidic acid, piperazine, pyrimethamine, quinidine, salbutiamine, streptomycin, and vancomycin

Alopecia - Allopurinol, anticoagulants, azathioprine, bromocriptine, beta-blockers, cyclophosphamide, hormones, NSAIDs, phenytoin, methotrexate (MTX), and valproate

Bullous pemphigoid - D-penicillamine, furosemide, neuroleptics, penicillins, phenacetin, psoralen plus UV-A, salicylazosulfapyridine, and sulfasalazine

Erythema nodosum - Halogens, oral contraceptives, penicillin, sulfonamides, and tetracycline

Erythroderma - Allopurinol, anticonvulsants, barbiturates, captopril, carbamazepine, cefoxitin, chloroquine, chlorpromazine, cimetidine, diltiazem, griseofulvin, lithium, nitrofurantoin, and sulfonamides

Fixed drug eruptions - Acetaminophen, anticonvulsants, aspirin/nonsteroidal anti-inflammatory drug (aspirin/NSAID) barbiturates, benzodiazepines, butalbital, dapsone, metronidazole, oral contraceptives, penicillins, phenacetin, phenolphthalein, sulfonamides, tetracyclines, and tolmetin

Hypersensitivity syndrome - Allopurinol, carbamazepine, dapsone, lamotrigine, minocycline, NSAIDs, phenobarbital, phenytoin, and sulfonamides

Lichenoid - Antimalarials, beta-blockers, captopril, diflunisal, furosemide, gold, levamisole, penicillamine, phenothiazine, tetracycline, and thiazides

Linear IgA dermatosis - Captopril, diclofenac, glibenclamide, lithium, and vancomycin

Lupus erythematosus

Maculopapular - ACE inhibitors, allopurinol, amoxicillin, ampicillin, anticonvulsants, barbiturates, carbamazepine, isoniazid, NSAIDs, phenothiazine, phenytoin, quinolones, sulfonamides, thiazides, and trimethoprim-sulfamethoxazole

Pemphigus

Photosensitivity - Amiodarone, chlorpromazine, furosemide, griseofulvin, lovastatin, phenothiazine, piroxicam, quinolones, sulfonamides, tetracycline, and thiazide

SJS - Allopurinol, anticonvulsants, aspirin/NSAIDS, barbiturates, carbamazepine, cimetidine, codeine, diltiazem, furosemide, griseofulvin, hydantoin, nitrogen mustard, penicillin, phenothiazine, phenylbutazone, phenytoin, rifampicin, sulfonamides, tetracyclines, and trimethoprim-sulfamethoxazole

TEN - Allopurinol, anticonvulsants, aspirin/NSAIDs, Fansidar, isoniazid, penicillins, phenytoin, prazosin, sulfonamides, tetracyclines, trimethoprim-sulfamethoxazole, and vancomycin

Urticaria - ACE inhibitors, aspirin/NSAIDs, blood products, cephalosporins, dextran, opiates, penicillin, peptide hormones, polymixin, radiocontrast dye, ranitidine, and vaccines

Vasculitis - Allopurinol, aspirin/NSAIDs, cimetidine, gold, hydralazine, penicillin, phenytoin, propylthiouracil, quinolones, sulfonamide, tetracycline, and thiazides

Vesiculobullous (other) - Aspirin/NSAIDs, barbiturates, captopril, cephalosporins, furosemide, griseofulvin, penicillamine, penicillins, sulfonamides, and thiazides

Alopecia - Lithium

Erythema multiforme - Risperidone, diazepam overdose, lithium plus trazodone concurrently, fluoxetine, sertraline, carbamazepine, barbiturates, and phenobarbital

Maculopapular/morbilliform - Carbamazepine, maprotiline, lithium, trazodone, desipramine, fluoxetine, alprazolam, bupropion, nefazodone, risperidone, chlorpromazine, and barbiturates

Photosensitivity - All antipsychotics, chlorpromazine, thioridazine, imipramine, doxepin, and barbiturates

Pigmentation - Chlorpromazine, thioridazine, haloperidol, clozapine, perphenazine, amitriptyline, and diazepam following dermabrasion

Urticaria - Lithium, trazodone, fluoxetine, imipramine, and chlordiazepoxide

Acneiform - Dactinomycin, fluoxymesterone, medroxyprogesterone, and vinblastine

Alopecia

Erythema multiforme - Busulfan, chlorambucil, cyclophosphamide, diethylstilbestrol (DES), etoposide, hydroxyurea, mechlorethamine, MTX, mitomycin C, mitotane, paclitaxel, and suramin

Erythema nodosum - Busulfan and DES

Fixed drug eruptions - Dacarbazine, hydroxyurea, paclitaxel, and procarbazine

Hyperpigmentation - Busulfan, nitrogen mustard, cyclophosphamide, ifosfamide, bischloroethylnitrosourea (BCNU; carmustine), fotemustine, cisplatin, thiotepa, fluorouracil, tegafur, MTX, bleomycin, dactinomycin, daunorubicin, doxorubicin, mithramycin, mitoxantrone, hydroxyurea, vinorelbine, procarbazine, docetaxel, and brequinar

Lichenoid - Hydroxyurea and tegafur

Lupus - Aminoglutethimide, DES, hydroxyurea, leuprolide, and tegafur

Maculopapular/morbilliform - Bleomycin, carboplatin, cis -dichloro- trans -dihydroxy- bis -isopropylamine platinum (CHIP), chlorambucil, cytarabine, docetaxel, DES, doxorubicin, etoposide, 5-fluorouracil (5-FU), hydroxyurea, MTX, mitomycin C, mitotane, mitoxantrone, paclitaxel, pentostatin, procarbazine, suramin, and thiotepa

TEN - Asparaginase, bleomycin, chlorambucil, cladribine, cytarabine, doxorubicin, 5-FU, MTX, plicamycin, procarbazine, and suramin

Urticaria - Amsacrine, bleomycin, busulfan, carboplatin, chlorambucil, cisplatin, cyclophosphamide, cytarabine, daunorubicin, diaziquone, didemnin, DES, docetaxel, doxorubicin, epirubicin, etoposide, 5-FU, mechlorethamine, melphalan, MTX, mitomycin C, mitotane, mitoxantrone, paclitaxel, pentostatin, procarbazine, teniposide, thiotepa, trimetrexate, vincristine, and zinostatin

Vasculitis - Busulfan, cyclophosphamide, cytarabine, mexamethylene bisacetamide (HMBA), hydroxyurea, levamisole, 6-mercaptopurine, MTX, mitoxantrone, and tamoxifen

Granulocyte colony-stimulating factor (G-CSF) - Sweet syndrome, exacerbation of preexisting psoriasis, leukocytoclastic vasculitis, localized pruritus, and localized erythema

Granulocyte-macrophage colony-stimulating factor (GM-CSF) - Maculopapular eruptions, exfoliative dermatitis, urticaria, pruritus, purpura, alopecia, flushing, epidermolysis, exacerbation of vasculitis, localized wheals, and localized erythema

Interleukin 3 (IL-3) - Hemorrhagic rash, facial flushing, thrombophlebitis, and urticaria

Erythropoietin (EPO) - Abnormal hair growth, widespread eczema, palpebral edema, and localized rash

Tumor necrosis factor a (TNF- a ) - Erythroderma and localized erythema

Interferon a (IFN- a ) - Alopecia, pruritus, exacerbation of preexisting herpes labialis, cutaneous vascular lesions, psoriasis, eosinophilic fascitis, anasarca, SLE, paraneoplastic pemphigus, and xerostomia

Interferon b (IFN- b ) - Localized reactions (common) and fatal pemphigus vulgaris (when used in combination with interleukin 2 [IL-2])

Interferon g (IFN- g ) - Increased relapses in melanoma and localized inflammation

Interleukin 1 a (IL-1 a ) - Phlebitis, mucositis, xerostomia, and Shwartzman reaction

Interleukin 1 b (IL-1 b ) - Phlebitis, erythema at surgical wound sites, and rash

IL-2 - Erythema, pruritus, desquamation, erythroderma, necrosis, urticaria, blisters, exacerbation of autoimmune skin disorders, flushing, telogen effluvium, cutaneous ulcers, erythema nodosum, TEN, and hypersensitivity to iodine contrast material

Interleukin 4 (IL-4) - Grover disease, papular rash, and facial/peripheral edema

Interleukin 6 (IL-6) - Diffuse erythematous scaling macules and papules

Careing:

Once the offending drug has been identified, discontinue it promptly. If the patient is on multiple medications and it is not possible to isolate which drug is the cause, reduce the number of medications to an absolute minimum and change remaining drugs to alternative agents when possible.

Severe reactions, such as SJS, TEN, and leukocytoclastic vasculitis, warrant hospital admission. Extensive cases of blistering drug eruptions may be managed best in a burn unit if available. Pay special attention to electrolyte balance and to signs of secondary infection. In TEN, perform ophthalmologic evaluation because adhesions can develop and result in blindness.

Hypersensitivity syndrome, a systemic reaction characterized by fever, sore throat, and skin rash with internal organ involvement, is potentially life threatening. Timely recognition of the syndrome and immediate discontinuation of the anticonvulsant or other offending drug is crucial. Patients may require liver transplantation if the drug is not stopped in time. Treatment with systemic corticosteroids has been advocated widely.

Perhaps because of variable times of onset or the similarity in clinical presentation to infectious illnesses, serum sickness, or serum sicknesslike reactions, diagnosis of hypersensitivity syndrome may be delayed.

Serum sickness is a type III hypersensitivity reaction mediated by the deposition of immune complexes in small vessels, activation of complement, and recruitment of granulocytes. Serum C3 and C4 complement levels are decreased markedly. Cutaneous signs typically begin with erythema on the sides of fingers, hands, and toes, progressing to widespread eruption that is most often morbilliform or urticarial. Visceral involvement may exist, and fever, arthralgia, and arthritis frequently are seen. Serum sickness has been noted to occur with vaccines containing horse serum derivatives, antithymocyte globulin for bone marrow failure, or human rabies vaccine.

Serum sicknesslike reaction has a similar clinical presentation to serum sickness, without the immune complex deposition. Renal involvement rarely is observed. Serum sicknesslike reactions usually are seen following antibiotic therapy with beta-lactam antibiotics, sulfonamides, and minocycline, as well as with streptokinase, propranolol, and NSAIDs. Cefaclor, a semisynthetic cephalosporin, has a notably high incidence of the reaction in children, approximately 1.1%. Serum sicknesslike reactions usually are mild and resolve spontaneously within days to weeks after drug withdrawal.

Treat TEN in a manner similar to serious burns. Hospitalization is required, often in an intensive care unit or, preferably, in a burn unit if available. Surgical debridement of the necrotic areas is critical, since the necrotic skin releases fas ligand toxic to the regenerating epidermis.