A young college student was seen for fatigue and an upper respiratory infection and started on amoxicillin for a sore throat. Six days later, she broke out with a red rash all over her body (Figure 154-1). She went to see her family physician back home with the rash and lymphadenopathy. A monospot was drawn and found to be positive. This morbilliform rash (like measles) is typical of an amoxicillin drug eruption in a person with mononucleosis. Amoxicillin was stopped, and diphenhydramine was used for the itching.
Cutaneous drug reactions are skin manifestations of drug hypersensitivity. Drug hypersensitivity may be defined as symptoms or signs initiated by a drug exposure at a dose normally tolerated by non-hypersensitive persons.1 Drug-induced adverse reactions are often classified as type A and type B. Type A reactions are common (80%) predictable side effects caused by a pharmacologic action of the drug, and type B reactions are uncommon (10% to 15%) and considered idiosyncratic, a result of individual predisposition (e.g., an enzyme defect).2 Cutaneous drug reactions range from mild skin eruptions (e.g., exanthem, urticaria, and angioedema) to severe cutaneous drug reactions (SCARs), the latter category including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome.3
Cutaneous drug reactions are common complications of drug therapy occurring in 2 to 3 percent of hospitalized patients.4
One study found that 45 percent of all adverse drug reactions were manifested in the skin.4
Approximately 1 in 6 adverse drug reactions represents drug hypersensitivity, and are allergic or non–immune-mediated (pseudoallergic) reactions.2
Maculopapular eruptions, also known as exanthematous drug eruptions, are the most frequent of all cutaneous drug reactions, representing 95 percent of skin reactions.5 They are often confused with viral exanthems. This occurs most commonly with β-lactams such as amoxicillin, but also with barbiturates, gentamicin, isoniazid, phenytoin, sulfonamides, thiazides, and trimethoprim-sulfamethoxazole (Figures 154-1 and 154-2).
Urticarial drug reactions are the second most common skin eruptions, representing approximately 5 percent of cutaneous drug reactions.5 This reaction can result from any drug but commonly occurs with aspirin, penicillin, sulfa, angiotensin-converting enzyme (ACE) inhibitors, aminoglycosides, and blood products. Urticaria results from immunoglobulin (Ig) E reactions within minutes to hours of drug administration (Figures 154-3 and 154-4).
Drug-induced hyperpigmentation occurs with antiarrhythmics (amiodarone), antibiotics (minocycline), NSAIDs, and chemotherapy agents (Adriamycin).
Fixed drug eruptions (FDEs) can occur with many medications, including phenolphthalein, doxycycline, ibuprofen, sulfonamide antibiotics, and barbiturates (Figures 154-5 to 154-8). FDEs are more commonly observed in males.
Erythema multiforme (EM) and SJS can occur secondary to drug reactions (Figure 154-9). Incidence of SJS is estimated at 1.2 per 6 million people.3
DRESS (drug reaction with eosinophilia and systemic symptoms) syndrome is also a severe adverse drug-induced reaction characterized by eosinophilia with liver involvement, fever, and lymphadenopathy. In a case series (N = 172), 44 drugs were associated with DRESS.6 DRESS syndrome is estimated to occur in 1 per 1000 to 1 per 10,000 exposures to antiepileptic drugs.7
Tables 154-1 lists the most common medications associated with allergic cutaneous drug reactions and the rates of reactions found.8
Table 154-2 lists the frequency of various classes of drugs associated with an eruption (in cases with <4 suspected drugs) based on a 5-year study.9
FIGURE 154-2
Maculopapular drug eruption in a 5-year-old boy with an upper respiratory infection started on amoxicillin for a questionable otitis media. Four days later he broke out with a red rash all over his face and body. This morbilliform rash (like measles) is typical of an amoxicillin drug eruption. (Used with permission from Robert Tunks, MD.)
FIGURE 154-4
Giant urticarial eruption (urticaria multiforme) in the patient in Figure 154-3 with drug reaction to sulfa. (Used with permission from Richard P. Usatine, MD.)
| Drug | Reactions, No. | Recipients, No. | Rate, Percent | 95 Percent Confidence Interval |
| Fluoroquinolones | 16 | 1015 | 1.6 | 0.8 to 2.3 |
| Amoxicillin | 40 | 3233 | 1.2 | 0.9 to 1.6 |
| Augmentin | 12 | 1000 | 1.2 | 0.5 to 1.9 |
| Penicillins | 63 | 5914 | 1.1 | 0.8 to 1.3 |
| Nitrofurantoin | 7 | 1085 | 0.6 | 0.2 to 1.1 |
| Tetracycline | 23 | 4981 | 0.5 | 0.3 to 0.7 |
| Macrolides | 5 | 1435 | 0.3 | 0.0 to 0.7 |
| Class of Drug | No. of Cases (N = 82) |
| Antibiotic | 37 |
| Antiepileptic | 12 |
| Phenytoin | 9 |
| Antiarrhythmic | 6 |
| Calcium ion inhibitors | 3 |
| Anticoagulant | 5 |
| Enoxaparin | 2 |
| Clopidogrel | 2 |
| Warfarin | 1 |
| Antifungal | 4 |
| Antigout | 4 |
| Proton pump inhibitors | 4 |
| ACE1 inhibitors | 3 |
| Contrast | 3 |
| Diuretics | 3 |
| Anti-inflammatory | 2 |
| Antiretroviral (HIV) | 2 |
| Antiviral | 2 |
| Beta blockers | 2 |
| Chemotherapeutic | 2 |
| Other | 11 |
