Fixed-drug reaction

Drug-induced cutaneous reactions tend to be immunologic in origin and relate to hypersensitivity, but some reactions are nonallergic. The pathogenesis of fixed-drug reactions is not well understood. 

Treatment of fixed drug reactions involves removal of the offending agent. Other therapeutic measures include corticosteroids, antihistamines to relieve itching, and perhaps cool water compresses on the affected area. 

Treatment of fixed drug reactions involves removal of the offending agent. Other therapeutic measures include corticosteroids, antihistamines to relieve itching, and perhaps cool water compresses on the affected area. Photosensitivity reactions typically resolve with drug discontinuation. Some patients benefit from topical corticosteroids and oral antihistamines, but these are relatively ineffective. Systemic corticosteroids (e.g., oral prednisone 1 mg/kg/day tapered over 3 weeks) is more effective for these patients. 

A reaction like lupus pernio, with purple discoloration, swelling, red papules, and desquamation of the distal parts of several toes, which resolved after drug suspension and recurred after resumption, has been observed (42), as have subcutaneous fat necrosis (SEDA-11, 92), and fixed drug reaction (SEDA-12, 84). 

Rashes of aU types may be caused by allergy to peniciUin. Henoch-Schonlein purpura with renal involvement has been a rare complication. Contact dermatitis is observed occasionally in pharmacists, nurses, and physicians who prepare penicilUn solutions. Fixed-drug reactions also have occurred. More severe reactions involving the skin are exfoliative dermatitis and exudative erythema multiforme. The incidence of rashes appears to be highest foUowing the use of ampicUlin ( 9%) rash follows the administration of ampiciUin in nearly all patients with infectious mononucleosis. 

NSAIDs can induce a number of other adverse reactions, including bleeding disorders, anemia, thrombocytopenia, erythema nodosum, erythema multiforme, fixed drug eruptions, toxic epidermal necrolysis, Stevens-Johnson syndrome, leukocytocla-sitc vasculitis, recurrent fever with exanthema and, of course, the well-known gastric cytotoxicity. 

The word dermatitis denotes an inflammatory erythematous rash. The disorders discussed in this chapter include contact dermatitis, seborrheic dermatitis, diaper dermatitis, and atopic dermatitis. Drug-induced skin disorders have been associated with most commonly used medications and may present as maculopapular eruptions, fixed-drug eruptions, and photosensitivity reactions. 

Hypersensitivity reactions, such as urticaria and angio-edema, are relatively common in subjects with aspirin hypersensitivity. Purpura, hemorrhagic vasculitis, erythema multiforme, Stevens-Johnson syndrome, and Lyell s syndrome have also been reported, but much less often. Fixed drug eruptions, probably hypersensitive in origin, are periodically described. In some patients they do not recur on rechallenge, that is the sensitivity disappears (74). 

Clarithromycin has been associated with fixed dmg emp-tions and hypersensitivity reactions (41,42). In one case a clarithromycin-induced fixed drug eruption was reproduced by oral provocation, whereas patch tests on both unaffected and residual pigmented skin were negative (43). 

Dermatological adverse effects are not uncommon with griseofulvin and are of considerable variety. The following have been described urticaria (28,29), photosensitivity eruptions (30), erythema multiforme (31), morbilliform rashes (32), serum sickness-like reactions (33), fixed drug eruption (29,34,35), Stevens-Johnson syndrome (36), vasculitis (37), toxic epidermal necrolysis (38,39), and lupus erythematosus (40,41). 

Other rarities reported sporadically (but all in more than one case) include the Koebner phenomenon (210), fixed drug eruptions (for example with iotalamate (211)), and delayed reactions of various types. Reports of severe drug eruptions have become more frequent since the introduction of the non-ionic contrast media, but this may simply be due to the fact that in recent years there has been greater awareness of such reactions (SEDA-16, 538) (SEDA-19, 427) (SEDA-22, 502). 

Loratadine caused erythematous, edematous, pruriginous skin eruptions in a 19-year-old woman who complained of at least three episodes of eruptions located at the same sites each time (6). An oral challenge with loratadine was positive, and cetirizine and ebastine caused no cutaneous reaction. Histopathology suggested a fixed drug eruption. 

Mechanisms of non-immediate reactions are unclear but may be immunological and non-immunological. Delayed reactions of the IgE type are known (131). Aminopenicillins seem to be an important cause of non-immediate reactions (132-134). The morbilliform rash that begins 1-10 days after amoxicillin can be caused by a delayed cell-mediated immune reaction (135) as can fixed drug eruptions (136,137), toxic epidermal necrolysis (138-140), bullous erythroderma (141), and contact eczema (142). Investigation of these disorders should include delayed readings of skin tests (135). In patients with chronic urticaria, penicillin allergy was demonstrated by cutaneous tests. 

Urticaria, fixed drug eruptions (131,134-137), erythema nodosum (138), photosensitivity reactions (139), and generalized skin reactions involving light-exposed areas (139-141) are less common. Topical silver sulfadiazine cause local reactions, consisting of rash, pruritus, or a burning sensation in 2.5% of patients (4,51). 

In a 1-year prospective study of 136 patients taking ticlopidine to prevent thrombosis after coronary stenting, 16 had adverse skin reactions (28). The most common were urticaria, pruritus, and maculopapular eruptions. Three patients had previously unreported reactions a fixed drug eruption, an eiythromelalgia-like eruption, and an erythema multiforme-hke eruption. 

Fixed drug eruptions have been analysed in 450 patients (130). The ratio of men to women was 10 11. The mean age of the men was 30 years, and that of the women 31 years. In 13% the fixed drug eruption had occurred for the first time, 2.7% had had more than 40 episodes. There was atopy in 11%, and 23% had a positive family history of drug reactions. Co-trimoxazole was the most common cause of fixed drug eruptions. Other antibiotics included tetracycline, metronidazole, amoxicillin, ampicillin, erythromycin, and clindamycin. 

Topical provocation of fixed drug eruption and positive reactions with co-trimoxazole are extremely rare and have never been seen on unaffected skin. 

Breathnach SM +, Adverse Drug Reactions and the Skin Blackwell, Oxford, 289 Fixed eruption... 

In many types of drug reactions, bullae and vesicles may be found in addition to other manifestations. Bullae are usually noted in erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, fixed eruptions when very intense, urticaria, vasculitis, porphyria cutanea tarda, and phototoxic reactions (from furosemide and nalidixic acid). Tense, thick-walled bullae can be seen in bromoderma and iododerma as well as in barbiturate overdosage. 

Morbilliform exanthema, fixed drug eruptions, and erythrodermia are thought to result from a cell-mediated reaction, i.e., T-lymphocytes as in contact sensitivity. However, the histologic pictures of both reactions differ in a number of features. Moreover, basophil infiltration, which is rather important in contact sensitivity, is often negligible in the tuberculin reaction. In spite of several differences between... 

In 1894 Brocq described a special type of drug reaction which cleared up rapidly when the drug was stopped, and reappeared in the same clinical distribution when the drug was restored. The incriminated drug was antipyrine. The mechanism of fixed eruptions is unknown (Amos 1976). 

Penicillin is a potent topical sensitizer and may cause contact dermatitis (Levine 1960 a Fellner 1976) it is therefore no longer used in ointments. Several other cutaneous manifestations of penicillin allergy, such as fixed drug eruption, erythema multiforme, the Stevens-Johnson syndrome, exfoliative dermatitis, epidermal necrolysis, erythema nodosum and cutaneous necrotizing angiitis have been described (Fellner 1976 Soter and Austen 1978 Wintraub et al. 1979 De Swar-TE 1972). The precise immunological mechanisms of these various forms of cutaneous reactions are usually not known. 

Fawcett and Pepys (1976) reported the case of a patient who developed immediate bronchospasm and an urticarial reaction after ingestion of a commercial combination of three tetracyclines no reactions could be elicited by oral challenge with the different tetracyclines, tartrazine, or the blue coating of the drug, whereas a provocation test with the commercial preparation was positive. Other clinical patterns, such as fixed drug eruptions (Kandil 1969 Delaney 1970 Csonka et al. 1971 Brown 1974 Shimizu and Shimao 1977 Pasricha and Shukla 1979), vascular purpura (Schoenfeld 1964) and a picture similar to systemic lupus erythematosus (SLE) (Sulkowski and Haserick 1964) have also been described. Contact dermatitis seems to be a very rare complication it was, however, observed after contact with oxytetracycline (Dohn 1962 Bojs and Moller 1974) and minocycline. In the latter case subsequent oral therapy with the same drug was followed by a systemic reaction and the sensitivity was confirmed by epicutaneous tests (Shelley and Heaton 1973). 

---