Acute exanthematous pustular drug eruption induced by mexiletine

ARTICLE

Mexiletine hydrochloride is an anti-arrhythmic drug. Various types of drug eruption due to mexiletine hydrochloride have been reported, including papulo-macular type eruption, erythema multiforme, erythroderma, urticaria, prurigo and, rarely, pustular formation [1-3]. Many patients develop fever and liver dysfunction during the clinical course. The average interval between the start of mexiletine hydrochloride and onset of the eruption is 40 days. Patch testing shows positive reaction in more than 95% of the cases, whereas lymphocyte stimulation test is positive in about 20%. In this report, we describe a patient developing acute exanthematous pustular eruption due to mexiletine, who also showed marked facial edema.

Case report

A 56-year-old man with arrhythmia had been treated with mexiletine hydrochloride 300 mg daily for 1 month. He developed erythemas on his body with high fever. Seven days before admission in our hospital, administration of mexiletine was stopped, and he was treated with prednisolone 20 mg daily for three days without effect. Under the diagnosis of drug eruption, he was hospitalized and prednisolone was stopped. Prior to onset, he did not have any drugs other than mexiletine hydrochloride. On physical examination, his face was erythematous and edematous, and he had difficulties opening the right eye (Fig. 1). His body was covered with numerous infiltrated erythematous patches. Erythema multiforme-like eruption was observed on his extremities, and purpura was also noted on his lower legs. Tiny pustules were disseminated on the surface of erythema on his chest, neck, and around the chin (Fig. 2). Laboratory data were as follows: WBC 16,700/µl with a differential count of 65% neutrophils, 20% eosinophils, 8% lymphocytes and 6% monocytes, GOT 72 U/l (normal; 13-35 U/l), GPT 129 U/l (normal; 8-48 U/l) and CRP 8.7 mg/dl (normal; < 0.6 mg/dl). The antibodies to enterovirus, adenovirus, Epstein-Barr virus, cytomegalovirus, hepatitis B or C virus were negative. The culture from a pustule was sterile. A biopsy from one of the pustular lesions on the chest showed a subcorneal abscess containing a number of neutrophils, and perivascular infiltration composed of lymphocytes, monocytes and eosinophils in the upper dermis (Fig. 3A, B). The eruption and liver dysfunction gradually improved within three weeks. One month after the regression of the eruption, patch tests were performed. Patch tests with 10% and 20% mexiletine hydrochloride in petrolatum showed positive reaction (whereas negative in 3 healthy volunteers), however, pustules were not provoked on the tested skin. The positive patch tests were not biopsied. A lymphocyte stimulation test by mexiletine hydrochloride was negative. A challenge test of mexiletine could not be performed.

Discussion

Pustular drug eruptions represent a distinct entity. They represent the absence of a personal or family history of psoriasis, spontaneous resolution without therapy, the presence of eosinophils in the inflammatory infiltrate, and absence of histological features of conventional psoriasis [4]. Drugs implicated include piperazine [5], streptomycin [6], carbamazepine [7, 8], isoniazid [9], cefradine [10], cefalexin [4, 11], cefoxitin [11], cefazolin [12], naproxen [13], norfloxacin [14] (Table I). Acute generalized exanthematous pustulosis (AGEP) usually occurs following either drug ingestion or viral infection. AGEP is remarkable for its short time to onset after the administration of the suspected drug. And after the causal drug had been stopped, spontaneous rapid resolution of the pustules was observed within ten days [15, 16].

The case presented developed numerous pustules relatively localized to the chest, neck, and around the chin. The pustules gradually regressed after withdrawal of mexiletine hydrochloride without the usage of systemic prednisolone, however, it took as long as 3 weeks until the eruption disappeared. It is known that skin lesions induced by mexiletine hydrochloride persist even after withdrawal of the drug. In the previously reported case [1], the skin eruption did not disappear completely for 4 weeks despite intravenous dexamethasone. We should consider drug-induced hypersensitivity syndrome in our case. Reactivation of human herpesvirus-6 can contribute to the development of a severe drug-induced hypersensitivity syndrome [17, 18]. Although we could not detect the human herpesvirus-6, the possibility remains that our case presented a hypersensitivity syndrome induced by mexiletine hydrochloride.

Mexiletine-induced pustular formation as has been seen in our case was previously reported by Kikuchi et al. [1]. They reported a 77-year-old man who developed a generalized erythematous skin eruption 45 days after the administration of mexiletine hydrochloride. There were numerous papules and infiltrated erythematous patches over the whole body, and several fine pustules were scattered on large confluent erythematous plaques on the flank, however there was no facial edema. He was treated with oral prednisolone, and the skin eruption disappeared completely one month later. In our case, marked facial edema was also induced, which was considered due to very strong exudative reaction. We conclude that pustules, infiltrated erythema and facial edema were the signs of drug eruption induced by mexiletine hydrochloride in our case. To our knowledge, this is the first case of pustular drug eruption presenting marked facial edema after the use of mexiletine. *

Article accepted on 26/4/01

REFERENCES

1. Kikuchi K, Tsunoda T, Tagami H. Generalized drug eruption due to mexiletine hydrochloride: topical provocation on previously involved skin. Contact Dermatitis 1991; 25: 70-2.

2. Yamazaki S, Katayama I, Kurumaji Y, Yokozeki H, Nishioka K. Contact urticaria induced by mexiletine hydrochloride in a patient receiving iontophoresis. Br J Dermatol 1994; 130: 538-40.

3. Higa K, Hirata K, Dan K. Mexiletine-induced severe skin eruption, fever, eosinophilia, atypical lymphocytosis, and liver dysfunction. Pain 1997; 73: 97-9.

4. Spencer JM, Silvers DN, Grossman ME. Pustular eruption after drug exposure; is it pustular psoriasis or a pustular drug eruption? Br J Dermatol 1994; 130: 514-9.

5. MacMilan AL. Generalized pustular drug rash. Dermatologica 1973; 146: 285-91.

6. Kushimoto H, Aoki T. Toxic erythema with generalized follicular pustules caused by streptomycin. Arch Dermatol 1981; 117: 444-5.

7. Staughton RCD, Rowland-Payne CME, Harper JI, McMichen H. Toxic pustuloderma-a new entity? J R Soc Med 1984; 77: 6-8.

8. Commens CA, Fischer GO. Toxic pustuloderma following carbamazepine therapy. Arch Dermatol 1988; 124: 178-9.

9. Yamasaki R, Yamasaki M, Kawasaki Y, Nagasako R. Generalized pustular dermatosis caused by isoniazid. Br J Dermatol 1985; 112: 504-6.

10. Kalb RE, Grossman ME. Pustular eruption following administration of cephradine. Cutis 1986; 38: 58-60.

11. Jackson H, Vion B, Levy PM. Generalized eruptive pustular drug rash due to cephalexin. Dermatologica 1988; 177: 292-4.

12. Foyol J, Benard P, Bonnetblanc JM. Pustular eruption following administration of cefazolin: a second case report. J Am Acad Dermatol 1988; 19: 571.

13. Grattan CE. Generalized eruptive pustular drug rash due to naproxen. Dermatologica 1989; 179: 57-8.

14. Shelly ED, Shelly WB. The subcorneal pustular drug eruption: an example induced by norfloxacin. Cutis 1988; 42: 24-7.

15. Roujeau JC, Sage PB, Bourseau C, Guillume JC, Bernard P, Lok C, Plantin P, Claudy A, Delavierre C, Vaillant L, Wechsler J, Danan G, Benichou C, Beylot C. Acute generalized exanthematous pustulosis. analysis of 63 cases. Arch Dermatol 1991; 127: 1333-8.

16. Tueb RM, Burg G. Acute generalized exanthematous pustulosis due to doxycycline. Dermatology 1993; 186: 75-8.

17. Suzuki Y, Inagi R, Aono T, Yamanishi K, Shiohara T. Human herpesvirus 6 infection as a risk factor for the development of severe drug-induced hypersensitivity syndrome. Arch Dermatol 1998; 134: 1108-12.

18. Tohyama M, Yahata Y, Yasukawa M, Inagi R, Urano Y, Yamanishi K, Hashimoto K. Severe hypersensitivity syndrome due to sulfasalazine associated with reactivation of human herpesvirus 6. Arch Dermatol 1998; 134: 1113-7.