Toxic epidermal necrolysis as a complication of treatment with voriconazole.

Abstract: An 81-year-old female received voriconazole in a 7-day treatment course for a symptomatic Candida krusei urinary tract infection. Four days after the last dose, she developed toxic epidermal necrolysis. She was treated with intravenous immunoglobulin, and her symptoms promptly resolved.

Key Words: toxic epidermal necrolysis, voriconazole

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Toxic epidermal necrolysis (TEN) is a disorder involving lesions of the skin and mucous membranes after exposure to drugs or infections. In 80% of cases, TEN is associated with a specific medication. (1,2) The most common medications reported with TEN include sulfonamide antibiotics, aminopenicillins, anticonvulsants, oxicam nonsteroidal anti-inflammatory drugs, and allopurinol. (3) In this case report, a case of TEN associated with voriconazole is presented after a 7-day treatment for a symptomatic Candida krusei urinary tract infection.

Case Report

An 81-year-old woman presented with a 3-day history of nausea, vomiting, and fever and a 1-day history of blanching erythematous macules on her back after receiving a 7-day course of voriconazole for a symptomatic C krusei urinary tract infection. The patient had no significant medical history. She had no known allergies and no unusual environmental exposures. The only medication she had taken was voriconazole. Her blood pressure was 134/87 mm Hg and her pulse was 86 beats per minute, with a temperature of 39[degrees]C. The patient appeared jaundiced, and her liver enzymes were elevated. She was admitted to the hospital for evaluation of jaundice. Over the next 2 days, the erythematous macules rapidly spread to involve the anterior trunk, arms, legs, feet, and face. The macules developed dusky-appearing centers and began to evolve into flaccid vesicles and bullae involving approximately 40% of her body surface area (Figure). In addition, she had bilateral conjunctival hyperemia, oral and vaginal mucosa ulcerations, and swelling of her tongue.

An upper endoscopic examination of her gastrointestinal tract, done as part of the jaundice evaluation, demonstrated extensive mucosal erosions. A mucosal biopsy was not done because it was thought that this erosive mucosal process was an extension of her cutaneous process. Ultrasound and computed tomographic imaging failed to reveal any hepatic ductal dilation, and her elevated liver enzymes and bilirubin were consistent with a cholestatic jaundice. The diagnosis of TEN with spots was made clinically and confirmed by a skin biopsy, which showed full-thickness epidermal necrosis with cleavage in the upper dermis and a cell-poor infiltrate with a predominance of macrophages and dendrocytes.

The patient was immediately transferred to a burn unit. Intravenous immunoglobulin at a dose of 0.75 g/kg per day for 4 days with supportive care was initiated. The patient defervesced, and her skin and mucosal lesions improved over the 13 days of her hospitalization. The patient was discharged on hospital day 14, and remains well at the time of this writing, with no sequelae.

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Discussion

The most common mucosal membranes involved in TEN are, in order of decreasing frequency, the oropharynx, eyes, genitalia, and anus. (4) In this patient, bilateral conjunctival hyperemia, oral, vaginal, and gastrointestinal mucosal ulcerations and swelling of her tongue occurred. The internal involvement most likely preceded her cutaneous eruption, accounting for her presenting symptoms of nausea, vomiting, and the jaundice noted at the time of admission.

The patient was taking no medications before her hospitalization, except for voriconazole. She denied taking any over-the-counter medications or herbs. Ten days before the initial development of the rash, she began 200 mg voriconazole for 1 day and then 100 mg every 12 hours for a total of 7 days, for a culture-proven symptomatic C krusei urinary tract infection. The last voriconazole dose was taken 4 days before the onset of the rash. The close temporal relation between the initiation of voriconazole and the appearance of the skin eruption, and because voriconazole was the only medication the patient had taken, the TEN was determined to be most likely caused by voriconazole.

Conclusion

Voriconazole is not known to be a medication commonly associated with TEN. Voriconazole is a new triazole with excellent in vitro activity against a variety of fungi. (5,6) Its efficacy and safety in the treatment of invasive fungal infections including pathogens such as Aspergillus and Candida species is well established. (7-9) However, in one study of 69 children, 2 (3%) children had treatment-related serious adverse events (ulcerated lips with rash, elevated hepatic transaminases or bilirubin). (10) The most commonly reported voriconazole-related adverse events included elevation in hepatic transaminases or bilirubin (n = 8), skin rash (n = 8), abnormal vision (n = 3), and a photosensitivity reaction (n = 3). The pathophysiologic mechanisms for voriconazole-induced TEN are not known but probably involve the interaction between immunologic mechanisms and reactive drug metabolites. (11-13) TEN should strongly be considered in individuals taking voriconazole with temporally related characteristic lesions of the skin and mucous membranes, since this disorder can cause considerable morbidity and mortality.

Accepted December 18, 2004.

References

1. Roujeau JC, Stern RS. Severe adverse cutaneous reactions to drugs. N Engl J Med 1994;331:1272-1285.

2. Roujeau JC, Guillaume JC, Fabre JP, et al. Toxic epidermal necrolysis (Lyell syndrome): incidence and drug etiology in France, 1981-1985. Arch Dermatol 1990;126:37-42.

3. Roujeau JC, Kelly JP, Naldi L, et al. Medication use and the risk of Stevens-Johnson syndrome or toxic epidermal necrolysis. N Engl J Med 1995;333:1600-1607.

4. Becker DS. Toxic epidermal necrolysis. Lancet 1998;351:1417-1420.

5. Hoffman HL, Rathbun RC. Review of the safety and efficacy of voriconazole.

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7. Perfeet JR, Marr KA, Walsh TJ, et al. Voriconazole treatment for less-common, emerging, or refractory fungal infections. Clin Infect Dis 2003;36:1122-1131.

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10. Walsh TJ, Lutsar I, Driscoll T, et al. Voriconazole in the treatment of aspergillosis, scedosporiosis and other invasive fungal infections in children. Pediatr Infect Dis J 2002;21:240-248.

11. Spielberg SP, Gordon GB, Blake DA, et al. Predisposition to phenytoin hepatotoxicity assessed in vitro. N Engl J Med 1981;305:722-727.

12. Shear NH, Spielberg SP, Grant DM, et al. Differences in metabolism of sulfonamides predisposing to idiosyncratic toxicity. Ann Intern Med 1986;105:179-184.

13. Wolkenstein P, Charue D, Laurent P, et al. Metabolic predisposition to cutaneous adverse drug reactions: role in toxic epidermal necrolysis caused by sulfonamides and anticonvulsants. Arch Dermatol 1995;131:544-551.

RELATED ARTICLE: Key Points

* The most common mucosal membranes involved in toxic epidermal necrolysis (TEN) are, in order of decreasing frequency, the oropharynx, eyes, genitalia, and anus.

* Voriconazole is not known to be a medication commonly associated with TEN.

* The most commonly reported voriconazole-related adverse events include elevation in hepatic transaminases or bilirubin, skin rash, abnormal vision, and a photosensitivity reaction.

* TEN should be strongly considered in individuals receiving voriconazole with temporally related characteristic lesions of the skin and mucous membranes, since this disorder can cause considerable morbidity and mortality.

David B. Huang, MD, MPH, Jashin J. Wu, MD, and Christopher J. Lahart, MD

From the Department of Medicine, Baylor College of Medicine, Houston, TX.

Reprint requests to Dr. David B. Huang, Baylor College of Medicine, Department of Medicine, One Baylor Plaza, BCM 286, Room N1319, Houston, TX 77030. Email: [e-mail]