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Introduction: Voriconazole is an alternative for amphotericin B in the treatment of invasive aspergillosis. Voriconazole has a high oral bioavailability and is therefore promising for outpatient treatment. It is well tolerated, but one noncomparative study reported (mild) cutaneous side-effects in 8.6% of the patients. Case 1, a man (24 years) with chronic granulomatous disease was diagnosed with probable invasive pulmonary aspergillosis according to the EORTC/MSG definitions. Outpatient treatment with oral voriconazole (200 mg BID) was started and the patient improved. After 8 weeks, he developed profound erythema in sun-exposed areas (face, hands). Voriconazole was stopped and the erythema resolved within 2 weeks. Six weeks later the patient relapsed. Voriconazole was reinstituted. Despite protective measures, he redeveloped profound skin erythema and friability in sun-exposed areas after 4 weeks. After 6 weeks, lesions evolved to desquamation and small ulcers at the hands. After 8 weeks, the patient had large areas with bulla, desquamation and superficial ulcerations on lips, face and hands. Voriconazole was switched to itraconazole oral solution and all lesions healed within 1 week. Case 2 (man, 52 years, diabetes mellitus) underwent aortobifemoral vascular grafting. He was reoperated for thrombotic problems. Multiple cultures of the explanted graft yielded Aspergillus fumigatus. The vascular graft infection was complicated with acro-ileiitis and arthritis of the right knee and ankle. Amphotericin B was given for 1 month. Thereafter the patient was discharged with oral voriconazole (200 mg BID). After 2 months, asymptomatic hyperpigmentation in sun-exposed areas was noticed. After 20 weeks small vesicles appeared in sun exposed areas (face, neck, arms and legs). The vesicles evolved to bulla (diameter 1–2 cm) and ruptured after a few days. Crustae were formed and the lesions healed in 2 weeks. New lesions continued to appear while old lesions were healing. Voriconazole was switched to itraconazole oral solution and all lesions resolved within 2 weeks. Discussion: Skin reactions, mainly rash, pruritus and phototoxic induced erythema, are known but mostly mild side-effects of voriconazole. More severe facial erythema and cheilitis were reported in five patients. We reported severe late-onset phototoxic skin reactions in two patients. Further postmarketing surveillance on the incidence and impact of these late-onset cutaneous side-effects is warranted.