Abstract
Voriconazole is a broad-spectrum triazole antifungal agent indicated for invasive aspergillosis, refractory Candida infections, and other emerging invasive fungal infections. Adverse cutaneous reactions associated with voriconazole therapy occur in fewer than 10% of treated patients and range from mild erythematous eruptions to life-threatening reactions such as the Stevens-Johnson syndrome and toxic epidermal necrolysis. Photosensitivity reactions are an uncommon but characteristic dermatitis in voriconazole recipients, particularly following chronic administration. We report a case of voriconazole-induced phototoxicity in a 50-year-old male with Candida parapsilosis endocarditis that reversed on discontinuation of the drug.
Keywords: Antifungal agents, Candida parapsilosis, Phototoxicity
Case Report
A 50-year-old male heroin user with a previous mitral valve replacement presented with 2 weeks of fatigue, fevers, and chills. Physical examination was remarkable for a 2/6 holosystolic murmur in the left lower sternal border, with radiation to the apex. Laboratory tests revealed a white blood cell count of 25,500 cells/mm3, elevated Westergren erythrocyte sedimentation rate of 95 mm/h, and urinalysis showed 5 to 10 red blood cells/hpf. Multiple blood cultures grew Candida parapsilosis. A transesophageal echocardiogram showed a large vegetation on the mitral valve bioprosthesis. He received combination surgical and medical therapy for prosthetic mitral valve endocarditis due to C. parapsilosis. The patient underwent replacement of his prosthetic mitral valve and completed a 7-week course of parenteral liposomal amphotericin B daily combined with oral flucytosine. Because the C. parapsilosis had a relatively high minimum inhibitory concentration to fluconazole (MIC=4 μg/mL), the patient was placed on long-term oral voriconazole therapy 200 mg twice daily for suppressive treatment.
Five months into voriconazole therapy, he developed a non-pruritic, non-tender, erythematous, macular eruption of sun-exposed skin areas, particularly on the face, neck, and hand (figure 1 ▶, panels A and B). He had minimal sun exposure, wore long clothing, and drove his car with closed windows. The rash on the neck and hand developed on his left side, presumably from sun exposure while driving. This photosensitivity reaction resolved (figure 1 ▶, panels C and D) over 6 weeks, after fluconazole was substituted for voriconazole.
Figure 1.
Panels (A) and (B) show voriconazole-induced photosensitivity of the face, lips, and neck. Panels (C) and (D) show resolution of the photosensitivity reaction 6 weeks after stopping voriconazole.
Comment
Voriconazole, a broad-spectrum triazole antifungal agent, is the first line therapy for invasive aspergillosis.1 It is also indicated for refractory Candida infections and other emerging invasive fungal infections, such as fusariosis and Scedosporium apiospermum.2–4 Similar to the other azole agents, the mechanism of action of voriconazole is inhibition of cytochrome P450-dependent 14α-lanosterol demethylation, a vital step in cell membrane ergosterol synthesis by fungi. The most common adverse effect of voriconazole therapy is reversible disturbance of vision (photopsia), occurring in 30% of patients.2
Dermatologic reactions, mostly mild rashes, are the second most common adverse consequence of voriconazole, occurring in fewer than 10% of treated patients.5,6 Severe reactions, such as Stevens-Johnson syndrome and toxic epidermal necrolysis, have been reported.2,7 In contrast to the other azole antifungal agents, photosensitivity is a more common dermatologic complication of voriconazole and is most often seen with prolonged treatment duration.5,8–10 Voriconazole-induced photosensitivity reactions include erythematous eruptions of sun-exposed areas, such as facial erythema, chelitis, hyperpigmentation of the hands, exfoliative dermatitis, discoid lupus erythematosus, and pseudoporphyria.5,8–14 In general, such reactions are rapidly reversible upon discontinuation of the drug. Our patient developed a mild phototoxicity reaction of the face, neck, and upper extremities that normalized soon after stopping voriconazole. The development of multifocal facial squamous cell carcinomas due to a severe photosensitivity reaction from long-term voriconazole therapy was recently described.15
The etiology of voriconazole-induced photosensitivity remains unclear, but may be due to indirect retinoid effects or direct phototoxic effects of voriconazole or one of its metabolites.5,9–11 Photosensitivity reactions appear to be idiosyncratic, rather than dose-dependent.2 Counseling and recommendations regarding avoidance of sun exposure and use of sunscreens may lessen or resolve a majority of cases of voriconazole-induced photosensitivity despite drug continuation.
In summary, we present a case of reversible voriconazole-induced photosensitivity in a patient receiving chronic antifungal therapy for an invasive Candida infection. This case highlights the importance of recognizing adverse dermatologic reactions noted with voriconazole, an azole antifungal agent whose clinical use continues to expand.
Potential Conflicts of Interest: Dr. Aronoff has received honoraria from AstraZeneca, Merck, and Pfizer for speaking.
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