The correct answer is E: Voriconazole.
Discussion: Voriconazole, an expanded-spectrum triazole, is a relatively recent addition to the antifungal armamentarium. This agent is used to treat a wide variety of opportunistic fungal infections, especially infections caused by Aspergillus, Candida, Fusarium, and Scedosporium species. The drug may be used as a primary therapy when amphotericin-B toxicity is intolerable; alternatively, voriconazole(Drug information on voriconazole) may be used as long-term prophylaxis against recurrence of selected fungal infections. Voriconazole has been particularly useful in solid organ transplant patients, HIV-infected individuals, and those who are immunocompromised or immunosuppressed as a result of therapeutic interventions related to underlying cancer. Aside from its excellent spectrum of antifungal activity, voriconazole has also gained widespread acceptance because it is generally well tolerated and has a high degree of oral bioavailability. Typical adverse events related to voriconazole include visual disturbances (30%), mild-to-moderate abnormalities of hepatic enzyme levels (10%), and nonspecific cutaneous drug eruptions (9%).[2,3]
Some years after approval, however, voriconazole was also recognized to be a photosensitizer of variable severity in both adult and pediatric patients.[4-6] Photosensitivity may manifest as easily arising sun-induced tender erythema, blistering sunburn, the appearance of extensive solar lentigines or freckles, or a porphyria-like eruption of the hands and face. It has been estimated that some type of photosensitivity reaction occurs in up to 1% of all patients who receive voriconazole for a duration of longer than 12 weeks. The exact mechanism of the phototoxicity is uncertain, but it may involve the primary metabolite voriconazole N-oxide. This metabolite may act as a chromophore, attracting both long- and short-wave ultraviolet light (UVA and UVB).
Following recognition of its photosensitizing effect, voriconazole was found to be associated with ultraviolet light–related cutaneous neoplasia, including actinic keratoses and squamous cell carcinoma.[7-14] Taken as a whole, the group of patients reported to date all developed significant phototoxicity prior to the onset of squamous cell carcinoma. Moreover, skin cancer generally developed after extended (12 to 60 months) voriconazole treatment. Mean age at onset of squamous cell carcinoma in this literature cohort was 38 years, considerably earlier than the average age of onset for squamous cell carcinoma in the general population (over 65 years). Cases often demonstrate a clinically aggressive pattern of growth (rapid enlargement, early metastases) compared with the typical sun-induced squamous cell carcinoma, and multifocal appearance has been the rule rather than the exception. Multivariate analysis in a large series indicated that voriconazole exposure was an independent risk factor for cutaneous squamous cell carcinoma, but that this risk was further augmented by residence in a sunny geographic location.
Of course, all patients reported to date have been subject to some form of iatrogenic immunosuppression or have a disease that is inherently immunocompromising. In these situations, the development of nonmelanoma skin cancer is already expected. Nonetheless, several analytic series have pointed out that the risk of squamous cell carcinoma is much greater in those who receive voriconazole compared with an otherwise similar group who do not receive the antifungal, despite a similar immunosuppressive regimen.[14,15] In addition, these skin cancers occur earlier and are more aggressive than skin cancers in comparably immunocompromised patients without a history of prolonged voriconazole exposure.
The precise role played by voriconazole, in conjunction with a patient's immune status, underlying disease state, and baseline lifelong sun exposure, remains to be established. Nonetheless, when an oncology patient develops a fungal infection that requires prolonged voriconazole administration, careful attention should be paid to the skin, with periodic total body examinations to search for cutaneous malignancy.
1. Walsh TJ, Lutsar I, Driscoll T, et al. Voriconazole in the treatment of asperigillosis, scedosporiosis and other invasive fungal infections in children. Pediatr Infect Dis J. 2002;21:240-48.
2. Johnson LB, Kauffman CA. Voriconazole: a new triazole antifungal agent. Clin Infect Di.s 2003;36:630-37.
3. Boyd AJ, Modi S, Howard SJ, et al. Adverse reactions to voriconazole. Clin Infect Dis. 2004;39:1241-44.
4. Racette AJ, Roenigk HH, Hansen R, et al. Photoaging and phototoxicity from long-term voriconazole treatment in a 15-year-old girl. J Am Acad Dermatol. 2005;52:581-85.
5. Auffret N, Janssen P, Chevalier R, et al. Voriconazole photosensitivity: 7 cases. Ann Dermatol Venereo.l 2006;133:330-32.
6. Malani AN, Aronoff DM. Voriconazole-induced photosensitivity. Clin Med Res. 2008;6:83-85.
7. Morice C, Acher A, Soufir N, et al. Multifocal aggressive squamous cell carcinoma induced by prolonged voriconazole therapy: a case report. Case Rep Med. 2010; Article 351084; Published December 16, 2010.
8. Ibrahim SF, Singer JP, Arron ST. Catastrophic squamous cell carcinoma in lung transplant patients treated with voriconazole. Dermatol Surg. 2010;36:1752-55.
9. McCarthy KL, Playford EG, Looke DF, et al. Severe photosensitivity causing multifocal squamous cell carcinomas secondary to prolonged voriconazole therapy. Clin Infect Dis. 2007;44:55-56.
10. Vanacker A, Fabre G, Van Dorpe J, et al. Aggressive cutaneous squamous cell carcinoma associated with prolonged voriconazole therapy in a renal transplant patient. Am J Transplant. 2008;8:877-80.
11. Brunel AS, Fraisse T, Lechiche V, et al. Multifocal squamous cell carcinomas in an HIV-infected patient with a long-term voriconazole therapy. AIDS 2008;22:905-06.
12. Epaulard O, Saint-Raymond C, Villier C, et al. Multiple aggressive squamous cell carcinomas associated with prolonged voriconazole therapy in four immunocompromised patients. Clin Microbiol Infect. 2010;16:1362-64.
13. Cowen EW, Nguyen JC, Miller DD, et al. Chronic phototoxicity and aggressive squamous cell carcinoma of the skin in children and adults during treatment with voriconazole. J Am Acad Dermatol. 2010;62:31-37.
14. Vadnerkar A, Nguyen MH, Mitsani D, et al. Voriconazole exposure and geographic location are independent risk factors for squamous cell carcinoma of the skin among lung transplant recipients. J Heart Lung Transplant. 2010;29:1240-44.
15. Feist A, Osborne SL, Thistlewaite PA. Voriconazole use increases the incidence of skin cancer in lung transplant recipients. J Heart Lung Transplant. 2009;28:S5242