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Observation
July 2016

Posaconazole Substitution for Voriconazole-Associated Phototoxic Effects

Author Affiliations
  • 1University of Miami Miller School of Medicine, Miami, Florida
  • 2Florida Atlantic University Internal Medicine Residency Program, Boca Raton
  • 3Dermatology Associates of the Palm Beaches Inc, Delray Beach, Florida
  • 4Dermatology Residency Program, Broward Health, Ft Lauderdale, Florida
JAMA Dermatol. 2016;152(7):839-841. doi:10.1001/jamadermatol.2016.0345

Voriconazole is used for long-term prophylaxis or treatment of fungal infections. Voriconazole-induced phototoxic effects and photocarcinogenesis is an independent risk factor for squamous cell carcinoma (SCC) development in organ transplant recipients.1 An alternative for patients at risk for cutaneous cancer has not been well studied. We describe a patient with voriconazole-induced photocarcinogenesis whose symptoms and tumor count improved after substitution with posaconazole.

Report of a Case

A light-skinned woman in her 70s had been receiving voriconazole and low-dose corticosteroids since 2008 for suppression of chronic Exophiala dermatitidis meningitis. The infection might have been due to tainted epidural corticosteroid administration. She had no history of hematologic cancer, solid organ transplantation, or other immunosuppressed state. History of skin cancer included melanoma in situ treated in 2002.

Several months after initiating voriconazole therapy, she developed widespread actinic damage and phototoxic effects (Figure 1A). Over 21 months (from March 2014 through December 2015), the patient had 348 actinic keratoses (AKs) treated, and 32 of 41 biopsies were positive for SCC. In addition, she was intolerant of topical chemotherapy with fluorouracil or imiquimod. She also required 3 Mohs surgical procedures for large SCCs on the arms.

Figure 1.
Improvement of Voriconazole-Associated Phototoxic Effects Following Posaconazole Substitution
Improvement of Voriconazole-Associated Phototoxic Effects Following Posaconazole Substitution

A, A woman in her 70s taking voriconazole for more than 5 years presented with phototoxic effects and severe actinic damage. B, One year after switching treatment to posaconazole, both phototoxic effects and tumor count decreased.

We anticipated that substitution with posaconazole, an agent with no reports of phototoxic effects, might decrease the photocarcinogenic process while maintaining her infection in stable condition. One year after switching, she demonstrated improvement in photosensitivity and actinic damage (Figure 1B).

We compared the number of AKs treated during the 6 months preceding posaconazole substitution with the number treated during the 6 months after, while allowing for an intermediate “transition” time in between. There was a decrease in the mean (SD) number of AKs from 22.2 (13.0) to 6.6 (8.2) and SCCs from 2.2 (2.9) to 0.6 (1.1) each month. In addition, no subsequent tumors met the criteria for Mohs surgery (Figure 2).2 She is now able to tolerate short pulse therapy with topical fluorouracil.

Figure 2.
Change of Cancerous and Precancerous Lesions Following Posaconazole Substitution
Change of Cancerous and Precancerous Lesions Following Posaconazole Substitution

A monthly lesion count is shown. The arrow indicates the date of posaconazole substitution for voriconazole, which also is the last date Mohs surgery was required.

Discussion

Treatment options for E dermatitidis, a dematiaceous fungus, are not well documented, but voriconazole is widely used for treatment and prophylaxis of fungal infections.1 However, 8% to 10% of patients experience dermatologic adverse effects including phototoxic effects, squamous cell carcinomas, pseudoporphyria, discoid lupus erythematosus, and accelerated photoaging.1 The decision to switch to another antifungal agent was not without risk of meningitis disease progression. However, a recent meta-analysis ranked posaconazole superior to voriconazole in preventing invasive fungal infections.3 We conclude that posaconazole may be a reasonable choice for patients requiring long-term antifungal therapy who are at risk of SCC, such as solid organ transplant recipients.

The mechanism of voriconazole-associated SCC is not known, though voriconazole N-oxide toxicity appears to be the most supported mechanism.4 A multistep photoinduced malignancy process ensues: erythema of the photoexposed area in the first year followed by the appearance of AKs in the second or third year then SCCs in the third or fourth year.4 Our patient followed a similar timeline after beginning voriconazole treatment.

Most voriconazole-associated SCC cases reported occur in organ transplant recipients who are markedly immunocompromised. At baseline, transplant patients are already at risk of cutaneous cancers; the addition of voriconazole appears to accelerate UV-induced skin damage.5 While our patient had been on a long-term treatment regimen of low-dose corticosteroids, she was relatively immunocompetent, suggesting that immunocompetent individuals may also be at risk for photocarcinogenic effects of voriconazole.6

Posaconazole appears to have a more favorable adverse effect profile than voriconazole.3 In a case series of 3 patients with voriconazole-associated SCC, posaconazole was replaced in 2 of 3 patients, with improvement of the photosensitivity reaction.6 While the present patient did not cease developing SCCs, tumor burden and quality of life improved. Considering that posaconazole has a favorable adverse effect profile, it should be considered more often for patients who are at risk of cutaneous cancer development.

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Article Information

Corresponding Author: John Strasswimmer, MD, PhD, Strasswimmer Mohs Surgery, 2605 W Atlantic Ave, D-204 Delray Beach, FL 33445 (strassmail2014@gmail.com).

Published Online: March 23, 2016. doi:10.1001/jamadermatol.2016.0345.

Conflict of Interest Disclosures: None reported.

References
1.
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Connolly  SM, Baker  DR, Coldiron  BM,  et al; Ad Hoc Task Force; Ratings Panel.  AAD/ACMS/ASDSA/ASMS 2012 appropriate use criteria for Mohs micrographic surgery: a report of the American Academy of Dermatology, American College of Mohs Surgery, American Society for Dermatologic Surgery Association, and the American Society for Mohs Surgery.  J Am Acad Dermatol. 2012;67(4):531-550.PubMedGoogle ScholarCrossref
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Zhao  YJ, Khoo  AL, Tan  G,  et al.  Network meta-analysis and pharmacoeconomic evaluation of fluconazole, itraconazole, posaconazole and voriconazole in invasive fungal infection prophylaxis.  Antimicrob Agents Chemother. 2015;60(1):376-386.PubMedGoogle ScholarCrossref
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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(1):31-37.PubMedGoogle ScholarCrossref
6.
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(9):1362-1364.PubMedGoogle ScholarCrossref
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