Lack of Allergic Cross-Reactivity between Fluconazole and Voriconazole

We report a patient with cerebral cryptococcosis who developed a systemic allergic reaction to fluconazole and was successfully challenged with voriconazole. This allergic reaction is likely to have a pathological mechanism different from that of hepatotoxicity without allergy, where others have reported a lack of cross-reaction between, and successful challenge with, fluconazole and voriconazole (6) and voriconazole and posaconazole (2).

A 65-year-old immunocompetent, human immunodeficiency virus-negative male developed confusion, weakness on the right side, and neglect. Magnetic resonance imaging demonstrated two lesions in the left frontal lobe and left parietal region. Brain biopsy confirmed Cryptococcus gattii. He commenced therapy with fluconazole at 400 mg daily. Other medications included phenytoin (300 mg at night), paracetamol (1 g four times daily [q.i.d.]), ranitidine (150 mg twice daily [b.i.d.]), and dexamethasone (4 mg b.i.d.) on a weaning schedule over 16 days. Liver function tests were normal. In the third week of treatment, the patient noted an itchy erythematous maculopapular rash involving his buttocks. The phenytoin was stopped, and the rash initially improved. Two weeks later, the rash recurred, this time involving his abdomen, torso, legs, and arms, and was associated with periorbital edema and right arm edema. There were no other features of anaphylaxis such as hypotension, dyspnea, or wheezing. The fluconazole was stopped, and antihistamines were begun. Over the next week, the patient developed an asymptomatic increase in his liver enzyme levels. His γ-glutamyl transpeptidase and alanine transaminase levels became elevated, reaching peaks of 626 U/liter and 58 U/liter, respectively (Fig. 1). There was concurrent eosinophilia with a peak of 2.5 × 10⁹/liter (Fig. 1). Skin biopsy showed an inflammatory cell infiltrate with the presence of eosinophils, consistent with a drug reaction. After resolution of the eosinophilia and liver function abnormalities, three options were considered. A desensitization to fluconazole was thought to be unacceptable given the severity of the systemic reaction and the presence of edema and eosinophilia. Use of a nonazole class of antifungals such as amphotericin would have necessitated long-term intravenous access and was not practical for the patient, who was keen to resume work as soon as possible. So due to the availability of an oral preparation, he underwent a supervised graded challenge with oral voriconazole, starting at a dose of 25 mg daily on day 1, 75 mg b.i.d. on day 2, 150 mg b.i.d. on day 3, 300 mg daily on day 4, and then 200 mg b.i.d. thereafter. There was no recurrence of symptoms, liver enzyme level elevation, or eosinophilia.

FIG. 1.

Changes in liver function test values and eosinophil count after initiation of antifungal therapy. GGT, γ-glutamyl transpeptidase; ALT, alanine transaminase.

The patient's cerebral cryptococcosis has continued to improve clinically and radiologically. At the time of writing, the patient was followed up for a period of 8 months. In this case, the absence of preexisting liver disease and the presence of eosinophilia, rash, and periorbital edema support an immunoallergic reaction to fluconazole.

While cutaneous side effects from fluconazole are common, hypersensitivity reactions are rare (Diflucan package insert; Pfizer Australia, Sydney, Australia). There are three reports of severe systemic hypersensitivity reactions involving rash, edema, hepatotoxicity, or eosinophilia (4, 5, 7), including an attempted rapid desensitization for a presumed immunoglobulin E-mediated reaction (5). Only one of these documented the presence of eosinophilia (7). None describes successful challenge with another azole. To our knowledge, there is one report of angioedema as a side effect of voriconazole; however, this was tolerable and did not require cessation of therapy (3). Other reports have documented the absence of cross-reactivity among azole derivatives, where itraconazole was used successfully in place of fluconazole in a patient with maculopapular rash diagnosed by oral challenge test (1).

We conclude from our experience with this case and review of the literature that severe hypersensitivity reactions to fluconazole can occur and that voriconazole can be successfully introduced without cross-sensitization occurring. In addition to documenting a systemic allergic reaction to fluconazole, our case demonstrates successful challenge with another azole. Hence, in situations of azole hypersensitivity, clinicians could consider cautious use of another azole before choosing another class of antifungal agent.