Short-Term and Low-Dose Oral FluconazoleTreatment Can Cause Stevens-JohnsonSyndrome in HIV-Negative Patients

We read with great interest an article on the association of fluconazole and Stevens-Johnson syndrome (SJS) by Thiyanaratnam et al. published in J Drugs Dermatol. 2010;9(10):1272-1274. In 2008, we reported the first case of SJS induced by fluconazole in a HIV-negative patient (Monastirli et al. Acta Derm Venereol. 2008;88:521-522.). Since then we have observed three further Caucasian HIV-negative patients, two 32- and 42-year-old females (patients 1 and 2) and one 59-year-old male (patient 3) with SJS due to this compound.

Mucocutaneous manifestations characteristic for SJS had developed 1-4 days after onset of treatment of vaginal candidiasis (patients 1 and 2) with 100-200 mg/day oral fluconazole (Flucodrug Caps, Med-One, Athens, Greece) and of candidal balanitis (patient 3) with 100 mg/day fluconazole (Figalol Caps; Biomedica-Chemica SA, Athens, Greece). All patients revealed multiple maculopapular target-like lesions with necrotic centers and in some cases with overlying blisters over the upper trunk and the extremities, whereas superficial ulcers and erosions were seen in their oral mucosa with edema, erosions, and crusts of the lips. Additionally, patients 1 and 2 showed a severe conjunctivitis. Bullous lesions and epidermal detachment affected about 6% (patient 3) and 8% (patients 1 and 2) of body surface.

The patients had received no other medications and had no history or evidence of autoimmune, neoplastic, or infectious diseases. Apart from cultures positive for Candida albicans, all routinely performed laboratory investigations were unremarkable. The clinical presentation taken together with the negative medication history and the laboratory investigations of the patients established the diagnosis of SJS, which was also supported by the histological findings in the biopsy skin specimens derived from patient 2 (apoptosis and necrosis of keratinocytes, vacuolization of basal layer, dermoepidermal detachment, and perivascular lymphocytic infiltration). Fluconazole was thought to be responsible for the occurrence of SJS, since it was the only drug administered to our patients prior to the onset of their rash and other possible etiological factors had been ruled out.

Subsequent to discontinuation of fluconazole upon admission, the patients were treated with intravenous methylprednisolone (80-160 mg/day for 3-6 days), oral and skin washings, and antiseptic eye drops (patients 1 and 2). All patients revealed a complete resolution of their mucocutaneous lesions within 3-4 weeks.

Fluconazole is a triazole antifungal agent widely used in the treatment of superficial and systemic fungal infections and in their prevention in immunocompromised patients. It acts through inhibition of cytochrome P450 14α-demethylase, which prevents the conversion of lanosterol to ergosterol, a basic structural component of the fungal cell membrane. The most common side effects of fluconazole are nausea, vomiting, headache, abdominal symptoms, elevation of liver function tests, and mucocutaneous lesions that are usually mild and include pruritus, urticaria, fixed drug eruption, maculopapular rash, exfoliative dermatitis, purpura, and angioedema.

SJS is an acute and potentially life-threatening mucocutaneous disorder of unclear pathogenesis, which is most commonly caused by drugs. A Medline search revealed that eight cases of fluconazole-induced SJS (including those three presented herein) have been reported. All but one SJS patients were HIV-negative and had received fluconazole at low doses (100-200 mg/day), in most cases over a period of 1-6 days. Presently, in package inserts and patient information leaflets of fluconazole-containing drugs the manufacturers claim that "rare cases of severe rashes with skin peeling have been reported in patients with AIDS," who commonly receive a long-term and high-dose fluconazole treatment and are regarded more prone to develop severe drug reactions. However, in view of the patients reported herein and elsewhere, it is clear that this antifungal agent is capable of causing SJS in immunocompetent individuals, even if it is administered to them at low doses and for a short period of time. Interestingly, at least at this juncture, the immunocompetent patients with fluconazole-induced SJS outnumber by far the HIV-positive patients with this disorder. It is, therefore, of essential importance that physicians are aware of this severe side effect of fluconazole and that the international regulatory authorities demand that patient information material about the side effects of this compound will be accordingly revised.

Efi Pasmatzi MD,^a Alexandra Monastirli MD,^a
Sophia Georgiou MD,^a
George Sgouros MD,^b Dionysios Tsambaos MD PhD^a
aDepartment of Dermatology, University of Patras, Rio-Patras, Greece
^bDepartment of Dermatology, Metaxa Cancer Hospital, Athens, Greece

The authors have no relevant conflicts of interest to disclose.