Antifungal azoles and other antifungal drugs for topical use

General Information

All the topically used azoles can cause local irritation, burning, and, if used intravaginally, burning, swelling, and discomfort during micturition. There is cross-sensitivity between econazole, enilconazole, miconazole, and probably all other phenethylimidazoles.

Contact allergy to topical imidazoles is rare, considering how commonly they are used. The imidazole derivatives most often reported to be allergens are miconazole, econazole, tioconazole, and isoconazole. As far as cross-reactivity is concerned, in one review, there were statistically significant associations between miconazole, econazole, and isoconazole; between sulconazole, miconazole, and econazole; and between isoconazole and tioconazole [ ].

Of 3049 outpatients who were patch-tested for contact dermatitis at the Department of Dermatology, Nippon Medical School Hospital from January 1984 to August 1994, 218 were patch-tested with topical antimycotic agents [ ]. There were 66 positive tests with imidazole derivatives, of whom 35 were allergic to the active ingredients: 16 were allergic to sulconazole, 11 to croconazole, 3 to tioconazole, 3 to miconazole, 1 to bifonazole, and 1 to clotrimazole. Exposure to croconazole occurred after a significantly shorter time with less drug than with sulconazole. Of the 35 patients who were allergic to an imidazole, 21 cross-reacted to other imidazoles.

Azoles

Bifonazole

Bifonazole has a broad spectrum of activity in vitro against dermatophytes, molds, yeasts, dimorphic fungi, and some Gram-positive bacteria. It has been used in a strength of 1% in creams, gels, solutions, and powders, applied once a day to treat superficial fungal infections of the skin, such as dermatophytoses, cutaneous candidiasis, and pityriasis versicolor [ ]. In a multicenter, double-blind, randomized, parallel-group comparison with flutrimazole cream 1% in the treatment of dermatomycoses in 449 patients the overall incidence of adverse effects (mainly mild local effects such as irritation or a burning sensation) was 5% [ ].

Clotrimazole

Clotrimazole was the first oral azole. While it was effective in deep mycoses, its limited absorption and induction of liver microsomal enzymes after a few days, leading to accelerated metabolism of the compound, as well as its toxicity, preclude its use for systemic therapy. Clotrimazole is therefore currently only used for topical therapy of mucocutaneous candidiasis.

Comparisons of fluconazole 200 mg/day with clotrimazole 10 mg 5 times/day in the prevention of thrush in patients with AIDS showed little difference in the occurrence of undesirable effects and abnormalities in laboratory measurements but less efficacy of clotrimazole [ , ].

Local problems can occur, including hypersensitivity reactions [ ]. In one case of contact allergy, patch-testing was positive with clotrimazole (5% in petroleum), itraconazole (1% in ether), and croconazole (1% in ether) [ ]. The authors reviewed the possible cross-reactions between the subgroups of imidazoles.

A 71-year-old woman had a severe exacerbation of vulval dermatitis for which she had been using Canesten (clotrimazole) cream [ ]. There was a positive patch-test reaction with clotrimazole (1% in petrolatum) and patch tests with the other constituents of Canesten were negative.

Topical vaginal administration of even relatively high doses of clotrimazole did not result in systemic toxicity [ ].

Croconazole

In one case of contact allergy, patch-testing was positive with clotrimazole (5% in petroleum), itraconazole (1% in ether), and croconazole (1% in ether) [ ]. The authors reviewed the possible cross-reactions between the subgroups of imidazoles.

Econazole

Econazole is used topically on the skin and also intravaginally, after which about 3–7% is absorbed. It can cause pruritus [ ] and vaginal burning [ ].

Enilconazole

Enilconazole is used in 10% solution/cream. Contact dermatitis has been reported [ , ].

Isoconazole

Isoconazole is mainly used for vaginal infections with Candida albicans . Contact dermatitis has been reported [ ], including an unusual case with a papulo-pustular reaction [ ].

Itraconazole

Lanoconazole (latoconazole)

Used in a 1% cream, lanoconazole is effective against Tinea , and is more active than clotrimazole or bifonazole. Several cases of contact dermatitis have been reported [ ].

Miconazole

See the monograph on miconazole.

Nimorazole

Nimorazole is believed to be active against Trichomonas vaginalis . No specific adverse effects have been described after local use.

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