Bifonazole

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Abstract
Bifonazole is a substituted imidazole antifungol agent structurally related to other drugs in this group. It possesses a broad spectrum of activity in vitro against dermatophytes, moulds, yeasts, dimorphic fungi and some Gram-positive bacteria. Both non-comparative and comparative clinical trials have clearly demonstrated the efficacy and safety of various formulations of bifonazole 1% (cream, gel, solution and powder) applied once daily in the treatment of superficial fungal infections of the skin such as dermatophytoses, cutaneous candidiasis and pityriasis versicolor. In comparative studies bifonazole was significantly superior to placebo and at least as effective as alternative imidazole antifungal drugs including clotrimazole, econazole, miconazole, oxiconazole and sulconazole. Preliminary studies in other superficial skin and nail infections/dermatoses suggest that bifonazole may be useful for treating onychomycoses (in a combination cream; bifonazole 1% plus urea 40%), otomycoses, erythrasma, sebopsoriasis, seborrhoeic dermatitis and rosacea. However, controlled trials are needed in each of these clinical settings to assess accurately its relative place in therapy. Thus, bifonazole is an effective and well-tolerated treatment for superficial fungal infections of the skin. Compared with the majority of topical antifungal drugs, which need to be applied at least twice daily, bifonazole offers the convenience of once daily administration, which may improve patient compliance. In standard in vitro susceptibility tests bifonazole has demonstrated a broad spectrum of antifungal activity, inhibiting the growth of dermatophytes, yeasts, moulds and dimorphic fungi, usually at concentrations of less than 4 mg/L. In comparative in vitro studies bifonazole has displayed a spectrum of activity similar to clotrimazole and miconazole; however, yeasts tended to be less susceptible to bifonazole. To overcome inconsistencies with standard in vitro tests, usually caused by variation in experimental conditions (pH, inoculum size, incubation time, type of media, etc.), the determination of relative inhibition factors (RIF) of antifungal drugs has been proposed. Using this system bifonazole was shown to have a range of activity against Candida spp., dermatophytes and Aspergillus spp. similar to other imidazole antifungals such as clotrimazole, econazole, ketoconazole, miconazole and tioconazole. Additionally, in vitro studies have demonstrated that bifonazole has greater fungicidal activity than clotrimazole against a small number of strains of dermatophytes and Candida spp. and that, like other imidazole antifungal agents, it is active against some bacterial species (Corynebacterium spp., staphylococci and streptococci, but not enterococci). In vivo animal studies have confirmed the activity of bifonazole in experimental dermatophytoses caused by Trichophyton spp. and in experimental candidiasis due to Candida albicans. In healthy volunteers bifonazole suppressed the wheal/flare response to intracutaneous histamine which indicates that it possesses anti-inflammatory activity. Like other imidazoles, it would seem that bifonazole exerts its antifungal effects by destroying the capacity of the fungal cell membrane to maintain the intracellular environment. A number of single- and multiple-dose studies in healthy volunteers and patients with superficial fungal infections have clearly shown that bifonazole is minimally absorbed following dermal application. The major fraction of the applied dose remains on the skin surface or in the layers of the stratum corneum, but despite the low level of systemic availability bifonazole has a high capacity for skin penetration and achieves concentrations several times higher than the MIC for most dermatophytes, even in the lower layers of the epidermis. The mean half-life of bifonazole in the stratum corneum has been calculated to be between 19 and 32 hours. Bifonazole has been evaluated in large numbers of patients presenting with a wide spectrum of superficial mycoses, including various tinea infections, cutaneous candidiasis and pityriasis versicolor. In controlled comparative trials involving patients with superficial fungal infections of the skin, bifonazole 1% formulations applied once daily were clearly superior to placebo and were generally of similar overall efficacy to other topical imidazoles such as clotrimazole, econazole, miconazole and sulconazole, which were usually applied twice daily. Indeed, the most significant finding in the comparative clinical trials in patients with dermatophytoses, cutaneous candidiasis or pityriasis versicolor has been that bifonazole need only be applied once daily — this is more convenient for the patient and may improve compliance compared with topical agents that must be applied more frequently. Results from a large multicentre study involving over 6000 patients with superficial fungal infections showed that bifonazole 1% cream or solution applied once daily produced complete clinical cure in 80 to 93% of patients in a mean of 19.6 days. Findings from other multicentre studies and from smaller clinical trials in specific indications such as tinea cruris, tinea corporis, tinea pedis, tinea pedis interdigitalis, tinea manuum, cutaneous candidiasis and pityriasis versicolor have, by and large, confirmed these rates of clinical cure and have shown the equieffectiveness of the different formulations of bifonazole. Bifonazole has also been used in the treatment of a number of miscellaneous infections such as onychomycoses, otomycoses, erythrasma, psoriasis, sebopsoriasis, seborrhoeic dermatitis and rosacea. Excellent results have been reported in many of these conditions but only small numbers of patients have been evaluated and the findings must be considered preliminary. Bifonazole 1% formulations have been very well tolerated and adverse effects have rarely resulted in cessation of therapy. In the largest study reported to date, involving 6747 patients, adverse events were experienced by 4.3% (which may be an overestimate given the similarity of side effects such as itching, burning, rash, erythema, etc. to the symptoms of the underlying infection), and treatment withdrawal was necessary in 1.8% of cases. For the treatment of dermatomycoses, topical preparations of bifonazole 1% (cream, gel, solution, and powder) should be applied once daily for 2 to 4 weeks. A longer duration of therapy may be needed for more resistant infections such as tinea pedis and tinea palmaris.