Tioconazole

Summary

Synopsis

Tioconazole ¹ is a substituted imidazole antimicrobial agent structurally related to other drugs in this group. It has been shown to have a broad spectrum of activity in vitro against dermatophytes and yeasts, as well as against some chlamydia, trichomonads and Gram-positive bacteria. Both open and controlled clinical trials have clearly demonstrated the efficacy and safety of topical preparations of tioconazole for treating superficial dermatophyte or yeast infections of the skin and vaginal candidiasis. In comparative studies it was at least as effective as alternative imidazole antifungal drugs, and in a few trials significantly greater efficacy has been reported for tioconazole, compared with clotrimazole, miconazole, econazole and systemic ketoconazole. Preliminary studies in other clinical areas suggest tioconazole may be useful for treating onychomycosis (in a special nail formulation), napkin-rash due to Candida albicans, impetigo, and vaginal trichomoniasis, although comparative studies are needed in each of these settings to clearly assess its relative place in therapy.

Thus, tioconazole is an effective and well tolerated treatment for vaginal candidiasis and superficial fungal infections of the skin.

Pharmacodynamic Studies

In standard in vitro sensitivity tests tioconazole has been shown to have activity against a wide range of fungi (mainly dermatophytes and yeasts), as well as some chlamydia, trichomonads and Gram-positive bacteria. For most organisms tested, minimum inhibitory concentrations of tioconazole were often 2- to 4-fold lower than for miconazole. However, some studies have not shown such marked differences between these 2 drugs. In such studies, variations in experimental conditions (type of media, presence of horse serum, inoculum size, and incubation time) produced unpredictable changes in the in vitro activity of tioconazole and other imidazole antifungal drugs.

Additional comparative studies have demonstrated that tioconazole has considerably greater fungicidal activity than clotrimazole, econazole, ketoconazole, and miconazole against Candida albicans and other Candida species. Tioconazole was also rapidly fungicidal against selected strains of Trichophyton rubrum and Trichophyton mentagrophytes. In vivo animal studies confirmed the activity of tioconazole against experimental candidiasis and experimental dermatophytosis but also showed that it was ineffective against experimental coccidioidomycosis.

The precise mechanism of action of tioconazole has not been conclusively established although, like other imidazole antifungal drugs, it appears to act primarily on cell membrane systems. Recent evidence suggests that it may have 2 modes of action: a fungistatic mechanism at low concentrations which seems to be related to inhibition of the synthesis of ergosterol a cell membrane component, and a fungicidal action at higher concentrations which is due to direct damage of the cell wall. Interestingly, in an in vitro system tioconazole was actively fungicidal against both logarithmic and stationary phase cells of Candida albicans and Candida parapsilosis, in contrast to other imidazoles tested which were inactive against stationary phase organisms.

Pharmacokinetic Studies

Minimal systemic absorption of tioconazole has been demonstrated following the application of 2% vaginal cream, 6% vaginal ointment or a 300mg pessary to women with vaginal candidiasis, 1 or 2% dermal cream to the skin of patients, and 28% nail solution to the forearm skin of volunteers. Animal studies have confirmed minimal systemic exposure after ^l4C-tioconazole was applied dermally or intravaginally.

Therapeutic Trials

Tioconazole has been studied in relatively large numbers of patients with superficial fungal infections of the skin or vaginal candidiasis and in a smaller number of patients with superficial bacterial infections, onychomycosis or vaginal trichomoniasis.

Open studies in patients with superficial dermatophyte or yeast infections of the skin demonstrated that once or twice daily treatment with topical tioconazole 1% cream resulted in complete (clinical and mycological) cure rates of between 60 and 98% within 2 to 6 weeks. One study showed that once daily administration was as effective as twice daily administration; if this is confirmed in a few additional trials it will be a worthwhile advantage, simplifying dosage regimens. In comparative clinical trials in patients with fungal skin infections tioconazole cream was significantly superior to placebo cream and produced rates of cure equivalent to those of alternative imidazole antifungal drugs. Indeed, some investigators reported trends in favour of tioconazole compared with miconazole dermal cream, and others significantly better cure rates with tioconazole compared with topical clotrimazole. Analysis of response rates according to the type of infecting organism generally did not identify any consistent significant differences between the various imidazole drugs. However, in isolated therapeutic trials tioconazole 1 or 2% cream was more effective against Trichophyton rubrum (than miconazole and clotrimazole), Trichophyton mentagrophytes (than miconazole, econazole, and clotrimazole), Malasse zia furfur (than miconazole and clotrimazole), and Candida albicans (than clotrimazole).

During a multicentre clinical trial tioconazole 1% cream cured 78% of infants with napkin rash primarily caused by Candida albicans and, in addition, also cured 8 of 17 infants with impetigo primarily caused by Staphylococcus aureus. Another unpublished multicentre study showed that a specially formulated 28% nail solution of tioconazole produced some degree of improvement in approximately 70% of patients. The results from these preliminary investigations are encouraging but comparative studies are needed to clearly define the relative place of tioconazole in the treatment of such infections.

Both multiple dose regimens (100mg as 2% cream or 1 vaginal pessary for 3, 6 or 14 consecutive nights) and a single dose regimen (300mg as a single dose of 6% ointment or 1 vaginal pessary) of tioconazole have been used in patients with vaginal candidiasis. Although the various formulations and dosage schedules have not been extensively compared, data from several individual clinical trials, and from an international research programme which pooled data from several trials, provide evidence that they produce comparably high (between 70 and 90%) rates of cure. Persistence of cure rates (4 to 6 weeks after treatment with tioconazole) were also very high (80 to 95%) in women with vaginal candidiasis. Most signs and symptoms of the disease such as pruritus, rash, burning, discharge, and dyspareunia were either completely alleviated by tioconazole, or treatment reduced them from being a severe problem to a minor one. Tioconazole caused no drug-related complications in pregnant women who were followed to term after treatment for candidiasis. In comparative clinical trials intravaginally administered tioconazole was at least as effective as other imidazole antifungal drugs; some studies demonstrated significant advantages compared with clotrimazole vaginal cream, econazole vaginal cream, and systemic ketoconazole. Significantly higher short term cure rates were observed for tioconazole compared with pooled data for various alternative imidazole antifungal agents, in an international clinical research programme which evaluated more than 1000 patients with vaginal candidiasis.

A preliminary study in 20 patients with vaginal trichomoniasis showed that intravaginal tioconazole (5g of 2% cream once nightly for 3 days) was effective in about 80% of patients. Symptoms of the disease were markedly reduced, 12 of 19 patients considered the treatment to be very good, and approximately 80% of the group were microbiologically cured 30 and 60 days after treatment. As encouraging as these results appear, additional comparative studies are essential to clearly define the relative place of tioconazole in the treatment of vaginal trichomoniasis.

Side Effects

Topical preparations of tioconazole have been well tolerated in the majority of patients. The only adverse experiences reported have been local reactions such as redness, burning and itching. In comparative clinical trials the incidence of such effects has generally been of the same order for tioconazole as for other imidazole antifungal drugs. In one comparative study tioconazole 6% vaginal ointment caused markedly fewer side effects than systemically administered ketoconazole.

Dosage and Administration

In dermatomycoses, topical preparations of tioconazole 1% (cream, powder, lotion, and spray solution) should be applied once daily (dermal cream) or twice daily, night and morning, and the duration of treatment should be individualised to take into account the site of infection and the invading pathogen. For the treatment of nail infections a 28% nail solution has been formulated and it should be applied twice daily for prolonged periods, usually of at least 6 months.

In vaginal candidiasis, various formulations of tioconazole are available for application deep into the vagina. The recommended dosage is 100mg (5g of 2% cream or a 100mg vaginal pessary) once nightly for 3 days for the majority of patients. Alternatively, a single dose of tioconazole 300mg (5ml of 6% ointment or a 300mg vaginal pessary) may be administered. This regimen may be repeated 1 week later for the small number of patients who improved with the first dose but did not achieve complete cure.