Efficacy of topical clotrimazole vs. topical tolnaftate in the treatment of otomycosis. A randomized controlled clinical trial / Eficácia do clotrimazol tópico versus tolnaftato tópico no tratamento da otomicose: um ensaio clínico controlado randomizado

Abstract Introduction: Otomycosis, an infection of the ear canal by fungi, is prevalent in hot and humid weather. Nevertheless, there is not sufficient evidence for the effectiveness of different topical antifungal treatments. Tolnaftate, is a topical antifungal agent described to be effective in the treatment of otomycosis. Currently there are not sufficient studies that prove its efficacy. Objectives: To compare the efficacy of clotrimazole and tolnaftate administration in the treatment of otomycosis. Material and methods: A controlled, randomized and open clinical trial included patients diagnosed with fungal external otitis who were treated with topical antifungals, randomized into two treatment groups: (1) clotrimazole cream; (2) tolnaftate solution. They were microscopically evaluated at one and two weeks of treatment to determine resolution of disease. Recurrence and complications were recorded. Demographic and clinical variables were collected and analyzed. Follow-up and final outcomes (absence of infection) were compared between groups. Results: Forty eight patients were included, 28 in the clotrimazole group and 20 in the tolnaftate group. Spring was the weather most commonly associated with otomycosis, while otic manipulation was the risk factor more common in both groups. Predominant symptoms were itching and otic fullness. Aspergillus niger organism was isolated most frequently. Treatment with clotrimazole resulted in 75% resolution vs 45% resolution with treatment with tolnaftate at one week of treatment (p = 0.007). The Tolnaftate treatment group demonstrated higher recurrence rates and treatment failures, 20% and 15% respectively. Conclusions: Clotrimazole cream treatment is more effective than tolnaftate for uncomplicated otomycosis. More studies are needed to corroborate our results.

Resumo Introdução: Otomicose, uma infecção fúngica do canal auditivo externo, é prevalente em climas quentes e úmidos. No entanto, a literatura não apresenta evidências suficientes sobre os diferentes tratamentos antifúngicos tópicos. O tolnaftato é um antifúngico tópico descrito como eficaz no tratamento da otomicose; entretanto, sua eficácia não está suficientemente comprovada. Objetivo: Comparar a eficácia do uso de clotrimazol e tolnaftato no tratamento da otomicose. Material e método: Ensaio clínico controlado e randomizado; incluiu pacientes diagnosticados com otite externa fúngica tratados com antifúngicos tópicos, randomizados em dois grupos de tratamento: 1) clotrimazole (creme); 2) solução de tolnaftato. Eles foram avaliados microscopicamente uma e duas semanas após o início do tratamento para avaliar a resolução da doença. Recorrência e intercorrências foram registradas; além disso, as variáveis demográficas e clínicas foram coletadas e analisadas. Os dados do acompanhamento e desfechos finais (ausência de infecção) foram comparados entre os grupos. Resultados: O estudo incluiu 48 pacientes, 28 dos quais foram alocados ao grupo clotrimazole e 20 ao grupo tolnaftato. A primavera foi a estação mais comum; a manipulação foi o fator de risco mais comum em ambos os grupos. Os sintomas mais comuns foram coceira e plenitude auricular. Aspergillus niger foi o micro-organismo mais comumente isolado. Após uma semana, o tratamento com clotrimazol apresentou uma taxa de resolução de 75% vs. 45% com o tratamento com tolnaftato (p = 0,007). O tratamento com tolnaftato apresentou maiores taxas de recidiva e falhas: 20% e 15%, respectivamente. Conclusões: Em casos de otomicose não complicada, o uso de clotrimazol (creme) é mais eficaz do que o de tolnaftato. Mais estudos são necessários para corroborar os presentes resultados.

Efficacy of topical clotrimazole vs. topical tolnaftate in the treatment of otomycosis. A randomized controlled clinical trial.

INTRODUCTION: Otomycosis, an infection of the ear canal by fungi, is prevalent in hot and humid weather. Nevertheless, there is not sufficient evidence for the effectiveness of different topical antifungal treatments. Tolnaftate, is a topical antifungal agent described to be effective in the treatment of otomycosis. Currently there are not sufficient studies that prove its efficacy. OBJECTIVES: To compare the efficacy of clotrimazole and tolnaftate administration in the treatment of otomycosis. MATERIAL AND METHODS: A controlled, randomized and open clinical trial included patients diagnosed with fungal external otitis who were treated with topical antifungals, randomized into two treatment groups: (1) clotrimazole cream; (2) tolnaftate solution. They were microscopically evaluated at one and two weeks of treatment to determine resolution of disease. Recurrence and complications were recorded. Demographic and clinical variables were collected and analyzed. Follow-up and final outcomes (absence of infection) were compared between groups. RESULTS: Forty eight patients were included, 28 in the clotrimazole group and 20 in the tolnaftate group. Spring was the weather most commonly associated with otomycosis, while otic manipulation was the risk factor more common in both groups. Predominant symptoms were itching and otic fullness. Aspergillus niger organism was isolated most frequently. Treatment with clotrimazole resulted in 75% resolution vs 45% resolution with treatment with tolnaftate at one week of treatment (p=0.007). The Tolnaftate treatment group demonstrated higher recurrence rates and treatment failures, 20% and 15% respectively. CONCLUSIONS: Clotrimazole cream treatment is more effective than tolnaftate for uncomplicated otomycosis. More studies are needed to corroborate our results.

Enhancement of the topical tolnaftate delivery for the treatment of tinea pedis via provesicular gel systems.

Tolnaftate is a thiocarbamate antifungal drug which is therapeutically active against dermatophytes that cause various forms of tinea. Due to the small amount of tolnaftate released from ordinary ointment bases and insufficient penetration through the infected skin layers the need to incorporate the drug in a more suitable pharmaceutical form has evolved. A provesicular system is one such form that can solve these problems. Once in contact with the skin, dilution with moisture occurs and the provesicular system rapidly transforms into a vesicular one. Provesicular systems were prepared according to full-factorial experimental design. Plain provesicular systems were compared with systems containing Phospholipon 80 H and Lipoid S45 as penetration enhancers. Design expert software was used to analyze the effect of formulation variables (type of Span used as well as the presence or the absence of the penetration enhancer and its type) on the dependent variables: percent encapsulation efficiency (EE%), vesicle size and percent in vitro drug released). Three formulations were chosen; a plain provesicular system (PV-2), one containing Phospholipon 80H (PV-6) and another containing Lipoid S45 (PV-10) with the goal to reveal the effect of penetration enhancer on morphology, rheological properties and ex vivo permeation using confocal laser scanning microscopy (CLSM). Analysis of CLSM results showed that the penetration enhancing effect for the tested formulations followed the order PV-10 > PV-6 > PV-2. Promising clinically active treatment for tinea patients could be expected as shown by the in vivo permeation results for the provesicular systems as suggested by the CLSM results.

Study of tolnaftate release from fatty acids containing ointment and penetration into human skin ex vivo.

Five fatty acids (oleic, linoleic, myristic, lauric and capric) were incorporated in 10% (w/w) into ointment formulation and their influence on lipophilic model drug tolnaftate release in vitro and enhancing effect on tolnaftate penetration into epidermis and dermis of human skin ex vivo were investigated. The prepared ointments were tested for homogeneity, pH and theological properties. In vitro release studies and ex vivo skin penetration experiments were carried out using Hanson and Bronaugh-type flow-through diffusion cells, respectively. Tolnaftate cumulative amount liberated from semisolids was assayed using UV-Vis spectrophotometer. After in vitro skin penetration studies, appropriately extracted human skin layers were analyzed for tolnaftate content using a validated HPLC method. Statistical analysis revealed that release rate of tolnaftate from control ointment and ointments with fatty acids was not significantly different and only 7.34-8.98% of drug was liberated into an acceptor medium after 6 h. Tolnaftate amount penetrating into 1 cm2 of epidermis from ointments containing oleic, linoleic, myristic and lauric acids was significantly greater (p < 0.05) than from the control ointment. Penetration enhancing ratios for these fatty acids for tolnaftate penetration into epidermis ranged from 1.48 to 1.75. In conclusion, fatty acids did not increase the liberation of tolnaftate from ointment formulation, but demonstrated their enhancing effect on tolnaftate penetration into human epidermis in vitro. Results from in vitro release experiments do not suit for prediction of the situation in the skin in vitro, if chemical penetration enhancers are incorporated into the ointment formulation.

Tolnaftate spray treatment during pregnancy.

Teratogenic studies of tolnaftate, an antifungal agent, in humans have not been published. The population-based data set of the Hungarian Case-Control Surveillance of Congenital Abnormalities, 1980-1996 contained 22843 fetuses or newborns with congenital abnormalities and 38151 matched controls without congenital abnormalities. The mothers of 13 cases and 13 controls were treated with tolnaftate spray during pregnancy. Four cases had congenital cardiovascular malformations in the group of cases (OR with 95% CI: 3.1, 1.0-9.7), but these cardiac defects were different. Thus, it is a signal for the potential teratogenic risk of tolnaftate in a case-control study, though the number of cases and controls were limited. Therefore, international collaboration is needed for the final conclusion.

[Therapeutic efficacy of a topical tolnaftate preparation in guinea pig model of tinea pedis].

The therapeutic efficacy of a topical antifungal ointment containing 2% tolnaftate was studied in a guinea pig model of tinea pedis using the following four topical antifungal preparations commercially available as reference drugs: variotin (3,000 U/g ointment); phenyl-11-iodo-10-undecynoate (0.5% ointment); siccanin (1% ointment); and clotrimazole (1% cream). After the infection fully developed, the infected animals were treated twice daily with the testing drug or reference drug for consecutive four weeks. Therapeutic efficacy was mainly evaluated on the basis of the extent of the yield of fungal cultures from the infected skin tissues (infection intensity) at the end of the treatment period. In animal groups treated with tolnaftate as well as with three reference drugs, siccanin, phenyl-11-iodo-10-undecynoate and clotrimazole, the average infection intensity was significantly lower than that for untreated control group (P < 0.05-0.005) although no culture-negative animal was seen in any treated animal group. Comparing with all the reference drugs, tolnaftate was the most highly effective and there was significant difference in the average infection intensity between a tolnaftate treated and each reference drug-treated groups (P < 0.01-0.005). These results confirm the clinical usefulness of the current tolnaftate preparation in the treatment of patients with tinea pedis and probably other clinical forms of dermatophytoses.

Determination of the physical state of drug in microcapsule and microsphere formulations.

Tolnaftate microcapsules and microspheres were prepared by gelatin-acacia coacervation and emulsion-solvent evaporation methods respectively. The physical state of the drug in these formulations was determined by using scanning electron microscopy (SEM), X-ray powder diffractometry, and differential scanning calorimetry (DSC). High pressure liquid chromatographic (HPLC) method was used for stability determination and polymer-drug interactions were evaluated using FTIR. The pros and cons of each method, in the assessment of the physical state of drug in these formulations, were investigated. SEM was found to be useful in obtaining a direct visual evidence of the presence of crystalline drug in the microspheres, but not for the microcapsule formulation. The DSC method was used to determine the physical state of the drug qualitatively in both these formulations. In the case of the microcapsules, accurate quantitation of the crystalline drug content by DSC was not possible because of the interference of thermal events. Powder X-ray diffractometric method was able to demonstrate the presence of crystalline drug and polymorphic changes, if any, in both these formulations. HPLC data revealed that the drug was stable in these formulations for at least 6 months. The FTIR studies indicated the absence of any drug interaction with the polymeric matrix materials, during preparation of these dosage forms.

Tea tree oil in the treatment of tinea pedis.

Tea tree oil (an essential oil derived primarily from the Australian native Melaleuca alternifolia) has been used as a topical antiseptic agent since the early part of this century for a wide variety of skin infections; however, to date, the evidence for its efficacy in fungal infections is still largely anecdotal. One hundred and four patients completed a randomized, double-blind trial to evaluate the efficacy of 10% w/w tea tree oil cream compared with 1% tolnaftate and placebo creams in the treatment of tinea pedis. Significantly more tolnaftate-treated patients (85%) than tea tree oil (30%) and placebo-treated patients (21%) showed conversion to negative culture at the end of therapy (p < 0.001); there was no statistically significant difference between tea tree oil and placebo groups. All three groups demonstrated improvement in clinical condition based on the four clinical parameters of scaling, inflammation, itching and burning. The tea tree oil group (24/37) and the tolnaftate group (19/33) showed significant improvement in clinical condition when compared to the placebo group (14/34; p = 0.022 and p = 0.018 respectively). Tea tree oil cream (10% w/w) appears to reduce the symptomatology of tinea pedis as effectively as tolnaftate 1% but is no more effective than placebo in achieving a mycological cure. This may be the basis for the popular use of tea tree oil in the treatment of tinea pedis.

Observations with Chinofungin powder.

Chinofungin powder was used in 75 recruits, in 40 cases for prevention, in 35 cases for the treatment of manifesting mycotic alteration. After a three-week treatment with the product recovery was obtained in 54.3%, improvement in 28.6% of the cases. No change was observed among the blastomycetic infection cases. In 5 of the 40 healthy individuals (12.5%) the cultivation became positive for fungus by the end of the three-week observations period. According to the opinion of the authors non-compliance was responsible for the infections which occurred during the preventive treatment.

Clinical examinations with chinofungin spray and chinofungin powder.

Tolnaftate is effective in the local treatment of dermatophyte infections. It is recommended primarily in infections caused by Trichophyton rubrum, Trichophyton mentagrophytes, Epidermophyton floccosum, Microsporum canis and Malassezia furfur. It may be useful as an adjuvant local therapy in chronic dermatophyte infections treated with griseofulvin.

Enhanced percutaneous absorption of homogenized tolnaftate/beta-cyclodextrin polymer ground mixture.

The absorption of tolnaftate after external application of tolnaftate-cyclodextrin polymer homogenized ground mixtures was investigated in comparison with that of tolnaftate alone and non-homogenized mixtures. To evaluate their percutaneous absorption, samples were applied to the shaved back skin of mice. It was found that homogenized ground mixture samples showed the highest level of percutaneous absorption, and also resulted in the highest blood level concentrations.

The treatment of dermatophytoses of the glabrous skin: a comparison of undecylenic acid and its salt versus tolnaftate.

In a double-blind study, the efficacy of 1% tolnaftate cream, 3% undecylenic acid and its zinc salt, and a placebo cream were tested in dermatophytosis of the glaborous skin and groin. Ninety-seven subjects completed the study: 33 received tolnaftate, 23 of these subjects were cured clinically and mycologically. Thirty-two subjects received 3% undecylenic acid and 20% zinc undecylenate as a cream. Of these, 21 were cured clinically and mycologically. Only three of the 32 subjects receiving placebo were cured clinically and mycologically. Both tolnaftate and undecylenic acid and its zinc salt are effective in this condition.

Treatment of onychomycosis by ODT therapy with 20% urea ointment and 2% tolnaftate ointment.

20 patients with distal onychomycosis were given daily application of an ointment containing 2% tolnaftate and an ointment containing 20% urea under ODT. Following this, 17 of 20 patients developed onychomalacia and seven of these developed onycholysis 1 or 2 weeks later. The separated nails were cut as short as possible. Similarly to those patients with onychomalacia alone, occlusive dressing technique was continuously performed until the newly developed nails became macroscopically normal and no fungi were observed microscopically (responders). Following treatment, out of 20 patients, 14 responded. 5 patients who had a short course of treatment did not respond. Side-effects such as pain, hemorrhage and infection did not occur.

Comparative merits of two topical corticosteroid antimicrobial drugs.

The anti-inflammatory and antimicrobial activities of two topical creams, one containing halcinonide, neomycin and nystatin (HNN), and the other betamethasone valerate, gentamicin, iodochlorhydroxyquin and tolnaftate (BGI), were compared in a randomized, parallel study of 154 patients (eighty-seven secondarily infected eczematous dermatoses; sixty-seven cutaneous candidiasis). Repeated clinical assessments showed that the two creams produced equivalent therapeutic responses both in patients with infected eczematous lesions and candidiasis. HNN and BGI creams eradicated the bacterial pathogens isolated prior to treatment in 80% and 76%, respectively, of the patients with eczematous dermatoses. The organism most frequently isolated in these patients was S. aureus. Local irritation prompting discontinuance of therapy occurred in just one patient receiving HNN, and two patients receiving BGI.

Comparison between undecylenic acid and tolnaftate in the treatment of tinea pedis.

A double-blind parallel study comparing tolnaftate cream with undecylenic acid ointment and a placebo ointment in the treatment of symptomatic tinea pedis was conducted on the warm, humid Texas Gulf Coast. In one hundred and three patients studied, both the clinical and mycological effects of the two antifungal agents were indistinguishable. Both were significantly more effective than the placebo.