Efficacy of Bifonazole and Clotrimazole in the Treatment of Pityriasis Versicolour

By Sana Saleem, Atiya Rahman, Naima Saghir, Sunaina Kumari, Sadia Abbasi, Zarin Manzoor

Affiliations

1. Department of Dermatology, PNS Shifa Hospital, Karachi, Pakistan

doi: 10.29271/jcpsppg.2025.01.141

ABSTRACT
Objective: To compare the efficacy of bifonazole and clotrimazole in the treatment of pityriasis versicolour (PV).
Study Design: A randomised controlled trial.
Place and Duration of the Study: Department of Dermatology, PNS Shifa Hospital, Karachi, Pakistan, from April 2024 to March 2025.
Methodology: A total of 176 patients with clinically and mycologically confirmed PV were randomly allocated into two groups, with 99 patients in each group. Group A received bifonazole (1% w/w), and Group B received clotrimazole (1% w/w). Both medicines were applied topically in a thin layer twice daily for one month on the affected skin. Clinical and mycological assessments were done at baseline, and then at the 2^nd and 4^th weeks after starting the treatment. After stopping the medication, the patients were monitored for a month to check for disease recurrence. Data analysis was done using the SPSS version 26. The Chi-square test was applied to compare efficacy between the two groups. An independent t-test was applied to compare the quantitative data. A value of p ≤0.05 was considered as statistically significant.
Results: The mean age of patients in Group A was 33.20 ± 9.8 years, and in Group B it was 31.37 ± 11.94 years. Male patients were dominant in both groups. In terms of baseline data, no significant difference was observed, as the p-value was >0.05. At week 4, 73 (83%) cases Group A and 66 (75%) in Group B showed both clinical and mycological cure, with no statistically significant difference between the two groups (p = 0.195). Recurrence occurred in 3 (3.4%) patients in the bifonazole group and 5 (5.6%) in the clotrimazole group. No side effects were observed in either group.
Conclusion: Bifonazole has comparable efficacy to clotrimazole for the management of PV.

Key Words: Bifonazole, Clotrimazole, Pityriasis versicolour, Superficial fungal infection.

INTRODUCTION

A persistent fungal infection of the skin, pityriasis versicolour (PV), is brought on by the growth of lipophilic yeasts (Malassezia species) in the stratum corneum. Malassezia globosa is the most commonly found specie linked to PV, while M. sympodialis and M. furfur are also commonly observed.¹ As a component of the natural skin flora, Malassezia is generally not harmful in PV instances unless it transforms into its mycelial form. Numerous factors, such as high temperatures and humidity, hyperhidrosis, immunosuppression, and genetic predisposition, might cause this. Therefore, compared to temperate regions, PV is more common in tropical climates (up to 40%).² PV is difficult to cure, as relapse following treatment can be as high as 80% within two years.³ PV is primarily found on the upper trunk and is considered by distinct or concrescent, scaly, discoloured, or depigmented patches.¹

PV has been treated using a variety of methods, including topical treatments as well as systemic antifungals with distinct mechanisms of action such as itraconazole, fluconazole, and keto- conazole.^2-5

Bifonazole and clotrimazole are two antifungal medications. Clotrimazole is an imidazole antifungal with a wide range of antifungal activity. By blocking cytochrome P-450-dependent enzyme lanosterol 14-alpha-demethylase, which alters permeability of cell membranes, it stops the production of ergosterol, the primary cell sterol of fungi. Additionally, it results in dangerously high quantities of hydrogen peroxide forming inside the cells and changes the activity of oxidative and peroxidative enzymes.^6,7 Cell death and destruction of internal organelles and cell membranes are the overall results.⁸ Bifonazole has a dual mechanism of action. First, it prevents the formation of fungal ergosterol by inhibiting the cytochrome P-450 enzyme (lanosterol 14α-demethylase), a crucial enzyme in the process. Second, it also directly inhibits HMG-CoA reductase, the enzyme that initiates the manufacture of ergosterol. Fungal cell death results from the destabilisation of the fungal cell membrane caused by this disruption of ergosterol production. At 1% strength in creams, gels, and solutions, it has been used to treat superficial cutaneous fungal infections such as dermatophytosis, candidiasis, and PV.^9,10

Previous studies have shown that both medicines are helpful, yet data remain scarce, especially in the local populations. Furthermore, relapse rates in PV remain high, emphasising the need for therapies that can enhance clearance and potentially reduce recurrence. This study was carried out to compare the efficacy of bifonazole and clotrimazole in treating PV in the local community.

METHODOLOGY

This randomised control trial was carried out over a period of 12 months from April 2024 to March 2025, after obtaining the approval from the Ethical Review Committee of PNS Shifa Hospital, Karachi, Pakistan (ERC/2023/DERM/84). The study was registered in the Iranian Registry of Clinical Trials (IRCT registration number: 79893). After taking written informed consent, a total of 176 patients with PV lesions, aged between 18 to 60 years of either gender, were included using a non-probability consecutive sampling technique. Patients with local inflammatory or infectious diseases and women who were pregnant or lactating were excluded. The OpenEpi calculator was used to calculate the sample size by taking the efficacy of clotrimazole as 80%¹⁰ and bifonazole cream as 95%,¹⁰ with a power of the test of 80%, and a level of significance of 5%. The calculated sample size was 88 in each group.

Patients were divided into two groups using the lottery method. Demographic details, including age, height, weight, duration and site of disease, and gender, were recorded on a proforma. Group A received bifonazole (1% w/w), and Group B received clotrimazole (1% w/w). Both medicines were applied in a thin layer topically twice daily for one month on the affected skin. Commercially available preparations of bifonazole and clotrimazole were used in the study. Assessments were done at the baseline, 2^nd week, and 4^th week after starting the treatment. Patients were followed up for one month after stopping the treatment for assessment of clinical and mycological cure, and then further followed up for another month to assess the disease recurrence and any local or systemic side effects. Efficacy of the treatment was labelled as positive if there was an absence of scaling and no skin lesion on clinical as well as on Wood’s light examination, negative skin scraping for fungal hyphae and no disease recurrence or side effects.

Data were analysed using the SPSS version 26 software. Mean ± SD were calculated for quantitative data, whereas frequencies and percentages were reported for categorical variables. Chi-square/Fisher's exact test was applied to compare efficacy between the two groups. An independent t-test was used to compare quantitative data after checking normality using the Shapiro-Wilk test. A p-value of ≤0.05 was considered significant.

RESULTS

The mean age was 33.20 ± 9.8 years in Group A and 31.37 ± 11.94 years in Group B. There were 57 (64.8%) men and 31 (35.2%) women in Group A, while Group B consisted of 62 (70.5%) men and 26 (29.5%) women. In terms of baseline data, no significant difference was observed, as the p-value was greater than 0.05, as shown in Table I.

At the end of two weeks of treatment, none of the patients achieved clinical and mycological cure in either group; however, at week-4, 73 (83%) of the cases achieved both clinical and mycological cure in the bifonazole group, whereas 66 (75%) cases achieved clinical and mycological cure in the clotrimazole group. The difference was not statistically significant (p = 0.195), as shown in Table II and III.

Recurrence occurred in 3 (4.1%) patients in the bifonazole group and in 5 (5.6%) patients in the clotrimazole group. However, no side effects were observed in either group.

Table I: Descriptive data of the patients.
 

Parameters	Groups		p-values
Descriptive data	Group A	Group B
Age (mean ± SD), years	33.20 ± 9.8	31.37 ± 11.94	0.270*
Duration of disease (mean ± SD), weeks	7.37 ± 6.57	6.58 ± 4.90	0.357*
Gender, n (%)       Male       Female	- 57 (64.8%) 31 (35.2%)	- 62 (70.5%) 26 (29.5%)	- 0.520*
Sites: n (%)       Neck       Face       Trunk       Face, Neck       Neck, trunk	- 24 (27.3%) 12 (13.6%) 20 (22.7%) 10 (11.4%) 22 (25%)	- 33 (37.5%) 8 (9.1%) 24 (27.3%) 12 (13.6%) 11 (2.3%)	- - 0.169**
*Independent t-test. **Chi-square test.

Table II: Comparison of clinical and mycological response of bifonazole versus clotrimazole in the treatment of PV.

Groups	Baseline		At week-2		At week-4		Follow-up
	Clinical fluorescence	Mycological hyphae	Clinical fluorescence	Mycological hyphae	Clinical fluorescence	Mycological hyphae	Clinical fluorescence	Mycological hyphae
Group-A Positive Negative	88 (100%) 0	88 (100%) 0	88 (100%) 0	88 (100%) 0	15 (17%) 73 (83%)	15 (17%) 73 (83%)	18 (20.5%) 70 (79.5%)	18 (20.5%) 70 (79.5%)
Group-B Positive Negative	88 (100%) 0	88 (100%) 0	88 (100%) 0	88 (100%) 0	22 (25%) 66 (75%)	22 (25%) 66 (75%)	27 (30.7) 61 (69.3%)	27 (30.7) 61 (69.3%)
p-values	-	-	-	-	0.195**	0.195**	0.120**	0.120**
**Chi-square test.

Table III: Comparison of the efficacy of bifonazole and clotrimazole in the treatment of PV.

Groups	Efficacy		p-value
	Yes (n, %)	No (n, %)
Bifonazole	73 (83%)	15 (17%)	0.195*
Clotrimazole	66 (75%)	22 (25%)
**Chi-square test.

DISCUSSION

PV is a common cutaneous yeast infection in adults. Itching is one of the main symptoms, along with unacceptably negative cosmetic implications. Even with proper treatment, PV recurs frequently.⁸ Even though clotrimazole is a routinely used and proven efficient treatment for PV, research is still being done to find other useful medications. Clotrimazole is cost-effective and efficacious, but has poor compliance due to its unpleasant odour and difficult application over a large surface area for prolonged duration.¹¹

The effectiveness of various PV treatment approaches has been investigated in numerous studies. For instance, topical clotrimazole was found to be more effective than oral griseofulvin, 1% diclophenac gel, a single 400 mg dose of itraconazole, and fluconazole.¹² In comparison to topical clotrimazole, other antifungal medications such as topical terbinafine,^13,14 and sertaconazole cream,¹⁵ have shown even greater effectiveness. Terbinafine hydrochloride, a novel antifungal lotion, was compared to clotrimazole lotion in a study conducted by Khosravi et al.¹⁶ on 68 patients. For two weeks, patients used lotions twice daily. Patients in the terbinafine hydrochloride and clotrimazole groups had cure rates of 91.9% and 71%, respectively, with a statistically significant difference (p <0.05). In the terbinafine and clotrimazole groups, the rates of complete clinical cure were 70.3% and 51.6%, respectively.

In previous comparative studies, bifonazole was significantly superior to placebo and other imidazole antifungal medicines, including clotrimazole, econazole, miconazole, oxiconazole, and sulconazole.^15-18 The potential of bifonazole in the treatment of PV remains largely unexplored. To the best of the authors’ knowledge, no study has ever been carried out to compare the efficacy of bifonazole and clotrimazole in the treatment of PV. This study was carried out to see the effectiveness of bifonazole versus cotrimazole in treating PV in order to fill this gap in the literature.

In the current study, mycological and clinical findings were positive in both groups till week-2; however, at week-4, in 83% of the cases, clinical and mycological cure was achieved in the bifonazole group, whereas, in the clotrimazole group, both clinical and mycological cure was achieved in 75% cases. Although there was no statistically significant difference in the complete cure rates between the two groups, bifonazole showed a slight numerical advantage, which suggests that bifonazole is an effective antifungal agent for both mycological and clinical treatments of patients with PV. Moreover, no side effects were reported in either group.

A review by Gupta and Foley on the antifungal treatment for PV revealed that complete cure occurred in 85% cases with 80% cases of PV treated with clotrimazole. Similarly, it has been reported that complete cure occurred in 95% cases, with 95% cases of PV treated with bifonazole cream.¹⁰

Dehghan et al. examined the effectiveness of 1% clotrimazole cream applied twice daily for 15 days vs. a single 400 mg dosage of fluconazole in individuals with PV. Following a four-week course of treatment, patients treated with clotrimazole cream showed a considerably higher clinical response than those treated with oral fluconazole (complete response 94.9% vs. 81.2%, respectively, p = 0.044).¹⁹ Balwada et al. compared topical 1% clotrimazole cream and 2% ketoconazole cream for PV patients. After 14 days, evaluation showed that 18/20 (90%) of the patients who received ketoconazole cream had recovered, whereas two cases had noticeable persistent lesions. Seventy out of twenty (85%) of the patients in the clotrimazole-treated group recovered.²⁰ Tatavarthi et al. conducted a clinical assessment of the effectiveness of sertaconazole 2% cream in the treatment of PV and compared it with clotrimazole 1% cream.²¹ In this study, sertaconazole was found to be safer and more effective than topical clotrimazole in treating patients with PV.

Azoles are recognised to have fungistatic and anti-inflammatory qualities. Bifonazole, on the other hand, possesses fungicidal properties and might, in theory, lead to improved treatment outcomes. The study's limited statistical power may have contributed to the lack of meaningful difference in the two groups' complete cure rates, suggesting that the advantages of bifonazole may have been understated. To validate these results, future research with a wider group of patients, including those with more severe or extensive PV, is required. However, it is important to note that regardless of the treatment chosen, all patients who experienced a complete clinical cure were also confirmed to be microscopically free of PV at the conclusion of the trial.²²

CONCLUSION

This study shows that bifonazole has better efficacy with a minimal recurrence rate as compared to the topical 1% clotrimazole in treating PV. These results imply that bifonazole may be a good substitute for PV treatment. To fully comprehend the long-term safety profile and possible side effects of bifonazole use, as well as its relative efficacy and cost-effectiveness in comparison to alternative treatment choices, more research is required.

ETHICAL APPROVAL:
Ethical approval was obtained from the Ethical Review Committee of PNS Shifa Hospital, Karachi, Pakistan (ERC/2023/DERM/84) and was registered in the Iranian Registry of Clinical Trials (IRCT registration number: 79893).

PATIENTS’ CONSENT:
Written informed consent was taken from all patients included in the study.

COMPETING INTEREST:
The authors declared no conflict of interest.

AUTHORS’ CONTRIBUTION:
SS, AR: Design of the work, acquisition, analysis, and interpretation of data.
NS: Interpreted data and results.
SK: Contributed to abstract writing and references.
SA, ZM: Provided resources for research work.
All authors approved the final version of the manuscript to be published.

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