Efficacy and Safety of Eberconazole vs Sertaconazole in Localised Tinea Infection.

BACKGROUND: Topical antifungals especially azole group of drugs are effective agents in the treatment of dermatophytoses producing 100% clinical and mycological cure. Each of them vary having specific characteristics to tackle several clinical challenges like high relapse rate, recurrences and quality of life. AIMS AND
OBJECTIVES: To compare the efficacy and safety of Eberconazole and Sertaconazole in tinea infection.
MATERIALS AND METHODS: This was a randomized, observer-blinded, parallel-group study conducted at a dermatology out-patient department (OPD) of tertiary care teaching hospital in Puducherry. 85 patients with tinea corporis and tinea cruris infections who visited the dermatology OPD were enrolled in this study. The treatment phase involved two groups receiving either Sertaconazole 2% cream or Eberconazole 1% applied topically twice daily for 4 weeks. At the end of treatment phase, there was a 'follow-up phase' at the end of 4 weeks, where the patients were assessed clinically and mycologically. The data were analyzed using descriptive statistics using MS Excel version 2019 and SPSS version 15 for Windows.
RESULTS: The primary efficacy variables namely change in pruritus, erythema, induration, scaling and mycological cure significantly improved in both the groups, as compared to baseline (P < 0.001), in the treatment phase and follow-up phase. Intergroup comparison with respect to pruritus and scaling showed significant difference (P < 0.001), suggestive of better reduction of pruritus and scaling scores at 4 weeks with Sertaconazole when compared to Eberconazole.
CONCLUSIONS: Sertaconazole was better than Eberconazole in relieving signs and symptoms of dermatophytoses, especially pruritus, thereby improving patients' quality of life. Copyright:

Introduction

Dermatophytosis is a superficial fungal infection of the hair, nails, or skin caused by the dermatophytes Trichophyton spp., Microsporum spp., and Epidermophyton.[1] This has been a common global problem for decades. The global prevalence of superficial mycotic infections shows that 20-25% of the world's population has been affected in the last few decades.[2] The prevalence of dermatophytosis in India ranges from 36.6-78.4% and in south India the prevalance of tinea corporis was found to be 63.27%.[3] Dermatophytoses characterized by 'ringed lesions' usually presents with inflammatory symptoms including pruritus affecting the quality of life of the patient. Apart from that it also increases the chances of secondary bacterial infections.[4]

Treatment of dermatophytosis consists of oral or topical antifungal drugs or a combination of both which depends on the severity, site and extent of infection. The diffferent classes of topical antifungal drugs for dermatophytosis include the polyenes, the azoles, and the allylamine/benzylamines.[5]

Topical antifungals are considered as the first-line therapy for superficial dermatomycoses because of their efficacy and low potential for systemic adverse effects. These drugs are available in various formulations to facilitate penetration and to improve efficacy.

Azoles block the lanosterol 14α-demethylase, an enzyme necessary for the biosynthesis of ergosterol which is an essential component of the fungal cell membrane thereby leading to inhibition of cell growth and cell death.[1] Sertaconazole, an imidazole antifungal agent, has both fungistatic and fungicidal activity with broad spectrum antifungal activity.[6] It has been found to have anti-inflammatory and antipruritic effects which has been attributed to increased compliance. Its higher lipophilicity and greater retention of drug in the stratum corneum leads to greater mycological cure rates and lesser chance of relapse.[7]

Eberconazole, an imidazole also has been found to have broad antimicrobial activity and good efficacy against dermatophytes.[8] It has anti-inflammatory activity and this effect has been attributed to the inhibition of 5-lipoxygenase.

There is paucity of clinical studies regarding the clinical efficacy and safety of Sertaconazole in treatment of tinea in comparison to Eberconazole which is equally efficacious. Various studies have compared Eberconazole with other topical antifungals.[91011] But clinical efficacy in comparison to Sertaconazole has not been done in the south Indian population where the prevalence of tinea is on a higher trend. Hence the present study was done to compare the efficacy and safety of Sertaconazole 2% cream with Eberconazole 1% for the treatment of superficial mycoses.

Materials and methodology

This study was designed as a randomized, observer-blind, parallel-group study in patients with dermatophytoses involving tinea corporis and tinea cruris infections. The study was conducted in the dermatology OPD of a tertiary care teaching hospital in Pondicherry. Permission was taken from the institutional ethics committee before commencement. The study is registered with Clinical Trial Registry India [CTRI/2017/08/009435]. Ethics committee approval is obtained and date of approval is 22.10.2016.

Adults between the age of 18 and 70 years, with clinical diagnosis and mycological confirmation (positive KOH test) for tinea corporis and tinea cruris infections, were included in the study. Patients were excluded from the study, if they had clinical diagnosis of tinea pedis/manum, received topical or oral antimycotics either one or four weeks prior to the initiation of the study respectively, history of hypersensitivity to study drugs, immunocompromised status, superadded bacterial infection or pregnant or lactating women.

A total of 90 study participants were screened and 5 among them were excluded as 4 of them did not fullfil the inclusion criteria and 1 was not willing to sign the written informed [Figure 1: Flow diagram of the study]. Patients fulfilling the selection criteria were randomized to receive the trial drugs as per the randomization schedule in 1:1 ratio. In the initial 'treatment phase' the groups received either Sertaconazole 2% cream applied topically twice daily for four weeks and Eberconazole 1% cream twice daily for four weeks. At the end of the treatment phase, there was a 'follow-up phase' at end of 4 weeks, where the patients were assessed clinically and mycologically.

Figure 1

Flow diagram of the study

Primary efficacy was based on clinical and mycologic assessment of tinea lesion at baseline and end of 'treatment phase'. Clinical assessment was based on the proportion of patients with symptoms and signs of tinea lesions namely pruritus, erythema, induration and scaling graded as none (0), mild (1), moderate (2) and severe (3) depending on intensity. Mycologic assessment was based on KOH mounting for dermatophytes. Only the observer was blinded for the assessment during the study. Safety and tolerability were assessed by monitoring treatment related adverse events at each visit.

Statistical methods

All randomized patients who received study medication and completed the study were included for analysis. The data obtained was represented as mean ± standard deviation and percentages, as applicable. Efficacy data and patient characteristics data were computed using MS Excel version 2019. Ordinal data within groups were analyzed using independent 't' test whereas intergroup comparison were analyzed by paired 't' test using SPSS version 15 for Windows.

Results

A total of 85 study participants were enrolled. The study participants included 63 (74.2%) male patients and 22 (25.8%) female patients belonging to the age group 30-40 years. Most of them were diagnosed to have tinea corporis (76.5%) and few were diagnosed to have tinea cruris infection (23.5%). 50% (42) of the study participants were having predisposing risk factors of fungal infections like diabetes, hypertension and smoking and alcohol addictions. Baseline characteristics of the study participants are summarized in Table 1.

Table 1

Baseline Demography

Group	Sertaconazole 2%	Eberconazole 1%
Number of patients	43	42
Sex, n (%)
Male	32 (74.4)	31 (73.8)
Female	11 (25.6)	11 (26.2)
Age (years)	31.65±15.03	34.36±12.83
Weight (kg)	60.51±11.57	61.29±10.71
Height (cm)	156.98±11.92	157±13.4
Type of Infection, n (%)
T.corporis	34 (79.1)	31 (73.8)
T.cruris	9 (20.9)	11 (26.2)
Mycological examination, n (%)	43 (100)	42 (100)
Risk factors
Diabetes	4 (9.3)	12 (28.6)
Hypertension	2 (4.7)	10 (23.8)
Smoking	3 (7)	2 (4.8)
Alcohol	5 (11.6)	4 (9.5)
Baseline Mean Score	6.3±2.37	5.66±2.93

Primary efficacy was decided based onclinical and mycologic assessment of tinea lesions at baseline and end of 'treatment phase' after 4 weeks. At baseline, most of the study participants were having diffferent grades of severity of the lesions as shown in Table 2. The resolution of pruritus (90.5%), erythema (83.3%) and scaling (85.7%) was seen in higher proportion of study participants of Sertaconazole group compared to Eberconazole group. Similarly the resoultion of induration (93%) was seen in higher proportion of Eberconazole group compared to Sertaconazole group.

Table 2

Comparison of Severity of Symptoms Between Sertaconazole and Eberconazole Group

Symptoms	Severity	Eberconazole 1%		Sertaconazole2%
		Baseline (%)	End of Treatment (after 4 weeks) (%)	Baseline (%)	End of Treatment (after 4 weeks) (%)
Erythema	None	0		32 (74.4)	35 (83.3)
	Mild	9 (20.9)	11 (25.6)	27 (64.3)	7 (16.7)
	Moderate	18 (41.9)	0	8 (19)	0
	Severe	16 (37.2)	0	7 (16.7)	0
Scaling	None	0	22 (51.2)	5 (11.9)	36 (85.7)
	Mild	23 (53.5)	14 (32.6)	27 (64.3)	6 (14.3)
	Moderate	20 (46.5)	7 (16.3)	10 (23.8)	0
	Severe	0	0	0	0
Induration	None	2 (4.7)	40 (93)	3 (7.1)	33 (78.6)
	Mild	30 (69.8)	3 (7)	23 (54.8)	9 (21.4)
	Moderate	10 (23.3)	0	12 (28.6)	0
	Severe	1 (2.3)	0	4 (9.5)	0
Pruritus	None	0	25 (58.1)	0	38 (90.5)
	Mild	25 (58.1)	17 (40.5)	24 (57.1)	4 (9.5)
	Moderate	17 (39.5)	1 (2.4)	10 (23.8)	0
	Severe	1 (2.3)	0	8 (19)	0

The clinical assessment parameters (pruritus, erythema, induration and scaling) were graded based on the severity of the lesions. The grades at the end of the treatment and follow-up phase showed significant improvement when compared to the baseline (P < 0.001) in both the groups. Intergroup comparison between the groups with respect to pruritus and scaling showed significant difference (P < 0.001) with Sertaconazole having better reduction in pruritus and scaling scores as as shown in Table 3 and Figure 2.

Table 3

Mean Scores of Primary Efficacy Parameters in Eberconazole and Sertaconazole Groups

Parameters	Baseline Score	4th Week
Sertaconazole group
Erythema	2.16±0.75	0.26±0.44*
Scaling	1.47±0.50	0.65±0.75*,€
Induration	1.23±0.57	0.07±0.25*
Pruritus	1.44±0.55	0.12±0.32*,€
Eberconazole group
Erythema	1.52±0.77	0.17±0.38*
Scaling	1.12±0.59	0.14±0.35*
Induration	1.40±0.77	0.21±0.41*
Pruritus	1.62±0.80	0.45±0.55*

Values are expressed as mean±SD; Data analyzed using paired and unpaired ‘t test’; *P<0.001 when comparing baseline and 4 weeks of erythema, induration, scaling and pruritis in eberconazole and sertaconazole groups. €P<0.001 when comparing scaling and pruritus at 4 weeks between eberconazole and sertaconazole groups.

Figure 2

Comparison of anti-pruritic action between Eberconazole and Sertaconazole

With respect to mycological assessment, at baseline, all the study participants had positive KOH test for dermatophytes. At the end of treatment phase, all the study participants showed negative mycological assessment (negative KOH test).

With regards to safety and tolerability, both the study drugs were safe and tolerated well by all the study participants. One patient in Sertaconazole group reported mild burning sensation at the site of drug application, which later disappeared without any intervention.

Discussion

Dermatophytosis (tinea), a superficial fungal infection, has several challenges related to the management including usage of fixed dose combination when not warranted, self-treatment and non-compliance of patients.[12] Comparison of studies done on superficial fungal infections in cities such as Kolkata, Ahmedabad, and Chennai during different time frames have revealed an increasing trend of dermatophytosis.[13]

In the present study analysis based on the data of 85 patients, males were affected more when compared to females and the maximum number of patients were of the age group 30-40 years. Both the study drugs showed significant reduction in signs and symptoms (pruritus, erythema, induration and scaling) of tinea infections as compared to baseline with P < 0.001. Significant improvement observed in both the groups as compared to baseline.

At end of 'treatment phase' greater proportion of patients in Sertaconazole group had absence of pruritus (90.5%), erythema (83.3%) and scaling (85.7%) as compared to Eberconazole. Sertaconazole group was having better reduction in pruritus and scaling scores (P < 0.001) as compared to Eberconazole group.

This could be attributed to the antipruritic and anti-inflammatory action of Sertaconazole due to its ability to reduce histamine release and other proinflammatory cytokines including PGE2.[1] Due to this factor better adherence to treatment and improved quality of life would be ensured over other antifungals. With respect to induration, patients on Eberconazole group had 93% recovery from induration at the end of treatment phase as compared to 78.6%. At the end of 'treatment phase' all patients showed negative mycological assessment in both treatment groups.

Cure rates were slightly higher with Sertaconazole but did not differ significantly from that of Eberconazole.

This suggests that though topical Eberconazole has proven superior to other topical azoles and allyllamines in several studies, the cure rates of the Sertaconazole was found to differ from that of Eberconazole especially with respect to pruritus, erythema and scaling. The differences between the two groups could be possibly due to the retention property of the drug and higher lipophilicity apart from fungicidal action of Sertaconazole.[6] Studies have found that topical Sertaconazole was as effective as Terbinafine in localized tinea infections.[1415] In the present study, both the treatments were well tolerated and found to be safe. Only one patient in Sertaconazole group had mild burning sensation at the application site from which he recovered without any intervention.

The management of dermatophytosis in India is practically experience-driven and in the current era we are in need of an evidence-based approach. The lesions may have significant impact on health and can compromise the quality of life significantly.[16] The international guidelines which are available are either outdated or focus only on a specific type of tinea and seem to have been disparate considering the current clinical scenario.[131718]

Rotta et al.,[5] in their meta-analysis evaluated the efficacy of antifungal treatment of 65 randomized controlled trials (RCTs) comparing different topical antifungal with one another or with placebo. They found no statistically significant differences among the antifungals concerning the outcome of mycologic cure at the end of treatment. Similarly, Cochrane review on the topical antifungal treatments for tinea cruris and tinea corporis suggested that the topical antifungals like azoles treatments were effective in terms of clinical and mycological cure rates.[19] The cost of Sertaconazole is higher compared to Eberconazole which has to be looked upon.

In this study blinding could not be done due to logistic constraints and hence, only an observer-blind procedure was implemented. Fungal culture and species identification could not be done. Furthermore, the effectiveness of the two topical drugs was not compared in other variants of tinea.

Conclusion

The results of the present study indicate that Sertaconazole was better than Eberconazole in relieving signs and symptoms of dermatophytoses especially pruritus thereby improving patients' quality of life.

Financial support and sponsorship

This study was funded by Mahatma Gandhi Medical College and Research Institute (Sri Balaji Vidyapeeth University), Puducherry.

Conflicts of interest

There are no conflicts of interest.