mycoses
Diagnosis,Therapy and Prophylaxis of Fungal Diseases
Original article
Combination treatment of oral terbinafine with topical terbinafine and 10% urea ointment in hyperkeratotic type tinea pedis Tian-Wei Shi,1,2,* Jiang-An Zhang,1,* Xian-Wei Zhang,3 Hong-Xing Yu,4 Yong-Bo Tang5 and Jian-Bin Yu1 1 Department of Dermatology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China, 2Department of Dermatology, People’s Hospital of Zhengzhou, Zhengzhou, China, 3Department of Surgery, Zhengzhou Children’s Hospital, Zhengzhou, China, 4Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China and 5Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China
Summary
Hyperkeratotic-type tinea pedis is chronic and recalcitrant to topical antifungal agents. Some topical antifungal agents are effective; however, long duration of therapy is required, which often reduce the treatment compliance of patients. To seek for short period therapy of hyperkeratotic type tinea pedis, in this study, we observed the efficacy and safety of treatment of topical terbinafine and 10% urea ointment combined oral terbinafine. Participants with hyperkeratotic type tinea pedis were randomly assigned to two groups. Patients in group I were treated with oral terbinafine for 2 weeks and topical terbinafine and 10% urea ointment for 4 weeks, whereas in group II, only the above topical agents were applied for 12 weeks. Clinical improvement rates and fungal eradication rates were compared between the two groups at 24 weeks after the initiation of treatment. The group I had stopped the topical therapy 8 weeks earlier than group II. There were no significant differences in mycological eradication rates and clinical improvement rates between the two groups, besides, no major side effects were noted in both groups. The short combination therapy with oral terbinafine was effective and safe; it should be a valuable option for patients with hyperkeratotic type tinea pedis.
Key words: Terbinafine, urea ointment, treatment, hyperkeratotic type, tinea pedis.
Introduction Tinea pedis is the most common fungal disease of skin all over the world. Treatment with topical antifungal agents in tinea pedis is conventional, and the duration of therapy is usually for up to 4 weeks.1 However, hyperkeratotic type tinea pedis, as a refractory type of tinea pedis, often has long-term hyperkeratosis symptoms and little response to the treatment.2 There were Correspondence: J.-B. Yu, Department of Dermatology, the First Affiliated Hospital of Zhengzhou University, 1 Jianshe Road, Zhengzhou 450052, China. Tel.: +86-13607668558. Fax: +86-37163858371. E-mail: [email protected] *Both authors contributed equally to this work. Submitted for publication 24 September 2013 Revised 7 March 2014 Accepted for publication 12 March 2014
© 2014 Blackwell Verlag GmbH
reports on effective therapy with only topical antifungal agents and urea ointment in hyperkeratotic type tinea pedis,3–5 but because of the long course of the treatment, patients usually could not keep compliance to complete the therapy. Therefore, we tried to seek for the treatment which not only worked effectively but also took short period. In this study, we evaluated the efficacy and safety of combination treatment of oral terbinafine with topical terbinafine cream and 10% urea ointment in hyperkeratotic type tinea pedis.
Subjects and methods Study participants
All patients with true hyperkeratotic type tinea pedis were Han people who came from outpatients of our hospitals. All participants gave their written informed consents before the trial enrolment. The study was
doi:10.1111/myc.12198
T.-W. Shi et al.
performed according to the Declaration of Helsinki Principles; and the protocol was approved by the hospital’s medical ethics committee. Inclusion and exclusion criteria for participants were as follows. Inclusion Criteria: (i) Patients had typical symptoms and must be diagnosed accurately. (ii) Patients must be above 18 years. (iii) Patients must be able to communicate effectively with the study personnel. (iv) Patients must be adequately informed of the properties and risks of the study and give written informed consents before screening. Exclusion criteria: (i) Patients who were 70 years old. (ii) Pregnant women or nursing mothers. (iii) Patients who had a known hypersensitivity or allergy to terbinafine or urea ointment. (iv) Patients who had other fungal infections, such as onychomycosis, tinea manus, etc. (v) Patients who had received systemic or topical antimycotic agents within 1 month before the trial enrolment. (6) Patients who had abnormal test values of hepatic function or severe liver or kidney disease or other systemic illnesses. (7) Patients who were taking drugs with known interactions to terbinafine or urea ointment. (8) Patients who were inappropriate candidates considered by doctors in this clinical trial. Trial design
This was a prospective, double-blind, randomised controlled trial with allocation ratio 1 : 1. Eligible patients who accepted allocation were randomly assigned to two groups according to randomisation procedures. Participants in group I were treated with oral and topical terbinafine as well as 10% urea ointment. In group II, oral placebo tablets and topical terbinafine cream as well as 10% urea ointment were applied. In both groups, oral terbinafine or placebo tablets were applied one tablet (250 mg) once daily for 2 weeks, terbinafine cream and 10% urea ointment were applied twice daily for 4 weeks in group I while for 12 weeks in group II. In group I, topical placebos were used after the 4-week treatment with terbinafine cream and 10% urea ointment. Patients were asked to keep regular return visits on the assessment days and to report adverse events during the treatment. Patients were evaluated at pretreatment and 2, 4, 8, 12, 24 weeks after the initiation of treatment. The treatment for participants could be terminated when his/her clinical symptoms disappeared and the results of mycological assessments were negative simultaneously. The treatment also should be terminated according to the judgement by investigators in charge in case of any adverse events.
2
Mycological assessments
On every visit day, direct microscopic examination and fungal culture were conducted at the same time; the assessment of mycological efficacy was divided into positive and negative. Mycological eradication (negative result) was considered when the direct microscopic examination and fungal culture were all negative. During each examination, specimens were collected from several involved lesions of patients to ensure reliable assessment. Clinical assessments
We evaluated the clinical symptoms and signs about hyperkeratosis, scales, fissures, erythema, itching and the extents were assessed in four grades: 0 = no symptoms; 1 = mild symptoms; 2 = moderate symptoms; 3 = severe symptoms. Improvements of clinical symptoms and signs were evaluated according to the following improvement ratings: remarkably improved (75% to 100% improvement); moderately improved (50% to 75% improvement); mildly improved (25% to 50% improvement); unchanged (0% to 25% improvement); aggravated. The amount of the remarkably improved and moderately improved cases was considered as the clinical improved cases. Adverse events assessment
Patients were asked to report adverse events during the treatment; and on each visit, the following laboratory tests would be conducted: blood routine test; urinalysis routine test; serum chemistry including ALT, AST, bilirubin, LDH, ALK, BUN, CRE and uric acid. Safety end points
All patients who received allocation were included in the safety analysis. Patients were carefully assessed on each visit for adverse events, including serious adverse symptoms and abnormal results of laboratory examination. If a serious adverse event appeared during the study, the adverse event reactions would be recorded, and then the patient would be followed up until the adverse reaction disappeared. If necessary, the patient would be discontinued from the study. Blinding methods
All the investigators and participants were blinded to the treatment allocation during the study. Only the
© 2014 Blackwell Verlag GmbH
Terbinafine and urea ointment in tinea pedis
project leader knew the randomisation code, but he had no contact with the study participants and the statistical data. The randomisation sequence would be concealed until the recruitment, collection of laboratory and clinical data, statistical analyses were all completed according to the rules. Statistics and analyses
T-test was used to the comparison of the baseline data between the two groups. The Chi-squared (v2) test was used to compare the clinical improvement rates and mycological eradication rates between the two groups. Value of P < 0.05 was considered significant difference. According to the 95% confidence intervals (95% CI) and clinical margin 15% (the numerical value of assessment data in group I minus that in group II), non-inferiority analyses would be conducted.
Results Baseline data
A total of 80 participants were randomly assigned to two groups with allocation ratio 1 : 1. Baseline demographic data and disease characteristics of the two groups were all balanced (Table 1). Three kinds of common dermatophytes (Trichophyton rubrum, Trichophyton mentagrophyte and Epidermophyton floccosum) and the other aetiological agents (Trichophyton megnini and yeast-like fungus) were observed by culture in the both groups, the rates of the agents in each groups were balanced well, too (Table 2). Efficacy results
After the follow-up stage of 24 weeks, the participants who completed all the return visits were 36 in group I Table 1 Demographic data, duration and average scores in both groups at baseline.
Group I Group II Statistic value
Sex (male/ female)
Age (years)
Duration (years)
Average scores
17/23 15/25 v2 = 0.208 (P1)
48.5 11.2 51.3 10.5 t = 1.153 (P2)
4.1 2.1 3.8 1.6 t = 0.719 (P3)
6.2 1.7 5.9 1.5 t = 0.837 (P4)
P1, P2, P3, P4 > 0.05. Comparisons of sex, age, duration, average scores between the two groups were not significant.
© 2014 Blackwell Verlag GmbH
while 34 in group II respectively. At the 12-week point, the follow-up for therapy efficacy in group I was 8 weeks, and in group II immediately after cessation of topical treatment (week 12) suggesting that the mycological rate in group II will, hence, be higher. We added the assessment results at the point of week 24, the scores of clinical evaluation at different stages in both groups are displayed in Fig. 1. The results displayed that the clinical improvement rates and fungal eradication rates between the two groups were not significantly different (Table 3), which demonstrated that the treatment efficacy in group I was non-inferiority to that in group II. Safety and tolerability
No serious adverse events or abnormal laboratory parameters were reported. Among patients who had mild adverse effects: each of the group I and group II had one patient who felt minor irritation. But the uncomfortable feeling was not significant enough to discontinue the following therapy. The participants demonstrated positive responses and the treatments were well tolerated.
Discussion Hyperkeratotic-type tinea pedis, which is classified into three types: true hyperkeratotic type, partial hyperkeratotic type and quasi-hyperkeratotic type,6–8 often has a long chronic duration. This disease always presents with severe erythema, rhagadia and thick, hyperkeratotic scale, which usually involve the entire plantar surface and sides of the feet.9 Because the scale on the plantar surface impedes and limits the absorption of the topical antifungal drugs, the topical antifungal used as sole therapy is often ineffective.10 By dissolving the intercellular matrix and augmenting the shedding of scales, urea cream could reduce the thickness of the horny layer and improve the dry skin.11 Therefore, topical urea cream is a potent tissue softener for hyperkeratotic skin. It can increase the efficacy of topical antifungal and improve the clinical symptoms in the treatment of hyperkeratotic type tinea pedis. Some researchers used topical urea to make it easy for the topical antifungals to penetrate the stratum corneum deep enough. Furthermore, some studies showed the usefulness of urea cream combined with topical antifungal agents in the treatment of hyperkeratotic type tinea pedis.4,5,12 However, for these topical treatments often require a long period of therapy, good patient compliance reduced. Because the duration of therapy
3
T.-W. Shi et al.
Table 2 Analysis of the aetiological agents in both groups at baseline.
Group I Group II Statistic value
Trichophyton rubrum Cases (rate)
Trichophyton mentagrophytes Cases (rate)
Epidermophyton floccosum Cases (rate)
Trichophyton megnini Cases (rate)
Yeast-like fungus Cases (rate)
28/40 (70%) 30/40 (75%) v2 = 0.251 (P1)
4/40 (10%) 3/40 (7.5%) v2 = 0.000 (P2)
3/40 (7.5%) 3/40 (7.5%) v2 = 0.180 (P3)
3/40 (7.5%) 2/40 (5%) v2 = 0.000 (P4)
2/40 (5%) 2/40 (5%) v2 = 0.263 (P5)
P1, P2, P3, P4, P5 > 0.05. Comparisons of dermatophytes between the two groups were not significant. Table 3 The efficacy analysis on per-protocol basis at 24 weeks.
Group I Group II v2-value 95% CI1
Clinical improvement cases (%)
Mycological eradication cases (%)
34/36 (94.44%) 32/34 (94.12%) v2a = 0.208 (Pa) ( 10.57%, 11.21%)
33/36 (91.67%) 31/34 (91.18%) v2b = 0.125 (Pb) ( 12.64%, 13.62%)
Pa > 0.05, Pb > 0.05. Comparisons of clinical improvement rates and mycological eradication rates between the two groups were not significant. 1
95% CI for the difference (rates in group I minus that in group II).
Figure 1 The scores of clinical evaluation at different visit points
in both groups.
was an important factor in determining patients’ compliance in treatment of hyperkeratotic type tinea pedis, the long duration of up to 12 weeks can reduce patient compliance and lead to treatment failure in the sole topical therapy. To seek for a shorter period treatment of hyperkeratotic-type tinea pedis, we applied combination therapy of oral terbinafine with topical treatment. Meanwhile, considering the true hyperkeratotic type involved all the sole and had the remarkable dermatologic symptoms, so we considered the treatment for the true hyperkeratotic type could also have a similar effect on the other two hyperkeratotic-type tinea pedis. Thus, we selected patients with true hyperkeratotic type as the subjects in this study.
4
As a result, we found that combination with oral terbinafine displayed similar efficacy and safety compared with the only topical applications. The results demonstrated that the combination treatment with oral terbinafine was non-inferior to the sole topical treatment; however, the therapy duration of the combination with oral terbinafine was shorter than that of sole topical treatment, which could improve treatment compliance of patients. As to the therapy mechanism, for affecting the integrity of the fungal cell wall by blocking the squalene epoxidase enzyme,13 terbinafine had a biocidal effect on dermatophytes,14 and its minimal inhibitory concentration against fungi was extremely lower than that of other drugs.15 Consequently this allylamine was the most potent antifungal agent in vitro against dermatophytes.16 As for the aetiological agents, T. rubrum, T. mentagrophytes and E. floccosum were the most common agents in patients with tinea pedis. In fact, these are the predominant dermatophytes in the United States, Europe and Asia.17 Some studies had demonstrated that the systemic treatment with terbinafine was effective for patients infected by these fungi.16,18 Since terbinafine could maintain a fungicidal level for several weeks even after the administration had stopped,19 and researchers verified that oral terbinafine not only had good efficacy in patients infected by Trichophyton spp but also required a much shorter duration of treatment.20 Therefore, this systemic antifungal drug can lead to better results and contribute to reduce the length of treatment.21 In this study, oral terbinafine could act from inside of the skin, which perhaps could overcome the deficiency that topical agents could not play a role for the limited absorption by the hyperkeratosis and thick scales, and so it could achieve a satisfying effect in a short period compared to the long-term sole topical treatment.
Conclusion In conclusion, this study confirmed that the short-term schedule of topical terbinafine cream and urea
© 2014 Blackwell Verlag GmbH
Terbinafine and urea ointment in tinea pedis
ointment combined with oral terbinafine was effective and safe in the treatment of hyperkeratotic-type tinea pedis. An additional advantage of this short schedule was the convenience of the patient, which would promote the treatment compliance. As a result, we recommend the treatment with topical terbinafine and 10% urea ointment combined oral terbinafine in the hyperkeratotic-type tinea pedis, especially to the patients who probably had poor compliance with the long period of therapy.
4
5
6 7
8
Acknowledgments We greatly appreciate professor Lu Nianzu (Department of Dermatology, the First Affiliated Hospital of Sun Yat-Sen University) for his outstanding work on the study and thank the patients who participated in this trial.
9 10 11
12
Funding statement 13
None. 14
Conflicts of interest No potential conflicts of interest were disclosed in this study.
15
16
17
References 18 1 2
3
Rand S. Overview: the treatment of dermatophytosis. J Am Acad Dermatol 2000; 43(5 Suppl.): S104–12. Savin R, Atton AV, Bergstresser PR et al. Efficacy of terbinafine 1% cream in the treatment of moccasin-type tinea pedis: result of placebo-controlled multicenter trials. J Am Acad Dermatol 1994; 30: 663–7. Tanuma H, Doi M, Sato N et al. Bifonazole (Mycospor cream) in the treatment of moccasin-type tinea pedis. Comparison between combination therapy of bifonazole cream+10% urea ointment (Urepearl) and occlusive dressing therapy with the same agents. Mycoses 2000; 43: 129–37.
© 2014 Blackwell Verlag GmbH
19
20
21
Tanuma H, Doi M, Ohta Y et al. Butenafine hydrochloride (Mentax) cream for the treatment of hyperkeratotic type tinea pedis and its transfer into the horny layer, with or without concomitant application of 20% urea ointment (Keratinamin). Mycoses 2001; 44: 287– 99. Tanuma H, Tanuma M, Abe M et al. Usefulness of lanoconazole (Astat) cream in the treatment of hyperkeratotic type tinea pedis. Comparative study of monotherapy and combination therapy with 10% urea ointment (Pastaron). Mycoses 2001; 44: 181–90. Tanuma H. Pathogenesis and treatment of hyperkeratotic tinea pedis in Japan. Mycoses 1999; 42: 21–9. Tanuma H, Doi M, Yaguchi A et al. Efficacy of oral fluconazole in tinea pedis of the hyperkeratotic type. Stratum corneum levels. Mycoses 1998; 41: 153–62. Morimoto K, Tanuma H, Kikuchi I et al. Pharmacokinetic investigation of oral itraconazole in stratum corneum level of tinea pedis. Mycoses 2004; 47: 104–14. Kemna ME, Elewski BE. A U.S. epidemiologic survey of superficial fungal diseases. J Am Acad Dermatol 1996; 35: 539–42. Elewski BE, Haley HR, Robbins CM. The use of 40% urea cream in the treatment of moccasin tinea pedis. Cutis 2004; 73: 355–7. Borelli C, Bielfeldt S, Borelli S et al. Cream or foam in pedal skin care: towards the ideal vehicle for urea used against dry skin. Int J Cosmet Sci 2011; 33: 37–43. Tanuma H, Doi M, Ohta Y et al. Usefulness of 1% terbinafine HCL (Lamisil) cream for hyperkeratotictype tinea pedis and its transfer into toe horny layer. Mycoses 2000; 43: 417–32. Welsh O, Vera-Cabrera L, Welsh E. Onychomycosis. Clin Dermatol 2010; 28: 151–9. Ryder NS. Terbinafine: mode of action and properties of the squalene epoxidase inhibition. Br J Dermatol 1992; 126(Suppl. 39): 2–7. Petranyi G, Meingassner JG, Miethe H. Activity of terbinafine in experimental fungal infections of laboratory animals. Antimicrob Agents Chemother 1998; 31: 1365–8. Succi IB, Bernardes-Engemann AR, Orofino-Costa R. Intermittent therapy with terbinafine and nail abrasion for dermatophyte toe onychomycosis: a pilot study. Mycoses 2013; 56: 327–32. Ameen M. Epidemiology of superficial fungal infections. Clin Dermatol 2010; 28: 197–201. Czaika VA, Lam PA. Trichophyton mentagrophytes cause underestimated contagious zoophilic fungal infection. Mycoses 2013; 1: 33–7. Gupta AK, Lynch LE, Kogan N et al. The use of an intermittent terbinafine regimen for the treatment of dermatophyte toenail onychomycosis. JEADV 2009; 23: 256–62. Gonzalez U, Seaton T, Bergus G et al. Systemic antifungal therapy for tinea capitis in children. Cochrane Database Sys Rev 2007; 17: CD004685. Lambert J, Richert B, Dezfoulian B et al. Epidemiology, physiopathology and treatment of a frequent ailment of tinea pedis. Rev Med Liege 2000; 55: 161–8.
5
Diagnosis,Therapy and Prophylaxis of Fungal Diseases
Original article
Combination treatment of oral terbinafine with topical terbinafine and 10% urea ointment in hyperkeratotic type tinea pedis Tian-Wei Shi,1,2,* Jiang-An Zhang,1,* Xian-Wei Zhang,3 Hong-Xing Yu,4 Yong-Bo Tang5 and Jian-Bin Yu1 1 Department of Dermatology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China, 2Department of Dermatology, People’s Hospital of Zhengzhou, Zhengzhou, China, 3Department of Surgery, Zhengzhou Children’s Hospital, Zhengzhou, China, 4Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China and 5Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China
Summary
Hyperkeratotic-type tinea pedis is chronic and recalcitrant to topical antifungal agents. Some topical antifungal agents are effective; however, long duration of therapy is required, which often reduce the treatment compliance of patients. To seek for short period therapy of hyperkeratotic type tinea pedis, in this study, we observed the efficacy and safety of treatment of topical terbinafine and 10% urea ointment combined oral terbinafine. Participants with hyperkeratotic type tinea pedis were randomly assigned to two groups. Patients in group I were treated with oral terbinafine for 2 weeks and topical terbinafine and 10% urea ointment for 4 weeks, whereas in group II, only the above topical agents were applied for 12 weeks. Clinical improvement rates and fungal eradication rates were compared between the two groups at 24 weeks after the initiation of treatment. The group I had stopped the topical therapy 8 weeks earlier than group II. There were no significant differences in mycological eradication rates and clinical improvement rates between the two groups, besides, no major side effects were noted in both groups. The short combination therapy with oral terbinafine was effective and safe; it should be a valuable option for patients with hyperkeratotic type tinea pedis.
Key words: Terbinafine, urea ointment, treatment, hyperkeratotic type, tinea pedis.
Introduction Tinea pedis is the most common fungal disease of skin all over the world. Treatment with topical antifungal agents in tinea pedis is conventional, and the duration of therapy is usually for up to 4 weeks.1 However, hyperkeratotic type tinea pedis, as a refractory type of tinea pedis, often has long-term hyperkeratosis symptoms and little response to the treatment.2 There were Correspondence: J.-B. Yu, Department of Dermatology, the First Affiliated Hospital of Zhengzhou University, 1 Jianshe Road, Zhengzhou 450052, China. Tel.: +86-13607668558. Fax: +86-37163858371. E-mail: [email protected] *Both authors contributed equally to this work. Submitted for publication 24 September 2013 Revised 7 March 2014 Accepted for publication 12 March 2014
© 2014 Blackwell Verlag GmbH
reports on effective therapy with only topical antifungal agents and urea ointment in hyperkeratotic type tinea pedis,3–5 but because of the long course of the treatment, patients usually could not keep compliance to complete the therapy. Therefore, we tried to seek for the treatment which not only worked effectively but also took short period. In this study, we evaluated the efficacy and safety of combination treatment of oral terbinafine with topical terbinafine cream and 10% urea ointment in hyperkeratotic type tinea pedis.
Subjects and methods Study participants
All patients with true hyperkeratotic type tinea pedis were Han people who came from outpatients of our hospitals. All participants gave their written informed consents before the trial enrolment. The study was
doi:10.1111/myc.12198
T.-W. Shi et al.
performed according to the Declaration of Helsinki Principles; and the protocol was approved by the hospital’s medical ethics committee. Inclusion and exclusion criteria for participants were as follows. Inclusion Criteria: (i) Patients had typical symptoms and must be diagnosed accurately. (ii) Patients must be above 18 years. (iii) Patients must be able to communicate effectively with the study personnel. (iv) Patients must be adequately informed of the properties and risks of the study and give written informed consents before screening. Exclusion criteria: (i) Patients who were 70 years old. (ii) Pregnant women or nursing mothers. (iii) Patients who had a known hypersensitivity or allergy to terbinafine or urea ointment. (iv) Patients who had other fungal infections, such as onychomycosis, tinea manus, etc. (v) Patients who had received systemic or topical antimycotic agents within 1 month before the trial enrolment. (6) Patients who had abnormal test values of hepatic function or severe liver or kidney disease or other systemic illnesses. (7) Patients who were taking drugs with known interactions to terbinafine or urea ointment. (8) Patients who were inappropriate candidates considered by doctors in this clinical trial. Trial design
This was a prospective, double-blind, randomised controlled trial with allocation ratio 1 : 1. Eligible patients who accepted allocation were randomly assigned to two groups according to randomisation procedures. Participants in group I were treated with oral and topical terbinafine as well as 10% urea ointment. In group II, oral placebo tablets and topical terbinafine cream as well as 10% urea ointment were applied. In both groups, oral terbinafine or placebo tablets were applied one tablet (250 mg) once daily for 2 weeks, terbinafine cream and 10% urea ointment were applied twice daily for 4 weeks in group I while for 12 weeks in group II. In group I, topical placebos were used after the 4-week treatment with terbinafine cream and 10% urea ointment. Patients were asked to keep regular return visits on the assessment days and to report adverse events during the treatment. Patients were evaluated at pretreatment and 2, 4, 8, 12, 24 weeks after the initiation of treatment. The treatment for participants could be terminated when his/her clinical symptoms disappeared and the results of mycological assessments were negative simultaneously. The treatment also should be terminated according to the judgement by investigators in charge in case of any adverse events.
2
Mycological assessments
On every visit day, direct microscopic examination and fungal culture were conducted at the same time; the assessment of mycological efficacy was divided into positive and negative. Mycological eradication (negative result) was considered when the direct microscopic examination and fungal culture were all negative. During each examination, specimens were collected from several involved lesions of patients to ensure reliable assessment. Clinical assessments
We evaluated the clinical symptoms and signs about hyperkeratosis, scales, fissures, erythema, itching and the extents were assessed in four grades: 0 = no symptoms; 1 = mild symptoms; 2 = moderate symptoms; 3 = severe symptoms. Improvements of clinical symptoms and signs were evaluated according to the following improvement ratings: remarkably improved (75% to 100% improvement); moderately improved (50% to 75% improvement); mildly improved (25% to 50% improvement); unchanged (0% to 25% improvement); aggravated. The amount of the remarkably improved and moderately improved cases was considered as the clinical improved cases. Adverse events assessment
Patients were asked to report adverse events during the treatment; and on each visit, the following laboratory tests would be conducted: blood routine test; urinalysis routine test; serum chemistry including ALT, AST, bilirubin, LDH, ALK, BUN, CRE and uric acid. Safety end points
All patients who received allocation were included in the safety analysis. Patients were carefully assessed on each visit for adverse events, including serious adverse symptoms and abnormal results of laboratory examination. If a serious adverse event appeared during the study, the adverse event reactions would be recorded, and then the patient would be followed up until the adverse reaction disappeared. If necessary, the patient would be discontinued from the study. Blinding methods
All the investigators and participants were blinded to the treatment allocation during the study. Only the
© 2014 Blackwell Verlag GmbH
Terbinafine and urea ointment in tinea pedis
project leader knew the randomisation code, but he had no contact with the study participants and the statistical data. The randomisation sequence would be concealed until the recruitment, collection of laboratory and clinical data, statistical analyses were all completed according to the rules. Statistics and analyses
T-test was used to the comparison of the baseline data between the two groups. The Chi-squared (v2) test was used to compare the clinical improvement rates and mycological eradication rates between the two groups. Value of P < 0.05 was considered significant difference. According to the 95% confidence intervals (95% CI) and clinical margin 15% (the numerical value of assessment data in group I minus that in group II), non-inferiority analyses would be conducted.
Results Baseline data
A total of 80 participants were randomly assigned to two groups with allocation ratio 1 : 1. Baseline demographic data and disease characteristics of the two groups were all balanced (Table 1). Three kinds of common dermatophytes (Trichophyton rubrum, Trichophyton mentagrophyte and Epidermophyton floccosum) and the other aetiological agents (Trichophyton megnini and yeast-like fungus) were observed by culture in the both groups, the rates of the agents in each groups were balanced well, too (Table 2). Efficacy results
After the follow-up stage of 24 weeks, the participants who completed all the return visits were 36 in group I Table 1 Demographic data, duration and average scores in both groups at baseline.
Group I Group II Statistic value
Sex (male/ female)
Age (years)
Duration (years)
Average scores
17/23 15/25 v2 = 0.208 (P1)
48.5 11.2 51.3 10.5 t = 1.153 (P2)
4.1 2.1 3.8 1.6 t = 0.719 (P3)
6.2 1.7 5.9 1.5 t = 0.837 (P4)
P1, P2, P3, P4 > 0.05. Comparisons of sex, age, duration, average scores between the two groups were not significant.
© 2014 Blackwell Verlag GmbH
while 34 in group II respectively. At the 12-week point, the follow-up for therapy efficacy in group I was 8 weeks, and in group II immediately after cessation of topical treatment (week 12) suggesting that the mycological rate in group II will, hence, be higher. We added the assessment results at the point of week 24, the scores of clinical evaluation at different stages in both groups are displayed in Fig. 1. The results displayed that the clinical improvement rates and fungal eradication rates between the two groups were not significantly different (Table 3), which demonstrated that the treatment efficacy in group I was non-inferiority to that in group II. Safety and tolerability
No serious adverse events or abnormal laboratory parameters were reported. Among patients who had mild adverse effects: each of the group I and group II had one patient who felt minor irritation. But the uncomfortable feeling was not significant enough to discontinue the following therapy. The participants demonstrated positive responses and the treatments were well tolerated.
Discussion Hyperkeratotic-type tinea pedis, which is classified into three types: true hyperkeratotic type, partial hyperkeratotic type and quasi-hyperkeratotic type,6–8 often has a long chronic duration. This disease always presents with severe erythema, rhagadia and thick, hyperkeratotic scale, which usually involve the entire plantar surface and sides of the feet.9 Because the scale on the plantar surface impedes and limits the absorption of the topical antifungal drugs, the topical antifungal used as sole therapy is often ineffective.10 By dissolving the intercellular matrix and augmenting the shedding of scales, urea cream could reduce the thickness of the horny layer and improve the dry skin.11 Therefore, topical urea cream is a potent tissue softener for hyperkeratotic skin. It can increase the efficacy of topical antifungal and improve the clinical symptoms in the treatment of hyperkeratotic type tinea pedis. Some researchers used topical urea to make it easy for the topical antifungals to penetrate the stratum corneum deep enough. Furthermore, some studies showed the usefulness of urea cream combined with topical antifungal agents in the treatment of hyperkeratotic type tinea pedis.4,5,12 However, for these topical treatments often require a long period of therapy, good patient compliance reduced. Because the duration of therapy
3
T.-W. Shi et al.
Table 2 Analysis of the aetiological agents in both groups at baseline.
Group I Group II Statistic value
Trichophyton rubrum Cases (rate)
Trichophyton mentagrophytes Cases (rate)
Epidermophyton floccosum Cases (rate)
Trichophyton megnini Cases (rate)
Yeast-like fungus Cases (rate)
28/40 (70%) 30/40 (75%) v2 = 0.251 (P1)
4/40 (10%) 3/40 (7.5%) v2 = 0.000 (P2)
3/40 (7.5%) 3/40 (7.5%) v2 = 0.180 (P3)
3/40 (7.5%) 2/40 (5%) v2 = 0.000 (P4)
2/40 (5%) 2/40 (5%) v2 = 0.263 (P5)
P1, P2, P3, P4, P5 > 0.05. Comparisons of dermatophytes between the two groups were not significant. Table 3 The efficacy analysis on per-protocol basis at 24 weeks.
Group I Group II v2-value 95% CI1
Clinical improvement cases (%)
Mycological eradication cases (%)
34/36 (94.44%) 32/34 (94.12%) v2a = 0.208 (Pa) ( 10.57%, 11.21%)
33/36 (91.67%) 31/34 (91.18%) v2b = 0.125 (Pb) ( 12.64%, 13.62%)
Pa > 0.05, Pb > 0.05. Comparisons of clinical improvement rates and mycological eradication rates between the two groups were not significant. 1
95% CI for the difference (rates in group I minus that in group II).
Figure 1 The scores of clinical evaluation at different visit points
in both groups.
was an important factor in determining patients’ compliance in treatment of hyperkeratotic type tinea pedis, the long duration of up to 12 weeks can reduce patient compliance and lead to treatment failure in the sole topical therapy. To seek for a shorter period treatment of hyperkeratotic-type tinea pedis, we applied combination therapy of oral terbinafine with topical treatment. Meanwhile, considering the true hyperkeratotic type involved all the sole and had the remarkable dermatologic symptoms, so we considered the treatment for the true hyperkeratotic type could also have a similar effect on the other two hyperkeratotic-type tinea pedis. Thus, we selected patients with true hyperkeratotic type as the subjects in this study.
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As a result, we found that combination with oral terbinafine displayed similar efficacy and safety compared with the only topical applications. The results demonstrated that the combination treatment with oral terbinafine was non-inferior to the sole topical treatment; however, the therapy duration of the combination with oral terbinafine was shorter than that of sole topical treatment, which could improve treatment compliance of patients. As to the therapy mechanism, for affecting the integrity of the fungal cell wall by blocking the squalene epoxidase enzyme,13 terbinafine had a biocidal effect on dermatophytes,14 and its minimal inhibitory concentration against fungi was extremely lower than that of other drugs.15 Consequently this allylamine was the most potent antifungal agent in vitro against dermatophytes.16 As for the aetiological agents, T. rubrum, T. mentagrophytes and E. floccosum were the most common agents in patients with tinea pedis. In fact, these are the predominant dermatophytes in the United States, Europe and Asia.17 Some studies had demonstrated that the systemic treatment with terbinafine was effective for patients infected by these fungi.16,18 Since terbinafine could maintain a fungicidal level for several weeks even after the administration had stopped,19 and researchers verified that oral terbinafine not only had good efficacy in patients infected by Trichophyton spp but also required a much shorter duration of treatment.20 Therefore, this systemic antifungal drug can lead to better results and contribute to reduce the length of treatment.21 In this study, oral terbinafine could act from inside of the skin, which perhaps could overcome the deficiency that topical agents could not play a role for the limited absorption by the hyperkeratosis and thick scales, and so it could achieve a satisfying effect in a short period compared to the long-term sole topical treatment.
Conclusion In conclusion, this study confirmed that the short-term schedule of topical terbinafine cream and urea
© 2014 Blackwell Verlag GmbH
Terbinafine and urea ointment in tinea pedis
ointment combined with oral terbinafine was effective and safe in the treatment of hyperkeratotic-type tinea pedis. An additional advantage of this short schedule was the convenience of the patient, which would promote the treatment compliance. As a result, we recommend the treatment with topical terbinafine and 10% urea ointment combined oral terbinafine in the hyperkeratotic-type tinea pedis, especially to the patients who probably had poor compliance with the long period of therapy.
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Acknowledgments We greatly appreciate professor Lu Nianzu (Department of Dermatology, the First Affiliated Hospital of Sun Yat-Sen University) for his outstanding work on the study and thank the patients who participated in this trial.
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12
Funding statement 13
None. 14
Conflicts of interest No potential conflicts of interest were disclosed in this study.
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References 18 1 2
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Rand S. Overview: the treatment of dermatophytosis. J Am Acad Dermatol 2000; 43(5 Suppl.): S104–12. Savin R, Atton AV, Bergstresser PR et al. Efficacy of terbinafine 1% cream in the treatment of moccasin-type tinea pedis: result of placebo-controlled multicenter trials. J Am Acad Dermatol 1994; 30: 663–7. Tanuma H, Doi M, Sato N et al. Bifonazole (Mycospor cream) in the treatment of moccasin-type tinea pedis. Comparison between combination therapy of bifonazole cream+10% urea ointment (Urepearl) and occlusive dressing therapy with the same agents. Mycoses 2000; 43: 129–37.
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Tanuma H, Doi M, Ohta Y et al. Butenafine hydrochloride (Mentax) cream for the treatment of hyperkeratotic type tinea pedis and its transfer into the horny layer, with or without concomitant application of 20% urea ointment (Keratinamin). Mycoses 2001; 44: 287– 99. Tanuma H, Tanuma M, Abe M et al. Usefulness of lanoconazole (Astat) cream in the treatment of hyperkeratotic type tinea pedis. Comparative study of monotherapy and combination therapy with 10% urea ointment (Pastaron). Mycoses 2001; 44: 181–90. Tanuma H. Pathogenesis and treatment of hyperkeratotic tinea pedis in Japan. Mycoses 1999; 42: 21–9. Tanuma H, Doi M, Yaguchi A et al. Efficacy of oral fluconazole in tinea pedis of the hyperkeratotic type. Stratum corneum levels. Mycoses 1998; 41: 153–62. Morimoto K, Tanuma H, Kikuchi I et al. Pharmacokinetic investigation of oral itraconazole in stratum corneum level of tinea pedis. Mycoses 2004; 47: 104–14. Kemna ME, Elewski BE. A U.S. epidemiologic survey of superficial fungal diseases. J Am Acad Dermatol 1996; 35: 539–42. Elewski BE, Haley HR, Robbins CM. The use of 40% urea cream in the treatment of moccasin tinea pedis. Cutis 2004; 73: 355–7. Borelli C, Bielfeldt S, Borelli S et al. Cream or foam in pedal skin care: towards the ideal vehicle for urea used against dry skin. Int J Cosmet Sci 2011; 33: 37–43. Tanuma H, Doi M, Ohta Y et al. Usefulness of 1% terbinafine HCL (Lamisil) cream for hyperkeratotictype tinea pedis and its transfer into toe horny layer. Mycoses 2000; 43: 417–32. Welsh O, Vera-Cabrera L, Welsh E. Onychomycosis. Clin Dermatol 2010; 28: 151–9. Ryder NS. Terbinafine: mode of action and properties of the squalene epoxidase inhibition. Br J Dermatol 1992; 126(Suppl. 39): 2–7. Petranyi G, Meingassner JG, Miethe H. Activity of terbinafine in experimental fungal infections of laboratory animals. Antimicrob Agents Chemother 1998; 31: 1365–8. Succi IB, Bernardes-Engemann AR, Orofino-Costa R. Intermittent therapy with terbinafine and nail abrasion for dermatophyte toe onychomycosis: a pilot study. Mycoses 2013; 56: 327–32. Ameen M. Epidemiology of superficial fungal infections. Clin Dermatol 2010; 28: 197–201. Czaika VA, Lam PA. Trichophyton mentagrophytes cause underestimated contagious zoophilic fungal infection. Mycoses 2013; 1: 33–7. Gupta AK, Lynch LE, Kogan N et al. The use of an intermittent terbinafine regimen for the treatment of dermatophyte toenail onychomycosis. JEADV 2009; 23: 256–62. Gonzalez U, Seaton T, Bergus G et al. Systemic antifungal therapy for tinea capitis in children. Cochrane Database Sys Rev 2007; 17: CD004685. Lambert J, Richert B, Dezfoulian B et al. Epidemiology, physiopathology and treatment of a frequent ailment of tinea pedis. Rev Med Liege 2000; 55: 161–8.
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