ORIGINAL RESEARCH ARTICLE

Am J Clin Dermatol 2007; 8 (6): 371-378 1175-0561/07/0006-0371/$44.95/0 2007 Adis Data Information BV. All rights reserved.

Comparative Study of 2% Sertaconazole Solution and Cream Formulations in Patients with Tinea Corporis, Tinea Pedis Interdigitalis, or a Corresponding Candidosis
Claudia Borelli,1 Gunther Kl ovekorn,2 Thomas-Matthias Ernst,3 Rolf-Hasso B odeker,4 Hans Christian Korting1 and Claudia Neumeister5
1 Department of Dermatology and Allergology, Ludwig-Maximilian-University, Munich, Germany 2 Medical Practice for Skin and Venereal Diseases, Gilching, Germany 3 Medical Practice for Skin and Venereal Diseases, Berlin, Germany 4 Institute for Medical Informatics, Justus Liebig University, Gieen, Germany 5 Department of Medical Science/Clinical Research, Dr. R. Pfleger GmbH, Bamberg, Germany

Abstract

Background: Based on the results of numerous preclinical and clinical studies, sertaconazole can be considered a safe and effective drug for the treatment of fungal skin infections. Objective: The objective of the study was to compare the efficacy of a solution containing 2% sertaconazole with the well established 2% sertaconazole cream formulation in patients with tinea corporis, tinea pedis interdigitalis, or a corresponding candidosis. Methods: This was a prospective, open-label, randomized, controlled, parallel-group, multicenter, noninferiority therapy study. Patients received either sertaconazole solution or cream twice daily for 28 days. The full analysis set comprised 160 patients in the solution group and 153 patients in the cream group. The primary efficacy parameter was a combination of culture test result and total clinical score. Efficacy was defined by eradication of the pathogen and reduction of the total clinical score between pretreatment and the final visit. Results: Efficacy was documented in 90.6% of patients using the solution and 88.9% of those using the cream (full analysis set). No adverse events occurred. Conclusion: Solution and cream formulations of 2% sertaconazole applied for 28 days were associated with comparable efficacy and safety in the treatment of fungal skin infections.

Background Mycoses of the human skin caused by dermatophytes or yeasts are common and widespread diseases. The therapeutic armamentarium for the treatment of mycotic infections of the skin comprises various different options, both with respect to the antifungal agent and its vehicle. With any given antifungal, use of various formulations may be necessary to achieve optimal treatment depending on the skin type, localization, size and characteristics of the lesion, and the special needs of a given patient.

Sertaconazole, an imidazole derivative, is used for the topical treatment of mycoses of the skin. This agent has demonstrated high in vitro[1-14] and in vivo[15-19] antifungal activity against a broad range of pathogenic yeasts and dermatophytes, together with antibacterial activity against Gram-positive bacteria.[20] In several in vitro studies sertaconazole has also been found to be equally active to, and frequently more active than, other azole antifungals.[9,10] The fungistatic and fungicidal activities of sertaconazole result from indirect effects on fungal cell membrane synthesis

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Table I. Distribution of gender, median, and corresponding 95% CIs of age (y), height (cm), and weight (kg) in patients with tinea or candidosis treated with 2% sertaconazole solution or cream (full analysis set) Demographic variable Sex (%) men women Age (y) [median (95% CI)] Height (cm) [median (95% CI)] Weight (kg) [median (95% CI)] 109 (68.13) 51 (31.88) 44.5 (42.0, 52.0) 174.0 (172.0, 175.0) 77.0 (75.0, 80.0) 107 (69.93) 46 (30.07) 48.0 (43.0, 54.0) 175.0 (173.0, 178.0) 79.0 (76.0, 83.0) Solution (n = 160) Cream (n = 153)

(inhibition of ergosterol biosynthesis) and direct effects on fungal membrane permeability/integrity.[6,7,21-23] Various clinical trials using a cream formulation of sertaconazole have shown excellent efficacy and safety for this agent in the treatment of different types of superficial mycosis.[15,18,19] For example, a double-blind, randomized, controlled, parallel-group, multicenter study of 631 patients found that patients treated with 2% sertaconazole cream were cured earlier and more likely to be cured than those treated with miconazole cream.[15] The most common adverse event following use of sertaconazole cream was localized erythema. No systemic adverse events or changes in laboratory parameters were observed in the two treatment groups. In 1992, Agut et al.[24] demonstrated equivalent pharmacokinetic behavior for cream and solution formulations of 2% sertaconazole. However, when this study was commenced, only the cream formulation of sertaconazole was available in Germany. Development of a solution formulation of sertaconazole is desirable because the availability of a solution would widen the range of treatment options, for example, for the treatment of large lesions or in the context of application to sites that are difficult to access because of limited patient mobility. The rationale of the study was to compare the efficacy and tolerability of a solution containing 2% sertaconazole with those of the well established 2% sertaconazole cream formulation (noninferiority hypothesis) in the hope of identifying an alternative formulation for the treatment of the most common fungal skin diseases. Material and Methods This clinical trial was conducted conforming to European Community Good Clinical Practice (EC-GCP) standards as a prospective, open-label, randomized, controlled, parallel-group, multicenter noninferiority therapy study in accordance with the Revised Declaration of Helsinki, local laws, and regulations. The final
1

study protocol was approved by the relevant Ethics Committees before the start of the study. According to the study protocol, 480 patients (240 patients in each therapy group) had to be recruited in total to obtain the required 160 patients in each therapy group with a confirmed fungal infection. Twenty-four centers in Germany, all dermatologic practices, participated in the study. After providing informed consent, eligible men and women aged 1870 years with presumed tinea corporis or tinea pedis interdigitalis as a result of dermatophytes, or a candidosis as a result of Candida species on corresponding parts of the body, were randomly assigned to one of the two therapy groups. One group received 2% sertaconazole solution provided in a pump spray and the other 2% sertaconazole cream formulation (Mykosert 1 Creme, Dr. R. Pfleger GmbH, Germany under license of Ferrer International, Barcelona, Spain). Study medication had to be applied twice daily for 28 days according to the treatment duration specified in the summary of product characteristics for the cream. There were three visits for each patient: a pretreatment visit (visit 1), an intermediate visit (visit 2) after 2 weeks, and the final visit (visit 3) after 2 further weeks of treatment. At each visit a specimen was obtained for culture and a clinical assessment of signs/symptoms was completed by the investigator. All culture tests were performed by a central laboratory (Labor L+S AG, D-97708 Bad Bocklet). The test conditions were two agar plates per sample (Sabouraud-Glucose-Agar with and without cicloheximide), aerobic, 30C 1C for 28 days, and daily readings. Identification of the pathogens was carried out up to the family/ genus level (dermatophytes or Candida species). The main inclusion criterion was a positive culture test at the pretreatment visit. As the result of the culture test was not available until 34 weeks after the pretreatment visit, patients were included on the basis of clinical signs and symptoms indicative of the various target diseases with a severity reflected by a total clinical score (TCS) of 6, and a positive finding on direct

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Table II. Distribution of the localization of the mycosis classified into three categories in patients with tinea or candidosis treated with 2% sertaconazole solution or cream (full analysis set) Therapy Localization of mycosis foot n Solution Cream All patients 125 108 233 % 78.13 70.59 74.44 trunk, groin n 32 42 74 % 20.00 27.45 23.64 combinations thereof n 3 3 6 % 1.88 1.96 1.92 160 153 313 Total (n)

microscopic examination. The TCS was determined by assessment of the following five signs and symptoms by the investigator: erythema, desquamation, vesicles, pustules, and itch (the latter was determined by investigator questioning). All signs and symptoms were assessed using an intensity scale that was defined as: 0 = absent, 1 = mild, 2 = moderate, and 3 = severe. The TCS was calculated by adding up the scores for each sign and symptom. Patients with systemic mycosis or mycosis of the hands, face, or scalp were excluded from the study. Patients experiencing oropharyngeal mycosis and/or vaginal mycosis were excluded from the study if fungal skin infection was located on an adjacent skin area. Pretreatment with antifungal drugs and immunosuppressive agents within 14 and 30 days, respectively, prior to study start was not allowed. Further exclusion criteria were pregnancy, lactation, or inadequate contraception in women of child-bearing potential; severe psychiatric illnesses; known allergies to sertaconazole or vehicle ingredients; and participation in another study within 30 days prior to study commencement. The dichotomous primary efficacy parameter was based on a combination of culture test and clinical assessment (TCS). Success was defined as eradication of the pathogen at the final visit and reduction of the TCS by at least two points between pretreatment and the final visit. In order to be able to reject the null hypothesis that the success rate associated with treatment with solution was inferior to the success rate associated with treatment with cream in favor of the alternative hypothesis, inclusion of 160 patients in

each group was required. Therefore, the following assumptions were made: the expected difference in proportions was 0.00, the success rate in the group treated with cream (cream) was 0.65, and the noninferiority range was 0.15 to . Because the result of the first culture test was not known until the intermediate examination, the assumption was made that 40% would meet the secondary exclusion criterion lack of verification of dermatophytes and/or Candida species by a positive culture test at the time of inclusion. The secondary parameters were the result of the culture test and the TCS (including the clinical signs and symptoms: erythema, desquamation, vesicles, pustules, and itching), which were analyzed separately. Adverse events were documented at the intermediate and final examinations.

Statistical Analyses

Data management and analyses were performed using Access 2000 (Microsoft, Redwood, WA,USA), SAS V8 (SAS Institute, Cary, NC, USA), TESTIMATE 6.0 (idv, Gauting, Germany), and StatXact 5.0 (Cytel, Cambridge, MA, USA). The analysis of the primary parameter was performed in the confirmatory sense using the exact R ohmel-Mansmann-Test. The secondary parameters were analyzed exploratively. In order to check for possible center effects, the secondary parameter result of culture test was analyzed in nonstratified and stratified manners.

Table III. Distribution of pathogens detected by culture test at the pretreatment visit in patients with tinea or candidosis treated with 2% sertaconazole solution or cream (full analysis set) Therapy Pathogens detected by culture test at pretreatment visit Candida spp. n Solution Cream All patients 8 12 20 % 5.00 7.84 6.39 dermatophytes n 147 138 285 % 91.88 90.20 91.05 Candida spp. and dermatophytes n 5 3 8 % 3.13 1.96 2.56 160 153 313 Total (n)

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Table IV. Frequency of success on the primary endpoint with corresponding 95% CIs in patients with tinea or candidosis treated with 2% sertaconazole solution or cream (full analysis set) Therapy Success on primary endpoint no n Solution Cream All patients 15 17 32 % 9.38 11.11 10.22 yes n 145 136 281 % 90.63 88.89 89.78 85.01, 94.66 82.81, 93.39 85.87, 92.90 160 153 313 95% CI total (n)

Results
Analysis Sets and Baseline Demographics

gory foot (in particular interdigital spaces), which was documented in 78.1% of patients in the solution group and 70.6% of patients in the cream group (table II).
Distribution of Pathogens

A total of 535 patients were recruited and randomized. All patients received at least two boxes of study medication, which meant that the sample size of the safety population (nSafety ) was 535. As the result of the first culture test was not known until visit 2 or visit 3, 39.6% of patients did not fulfil the main inclusion criterion of positive culture test at pretreatment visit and therefore were not included in the full analysis set (FAS). Taking into account the intention-to-treat principle on the one hand and the International Conference on Harmonization E9 guideline (circumstances that might lead to excluding randomized subjects from the full analysis set)[25] on the other, 313 patients (nFAS) were included in the FAS, consisting of 160 treated with solution (nsolution) and 153 treated with cream (ncream). Excluding patients with relevant protocol violations (n = 68) or premature study termination (n = 11), the per-protocol set (PP) encompassed 234 patients (nPP), of which nsolution = 124 and ncream = 110. The demographic data of patients in the FAS are shown in table I.
Localization of Mycosis

The culture test detected the pathogens Candida, dermatophytes, and a combination of both. The results of the culture tests at pretreatment examination indicated that the mycosis was most frequently caused by dermatophytes alone (91.1% of all patients). Candida alone was found in only 6.4% of all patients. The distribution of pathogens detected by culture test at the pretreatment visit in the FAS subdivided by therapy group is shown in table III.
Primary Efficacy Parameter

The localization of the mycosis was recorded at the pretreatment visit. For analysis, the localizations were combined into three categories. The main localization of the mycosis was in the cate-

Analysis of the primary efficacy parameter in the FAS showed that success was achieved in 145 of 160 patients (90.6%) in the solution group, and 136 of 153 patients (88.9%) in the cream group (table IV). The observed success rates were comparable in both treatment groups (difference between success rates: solution minus cream p = 0.017). Similar results were obtained when analysing the PP set. Success when using the solution could be observed in 114 of 124 patients (91.9%), and when using cream in 100 of 110 patients (90.9%) with p = 0.010. The one-sided 97.5% CI was a subset of the noninferiority region in both analyses. Sertaconazole solution was proven to be equally efficacious to sertaconazole cream in both analysis sets.

Table V. Frequency of a negative culture test result at visit 3 with corresponding 95% CIs in patients with tinea or candidosis treated with 2% sertaconazole solution or cream (full analysis set)a Therapy Result of culture test at final examination negative n Solution Cream All patients a 145 137 282 % 90.63 89.54 90.10 95% CI 85.01, 94.66 83.57, 93.90 86.24, 93.17 positive n 15 16 31 % 9.38 10.46 9.90 160 153 313 total (n)

Under the hypothesis that the probability of success was the same in both therapy groups, the computed p-value in the stratified analysis was pCochran-Mantel-Haenszel = 0.631. The p-value for the non-stratified analysis was pFishers exact = 0.850.
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Severe Moderate Mild Absent 160 Patients 120 80 40 0

22 11 33 23 108 108 100 102 99 94 30 33 21 24 52 47

Solution Cream Visit 1

Solution Cream Visit 2

Solution Cream Visit 3

group, and from 95.4% to 9.9% in the cream group. The proportion of patients with moderate or severe itch was reduced from 81.9% at the pretreatment visit to 1.3% at the final visit in the solution group, and from 84.3% to 3.3% in the cream group. Vesicles and pustules were comparatively less frequent at the pretreatment visit (moderate or severe frequencies were 23% and 10%, respectively) and data for these signs/symptoms are therefore not shown.
Safety

Fig. 1. Severity of erythema at the pretreatment (visit 1), intermediate (visit 2), and final visit (visit 3) in patients with tinea or candidosis treated with 2% sertaconazole solution or cream (full analysis set). Exact patient numbers <10 are not shown in the figure. Secondary Efficacy Parameters

Each component of the primary parameter (result of the culture test at the final visit and the difference in the TCS between pretreatment and the final visit) was analyzed separately. In the FAS, 145 patients (90.6%) in the solution group, and 137 patients (89.5%) in the cream group showed a negative culture test result at the final visit (table V). Monitoring for possible center effects revealed no evidence of a difference between the cream and the solution group by either nonstratified (pFishers exact = 0.850) or stratified (pCochrane-Mantel-Haenszel = 0.631) analysis, i.e. there is no center effect. The maximum change in TCS was an improvement of 13 points in both treatment groups between pretreatment and the final visit. The median change in the TCS between pretreatment and the final visit was an improvement of six points in the solution group compared with seven points in the cream group. In the PP set, 114 patients (91.9%) in the solution group and 101 patients (91.8%) in the cream group showed a negative culture test result at the final visit. The median change in TCS was an improvement of six points in the solution group and six and onehalf points in the cream group. For these two secondary parameters, there was no evidence of any difference between the cream and the solution concerning either the occurrence of a negative culture test result or in change of TCS. Changes in erythema, desquamation and itch during the study in the FAS are shown in figures 1, 2, and 3, respectively. The proportion of patients with moderate or severe erythema was reduced from 86.3% at the pretreatment visit to 2.6% at the final visit in the solution group, and from 92.2% to 6.6% in the cream group. The proportion of patients with moderate or severe desquamation was reduced from 96.3% to 16.8% in the solution
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At the intermediate and final visits, patients were asked if any adverse event had occurred since the previous visit. No patients reported a serious adverse event. 16 (6.1%) of patients applying the solution and 20 (7.4%) of those applying cream reported at least one adverse event occurring during the study (table VI). Of the 18 adverse events reported by 16 patients in the solution group, only three events (eczema in two patients, itch in one patient) were considered to be possibly related to use of sertaconazole solution. Of the 21 adverse events reported by 20 patients in the cream group, again only three events (itch in two patients, mild burning in one patient) were considered to be possibly related to use of sertaconazole cream. Thus, in both treatment groups, adverse events that were considered possibly related to study medication occurred in only 1.1% of patients.
Summary

The confirmatory analysis showed evidence of a noninferior antifungal effect of sertaconazole solution versus the well established reference drug sertaconazole cream. Thus, sertaconazole solution was proven to be at least therapeutically equivalent to the cream. The incidence of active investigational medicinal productrelated adverse events was low and no serious adverse events were reported.
Severe Moderate Mild Absent 160 Patients 120 80 40 0 Solution Cream Visit 1
85 90 95 69 56 15 41 27 25 78 101 51 17 67 12 69

Solution Cream Visit 2

Solution Cream Visit 3

Fig. 2. Severity of desquamation at the pretreatment (visit 1), intermediate (visit 2), and final visit (visit 3) in patients with tinea or candidosis treated with 2% sertaconazole solution or cream (full analysis set). Exact patient numbers <10 are not shown in the figure.
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Severe Moderate Mild Absent 160 Patients 120 80 40

20 58 57 66 73 72 74 19 61 77 131 132 18 11 22 14

Solution Cream Visit 1

Solution Cream Visit 2

Solution Cream Visit 3

Fig. 3. Severity of itching at the pretreatment (visit 1), intermediate (visit 2), and final visit (visit 3) in patients with tinea or candidosis treated with 2% sertaconazole solution or cream (full analysis set). Exact patient numbers <10 are not shown in the figure.

Discussion The current German guideline on tinea of glabrous skin (Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften-Leitlinie Nr. 013/002) states, in agreement with other guidelines,[26] that this type of fungal disease should, as a rule, be treated topically using representatives of accepted classes of active pharmaceutical ingredients. Azoles are named as the first class of drugs of choice followed by hydroxypyridones, allylamines, and morpholines. Sertaconazole is one of six individual topical azoles specifically referred to in the German guidelines. The guideline also states that the appropriate formulation should be selected for treatment of any individual case. In addition, the guideline states that, depending on the localization and type of manifestation of the infection, several different formulations might be of use. The formulation types named, in order, are cream, solution, (liposome) gel, paste, and powder. The statement, however, was based on the opinion of a panel of experts, as reflected by its classification as a so-called level 1 guideline. On the subject of the relative relevance of various topical formulations for use in skin disease, it is peculiar that even recent comprehensive reviews of various aspects of dermatologic vehicles have stated that selection of the type of vehicle should be based on a a few simple factors, as described by the authors of leading German textbooks published as early as 1982.[27,28] The factors named comprise

acuity and type of the disease, skin type, skin status, localization of the disease, environmental factors, and cosmetic considerations. Considering this information as a whole, current recommendations on selection of dermatologic vehicles should not only be called eminence-based, but also evidence-based at least up to a point. However, the best evidence available in this context appears to be only partially illuminating. Nevertheless, even in recent times, pharmaceutical companies have tended to meet clinicians expectations in terms of providing a variety of formulations when a new topical antifungal agent is introduced. This is particularly the case with the frequently used allylamine terbinafine.[29] Indeed, a variety of terbinafine formulations incorporating cream and solution were evaluated in the systematic review by Korting et al.[29] However, while the superiority of various formulations including the active pharmaceutical ingredient over vehicles has been demonstrated, no comparative trials have been published that provide an indication of the relative efficacy and safety of the terbinafine formulations. The comparatively new agent sertaconazole has also been formulated in different versions, including gel, cream, powder, and solution.[20] However, a recent review also did not provide any information on the relative efficacy and safety of the various formulations.[20] The aim of the present trial was to address the relative efficacy and safety of two frequently used formulations of a topical antifungal, i.e. cream and solution. As with other topical antifungal agents, sertaconazole cream was introduced first and has thus attained the role of standard therapy. The data obtained within the trial were obtained in a clinical study that addressed the subject of noninferiority in a confirmatory manner. Use of rigorous methods is clearly important when conducting clinical trials to assess equivalence.[30] No placebo group was included in this study for two reasons. First, the superiority of sertaconazole[31] and of azole antifungals in general compared with placebo has already been proven.[29] Second, there was no reason to believe before the trial that one of the formulation types would be proven to be definitely superior and it was not the aim of

Table VI. Frequency of adverse events during the study in patients with tinea or candidosis treated with 2% sertaconazole solution or cream (safety set) Therapy Any adverse event during study not n Solution Cream All patients a 11 4 15 knowna % 4.18 1.47 2.80 no n 236 248 484 % 89.73 91.18 90.47 yes n 16 20 36 % 6.08 7.35 6.73 263 272 535 Total (n)

Information regarding the possible occurrence of an adverse event is missing.

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the study to show superiority against placebo but rather equal efficacy of two different formulations of the same active substance. It is important to note that a certain degree of spontaneous recovery (e.g. in one study, the cure rate was 24% in the placebo group compared with 60% in the miconazole group[32]) was not taken into account in this study. Nevertheless, the high cure rates in this study suggest an excellent efficacy for sertaconazole, and we believe that this type of evaluation has become widely accepted, as evidenced by the increasing number of clinical trials comparing a particular drug to an active control.[33] Proving the noninferiority of sertaconazole solution compared with sertaconazole cream in a clinical context primarily means that doctors treating patients with tinea of glabrous skin can feel free to select the type of formulation to be used according to current recommendations. However, the design of this trial means that it cannot answer the question of whether subgroups of patients with tinea of glabrous skin might benefit more from a topical antifungal cream or a solution, and in particular sertaconazole cream or solution. Answers to such questions can only be obtained from specialized trials. In the context of sertaconazole solution it might be particularly rewarding to perform another trial comparing the solution with the cream in patients with a particularly exudative type of tinea, for example, in the toe-webs. Conclusion The results of this study show that sertaconazole solution is at least therapeutically equivalent to the cream formulation. Sertaconazole solution is a new and safe therapeutic option for the treatment of tinea corporis, tinea interdigitalis pedis, and cutaneous candidosis. Acknowledgments
The trial was funded by Dr. R. Pfleger GmbH, Bamberg, Germany and Ferrer International, Barcelona, Spain. Dr Neumeister is an employee of Dr. R. Pfleger GmbH, Bamberg, Germany. Some of the authors and study group members received compensation for their contribution to the trial. The authors are grateful to the additional members of the P183-Sertaconazole Study Group encompassing Dr S. Baeblich (Berlin), Dr N. Fischer (M unchen), Dr H. G orlich (Berlin), Dr R. Gollhausen (Dachau), Dr K. Winkelspecht/Dr D. Hiller (Bamberg), Dr K.G. Meyer (Berlin), Dr M. Miehe (Berlin), Dr P. Schnabel (M unchen), Dr K. Stojanow (Berlin), Dr V. von Liebe (M unchen), Dr G. von Hake (Frankfurt), Dr D. Greiner (Oberursel), Dr U. Wichmann-Henricks (Gr unberg), Dr W. Brinkmann (Herborn), Dr E. Klaubert (Offenbach), Dr S. Heilmann (Marburg), Dr E. Thomas (Marburg), Dr M. Gro (Bamberg), Dr B. W unscher (Amberg), Dr D. Konietzko (Bamberg), Dr G. Falker (Frankenberg), and Dr R. Bartelt (Frankfurt).
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The authors would like to thank Anna Wolf for proofreading and Christine Scheibelhut for valuable assistance in data management and data analysis.

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Correspondence: Dr Claudia Borelli, Department of Dermatology and Allergology, Ludwig-Maximilian-University, Frauenlobstrasse 911, Munich, D-80337, Germany. E-mail: claudia.borelli@med.uni-muenchen.de

2007 Adis Data Information BV. All rights reserved.

Am J Clin Dermatol 2007; 8 (6)