New Antifungal Agents and New Formulations Against Dermatophytes

A variety of oral and topical antifungal agents are available for the treatment of superficial fungal infections caused by dermatophytes. This review builds on the antifungal therapy update published in this journal for the first special issue on Dermatophytosis (Gupta and Cooper 2008;166:353–67). Since 2008, there have not been additions to the oral antifungal armamentarium, with terbinafine, itraconazole, and fluconazole still in widespread use, albeit for generally more severe or recalcitrant infections. Griseofulvin is used in the treatment of tinea capitis. Oral ketoconazole has fallen out of favor in many jurisdictions due to risks of hepatotoxicity. Topical antifungals, applied once or twice daily, are the primary treatment for tinea pedis, tinea corporis/tinea cruris, and mild cases of tinea unguium. Newer topical antifungal agents introduced include the azoles, efinaconazole, luliconazole, and sertaconazole, and the oxaborole, tavaborole. Research is focused on developing formulations of existing topical antifungals that utilize novel delivery systems in order to enhance treatment efficacy and compliance.     

Dermatophytes

Dermatophytes are keratinophilic fungi that are responsible for common infections such as tinea pedis, tinea capitis, and tinea unguium. Their wide prevalence is mainly due to the existence of large human and animal reservoirs coupled with their ease of transmission from one host to another and their high inherent resistance to harsh environmental conditions. Although normally noninvasive, dermatophytic infections may rarely disseminate, particularly in immunocompromised hosts. In spite of the multitude of options now available for the diagnosis and treatment of dermatophytic infection, certain forms, such tinea unguium, are often challenging to manage.     

足癣患者治疗现状调查

目的了解中国足癣患者的治疗现状,加强临床医生对相关诊治指南推荐方案的认知和理解。方法中国医师协会皮肤科医师分会组织全国9家医院进行中国足癣患者治疗现状问卷调查。结果共收集到问卷690份,结果显示我国足癣患者大多数选择自行购买外用抗真菌药物治疗,最常选用的外用药物为咪唑类药物,往往以瘙痒和／或皮疹消失作为停止治疗的依据,治疗最长时间中位数为2周,在治疗足癣的疗程上显示出明显不足。足癣患者常合并甲真菌病等其他皮肤癣菌病,同时其家庭成员患病率也较高,在治疗足癣患者的同时,应积极治疗其合并的其他皮肤癣菌病,也应同时对患者家庭成员进行治疗。结论本研究对更加有针对性地制定合理足癣预防和治疗方案并加强患者宣教具有重要作用。     

Dermatology for the practicing allergist: Tinea pedis and its complications

Tinea pedis is a chronic fungal infection of the feet, very often observed in patients who are immuno-suppressed or have diabetes mellitus. The practicing allergist may be called upon to treat this disease for various reasons. Sometimes tinea infection may be mistaken for atopic dermatitis or allergic eczema. In other patients, tinea pedis may complicate allergy and asthma and may contribute to refractory atopic disease. Patients with recurrent cellulitis may be referred to the allergist/immunologist for an immune evaluation and discovered to have tinea pedis as a predisposing factor. From a molecular standpoint, superficial fungal infections may induce a type2 T helper cell response (Th2) that can aggravate atopy. Th2 cytokines may induce eosinophil recruitment and immunoglobulin E (IgE) class switching by B cells, thereby leading to exacerbation of atopic conditions. Three groups of fungal pathogens, referred to as dermatophytes, have been shown to cause tinea pedis: Trychophyton sp, Epidermophyton sp, and Microsporum sp. The disease manifests as a pruritic, erythematous, scaly eruption on the foot and depending on its location, three variants have been described: interdigital type, moccasin type, and vesiculobullous type. Tinea pedis may be associated with recurrent cellulitis, as the fungal pathogens provide a portal for bacterial invasion of subcutaneous tissues. In some cases of refractory asthma, treatment of the associated tinea pedis infection may induce remission in airway disease. Very often, protracted topical and/or oral antifungal agents are required to treat this often frustrating and morbid disease. An evaluation for underlying immuno-suppression or diabetes may be indicated in patients with refractory disease.     

A prospective epidemiologic survey on the prevalence of onychomycosis and dermatophytosis in male boarding school residents

Dermatophyte infections and onychomycosis are not usually serious in term of mortality; however, they may have significant clinical consequences such as secondary bacterial infections, chronicity, therapeutic difficulties and esthetic disfigurement in addition to serving as a reservoir of infection. Our aim was to determine the prevalence of onychomycosis and dermatophytosis in a selected high risk group, consisting of male boarding school residents. A total of 410 males inhabiting two houses were evaluated by two dermatologists. In cases of clinical suspicion, appropriate samples were taken for direct microscopy and culture. The results showed that the prevalences of tinea pedis (athletes foot) and pure pedal onychomycosis were 51.5% (n:211) and 4.4% (n:18), respectively. Thirty cases of those with tinea pedis were complicated by toenail onychomycosis. Tinea cruris was present only in five cases with tinea pedis. Interestingly 71.1% of those with tinea pedis and 45.8% of those with onychomycosis, associated with or without tinea pedis were unaware of their diseases. The most common fungal isolate was Trichophyton rubrum (76.6%) followed by Epidermophyton floccosum (11.6%), T. interdigitale (10.55%). Approximately one third of the cultures from nail specimens yielded pure growths of nondermatophyte moulds or Candida albicans. In conclusion, we found unexpectedly high prevalences of occult athletes foot and toenail onychomycosis among the male residents of student houses. Our results indicate that health-care workers of such common boarding-houses should be more aware of clinical and subclinical dermatophyte infections and onychomycosis, and have more active approaches to educational measures and management strategies to prevent further infections. To our knowledge, this is the first epidemiologic study on the prevalences of dermatophytosis and onychomycosis in boarding-houses from Turkey.     

口服特比萘芬联合外用联苯苄唑乳膏治疗足癣长期临床研究

目的 为足癣治疗提供较理想的方案.方法 盐酸特比萘芬250 mg,口服1次/d;1%联苯苄唑乳膏,外用1次/d.250例足癣患者随机入组.A组口服1周加外用1周,B组口服1周加外用2周,C组口服2周加外用1周,D组口服2周加外用2周,E组单独外用4周.在治疗结束时、治疗结束后4周、24周、40周、56周、72周时对各组的疗效、复发率进行评价.结果 在停药后第24周时,A、B、C、D组与E组疗效比较差异有统计学意义.在停药后第40周、56周、72周时,D组与A、B组疗效比较差异也出现统计学意义.在停药后24周、40周时,A、B、C、D组真菌学疗效与E组比较差异有统计学意义.在停药56周、72周时,D组与A、B组真菌学疗效比较差异也出现统计学意义.在停药40周时,A、B、C、D组与E组复发率比较差异有统计学意义.在停药56周、72周时,D组与A、B组复发率比较差异也出现统计学意义.结论 口服特比萘芬2周联合外用1%联苯苄唑乳膏2周治疗足癣的有效率和真菌学疗效最高,复发率最低.     

Prevalence of Dermatophytoses in the Zarqa District of Jordan

A total of 350 clinically suspected cases of dermatomycoses were examined for causative fungi during July 1997 to September 1998. Mycotic infection was demonstrable by microscopy and culture in 199 (56.8%) cases. The most common superficial mycotic infections were tinea pedis (35.2%) followed by tinea capitis (23.1%), tinea unguium (21.6%) and tinea corporis (10.6%). Most of the infected patients were 1–9, 20–29 and 30–39 years old. Men were mainly infected with tinea cruris and tinea pedis, while women were infected with tinea pedis, tinea unguium and tinea capitis. The frequencies of etiological agents isolated from patients were as follows: Trichophyton mentagrophytes var. interdigitale (32.7%), T. rubrum (28.6%), Epidermophyton floccosum (20.1%), Microsporum canis (11.1%), T.schoenleinii (4%), T.verrucosum (2%), T.violaceum (1%), and M. gypseum (0.5%). The number of infections varied with the seasons. The highest number of cases of tinea pedis and tinea cruris occurred in the summer months, while tinea capitis, tinea corporis and tinea unguium occurred in the spring and winter months. This revised version was published online in June 2006 with corrections to the Cover Date.     

New data on the epidemiology of Tinea cruris in Israel

Among 250 patients with tinea cruris (160 males, 90 females) lesions of both tinea pedis and tinea unguium were found in 221 and lesions of only tinea pedis in another 25. The four children were free of associated dermatophytic lesions. The predominant causative agent was T. rubrum, which was also found to be responsible for the hairy area invasion of the beard and pubis in 12 patients and for the widespread lesions of tinea corporis in 10 patients with lymphoma. None of these patients had noticed the discrete nail and foot involvement. It is therefore recommended that all patients with tinea cruris be subjected to careful examination of all possible mycotic foci, particularly the feet and nails.     

Epidemiology of dermatophytoses: retrospective analysis from 2005 to 2010 and comparison with previous data from 1975

Dermatophyte infections are extremely frequent worldwide and their epidemiological features vary according to the geographical area and have changed in the last decades. We studied the spectrum of dermatophytoses by means of a retrospective analysis involving 6,133 patients referred to the Mycology Service of the Dermatology Clinic of Policlinico Hospital - University of Bari, Italy during the period 2005-2010. The most frequent clinical forms were tinea unguium (39.2% of the total dermatophytoses), tinea corporis (22.7%) and tinea pedis (20.4%). There was a predominance of women for tinea unguium and corporis and of men for tinea pedis and especially tinea cruris. T. rubrum was the prevalent causative agent, implicated in 64% of total cases, followed by M. canis (14%) and T. mentagrophytes (10%). The retrospective evaluation of epidemiological data collected at our Clinic since 1975 showed a gradual decrease in the frequency of tinea cruris, tinea corporis, and tinea capitis over time. On the contrary, during the past two decades, there has been a progressive increase in the frequency of tinea pedis and especially of tinea unguium. In parallel with this changing pattern, the frequency of isolation of T. rubrum has shown a continuous increase during the last 35 years, whereas a progressive decline of the etiological role of T. violaceum, M. canis and even more of E. floccosum has been noted.     

甲癣局部用药体外药效实验方法研究进展

甲真菌病是皮肤科的常见病,是由皮肤癣菌、酵母菌和非皮肤癣菌性霉菌侵犯甲板和(或)甲床所致的病变,其中由皮肤癣菌感染引起的甲真菌病称为甲癣。人甲板中角蛋白硬、厚且致密,从而形成一个完美屏障。针对甲板的特殊解剖结构,需要局部治疗药物具备穿透指甲屏障,体现高活性抗皮肤癣菌的特质。目前,甲癣的局部用药体外药效学研究没有统一的标准,缺乏指导依据。本文查阅近年来文献报道,综述甲癣局部治疗药物的体外药敏实验、药物与甲板内角蛋白亲和力实验以及药物在甲板内的渗透等,并阐述上述实验方法的模型选择、方式方法及方法间的比较,以推荐适合化合物筛选的方法。     

Epidemiology of superficial mycosis (tinea pedis, onychomycosis) in elementary school children in Istanbul, Turkey

The purpose of this study is to determine the prevalence of tinea pedis and onychomycosis in children of elementary school age and to examine the socio-demographic attributes that may be effective in correlation of both mycoses. 3,390 female and 3,768 male children between ages 6-14 have been examined in seven schools. Skin scrapings and nail samples were taken from 13 students who were suspected to have tinea pedis and from 49 students who were suspected to have onychomycosis. According to direct microscopy (10-15% KOH+calcofluor white) and culturel examination (Sabouraud dextrose agar and dermatophyte test medium) 11 students were diagnosed as tinea pedis and 24 were diagnosed as onychomycosis. Trichophyton rubrum was isolated in 3 students with tinea pedis whose culture was positive and five Candida albicans, five Candida glabrata and one Candida tropicalis cases were isolated from 11 samples with onychomycosis. Tinea pedis prevalence has been found to be 3.3%0. Differences between onychomycosis prevalence based on age have been found to be significant (p < 0.001). In conclusion, it has been determined that the prevalence of tinea pedis and onychomycosis among children is low. Candida spp. was isolated from all of the 14 samples diagnosed as onychomycosis. Our study shows similar results with previous studies done in Turkey and that Trichophyton rubrum continues to be the most isolated agent.     

中国基层医疗机构手癣和足癣诊治现状调查

目的了解基层医生有关手癣、足癣的诊治现状,分析影响因素,制定有针对性的措施。方法通过网络平台对全国19个省市的基层医生进行问卷调查。结果共回收完整问卷729份。结果显示:①约20%的基层医生对手、足癣的发病因素方面存在认识不足,约50%的基层医生对受侵犯皮肤的组织定位存在误区。②基层医生对手、足癣鉴别诊断的重要性重视不够,真菌镜检设备使用率不足一半。③基层医生能正确选用外用抗真菌药,硝酸咪康唑乳膏使用率超过80%。④仍有10.70%的基层医生推荐使用外用糖皮质激素治疗手、足癣。结论基层医生在手、足癣的规范诊疗方面仍有待提高。     

Pathogenic Dermatophytes Survive in Nail Lesions During Oral Terbinafine Treatment for Tinea Unguium

Tinea unguium caused by dermatophyte species are usually treated with oral antimycotic, terbinafine (TBF). To understand the mechanisms of improvement and recalcitrance of tinea unguium by oral TBF treatment, a method of quantifying dermatophyte viability in the nail was developed, and the viability of dermatophytes was analyzed in toenail lesions of 14 patients with KOH-positive tinea unguium treated with oral TBF 125 mg/day for up to 16 weeks. Mycological tests, including KOH examination and fungal culture, and targeted quantitative real-time PCR for internal transcribed spacer (ITS) region, including rRNA, were demonstrated at the initial visit and after 8 and 16 weeks of treatment. Assays in eight patients showed that average ITS DNA amount significantly decreased, to 44% at 8 weeks and 36% at 16 weeks compared with 100% at initial visit. No significant difference was observed between at 8 and 16 weeks, despite the TBF concentration in the nail supposedly more than 10-fold higher than the minimum fungicidal concentration for dermatophytes. This finding suggests the pathogenic dermatophytes in nail lesions could survive in a dormant form, such as arthroconidia, during oral TBF treatment. Both antimycotic activity and nail growth are important factors in treatment of tinea unguium.     

Etiologic and epidemiologic study of dermatomycoses in Navarra (Spain)

We review the etiology of the dermatophytosis in Navarra (Spain) over a 5-year period and it is compared with previous studies. We have isolated 312 strains of dermatophyte fungi in 285 patients (188 men and 97 women). Trichophyton rubrum was the most frequently isolated species (58.6%) followed by Trichophyton mentagrophytes (26.2%) and Microsporum canis (10.5%). Concerning the location of the lesions, tinea pedis was the clinical pattern found in the greatest number of patients, followed by tinea corporis, tinea unguium and tinea capitis. Twenty eight percent of the isolations were accomplished in October and November. More than half of those patients questioned had had epidemiological contact with animals or practiced sports. The rise of tinea pedis in our region is emphasised. The possible causes of this increment are analyzed and some recommendations for its control are made.     

Updates on the Epidemiology of Dermatophyte Infections

The spectrum of dermatophytes isolated from skin lesions had changed in last 70 years. Before the Second World War in Germany, Microsporum audouinii and Epidermophyton floccosum ranked the first, whereas Trichophyton rubrum is the most common dermatophyte since the fifties of last century, accounting for 80-90% of the strains, followed by T. mentagrophytes. This evolution is typical for Central and North Europe and it needs to be connected with the increase in the incidence of tinea pedis. In contrast, in Southern Europe and in Arabic countries, zoophilic dermatophytes, such as Microsporum canis or Trichophyton verrucosum, are the most frequently isolated. In Europe, especially in Mediterranean countries, the incidence of M. canis infection has strongly increased during the recent years and this dermatophyte is now the most prevalent in tinea capitis in children. An analysis of the frequency and distribution of tinea pedis in different occupations and leisure-time activities as well as the routes of infection are reported. The spreading of this disease in most developed countries of the world represents a considerable economic problem, since it was accompanied by a parallel increase in the frequency of onychomycosis which implies, as tinea pedis, large financial charges. In poor developing countries, mycoses appear endemically, primarily with children, and their treatment often fails because of the lack of efficient antifungals. The particular epidemiological situations of dermatophytoses and the pathogenic spectrum of dermatophytes are examined at the example of numerous countries.     

Griseofulvin in the treatment of dermatomycoses and onychomycoses produced by dermatophytes of the Trichophyton group

Summary Based on observations on the therapy of 128 patients affected with tinea unguium, tinea manus et pedis, tinea granulomatosa nodularis (Granuloma Majocchi), tinea cruris, tinea corporis, tinea barbae and tinea capitis due to infection with dermatophytes of theTrichophyton group, determinations were made for the absolute and relative indication of griseofulvin in the treatment of these mycoses. For each affection, comparisons were made between the therapeutic results obtained by combined therapy with oral griseofulvin (uniform daily dose 1 g for each case) and local therapy with 1 % water solution organic dyes, coal tar on the one hand, and mere local therapy as described above, on the other. For treatment, griseofulvin of different production was available: British Grisovin, Likuden and Likuden M from West-Germany, and Griseofulvin produced in the German Democratic Republic. No essential differences were found in the therapeutic effect of the individual preparations, the tolerance, however, was found to be best with Likuden. On the basis of comparisons made for the results of the individual methods of treatment, griseofulvin therapy was found to be an absolute indication of the mycotic diseases as follows: tinea capitis, tinea cruris follicularis trichophytica and tinea unguium. A relative indication was found to be tinea corporis, tinea barbae, tinea cruris, and tinea manus et pedis.All patients were subjected to microscopic and culture examination. The frequency of the individual dermatophytes was as follows:Trichophyton rubrum in 56 cases,Trichophyton verrucosum in 19 cases,Trichophyton mentagrophytes in 16 cases, andTrichophyton violaceum in 1 case. Thirty six cases showed negative cultures.In conclusion, the author recommends individual selection of patients for the griseofulvin therapy.     

特比萘芬短程口服加外用特比萘芬治疗中重度皮肤癣菌病的临床对照研究

目的为治疗中、重度皮肤癣菌病选择合适的方法。方法采用开放、随机对照的平行研究。将临床和真菌镜检确诊的中重度体、股癣和手、足癣患者随机分入A、B、C、D四组,A组口服特比萘芬片联合外用特比萘芬乳膏,疗程7d;B组常规口服特比萘芬片,疗程14d;C组常规外用特比萘芬乳膏,疗程14d;D组外用联苯苄唑乳膏,疗程4周。对各组的临床疗效、安全性、患者对治疗的满意度等进行分析。结果①真菌学疗效:停药后4周时A组手、足癣患者的真菌清除率最高为96.65%,与D组比较(65.00%)差异有显著性。②临床疗效:停药后2周和4周时A组手足癣患者的治愈率分别为93.33%和90.00%,与D组(68%、64%)比较差异有显著性。③患者满意度:在本研究的四组中,A组患者对疗效的满意度最高,与C组、D组比较差异有显著性;患者的综合满意度(包括对治疗费用、安全性等方面)A组最高,与C组、D组比较差异有显著性。D组患者对费用的接受程度最高,A组优于B组,有极显著的统计学差异。治疗结束后患者对安全性的接受程度四组间没有显著差异。结论特比萘芬口服加外用1周的“1 1”短程联合疗法治疗中、重度皮肤癣菌病的疗效高、疗程短、依从性好,患者满意度高。     

Achievement of complete mycological cure by topical antifungal agent NND-502 in guinea pig model of tinea pedis

We examined the therapeutic effect of a 1% cream preparation of NND-502, a novel topical antifungal agent, in a guinea pig tinea pedis model produced by infecting the plantar skin of guinea pigs with Trichophyton mentagrophytes. Animals developing tinea pedis were divided into two groups: an untreated control group and a treated group. In the latter group, after confirming infection had been established, the infected animals were topically treated with the NND-502 cream once daily for one week. The animals were reared in a clean environment free from exposure to exogenous dermatophytes. At one week (5 weeks post-infection), 6 weeks (10 weeks post-infection) and 16 weeks (20 weeks post-infection) after completion of the treatment, plantar skin samples were taken from a certain number of both groups of animals. The results demonstrated that all of the animals in the untreated control group and none of those in the treated group were culture-positive in this animal model of tinea pedis. The topical treatment with NND-502 achieved a mycological cure. Thus NND-502 can be considered a promising candidate as a new anti-dermatophytic agent for topical use.     

First Case of <Emphasis Type="Italic">Trichophyton soudanense</Emphasis> Isolated in Tunisia

This is a first case of Trichophyton soudanense isolated from Ivoiran student in Tunisia. A 24-year-old man was addressed for extensive erythematous, scaling lesions. Examination disclosed tinea capitis, tinea corporis, tinea pedis, and onychomycosis of toenails and fingernails. Isolates were identified as Trichophyton soudanense on the basis of macroscopy and microscopy colony characteristics. The patient was treated with fluconazole, topical econazole, and ciclopiroxolamine varnish. Although T. soudanense was identified since the late 1950s outside the African continent especially in the North America, Brazil, Australia, and many European countries, this is the first case reported in Tunisia. Accessibility to our universities for African students makes possible the emergence of this dermatophyte.     

Tinea unguium in the north-west of Iran (1996-2004)

Tinea unguium is a common mycosis in many part of the world including Iran. The prevalence of this mycosis varied depending on time, health level and geographical location. To stabilise the etiological, epidemiological and risk factors of tinea unguium in North-west Iran, a study of patients with suspected dermatophyte infections of their nails was carried out between 1996 and 2004. During this study 590 (354 females and 236 males) patients with clinical presentation of fungal infection in fingernails, toenails or in the both sites, were investigated using direct microscopy and culture of clinical samples. Tinea unguium was documented in 41 cases (7%) and among positive cases, 16 cases (39% total positive cases) were female and 25 cases (61% total positive cases) were male. Seventeen patients (41% total positive cases) had tinea unguium in their finger nails and 24 patients (59% total positive cases) had infection in their toe nails. According to the isolated etiologic agent, 66% (19 cases) of tinea unguium infections were caused by zoophilic drematophytes, 31% (9 cases) were caused by anthropophilic drematophytes and 3% (1 case) were caused by geophilic dermatophytes. With regard of sex, tinea unguium did not show a significant difference. The highest prevalence of tinea unguium was found in patients between 11 and 40 years of age. In conclusion the current results identified the etiological agents and epidemiological aspects of tinea unguium in North-west Iran. Tinea unguium in this region is associated with animal husbandry and direct or indirect contact with their products (wool, leather).