[Malassezia spp.: interactions with topically applied lipids-a review : Malassezia and topically applied lipids]. / Malassezia spp.: Wechselwirkungen mit Lipidbestandteilen von Topika ­ eine Übersicht : Malassezia und Topika.

Lipophilic Malassezia yeasts are an important part of the human resident skin flora, especially in seborrheic areas. Besides mutualistic interactions with the host they are also linked to diseases although the specific causes are not yet comprehensively understood. The amount of available lipids on the skin correlates with the Malassezia density and also with the occurrence of certain diseases like tinea versicolor. Here, the naturally produced lipids of the sebaceous glands play a role. Hardly studied thus far is the impact of topically applied lipids. Here, growth promotion as well as inhibition of Malassezia cells as well as the production of new metabolites through ester cleavage are possible. One example is the release of antimicrobial fatty acids from hydroxypropyl caprylate through the action of Malassezia lipases. This "self-kill" principle results in the reduction of the amount of Malassezia cells and can be applied as new therapy option for dandruff treatment. A better understanding of the interaction between topica and Malassezia would increase their skin tolerance and open new therapy options.

[Tinea capitis-diagnostic measures in an outbreak situation : Case report and review of the literature]. / Tinea capitis ­ diagnostische Maßnahmen in der Ausbruchssituation : Fallbericht und Literaturübersicht.

In a preschool a long-lasting outbreak of Trichophyton (T.) tonsurans tinea capitis was stopped by a concurrent screening of all persons at-risk (N = 264) with the hairbrush technique and a therapy based on clinical picture as well as on the quantitative results of the culture. In addition to the 5 symptomatic patients 10 asymptomatic carriers undetected until now were especially important as vectors. With the rising incidence of T. tonsurans and T. violaceum and the return of Microsporum (M.) audouinii in central Europe such outbreaks are likely to occur more frequently. According to the literature an early and comprehensive screening of the entire at-risk population, a combined antimycotic therapy of the symptomatic and at least a topical therapy of the asymptomatic as well as measures of decontamination are important conditions for successful outbreak management. In our hands the hairbrush technique is a reliable, painless and easy-to-perform screening method which also allows a quantification of fungal load.

[Trichophyton mentagrophytes-from snow leopard to man : A molecular approach for uncovering the chain of infection]. / Trichophyton mentagrophytes ­ vom Schneeleoparden zum Menschen : Ein molekularer Ansatz zur Aufdeckung der Infektionskette.

Sources of infection for Trichophyton (T.) mentagrophytes-a zoophilic dermatophyte-comprise pet rodents (guinea pigs, mice, rabbits) and sometimes cats. Human infections due to dermatophytes after contact with zoo animals, however, are extreme rare. Four zoo keepers from Basel Zoo were diagnosed to suffer from tinea manus and tinea corporis due to T. mentagrophytes. The 22-year-old daughter of one zoo keeper was also infected with tinea corporis after having worked in the snow leopard section for one day. The strain of the index patient was confirmed by a direct uniplex-PCR-EIA and sequence analysis of the ribosomal internal transcribed spacer (ITS) region (18S rRNA, ITS1, 5.8S rRNA, ITS2, 28S rRNA) as T. mentagrophytes. Three young snow leopards from Basel Zoo were identified as the origin of the fungal skin infection. The transmission occurred due to direct contact of the zoo keepers with the young snow leopards when removing hedgehog ticks (Ixodes hexagonus). Two adult snow leopards had developed focal alopecia of the facial region which was diagnosed as dermatomycoses due to T. mentagrophytes by the zoo veterinarians. By sequence analysis, both the strains from the animals and a single strain of the index patient showed 100% accordance proving transmission of T. mentagrophytes from animals to the zoo keepers. Molecular biological identification revealed a strong relationship to a strain of T. mentagrophytes from European mink (Mustela lutreola) from Finland. Treatment of patients was started using topical ointment with azole antifungals, and oral terbinafine 250 mg once daily for 4 weeks. Both adult snow leopards and the asymptomatic young animals were treated with oral itraconazole.

New insights on the antibacterial efficacy of miconazole in vitro.

Miconazole is a broad-spectrum antifungal used in topical preparations. In the present investigation the minimal inhibitory concentration (MIC) of miconazole for eighty wild type strains of gram-positive and gram-negative bacteria isolated from infected skin lesions was assessed using a modified agar dilution test (adapted to CLSI, Clinical Laboratory Standards Institute). 14 ATCC reference strains served as controls. Miconazole was found efficacious against gram-positive aerobic bacteria (n=62 species), the MICs against Staphylococcus (S.) aureus, S. spp., Streptococcus spp. und Enterococcus spp. ranged between 0.78 and 6.25 µg/mL. Interestingly, there were no differences in susceptibility between methicillin-susceptible (MSSA, 3) methicillin-resistant (MRSA, 6) and fusidic acid-resistant (FRSA, 2) S. aureus isolates. Strains of Streptococcus pyogenes (A-streptococci) (8) were found to be slightly more sensitive (0.78-1.563 µg/mL), while for gram-negative bacteria, no efficacy was found within the concentrations tested (MIC >200 µg/mL). In conclusion, for the gram-positive aerobic bacteria the MICs of miconazole were found within a range which is much lower than the concentration of miconazole used in topical preparations (2%). Thus topically applied miconazole might be a therapeutic option in skin infections especially caused by gram-positive bacteria even by those strains which are resistant to antibiotics.

[Dermatophyte : Current situation]. / Dermatophytid : Aktuelle Bestandsaufnahme.

Currently, a mycid is defined as hyperergic reaction that develops from a remote localized infection and in which no fungus is detectable. Criteria for a mycid caused by a dermatophyte (dermatophytid) are (1) proven dermatophytosis elsewhere, (2) no evidence for fungal elements in the lesions of the -id reaction, (3) initially often worsening of the lesions under therapy with highly potent systemic antimycotics, and (4) clearing after the dermatophytosis has been treated sufficiently. The most common dermatophytid is a symmetrical dyshidrotic mycid of the hands in connection with an often highly inflammatory mycotic infection of the feet especially by Trichophyton mentagrophytes. In addition to lichen trichophyticus, dermatophytids associated with tinea capitis may show high clinical variability. They often occur under systemic antimycotic therapy and have to be differentiated from drug reactions. In addition to systemic antimycotic therapy and, if necessary, a short-term application of oral glucocorticoidsteroids, a topical combination of an antifungal and a glucocorticosteroid is effective. It leads to an immediate reduction of inflammation and pruritus, especially if initiation of systemic antifungal therapy has resulted in a flare-up reaction (overtreatment phenomenon).

Precipitation of free fatty acids generated by Malassezia - a possible explanation for the positive effects of lithium succinate in seborrhoeic dermatitis.

BACKGROUND: Lithium succinate and gluconate are effective alternative options licensed for the topical treatment of seborrhoeic dermatitis (SD). OBJECTIVE: Their mode of action is not fully elucidated. Minimal inhibitory concentrations against Malassezia (M.) yeasts, which play an important role in SD, are very high. METHODS: An assay based on the hydrolysis of ethyl octanoate enables us to test the hydrolytic activity of reference strains of the species M. globosa, M. sympodialis and M. furfur solely without interference by fungal growth as the free octanoic acid generated has antifungal activity. RESULTS: In this assay the presence of alkali salts (lithium, sodium and potassium succinate resp.) in concentrations of 2%, 4% and 8% does not influence hydrolytic activity but the availability of the generated free fatty acid in a dose-dependent manner which was analysed by means of high-performance thin layer chromatography and densitometry. This was best effected with the lithium, followed by the sodium and only to a low degree by the potassium salt. As shown by attenuated total reflection Fourier transform infrared spectroscopy the free fatty acid reacted to the respective alkali soap and precipitate from solution. The alkali soaps could not be utilized by the M. spp. as shown in a modified Tween auxanogram and in lack of fungal growth by ethyl oleate in the presence of 8% lithium succinate. CONCLUSION: The effect of lithium succinate on growth of M. yeasts and presumably in SD can be explained by a precipitation of free fatty acids as alkali soaps limiting their availability for the growth of these lipid-dependent yeasts.

[Treatment of dermatoses : Significance and use of glucocorticoids in fixed combination with antifungals]. / Versorgung von Hauterkrankungen : Stellenwert und Einsatz von Glukokortikosteroiden in fixer Kombination mit Antimykotika.

Treating eczema with fungal and/or bacterial superinfections or superficial mycoses are a common problem in daily practice. A fungal superinfection as a consequence of a diminished skin barrier might complicate the course of eczema. In addition, in an inflammatory superficial mycotic infection a delayed-type hypersensitivity reaction may result in healing of the lesion, but might also be responsible for irreversible damage of epidermal structures. An example is permanent hair loss by scarring alopecia in the context of inflammatory tinea capitis. In both cases, combination of an antifungal and a glucocorticoid is appropriate in therapy, preferentially in topical application. The use of azole antimycotics is especially helpful, as they are also effective against gram-positive bacteria.

[Terbinafine : Drug-induced lupus erythematodes and triggering of psoriatic skin lesions]. / Terbinafin : Medikamenteninduzierter Lupus erythematodes und Triggerung psoriatischer Hautveränderungen.

Based on the technical information that oral terbinafine must be used with caution in patients with pre-existing psoriasis or lupus erythematosus, the literature was summarized. Terbinafine belongs to the drugs able to induce subcutaneous lupus erythematosus (SCLE)-with a relatively high risk. The clinical picture of terbinafine-induced SCLE may be highly variable and can also include erythema exsudativum multiforme-like or bullous lesions. Thus, differentiation of terbinafine-induced Stevens-Johnson syndrome or toxic epidermal necrolysis may be difficult. Therefore, terbinafine should be prescribed with caution in patients who show light sensitivity, arthralgias, positive antinuclear antibodies or have a history of SLE or SCLE. Case reports include wide-spread, but mostly nonlife-threatening courses, which did not require systemic therapy with steroids or antimalarials in every case. Terbinafine is also able to induce or to aggravate psoriasis. The latency period seems to be rather short (<4 weeks). Terbinafine therefore is not first choice if a systemic therapy with antimycotics is indicated in a patient with psoriasis or psoriatic diathesis. Azole derivatives according to the guidelines may be used as an alternative.

[Sports-associated dermatophytoses : An overview]. / Sportassoziierte Dermatophytosen : Ein Überblick.

Because of high exposure (e. g. swimmers and athletes competing on mats) and disposition (e. g. microtraumata of the skin in runners) athletes are prone to a higher risk for mycotic infections by dermatophytes. In disciplines with close contact during competition-especially wrestlers and judoists-infections by the anthropophilic Trichophyton (T.) tonsurans are most important (tinea gladiatorum). These infections are highly contagious and often cause small epidemics especially if the primary source of infection is not promptly recognized. The environment of the athletes (e. g. mats) and asymptomatic carriers may be sources of further spread. Tinea pedis with its clinical manifestations seems to be often underdiagnosed and insufficiently treated. Environmental contamination by fungal spores may be responsible for the significantly higher level of mycotic infections of the feet in children and adolescents active in sports. There is a higher risk for spread of the infection to the toe nails (onychomycosis) and for consecutive infections by bacteria (e. g. erysipelas). More rarely infections by zoophilic or geophilic dermatophytes are seen in athletes (e.g. equestrians). Education and more intensive measures of prevention and environmental decontamination are essential for all dermatophytoses associated with sports.

[Requirements for mycological diagnostics in accordance with the guideline of the German Medical Association for quality assurance of medical laboratory tests]. / Anforderungen für die mykologische Diagnostik entsprechend der Richtlinie der Bundesärztekammer (Rili-BÄK) zur Qualitätssicherung laboratoriumsmedizinischer Untersuchungen.

The ability of recognizing various clinical manifestations of mucocutaneous mycosis, making a diagnosis, and establishing a treatment is part of a dermatologist's daily routine. However, due to the fact that clinical manifestations, laboratory diagnostics, and treatment are performed in one hand, laboratory findings are properly classified and interpreted. Since new binding guidelines of the German Medical Association on quality assurance measures in medical laboratory testing came into force, there is much concern among dermatologists of how to comply with these new regulations. It is the intention of the authors to help our readers to implement these new rules in order to make sure that mycological diagnostics continue to be part of a dermatologist's professional work.

Guideline: vulvovaginal candidosis (AWMF 015/072), S2k (excluding chronic mucocutaneous candidosis).

The oestrogenised vagina is colonised by Candida species in at least 20% of women; in late pregnancy and in immunosuppressed patients, this increases to at least 30%. In most cases, Candida albicans is involved. Host factors, particularly local defence mechanisms, gene polymorphisms, allergies, serum glucose levels, antibiotics, psycho-social stress and oestrogens influence the risk of candidal vulvovaginitis. Non-albicans species, particularly Candida glabrata, and in rare cases also Saccharomyces cerevisiae, cause less than 10% of all cases of vulvovaginitis with some regional variation; these are generally associated with milder signs and symptoms than normally seen with a C. albicans-associated vaginitis. Typical symptoms include premenstrual itching, burning, redness and odourless discharge. Although itching and redness of the introitus and vagina are typical symptoms, only 35-40% of women reporting genital itching in fact suffer from vulvovaginal candidosis. Medical history, clinical examination and microscopic examination of vaginal content using 400× optical magnification, or preferably phase contrast microscopy, are essential for diagnosis. In clinically and microscopically unclear cases and in chronically recurring cases, a fungal culture for pathogen determination should be performed. In the event of non-C. albicans species, the minimum inhibitory concentration (MIC) should also be determined. Chronic mucocutaneous candidosis, a rarer disorder which can occur in both sexes, has other causes and requires different diagnostic and treatment measures. Treatment with all antimycotic agents on the market (polyenes such as nystatin; imidazoles such as clotrimazole; and many others including ciclopirox olamine) is easy to administer in acute cases and is successful in more than 80% of cases. All vaginal preparations of polyenes, imidazoles and ciclopirox olamine and oral triazoles (fluconazole, itraconazole) are equally effective (Table ); however, oral triazoles should not be administered during pregnancy according to the manufacturers. C. glabrata is not sufficiently sensitive to the usual dosages of antimycotic agents approved for gynaecological use. In other countries, vaginal suppositories of boric acid (600 mg, 1-2 times daily for 14 days) or flucytosine are recommended. Boric acid treatment is not allowed in Germany and flucytosine is not available. Eight hundred-milligram oral fluconazole per day for 2-3 weeks is therefore recommended in Germany. Due to the clinical persistence of C. glabrata despite treatment with high-dose fluconazole, oral posaconazole and, more recently, echinocandins such as micafungin are under discussion; echinocandins are very expensive, are not approved for this indication and are not supported by clinical evidence of their efficacy. In cases of vulvovaginal candidosis, resistance to C. albicans does not play a significant role in the use of polyenes or azoles. Candida krusei is resistant to the triazoles, fluconazole and itraconazole. For this reason, local imidazole, ciclopirox olamine or nystatin should be used. There are no studies to support this recommendation, however. Side effects, toxicity, embryotoxicity and allergies are not clinically significant. Vaginal treatment with clotrimazole in the first trimester of a pregnancy reduces the rate of premature births. Although it is not necessary to treat a vaginal colonisation of Candida in healthy women, vaginal administration of antimycotics is often recommended in the third trimester of pregnancy in Germany to reduce the rate of oral thrush and napkin dermatitis in healthy full-term newborns. Chronic recurrent vulvovaginal candidosis continues to be treated in intervals using suppressive therapy as long as immunological treatments are not available. The relapse rate associated with weekly or monthly oral fluconazole treatment over 6 months is approximately 50% after the conclusion of suppressive therapy according to current studies. Good results have been achieved with a fluconazole regimen using an initial 200 mg fluconazole per day on 3 days in the first week and a dosage-reduced maintenance therapy with 200 mg once a month for 1 year when the patient is free of symptoms and fungal infection (Table ). Future studies should include Candida autovaccination, antibodies to Candida virulence factors and other immunological experiments. Probiotics with appropriate lactobacillus strains should also be examined in future studies on the basis of encouraging initial results. Because of the high rate of false indications, OTC treatment (self-treatment by the patient) should be discouraged.

[Cutaneous Malassezia infections and Malassezia associated dermatoses: An update]. / Kutane Malassezia-Infektionen und Malassezia-assoziierte Dermatosen : Ein Update.

The lipophilic yeast fungus Malassezia (M.) spp. is the only fungal genus or species which is part of the physiological human microbiome. Today, at least 14 different Malassezia species are known; most of them can only be identified using molecular biological techniques. As a facultative pathogenic microorganism, Malassezia represents the causative agent both of superficial cutaneous infections and of blood stream infections. Pityriasis versicolor is the probably most frequent infection caused by Malassezia. Less common, Malassezia folliculitis occurs. There is only an episodic report on Malassezia-induced onychomycosis. Seborrhoeic dermatitis represents a Malassezia-associated inflammatory dermatosis. In addition, Malassezia allergenes should be considered as the trigger of "Head-Neck"-type atopic dermatitis. Ketoconazole possesses the strongest in vitro activity against Malassezia, and represents the treatment of choice for topical therapy of pityriasis versicolor. Alternatives include other azole antifungals but also the allylamine terbinafine and the hydroxypyridone antifungal agent ciclopirox olamine. "Antiseborrhoeic" agents, e.g. zinc pyrithione, selenium disulfide, and salicylic acid, are also effective in pityriasis versicolor. The drug of choice for oral treatment of pityriasis versicolor is itraconazole; an effective alternative represents fluconazole. Seborrhoeic dermatitis is best treated with topical medication, including topical corticosteroids and antifungal agents like ketoconazole or sertaconazole. Calcineurin inhibitors, e.g. pimecrolimus and tacrolimus, are reliable in seborrhoeic dermatitis, however are used off-label.

[Tropical and travel-related dermatomycoses: Part 1: Dermatophytoses]. / Tropen- und Reise-assoziierte Dermatomykosen : Teil 1: Dermatophytosen.

Today, tropical and travel-related dermatomycoses must be increasingly anticipated to present in dermatological offices and clinics. Skin infections due to dermatophytes or other fungi may occur after a journey in countries with a high prevalence for the respective causative fungal pathogen, e.g., tinea corporis due to Trichophyton soudanense. Otherwise, more frequently, single infections and even localized outbreaks due to "exotic" or "imported" pathogens of dermatophytoses occur. These epidemics are observed in childcare facilities in Germany and in other European countries. Source of infection are immigrants from Africa and sometimes from Asian countries. Furthermore, African children, and sometimes also adults, are often only asymptomatic carriers of such anthropophilic dermatophytes. Outbreaks of dermatophyte infections with one and more affected children and also adult staff and teachers due to Trichophyton violaceum or Microsporum audouinii in kindergartens and schools are not a rarity these days. Further tropical and travel-associated dermatophytes are Trichophyton tonsurans, Trichophyton schoenleinii, and Trichophyton concentricum. Tinea capitis should be treated in a species-specific manner. Griseofulvin is the treatment of choice for infections due to Microsporum species. In contrast, tinea capitis due to Trichophyton species has to be treated by terbinafine, however, because the agent is not approved for children in Germany, only after receiving written consent of parents. Alternatives are fluconazole and itraconazole. Onset and aggravation of tinea pedis during travel has its origin in a preexisting neglected fungal infection of the feet. In the tropics, exacerbations and secondary bacterial complications of tinea pedis develop under distinctly promoting conditions.

[Tropical and travel-related dermatomycoses : Part 2: cutaneous infections due to yeasts, moulds, and dimorphic fungi]. / Tropen- und Reise-assoziierte Dermatomykosen : Teil 2: Kutane Infektionen durch Hefepilze, Schimmelpilze und dimorphe Pilze.

Besides dermatophytoses, a broad range of cutaneous infections due to yeasts and moulds may occur in subtropical and tropical countries where they can affect travellers. Not to be forgotten are endemic occurring dimorphic or biphasic fungi in countries with hot climate, which cause systemic and secondary cutaneous infections in immunosuppressed and immunocompetent people. In the tropics, the prevalence of pityriasis versicolor, caused by the lipophilic yeast Malassezia spp., is about 30-40 %, in distinct areas even 50 %. Increased hyperhidrosis under tropical conditions and simultaneously humidity congestion have to be considered as significant disposing factors for pityriasis versicolor. In tropical countries, therefore, an exacerbation of a preexisting pityriasis versicolor in travellers is not rare. Today, mostly genital yeast infections due to the new species Candida africana can be found worldwide. Due to migration from Africa this yeast pathogen has reached Germany and Europe. Eumycetomas due to mould fungi are rarely diagnosed in Europe. These deep cutaneous mould infections are only found in immigrants from African countries. The therapy of eumycetoma is protracted and often not successful. Cutaneous cryptococcoses due to the yeast species Cryptococcus neoformans and Cryptococcus gattii occur worldwide; however, they are found more frequently in the tropics. Immunosuppressed patients, especially those with HIV/AIDS, are affected by cryptococcoses. Furthermore, Cryptococcus gattii also causes infections in immunocompetent hosts in Central Africa, Australia, California, and Central America.Rarely found are infections due to dimorphic fungi after travel to countries where these fungal pathogens are endemic. In individual cases, cutaneous or lymphogenic transferred sporotrichosis due to Sporothrix schenkii can occur. Furthermore, scarcely known is secondary cutaneous coccidioidomycosis due to Coccidioides immitis after travelling to desert-like endemic regions in southwestern states of the United States and in Latin America, where primary respiratory infection due to this biphasic fungus can be acquired. The antifungal agent itraconazole is the treatment of choice for sporotrichosis and coccidioidomycosis. Talaromyces marneffei-until recently known as Penicillium marneffei-is only found in Southeastern Asia. Mycosis due to this dimorphic fungus has to be considered as an AIDS-defining opportunistic infection. After hematogeneous spread, Talaromyces marneffei affects the skin and mucous membranes of the mouth. Amphotericin B and itraconazole can be used for therapy.

[Majocchi granuloma. Advantages of optical brightener staining in a case report]. / Granuloma trichophyticum Majocchi. Nutzen der Blankophor-Färbung an einem Fallbeispiel.

A patient presented with Majocchi granuloma caused by T. rubrum. By the use of optical brighteners, fungal elements in the deep dermis could be detected more sensitive than with PAS staining. Healing was achieved by long-term use of oral terbinafine (250 mg per day 12 weeks, followed by 250 mg once per week for another 12 weeks).

[Dark nail: clinical findings, diagnostics and therapy of melanonychia]. / Dunkler Nagel : Klinik, Diagnostik und Therapie der Melanonychie.

BACKGROUND: A dark colored pigmentation of nails can be due to a subungual malignant melanoma. There are, however, many other benign causes and this differentiation is an important challenge in dermatological practice. PROBLEM: When should nail pigmentation be clarified by histological investigations? MATERIAL AND METHODS: This article gives a survey of the literature on this topic and a review of own experiences with clinical case examples. The various causes of melanonychia are presented and criteria for the early recognition of melanoma of the nail matrix are formulated. RESULTS: The width and depth of color of longitudinal melanonychia do not allow any conclusions on the dignity. If the nail striation is proximally broader than distally, this is evidence of a proliferative event. Confirmation of a subungual hemorrhage does not exclude a malignancy per se. Also detection of pigmentation due to fungi does not exclude the additional presence of a subungual melanoma. A systematic clinical analysis using clear criteria leads to a working diagnosis and suitable treatment. CONCLUSION: An early and correct designation of nail pigmentation can avoid unnecessary nail interventions but can also be life saving.

[Trichophyton rubrum onychomycosis with secondary Aspergillus versicolor infection in a 12-year-old girl: successful topical therapy with terbinafine-urea ointment]. / Onychomykose durch Trichophyton rubrum und Sekundärinfektion durch Aspergillus versicolor bei einer 12-jährigen Patientin : Erfolgreiche topische Therapie mit einer Terbinafin/Harnstoffzubereitung.

CASE REPORT: A 12-year-old with a functional circulatory disturbance had toe nail onychomycosis caused by Trichophyton rubrum. There were no other underlying diseases. THERAPY AND OUTCOME: Oral therapy with terbinafine 125 mg once weekly in addition to ciclopirox nail lacquer was ineffective. Two years later the disease worsened and A. versicolor was found in pure culture. A preparation of 10% terbinafine HCl in a 20% urea ointment (Onychomal®) applied daily for 4 weeks, then once weekly resulted in complete cure after 7 months.

Efficacy, safety and tolerability of topical terbinafine nail solution in patients with mild-to-moderate toenail onychomycosis: results from three randomized studies using double-blind vehicle-controlled and open-label active-controlled designs.

BACKGROUND: Terbinafine nail solution (TNS) was developed for the treatment of onychomycosis. OBJECTIVE: To assess the efficacy of TNS vs. vehicle and amorolfine 5% nail lacquer. METHODS: Subjects with mild-to-moderate toe onychomycosis (25% to ≤75% nail-involvement, matrix uninvolved) were randomized to receive either TNS or vehicle in two double-blind studies, and to TNS or amorolfine in an active-controlled, open-label study. Primary endpoint was complete cure (no residual clinical involvement and negative mycology) at week 52. Secondary endpoints were mycological cure (negative mycology defined as negative KOH microscopy and negative culture) and clinical effectiveness (≤10% residual-involvement and negative mycology) at week 52. RESULTS: Complete cure was not different between TNS vs. vehicle and amorolfine. Mycological cure was higher with TNS vs. vehicle, as was clinical effectiveness with TNS vs. vehicle, and TNS and amorolfine were not different for secondary efficacy endpoints. Patients achieving mycological cure had a better clinical outcome, and efficacy was improved in subjects with milder disease. Post hoc analysis suggests that nail thickness is an important prognostic factor. Moreover, mycological cure may require 6 months of treatment regimen while complete cure and clinical effectiveness may be achievable only after 10 months. A simulation study suggests that longer treatment duration would have resulted in higher complete cure with TNS vs. vehicle. Study treatments were well-tolerated. CONCLUSION: Primary efficacy objectives were not met in the studies reported herein. Possible reasons for failure to achieve significant outcomes include insufficient length of treatment; stringency of primary endpoint and severity of nail involvement of study population.