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In recent years, therapy-refractory courses of dermatophytoses have increasingly become the focus of attention. The most frequent pathogens are Trichophyton (T.) rubrum and T. mentagrophytes. In addition to local therapy, first-line treatment includes terbinafine, an allylamine antifungal agent that acts by inhibiting squalene epoxidase and thus interfering with ergosterol synthesis. In refractory cases, terbinafine resistance due to point mutation in the squalene epoxidase gene has been frequently detected.The aim is to present specific aspects in the epidemiology of dermatophytoses with terbinafine resistance and to illustrate them on the basis of four patient cases including diagnostic procedures.A review of handbook knowledge, a selective literature search, and a review of four patient cases were performed.Detection of the terbinafine resistance was performed by in vitro testing using the breakpoint method as well as sequencing of the Trichophyton isolate and detection of the point mutation with amino acid substitution at position L393F or F397L of squalene epoxidase.In refractory and recurrent dermatophytoses, terbinafine resistance should be considered, especially in T. mentagrophytes and T. rubrum, and in vitro resistance testing of the dermatophyte and point mutation analysis of squalene epoxidase (SQLE) should be performed. Therapeutically, intermittent administration of itraconazole in combination with antifungal local therapy is recommended. Nevertheless, a recurrent course is to be expected and long-term therapy with itraconazole is usually necessary.HINTERGRUND: In den letzten Jahren sind therapierefraktäre Verläufe von Dermatophytosen immer mehr in den Fokus getreten. Häufigste Erreger hierbei sind Trichophyton (T.) rubrum und T. mentagrophytes. Die Behandlung umfasst neben lokaltherapeutischen Maßnahmen als Erstlinientherapie Terbinafin, ein Allylamin-Antimykotikum, das durch Inhibition der Squalenepoxidase und somit Störung der Ergosterolsynthese wirkt. Bei therapierefraktären Verläufen konnte mittlerweile gehäuft eine Terbinafin-Resistenz durch Punktmutation im Gen der Squalenepoxidase nachgewiesen werden.Es erfolgen die Darstellung spezieller Aspekte in der Epidemiologie der Dermatophytosen mit Terbinafin-Resistenz sowie Veranschaulichung anhand von 4 Patienten inklusive praxisrelevanter Aspekte bei der Diagnostik.Es wurden eine Aufarbeitung von Handbuchwissen, eine selektive Literaturrecherche sowie eine Aufarbeitung von 4 Patienten mit Dermatophytosen und einer Onychomykose durch Terbinafin-resistente Isolate von T. rubrum vorgenommen.Der Nachweis der Terbinafin-Resistenz erfolgt durch In-vitro-Testung mittels Breakpoint-Methode sowie Sequenzierung des Trichophyton-Isolates und Nachweis der Punktmutation mit Aminosäuresubstitution an Position L393F oder F397L des Gens der Squalenepoxidase.Bei therapierefraktären und rezidivierenden Dermatophytosen sollte vor allem bei T. mentagrophytes und T. rubrum an eine Terbinafin-Resistenz gedacht werden, und eine In-vitro-Resistenztestung des Dermatophyten sowie eine Punktmutationsanalyse der Squalenepoxidase (SQLE) sollten erfolgen. Therapeutisch wird die intermittierende Gabe von Itraconazol in Kombination mit einer antimykotischen Lokaltherapie empfohlen. Dennoch ist mit einem rezidivierenden Verlauf zu rechnen und in der Regel eine Langzeittherapie mit Itraconazol notwendig.

This article reports on a patient suffering from terbinafine-resistant tinea corporis acquired in Asia. Trichophyton mentagrophytes type VIII was first isolated in India. In the past few years, it has gained clinical relevance by causing terbinafine-resistant tinea corporis and cruris. Therefore, in cases of recalcitrant tinea in persons returning from Asia, systemic itraconazole should be started. Specially formulated itraconazole enables high bioavailability despite lower dosage.Wir berichten über eine Terbinafin-resistente Tinea corporis bei einem Reiserückkehrer aus Asien. Der erstmals in Indien isolierte Genotyp VIII von Trichophyton mentagrophytes hat in den vergangenen Jahren als Erreger der Tinea corporis und Tinea cruris zugenommen und aufgrund seiner häufigen Resistenz gegenüber Terbinafin an Relevanz gewonnen. Insbesondere nach Reisen nach Asien sollte daher bei therapierefraktärer Tinea die systemische Therapie auf Itraconazol umgestellt werden. Mit Itraconazol in veränderter Darreichung kann eine erhöhte Bioverfügbarkeit bei niedrigerer Dosierung erreicht werden.

Trichophyton (T.) tonsurans is considered as the main causative agent of tinea gladiatorum (ringworm) in contact and martial arts worldwide and regularly leads to outbreaks. In the national wrestling squad in Leipzig, dermatophytoses occurred frequently and recurrently in children and adolescents for over a 2-year period. The wrestlers came to the dermatologist's office for clinical examination and sampling. Dermal scales and hair roots as well as smears were examined mycologically with fluorescence optical preparation, fungal culture, and polymerase chain reaction (PCR) for dermatophyte DNA. Sequencing of the dermatophyte rDNA served as culture confirmation test. Environmental investigations in the wrestler training center included contact cultures and smears from surfaces, in particular from the mats. T. tonsurans was culturally and/or with PCR detectable in 21 out of 25 children and adolescents plus one trainer. T. tonsurans grew in one of ten contact cultures of mats and floors in the wrestling training center, and T. interdigitale was found in another culture. Smears from the mats resulted in a culture of T. tonsurans detection twice. The PCR was positive for T. tonsurans three times. Within 14 days, T. tonsurans developed small, flat, radiating, granular and white-colored colonies with a mahogany-brown reverse side on the fungal culture media. The sequencing of the internal transcribed spacer (ITS) region of the rDNA and the translation elongation factor 1 α (TEF 1 α) gene confirmed the species T. tonsurans in all cases. T. interdigitale that was found from a mat was also identified by sequencing. Eight T. tonsurans strains were subjected to in vitro susceptibility testing to terbinafine. All isolates were sensitive to terbinafine in vitro with minimal inhibitory concentrations of ≤ 0.1 µg/ml.Trichophyton (T.) tonsurans gilt bei Kontakt- und Kampfsportarten weltweit als Haupterreger der Tinea gladiatorum und führt regelmäßig zu Ausbrüchen. In Leipzig treten im nationalen Ringerkader seit über 2 Jahren bis heute gehäuft und rezidivierend Dermatophytosen bei Kindern und Jugendlichen auf. Die Ringer wurden in der Hautarztpraxis zur klinischen Untersuchung und Probeentnahme vorstellig. Hautschuppen und Haarwurzeln sowie Abstriche wurden entnommen und mykologisch mit fluoreszenzoptischem Präparat, Pilzkultur und Polymerasekettenreaktion (PCR) auf Dermatophyten-DNA (Desoxyribonukleinsäure) untersucht. Die Sequenzierung der r(ribosomale)DNA der Dermatophyten diente als Kulturbestätigungstest. Umgebungsuntersuchungen in der Ringerhalle umfassten Abklatschkulturen und Abstriche von Oberflächen, insbesondere von den Matten. T. tonsurans war bei 21 von 25 Kindern und Jugendlichen sowie 1 Trainer kulturell und/oder mit PCR nachweisbar. In 1 von 10 Abklatschkulturen von Matten und Fußböden wuchs T. tonsurans, eine weitere Kultur wies T. interdigitale nach. Abstriche von den Matten ergaben 2‑mal einen kulturellen T.-tonsurans-Nachweis, 3‑mal war die PCR auf T. tonsurans positiv. Auf den Pilznährmedien entwickelte T. tonsurans innerhalb von 14 Tagen kleine, flache, ausstrahlende, granuläre und weiß gefärbte Kolonien mit mahagonibrauner Rückseite. Die Sequenzierung der Internal-Transcribed-Spacer(ITS)-Region der rDNA sowie des TEF1‑α(„translation elongation factor 1 α“)-Gens bestätigte die Spezies T. tonsurans in allen Fällen. T. interdigitale, isoliert von einer Matte, wurde ebenfalls mit Sequenzierung identifiziert. Acht T.-tonsurans-Stämme wurden einer In-vitro-Empfindlichkeitstestung gegen Terbinafin unterzogen. Alle Isolate waren mit minimalen Hemmkonzentrationen von ≤ 0,1 µg/ml in vitro empfindlich gegen Terbinafin.

Die Kälberflechte ist eine durch Tiere übertragene Pilzinfektion, die berufsbedingt auftreten und nach Nr. 3102 BKV (Berufskrankheiten-Verordnung) als Berufskrankheit anerkannt werden kann. Die durch Trichophyton verrucosum ausgelöste Zoonose zeichnet sich häufig durch einen schweren klinischen Verlauf aus, der nicht selten als bakterielle Infektion fehlgedeutet und primär antibiotisch behandelt wird. Die Gewinnung und mykologische Untersuchung von Schuppenmaterial ist diagnostisch entscheidend; auch eine Biopsie kann wegweisend sein. Die orale Therapie erfolgt leitliniengemäß mit Terbinafin. Zudem ist zum Schutz vor Reinfektionen auf besondere Hygienemaßnahmen in Ställen zu achten.

A 6 month-old-female infant from Bahrain visiting Germany with her family for a holiday was seen by us for extensive dermatophytosis of the back, buttocks, chest and groins. Topical treatment by terbinafine for over 2 months was not successful. Other family members including adults and children were treated in Bahrain with topical antifungals and oral voriconazole which was not helpful. Mycological examination performed in Germany revealed the detection of the zoophilic dermatophyte Trichophyton (T.) mentagrophytes. The newly described genotype VIII within the species T. mentagrophytes was identified by sequencing of the "internal transcribed spacer" (ITS) region of the fungal rDNA. This genotype of T. mentagrophytes is the main causative agent of the current epidemic of chronic recalcitrant dermatophytoses in India. Transmission of this Indian genotype of T. mentagrophytes to other countries due to globalization is a serious issue to be considered. Moreover, a significant percentage of these Indian T. mentagrophytes strains are resistant to terbinafine both in vitro and by the way of genetic point mutations in the squalene epoxidase (SQLE) gene. Some are also found to be partially resistant against itraconazole and voriconazole. The point mutation TTC/TTA was found by SQLE mutation analysis in this particular T. mentagrophyte isolate from Bahrain. This point mutation is closely associated with F397L amino acid substitution of the enzyme indicative of in vitro resistance of the dermatophyte against terbinafine. The girl was successfully treated by topical miconazole and later by ciclopirox olamine. This is the first report on an infection due to a terbinafine-resistant T. mentagrophytes strain of the ITS genotype VIII from India in Germany.

Tinea barbae represents a very rare dermatophytosis. We report on a tinea barbae profunda following a journey to Southeast Asia. After travel to Thailand, a businessman was affected by a foudroyant proceeding abscessing infection of the upper lip and beard area. The initial therapy with oral acyclovir and oral ciprofloxacin, which later was changed to ampicillin plus sulbactam, intravenously, was unsuccessful. In a biopsy sample, histologically, with Grocott-Gomori's methenamine silver stain, fungal mycelium was apparent in the tissue. Thereupon, terbinafine 250 mg was given for 4 weeks, topically, a 1% ciclopiroxolamine-containing cream. In fungal culture, T. mentagrophytes were found to grow. Meanwhile, the patient's German wife suffered from a tinea faciei. From skin scrapings from the cheek, T. mentagrophytes was also cultivated. This zoophilic dermatophyte was identical with other zoophilic strains of T. mentagrophytes currently found in Germany, which were also acquired in Thailand. The patient had contact with Thai female sex workers who must be considered as a source of infection of the dermatophytosis. There was no animal contact, neither in Thailand, nor in Germany. The infection chain of the dermatophytosis from Thailand probably reached from a female sex worker via the here described patient to his wife in Germany. This pathway of infection has been known for 1 or 2 years, but until now, in Germany, Switzerland, and Austria exclusively via pubogenital infections (tinea genitalis profunda) due to T. mentagrophytes after journeys to Southeast Asia. For treatment, oral antifungal agents should be used, first of all terbinafine, alternatively fluconazole or itraconazole.

The allylamine terbinafine is the probably most frequently prescribed systemic antifungal agent in Germany for the treatment of dermatomycoses and onychomycoses. According to the German drug law, terbinafine is approved for patients who are 18 years and older; however, this antifungal agent is increasingly used off-label for treatment of onychomycoses and tinea capitis in children. Terbinafine is associated with only a few interactions with other drugs, which is why terbinafine can generally be used without problems in older and multimorbid patients. Nevertheless, some potential interactions of terbinafine with certain drug substances are known, including substances of the group of antidepressants/antipsychotics and some cardiovascular drugs. Decisive for the relevance of interactions is-along with the therapeutic index of the substrate and the possible alternative degradation pathways-the genetically determined type of metabolism. When combining terbinafine with tricyclic antidepressants or selective serotonin reuptake inhibitors and serotonin/noradrenalin reuptake inhibitors, the clinical response and potential side effects must be monitored. Problematic is the use of terbinafine with simultaneous treatment with tamoxifen. The administration of potent CYP2D6 inhibitors leads to a diminished efficacy of tamoxifen because one of its most important active metabolites-endoxifen-is not sufficiently available. Therefore, combination of tamoxifen and terbinafine should be avoided. In conclusion, the number of substances which are able to cause clinically relevant interactions in case of simultaneously administration with terbinafine is clear and should be manageable in the dermatological office with adequate monitoring.

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.

Moulds or non-dermatophyte moulds (NDM) are being increasingly isolated as causative agent of onychomycoses. Known causes of a NDM-OM are Scopulariopsis brevicaulis, Fusarium, Aspergillus, Acremonium, Neoscytalidium dimidiatum, Arthrographis kalrae, and Chaetomium. In this article, 5 patients with suspected nail infection due to Onychocola canadensis are reported for the first time in Germany. Systemic antifungal agents are not considered to be effective in NDM onychomycosis. In individual cases, however, terbinafine seems to be effective in Onychocola canadensis infection of the nails. Treatment of choice represents, however, nontraumatic nail avulsion using 40 % urea ointment followed by antifungal nail lacquer with ciclopirox olamine or amorolfine.

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).

A 12-year-old with a functional circulatory disturbance had toe nail onychomycosis caused by Trichophyton rubrum. There were no other underlying diseases.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.

A woman developed subacute cutaneous lupus erythematosus (SCLE) in 1995 and 2013, each time 6 weeks after initiation of terbinafine therapy. Within the heterogeneous group of drug-induced SCLE terbinafine is considered the most common cause. The clinical, histopathological and laboratory findings of idiopathic and drug-induced SCLE are largely identical. The pathogenesis of drug-induced SCLE is not known. Cytotoxic and immunological mechanisms are considered likely. The treatment of drug-induced SCLE is discontinuation of the suspected drug. In addition, corticosteroids are recommended alone or in combination with chloroquine or hydroxychloroquine.

Trichophyton (T.) species of Arthroderma (A.) benhamiae is a new emerging pathogen of dermatomycoses in children and adolescents. This zoophilic fungus seems to be more common than other zoophilic dermatophytes, e. g. Microsporum canis transmitted from cats to humans, zoophilic strains of T. interdigitale, and T. verrucosum as cause of ringworm of cattle. Trichophyton species of A. benhamiae is transmitted from guinea pigs (Cavia porcellus form. domestica) to human beings and causes highly inflammatory dermatomycoses both of the face and the scalp. When this dermatophyte produces purulent abscess-forming deep cutaneous infections of the scalp known as kerions, they are both a diagnostic and in particular a therapeutic challenge.

Free oxygen species are able to destroy cells due to their cytotoxic effect, which is based on lipid peroxidation, enzyme oxidation and protein oxidation. We analyzed the ability of six different Malassezia (M.) species to generate reactive oxygen species (ROS), using the lucigenin-amplified chemiluminescence. Further investigations showed the effect of different concentrations of terbinafine on ROS generation by M. furfur and M. pachydermatis after 10, 30 and 60 minutes.All of the investigated Malassezia species (M. furfur, M. globosa, M. sympodialis, M. slooffiae, M. obtusa, M. pachydermatis) was able to generate reactive oxygen species. Terbinafine inhibited free radical production by M. furfur and M. pachydermatis.Dependent on their cell concentrations, M. species have the ability to generate ROS. The ability of the different Malassezia species to produce ROS should be considered as one further virulence factor of this yeast. The antifungal agent terbinafine (concentrations from 100 microg to 1 microg ml -1) reduced ROS production by M. furfur and M. pachydermatis. Terbinafine acts as oxygen species scavenger. This could be an additional mechanism supporting the classic antifungal effect of this agent, the inhibition of ergosterol synthesis.

Superficial fungal infections are common and worldwide in distribution. Latest estimates suggest one- third of the population in Europe has a fungal infection of their feet, with dermatophyte infections of the skin of the feet (tinea pedis) most common. Tinea pedis interdigitalis is by far most common and can be effectively treated topically. Common agents include azoles, hydroxypyridones and allylamines, with morpholines used less frequently. While most antifungals have mainly fungistatic effects on dermatophytes, the causative agents of tinea pedis, terbinafine--an allylamine--is fungicidal. Due to this feature shorter treatment periods are possible using topical terbinafine. For effective treatment of uncomplicated tinea pedis interdigitalis, azole cream preparations are often used twice daily for four weeks whereas 1% terbinafine cream can be applied once a day for one week. Since 2006, 1% terbinafine is also available as a film-forming solution (FFS), which makes single-dose treatment possible. FFS may prove superior in daily practice with increased compliance and thus reduced recurrences.

A 68-year-old man presented with a one month history of painful blue-red papules and nodules on an erythematous base on the top of his feet, as well as dystrophic toenails. He had undergone renal transplantation six months previously for membranous glomerulonephritis, and was immunosuppressed with tacrolimus 3 g, mycophenolate mofetil 1500 mg and prednisolone 5 mg daily. His tacrolimus level was 29.8 ng/ml (expected level 6-8 ng/ml). Even though the cutaneous lesions strongly suggested Kaposi sarcoma, the histological examination revealed a dermal abscess in which hyphae and spores were seen with PAS staining. ELISA-PCR of the biopsy identified Trichophyton rubrum, which was also grown on culture of the biopsy tissue. The diagnosis of Majocchi granuloma secondary to excessive immunosuppression was made. Systemic treatment with terbinafine 250 mg per day and topical ciclopirox olamine completely cured the granulomatous skin lesions, and later the nails.

A 65-year-old patient presented with grey-brownish maculae localized on the face. He had been treated with oral terbinafine due to onychomycosis, and the first spots manifested after 4 weeks of therapy. Other drugs were not taken by the patient, who was otherwise in a healthy condition. Histology showed melanin localized within macrophages in the upper and lower dermis. Cutaneous side effects are well described in patients treated with terbinafine and usually present as urticaria or eczema. Severe reactions may occur in rare cases. Hyperpigmentation has not yet been described as a consequence of oral terbinafine. Grey hyperpigmentation as it occurred in our patient has been described as a side effect of therapy with minocycline, amiodarone, tricyclic antidepressants, or heavy metals. This case report shows that drug-induced hyperpigmentation should also be considered if the patient takes drugs not known for this kind of side effect.