Dermatophyte infections, particularly those caused by Trichophyton species, represent a significant global health concern due to their high prevalence and increasing resistance to commonly used antifungal agents. While traditionally regarded as treatable with topical or systemic antifungals such as terbinafine and azoles, recent epidemiological shifts and misuse of antifungal medications have led to the emergence of multidrug-resistant strains, most notably Trichophyton indotineae (T. mentagrophytes subtype VIII). Resistance is often associated with genetic mutations in target enzymes and overexpression of efflux pumps. Inadequate treatment regimens, prolonged monotherapies, and combination with corticosteroids further exacerbate the selection of resistant isolates. Antifungal stewardship (AFS) is essential to combat resistance development. This includes targeted therapy based on mycological diagnostics, identification of the causative species, and appropriate patient education. Current antifungal therapies are limited to a few drug classes, and their efficacy is challenged by poor tissue penetration and subtherapeutic drug levels at infection sites. Innovative formulations and delivery systems may improve bioavailability and therapeutic outcomes. Combination therapies and the use of efflux pump inhibitors may offer additional options for recalcitrant infections. Ultimately, the growing resistance among Trichophyton species highlights an urgent need for novel antifungal agents, advanced diagnostics, and globally coordinated stewardship programs to safeguard the future of dermatomycosis treatment.

The growing prevalence of resistant dermatophyte isolates, particularly from Trichophyton indotineae (synonym: T. mentagrophytes ITS genotype VIII) but also from T. rubrum may lead to increasing numbers of difficult-to-treat dermatomycoses. Terbinafine resistance in T. indotineae or T. rubrum is caused by point mutations that alter specific positions in the Erg1 gene encoding squalene epoxidase, thereby, preventing effective binding of terbinafine to the enzyme. In T. indotineae, two different forms of genomic amplification of Erg11B that lead to azole resistance have been identified. Like Erg11A, Erg11B encodes a form of sterol-14-α-demethylase, whose enzymatic activity is inhibited by azole binding. In T. indotineae as well as in T. rubrum, point mutations in Erg11B have been identified that result in altered amino acid sequences and prevent binding of specific classes of azoles. Another resistance mechanism involves increased expression of transporter proteins responsible for drug efflux. The combination of these various mechanisms presents a major challenge for diagnostics and requires adaptation of both the diagnostic approach and the subsequent therapeutic strategies.

The treatment of azole-resistant Trichophyton indotineae poses a significant challenge for clinicians worldwide. Resistance mechanisms include amino acid substitutions in the sterol 14-α demethylase gene Erg11B, as well as overexpression of Erg11B. Additionally, efflux mechanisms mediated by fungal transporter proteins contribute to antifungal resistance. Therefore, the inhibition of fungal efflux transporters using known inhibitors could be a promising strategy to prevent treatment failure. The inhibitory effects of itraconazole in combination with various efflux pump inhibitors were evaluated. Co-treatment with quinine hydrochloride and itraconazole did not lead to a significant reduction in the inhibitory concentration (IC) values in T. indotineae isolates. In contrast, ritonavir lowered IC values by approximately 50% without affecting fungal growth when applied as monotherapy. The most pronounced effect was observed with sertraline, which demonstrated intrinsic antifungal activity at higher concentrations. When combined with itraconazole, sertraline reduced IC values to below 10% in both susceptible and resistant strains, enhancing itraconazole efficacy markedly. The increasing prevalence of antifungal resistance is a growing global health concern. These findings suggest that sertraline holds considerable potential as an adjunctive therapy for the treatment of dermatomycoses.

ABSTRACT We hereby present the case of a patient with tinea incognita, who had received treatment with glucocorticosteroids and antibiotics for several months. Further diagnostic testing identified Trichophyton indotineae as the pathogen causing tinea corporis and cruris. The Erg1 gene encoding squalene epoxidase showed wild‐type information; therefore, we treated systemically with terbinafine. We observed a prolonged course of the disease despite systemic treatment with terbinafine. After the initial clinical response, new lesions occurred in which mycologic testing revealed T. indotineae again, and expression analyses showed upregulation of MDR transporter genes and heat shock proteins HSP60 and HSP90 in the isolate obtained from the relapse. These findings suggest a better adaptation to body temperature and increased efflux of antifungals. The relapse isolate showed increased inhibitory concentrations for terbinafine, accompanied by decreased values for itraconazole. We obtained mycologic cure by systemic itraconazole and topical miconazole nitrate. This case highlights the importance of mycologic diagnostics through quantitative Real‐Time PCR, including assessment of more than just the ergosterol ( Erg ) biosynthesis genes. It raises consciousness about tinea incognita and the ever‐emerging threat of terbinafine‐resistant dermatomycoses.

Die zunehmende Anzahl schwierig zu behandelnder Dermatomykosen beruht auf der gestiegenen Anzahl resistenter Isolate, insbesondere durch Trichophyton (T.) indotineae (syn. T. mentagrophytes ITS Genotyp VIII), aber zunehmend auch durch T. rubrum. Terbinafin-Resistenz in T. indotineae oder T. rubrum beruht auf Punktmutationen, die bestimmte Positionen im Erg1-Gen für die Squalen-Epoxidase ändern und die effiziente Bindung von Terbinafin an das Enzym verhindern. In T. indotineae wurden 2 verschiedene Formen der genomischen Amplifikation von Erg11B gefunden, die zur Azol-Resistenz führen. Erg11B kodiert wie Erg11A für eine Form der Sterol-14-α-Demethylase, die durch die Bindung von Azolen in ihrer Enzymaktivität gehemmt wird. In T. indotineae wie auch in T. rubrum wurden Erg11B-Punktmutationen identifiziert, die zu veränderten Aminosäuresequenzen führen und die Bindung von Azolen bestimmter Substanzklassen verhindern. Ein weiterer Weg zur Resistenz wird durch die Expressionssteigerung von Transportern ermöglicht, die am Efflux der Medikamente beteiligt sind. Die Kombination der verschiedenen Mechanismen bedeutet für die Diagnostik eine große Herausforderung und erfordert eine Anpassung sowohl des diagnostischen Regimes als auch der daraus abzuleitenden Therapie.

Azole resistance in dermatophytes, particularly Trichophyton indotineae, has become a growing global concern. Current antifungal susceptibility testing protocols (EUCAST, CLSI) have limitations in reproducibility and sensitivity. This study aimed to evaluate how medium composition, incubation temperature, and spore concentration influence itraconazole susceptibility testing across various dermatophyte species. Thirty-eight clinical isolates representing Trichophyton, Microsporum, and Epidermophyton species were tested using a microplate laser nephelometry system (MLN). IC50 values for itraconazole were determined in three different media (Sabouraud glucose (SG), RPMI-based (RG), and RG supplemented with casein (RGC)) at 28 °C and 34 °C. Effects of spore concentration on growth dynamics and lag phase were also analyzed. SG medium provided clear phenotypic separation between resistant and sensitive isolates. In contrast, RG and RGC showed overlapping IC50 values. Lower spore concentrations revealed underlying growth differences, which were masked at higher inoculum levels. Temperature and media composition significantly affected IC50 outcomes. Genotypic analysis confirmed resistance-associated Erg11B point mutations and genomic amplifications in T. indotineae, particularly in combination with Erg1 mutations, forming distinct subpopulations. SG medium combined with reduced spore concentrations offered improved differentiation of resistant versus sensitive strains. These findings support the development of more accurate susceptibility testing protocols and highlight the need to establish species-specific ECOFF values for dermatophytes.

Trichophyton indotineae is an emerging pathogen causing recalcitrant skin infections and exhibiting multiple resistances to azoles and allylamines. Squalene epoxidase erg1Ala448Thr mutants often show association with azole resistance. RT-PCR gene expression analysis helps to elucidate the connection between ergosterol biosynthesis regulation and efflux control through the activation of multidrug resistance (MDR) and major facilitator superfamily (MFS1) transporters as well as heat shock proteins (HSP). Several T. indotineae isolates demonstrated a heat-dependent increase of Erg11B transcripts combined with downregulation of Erg1, suggesting a protective role for Erg11B. They also showed persistent upregulation of MFS1. The addition of fluconazole or voriconazole induced the expression of Erg11A, MDR3 and, to a lesser extent, Erg11B and Erg1. The azole-resistant erg1Ala448Thr mutant UKJ 476/21 exhibited exceptionally high transcript levels of sterol 14-αdemethylase Erg11B, combined with the inability of HSP60 and HSP90 to respond to increasing growth temperatures. Itraconazole demonstrated similar effects in a few T. indotineae isolates, but terbinafine did not enhance Erg1 transcription at all. Overexpression of Erg11B may explain the multiple azole resistance phenotype, whereas Erg11B point mutations are not associated with resistance to azoles used for medical treatment.

ZusammenfassungDas Fachgebiet der Mykologie umfasst die genaue Kenntnis der Pilze und der durch diese Erreger ausgelösten Haut-, Haar-, Nagel- und Schleimhauterkrankungen. Die korrekte Probenahme und darauffolgende umfassende mykologische Diagnostik mit konventionellen und zunehmend eingesetzten molekularen Methoden ist elementar für die Identifizierung der Erreger. Nur dadurch ist eine zielgerichtete und erfolgreiche antimykotische Therapie möglich. Gleichzeitig können differenzialdiagnostisch infektiöse Dermatosen anderer Genese und nicht-infektiöse Haut- und Nagelerkrankungen ausgeschlossen werden. Alles das wird strukturiert im vorliegenden Zertifikat zur Dermatomykologie thematisiert. Auf die Qualitätssicherung der Mykologie wird ebenfalls in diesem Curriculum eingegangen.Die Deutsche Dermatologische Akademie (DDA) hat daher mit dem Zertifikat „Mykologie – Diagnostik und Therapie von Dermatomykosen“ ein weiteres wichtiges Fortbildungsangebot für ein Teilgebiet der Dermatologie geschaffen. Die Fortbildungsinhalte für dieses Zertifikat werden in einem ganztägigen Modul (8 Stunden) vermittelt; auch eine Aufteilung in Halbtage im Rahmen größerer Fortbildungsveranstaltungen ist möglich. Die Seminare und v.a. auch Kurse (Workshops und praktisch-mikroskopische Kurse) sind interaktiv; bestimmend sind die praxisorientierte Präsentation des Wissens und die kollegiale Diskussion mit ausgewiesenen Experten auf dem Gebiet der Pilzinfektionen der Haut.

Trichophyton (T.) mentagrophytes ITS genotype VIII, also known as Trichophyton indotineae, is a new species of the T. mentagrophytes/T. interdigitale complex and its first records, albeit under a different species name, are from the Indian subcontinent, Middle Eastern Asia, and West Asia. T. mentagrophytes genotype VIII (T. indotineae) has spread globally and has now been documented in over 30 countries. The aim of this study was to investigate the occurrence and proportion of terbinafine- and itraconazole-resistant isolates of T. mentagrophytes ITS genotype VIII (T. indotineae) in Bangladesh. This was part of an official collaborative project between IADVL (Indian Association of Dermatologists, Venereologists, and Leprologists) and Bangabandhu Sheikh Mujib Medical University (BSMMU), Bangladesh. Over a period of 6 months, ninety-nine patients of chronic recalcitrant tinea corporis were recruited from BSMMU hospital. Species identification was performed by fungal culture and morphological observation of the upper and lower surfaces of fungal colonies, as well as by using fluorescent microscopy. In addition, a PCR (polymerase chain reaction)-ELISA was performed to group the patients into those with the T. mentagrophytes/T. interdigitale complex. The internal transcribed spacer (ITS) gene was sequenced. Samples were tested for resistance to terbinafine and itraconazole by mutational analyses of the squalene epoxidase (SQLE) and the ergosterol 11B (ERG11B) genes. A total of 79/99 samples showed a positive culture. In 76 of these isolates, T. mentagrophytes ITS genotype VIII (T. indotineae) could be reliably identified both by culture and molecular testing. Resistance testing revealed terbinafine resistance in 49 and itraconazole resistance in 21 patients. Among these, 11 patients were resistant to both the antifungal agents. Mutations L393S, L393F, F397L, and F397I of the SQLE gene were associated with terbinafine resistance. Resistance to itraconazole could not be explained by mutations in the ERG11B gene. Infections with T. mentagrophytes ITS genotype VIII (T. indotineae) have become a public health issue with potentially global ramifications. About 62% of samples from Bangladesh showed resistance to terbinafine, making oral itraconazole the most effective drug currently available, although resistance to itraconazole and both terbinafine and itraconazole also exists.

For more than 30 years, an 82-year-old man has been suffering from tinea corporis generalisata in the sense of Trichophyton rubrum syndrome. The patient received long-term treatment with terbinafine. Fluconazole had no effect. There was an increase in liver enzymes with itraconazole. Super bioavailability (SUBA) itraconazole was initially not tolerated. A therapy attempt with voriconazole was successful, but was stopped due to side effects. The Trichophyton (T.) rubrum strain isolated from skin scales was tested for terbinafine resistance using the breakpoint method and found to be (still) sensitive. Sequencing of the squalene epoxidase (SQLE) gene revealed a previously unknown point mutation of the codon for isoleucine ATC -> ACC with amino acid substitution I479T (isoleucine479 threonine). Long-term therapy with terbinafine 250 mg had been given every 3 days since 2018. In addition, bifonazole cream, ciclopirox solution, and occasionally terbinafine cream were used. The skin condition was stable until an exacerbation of the dermatophytosis in 2021. There were erythematosquamous, partly atrophic, centrifugal, scaly, confluent plaques on the integument and the extremities. Fingernails and toenails had white to yellow-brown discoloration, and were hyperkeratotic and totally dystrophic. T. rubrum was cultured from skin scales from the integument, from the feet, from nail shavings from the fingernails and also toenails and detected by PCR. In the breakpoint test, the T. rubrum isolates from tinea corporis and nail samples showed a minimum inhibitory concentration (MIC) of 0.5 mu g ml-1 (terbinafine resistance in vitro). Sequencing of the SQLE gene of the T. rubrum isolate revealed evidence of a further point mutation that led to amino acid substitution I479V (isoleucine 479 valine). Long-term therapy was started with SUBA itraconazole: 14 days 2 x 1 capsule daily, then twice weekly administration of 2 x 50 mg. During breaks in therapy, the mycosis regularly flared up again. Finally, 50 mg SUBA itraconazole was given 5 days a week, which completely suppressed the dermatophytosis. Topically, ciclopirox and miconazole cream were used alternately. In conclusion, in the case of recurrent and therapy-refractory dermatophytoses caused by T. rubrum, terbinafine resistance must also be considered in individual cases. An in vitro resistance test and point mutation analysis of the squalene epoxidase gene confirms the diagnosis. Itraconazole, also in the form of SUBA itraconazole, is the drug of choice for the oral antifungal treatment of these patients.

Trichophyton quinckeanum, the causative agent of mouse favus, has been responsible for several infections of animal owners in recent years and showed an infection peak around 2020 in Jena, Thuringia. The isolated T. quinckeanum strains from Thuringia differ in some positions of the ITS region compared to strains from the IHEM collection as well as to Trichophyton schoenleinii. All T. quinckeanum strains of the new genotype show up to a 100-fold increased itraconazole resistance as measured by microplate laser nephelometry (MLN) assays. Analysis of genes involved in Trichophyton indotineae azole resistance, such as Erg1, which encodes squalene epoxidase, and Erg11B, one of two copies of the sterol 14-α demethylase gene, show a 100% identity between the two T. quinckeanum genotypes. In contrast, Erg11A fragments differ in 15-nucleotide positions between both T. quinckeanum genotypes, resulting in the unique amino acid substitution Ala256Ser in resistant strains. The new T. quinckeanum genotype may have evolved through interspecies mating. Mating type analysis showed a nearly 100% identity of the minus type MAT1-1-1 fragment for all T. quinckeanum isolates. The closely related Trichophyton schoenleinii belongs to the plus mating type and has 100% identical fragments of Erg1 and Erg11B. Erg11A protein sequences of T. schoenleinii and T. quinckeanum showed increased diversity.

Seit mehr als 30 Jahren leidet ein jetzt 82-jähriger Patient an einer Tinea corporis generalisata im Sinne eines Trichophyton-rubrum-Syndroms. Behandelt wurde über lange Zeit mit Terbinafin. Fluconazol hatte keinen Effekt. Unter Itraconazol kam es zu einer Erhöhung der Leberenzyme. Super-Bioavailability(SUBA)-Itraconazol wurde zunächst nicht vertragen. Ein Therapieversuch mit Voriconazol war erfolgreich, musste aber wegen Nebenwirkungen abgebrochen werden. Der aus Hautschuppen isolierte Trichophyton(T.)-rubrum-Stamm wurde mittels Breakpoint-Methode auf Terbinafin-Resistenz getestet und als (noch) sensibel befunden. Durch Sequenzierung des Squalenepoxidase(SQLE)-Gens fand sich eine bis dahin nicht bekannte Punktmutation im Codon für Isoleucin ATC → ACC mit Aminosäuresubstitution I479T (Isoleucin 479 Threonin). Seit 2018 erfolgte eine Langzeittherapie mit Terbinafin 250 mg alle 3 Tage. Außerdem kamen Bifonazol-Creme, Ciclopirox-Lösung, zeitweise Terbinafin-Creme zur Anwendung. Der Hautzustand war stabil bis zu einer Exazerbation der Dermatophytose im Jahr 2021. Am Integument und den Extremitäten bestanden jetzt erythematosquamöse, teils atrophische, zentrifugale, randbetonte, schuppende und konfluierende Plaques. Finger- und Zehennägel waren weiß bis gelbbraun verfärbt, hyperkeratotisch und total dystrophisch verändert. Aus Hautschuppen vom Integument, den Füßen, Nagelspänen der Finger- und auch Zehennägel ließ sich jeweils T. rubrum kulturell anzüchten und mit Polymerasekettenreaktion (PCR) nachweisen. Im Breakpoint-Test wies das Isolat von T. rubrum von der Tinea corporis und aus Nagelspänen eine minimale Hemmkonzentration (MHK) von 0,5 µg/ml (entspricht Terbinafin-Resistenz in vitro) auf. Die Sequenzierung des SQLE-Gens des T.-rubrum-Isolats erbrachte den Nachweis einer weiteren Punktmutation, die zur Aminosäuresubstitution I479V (Isoleucin 479 Valin) führte. Mit SUBA-Itraconazol wurde eine Langzeittherapie gestartet: 14 Tage 2‑mal 1 Kapsel täglich, danach1-mal wöchentliche Gabe von 2‑mal 50 mg. Bei Therapiepausen flammte die Mykose regelmäßig wieder auf. Zuletzt wurden 50 mg SUBA-Itraconazol an 5 Tagen pro Woche gegeben, worunter die Dermatophytose vollständig unterdrückt wird. Topisch kamen Ciclopirox- und Miconazol-Creme im Wechsel zur Anwendung. Schlussfolgernd ergibt sich, dass bei rezidivierenden und therapierefraktären Dermatophytosen durch T. rubrum im Einzelfall auch an eine Terbinafin-Resistenz gedacht werden muss. Eine In-vitro-Resistenztestung sowie Punktmutationsanalyse des Gens der Squalenepoxidase sichert die Diagnose. Itraconazol, auch in Form des SUBA-Itraconazol, ist das Mittel der Wahl zur oralen antimykotischen Behandlung dieser Patienten.

Abstract Dermal fungal infections seem to have increased over recent years. There is further a shift from anthropophilic dermatophytes to a growing prevalence of zoophilic species and the emergence of resistant strains. New antifungals are needed to combat these fungi and their resting spores. This study aimed to investigate the sporicidal effects of sertaconazole nitrate using microplate laser nephelometry against the microconidia of Trichophyton, chlamydospores of Epidermophyton, blastospores of Candida, and conidia of the mold Scopulariopsis brevicaulis. The results obtained were compared with those from ciclopirox olamine and terbinafine. The sporicidal activity was further determined using infected three‐dimensional full skin models to determine the antifungal effects in the presence of human cells. Sertaconazole nitrate inhibited the growth of dermatophytes, molds, and yeasts. Ciclopirox olamine also had good antifungal activity, although higher concentrations were needed compared to sertaconazole nitrate. Terbinafine was highly effective against most dermatophytes, but higher concentrations were required to kill the resistant strain Trichophyton indotineae. Sertaconazole nitrate, ciclopirox olamine, and terbinafine had no negative effects on full skin models. Sertaconazole nitrate reduced the growth of fungal and yeast spores over 72 h. Ciclopirox olamine and terbinafine also inhibited the growth of dermatophytes and molds but had significantly lower effects on the yeast. Sertaconazole nitrate might have advantages over the commonly used antifungals ciclopirox olamine and terbinafine in combating resting spores, which persist in the tissues, and thus in the therapy of recurring dermatomycoses.

The number of Trichophyton quinckeanum infections has increased significantly in recent years. In 2020 in particular, the number of cases increased fivefold compared to 2015. Infections multiplied, especially in the second half of the year, which correlated with the upsurge in field mouse populations. Typical vectors are mice and rats as well as dogs and cats, which hunt the rodents. The animals are usually asymptomatic. In humans, on the other hand, the course is usually more inflammatory corresponding to other zoophilic mycoses. Typical clinical manifestations of the infections are tinea corporis and tinea capitis. Treatment of T. quinckeanum infections is similar to other dermatophyte infections, depending on the severity, location and age of the patient as well as the immune status, previous illnesses and medication. The duration of local therapy should be at least 4 weeks and continued for up to 14 days after the normalization of the skin presentation. Systemic treatment should take place with terbinafine 250 mg once a day orally (in adults). Alternatives are itraconazole, fluconazole and griseofulvin. Only the preparation griseofulvin, which is no longer available in Germany, is approved for children. Alternatively, terbinafine, itraconazole or fluconazole can also be used in children as an "off-label" treatment in an individual healing attempt.