Trichophyton indotineae-An Emerging Pathogen Causing Recalcitrant Dermatophytoses in India and Worldwide-A Multidimensional Perspective.

Trichophyton (T.) indotineae is a newly identified dermatophyte species that has been found in a near-epidemic form on the Indian subcontinent. There is evidence of its spread from the Indian subcontinent to a number of countries worldwide. The fungus is identical to genotype VIII within the T. mentagrophytes/T. interdigitale species complex, which was described in 2019 by sequencing the Internal Transcribed Spacer (ITS) region of ribosomal DNA of the dermatophyte. More than 10 ITS genotypes of T. interdigitale and T. mentagrophytes can now be identified. T. indotineae causes inflammatory and itchy, often widespread, dermatophytosis affecting the groins, gluteal region, trunk, and face. Patients of all ages and genders are affected. The new species has largely displaced other previously prevalent dermatophytes on the Indian subcontinent. T. indotineae has become a problematic dermatophyte due to its predominantly in vitro genetic resistance to terbinafine owing to point mutations of the squalene epoxidase gene. It also displays in vivo resistance to terbinafine. The most efficacious drug currently available for this terbinafine-resistant dermatophytoses, based on sound evidence, is itraconazole.

[Clinical picture, causative agents and diagnostics of dermatomycoses]. / Klinik, Erreger und Diagnostik von Dermatomykosen.

Dermatomycoses affect free skin, hairy scalp, fingernails and toenails. In addition, oral mucosa and genital mucosa can also be affected by fungal infections. The most common pathogens causing skin fungal infections are dermatophytes. They are responsible for, among others, tinea corporis, tinea capitis and onychomycosis (tinea unguium). Mainly anthropophilic dermatophytes are found as pathogens. In the case of tinea capitis-at least in Europe and in German-speaking countries-zoophilic skin fungi must also be considered. Rarely, geophilic dermatophytes can also be isolated. Yeast infections of the skin, mostly caused by Candida albicans, primarily affect the intertriginous skin areas, for example, the groin region, but also the submammary area and the spaces between the fingers and toes. Elderly patients are often affected, but also infants and, in particular, immunocompromised patients. These patient groups are also more frequently affected by oral mucosal infections caused by Candida albicans and other Candida species. Pseudomembranous candidiasis of the oral mucosa and tongue typically affects patients with HIV/AIDS. Mold infections in dermatology are relevant in onychomycosis of the big toenail. The causative agent is usually Scopulariopsis brevicaulis. Cutaneous mold infections are rare and only occur in immunocompromised patients. The mycological diagnosis of dermatomycoses is based on the microscopic, if possible fluorescence-optical detection of fungal hyphae and spores from skin scales, nail shavings and hair roots. The culture detection of dermatophytes, yeasts and molds allows the identification of the causative fungal species, but often fails, especially in patients who have already been treated with antifungal agents. In view of the high sensitivity and specificity of the molecular methods for fungal detection compared to culture, polymerase chain reaction (PCR) must realistically be regarded as the gold standard for dermatophytosis diagnostics. However, it should not be neglected that the three pillars of diagnostics-preparation, culture, PCR-currently deliver the best results.

The unprecedented epidemic-like scenario of dermatophytosis in India: III. Antifungal resistance and treatment options.

One of the canonical features of the current outbreak of dermatophytosis in India is its unresponsiveness to treatment in majority of cases. Though there appears to be discordance between in vivo and in vitro resistance, demonstration of in vitro resistance of dermatophytes to antifungals by antifungal susceptibility testing is essential as it may help in appropriate management. The practical problem in the interpretation of antifungal susceptibility testing is the absence of clinical breakpoints and epidemiologic cutoff values. In their absence, evaluation of the upper limit of a minimal inhibitory concentration of wild type isolates may be beneficial for managing dermatophytosis and monitoring the emergence of isolates with reduced susceptibility. In the current scenario, most of the cases are unresponsive to standard dosages and duration of treatment recommended until now. This has resulted in many ex-cathedra modalities of treatment that are being pursued without any evidence. There is an urgent need to carry out methodical research to develop an evidence base to formulate a rational management approach in the current scenario.

The unprecedented epidemic-like scenario of dermatophytosis in India: II. Diagnostic methods and taxonomical aspects.

Trichophyton (T.) mentagrophytes now accounts for an overwhelming majority of clinical cases in India, a new "Indian genotype" (T. mentagrophytes ITS genotype VIII) having been isolated from skin samples obtained from cases across a wide geographical distribution in this country. The conventional diagnostic methods, like fungal culture, are, however, inadequate for diagnosing this agent. Thus, molecular methods of diagnosis are necessary for proper characterization of the causative agent. The shift in the predominant agent of dermatophytosis from T. rubrum to T. mentagrophytes, within a relatively short span of time, is without historic parallel. The apparent ease of transmission of a zoophilic fungus among human hosts can also be explained by means of mycological phenomena, like anthropization.

Taxonomy of the Trichophyton mentagrophytes/T. interdigitale Species Complex Harboring the Highly Virulent, Multiresistant Genotype T. indotineae.

A severe outbreak of highly virulent and multi-resistant dermatophytosis by species in the Trichophyton mentagrophytes/T. interdigitale complex is ongoing in India. The correct identity of the etiologic agent is a much-debated issue. In order to define species limits, a taxonomic study was undertaken combining molecular, morphological, and physiological characteristics as evidence of classification. Molecular characteristics show that T. mentagrophytes s. str. and T. interdigitale s. str. can be distinguished with difficulty from each other, but are unambiguously different from the Indian genotype, T. indotineae by sequences of the HMG gene. The entities were confirmed by multilocus analysis using tanglegrams. Phenotypic characters of morphology and physiology are not diagnostic, but statistically significant differences are observed between the molecular siblings. These properties may be drivers of separate evolutionary trends. Trichophyton mentagrophytes represents the ancestral, homothallic cloud of genotypes with a probable geophilic lifestyle, while T. indotineae and T. interdigitale behave as anthropophilic, clonal offshoots. The origin of T. indotineae, which currently causes a significant public health problem, is zoonotic, and its emergence is likely due to widespread misuse of antifungals.

The unprecedented epidemic-like scenario of dermatophytosis in India: I. Epidemiology, risk factors and clinical features.

Dermatophytosis has attained unprecedented dimensions in recent years in India. Its clinical presentation is now multifarious, often with atypical morphology, severe forms and unusually extensive disease in all age groups. We hesitate to call it an epidemic owing to the lack of population-based prevalence surveys. In this part of the review, we discuss the epidemiology and clinical features of this contemporary problem. While the epidemiology is marked by a stark increase in the number of chronic, relapsing and recurrent cases, the clinical distribution is marked by a disproportionate rise in the number of cases with tinea corporis and cruris, cases presenting with the involvement of extensive areas, and tinea faciei.

Topical corticosteroid induced ulcerated striae

Abstract We report four cases of ulcerated striae following misuse of fixed dose combinations creams containing clobetasol propionate with antifungal and antibacterial agents.

Topical corticosteroid induced ulcerated striae.

We report four cases of ulcerated striae following misuse of fixed dose combinations creams containing clobetasol propionate with antifungal and antibacterial agents.

Spread of Terbinafine-Resistant Trichophyton mentagrophytes Type VIII (India) in Germany-"The Tip of the Iceberg?"

Chronic recalcitrant dermatophytoses, due to Trichophyton (T.) mentagrophytes Type VIII are on the rise in India and are noteworthy for their predominance. It would not be wrong to assume that travel and migration would be responsible for the spread of T. mentagrophytes Type VIII from India, with many strains resistant to terbinafine, to other parts of the world. From September 2016 until March 2020, a total of 29 strains of T. mentagrophytes Type VIII (India) were isolated. All patients were residents of Germany: 12 females, 15 males and the gender of the remaining two was not assignable. Patients originated from India (11), Pakistan (two), Bangladesh (one), Iraq (two), Bahrain (one), Libya (one) and other unspecified countries (10). At least two patients were German-born residents. Most samples (21) were collected in 2019 and 2020. All 29 T. mentagrophytes isolates were sequenced (internal transcribed spacer (ITS) and translation elongation factor 1-α gene (TEF1-α)). All were identified as genotype VIII (India) of T. mentagrophytes. In vitro resistance testing revealed 13/29 strains (45%) to be terbinafine-resistant with minimum inhibitory concentration (MIC) breakpoints ≥0.2 µg/mL. The remaining 16 strains (55%) were terbinafine-sensitive. Point mutation analysis revealed that 10/13 resistant strains exhibited Phe397Leu amino acid substitution of squalene epoxidase (SQLE), indicative for in vitro resistance to terbinafine. Two resistant strains showed combined Phe397Leu and Ala448Thr amino acid substitutions, and one strain a single Leu393Phe amino acid substitution. Out of 16 terbinafine-sensitive strains, in eight Ala448Thr, and in one Ala448Thr +, new Val444 Ile amino acid substitutions were detected. Resistance to both itraconazole and voriconazole was observed in three out of 13 analyzed strains. Treatment included topical ciclopirox olamine plus topical miconazole or sertaconazole. Oral itraconazole 200 mg twice daily for four to eight weeks was found to be adequate. Terbinafine-resistant T. mentagrophytes Type VIII are being increasingly isolated. In Germany, transmission of T. mentagrophytes Type VIII from the Indian subcontinent to Europe should be viewed as a significant public health issue.

A curious observation of passive transfer of steroid antifungal combination creams to the scrotum in patients of tinea cruris-Is this forme fruste of red scrotum syndrome?

We report 16 patients of tinea cruris who presented with an asymptomatic red scrotum due to fixed dose combination creams containing antifungal agents and topical steroids applied to the thighs as a treatment of tinea cruris. The erythema resolved upon starting appropriate treatment with single molecule antifungal creams and oral antifungal drugs in about six weeks' time in majority of cases. We propose that this clinical presentation may be akin to red scrotum syndrome (RSS). Due to its asymptomatic nature in most of the cases, we propose that this could be a forme fruste of RSS.

Indian Trichophyton mentagrophytes squalene epoxidase erg1 double mutants show high proportion of combined fluconazole and terbinafine resistance.

BACKGROUND: The Indian ITS genotype VIII Trichophyton mentagrophytes population shows a high amount of different erg1 (ergosterol) mutants encoding for squalene epoxidase, which catalyses the first step of ergosterol biosynthesis. OBJECTIVES: Illumination of the implication of point mutations at position Ala448Thr in single and double erg1 T mentagrophytes mutants because mutants of this type were abundantly found within the Indian fungal population. METHODS: Growth in fluconazole or terbinafine containing medium was analysed using a microplate-laser-nephelometry (MLN)-based growth assay. RESULTS: Ala 448 Thr erg1 single mutants were terbinafine sensitive, but about 50% of isolates showed an increased fluconazole resistance, whereas 95% of the double mutants (Phe 397 Leu, Ala 448Thr) demonstrated combined terbinafine and increased fluconazole resistance. CONCLUSION: The new Indian T mentagrophytes populations show several point mutations in erg1. Point mutations at position 397 were previously described and cause terbinafine resistance. A large part of the double mutants exhibit resistance to terbinafine and fluconazole, demonstrating a selective advantage of the combination of both mutations.