Clinical Use of Super-Bioavailable Itraconazole for the Management of Dermatophytosis: Consensus Statement by Dermatologists from India via the Modified Delphi Technique.

Super-bioavailable itraconazole (SB ITZ) overcomes the limitations of conventional itraconazole (CITZ) such as interindividual variability and reduced bioavailability. It has been approved for systemic mycoses in Australia and Europe as 50 mg and the USA as 65 mg and in India as 50 mg, 65 mg, 100 mg, and 130 mg. However, data on the ideal dose and duration of SB ITZ treatment in managing dermatophytosis are insufficient. This consensus discusses the suitability, dosage, duration of treatment, and relevance of using SB ITZ in managing dermatophytosis in different clinical scenarios. Sixteen dermatologists (>15 years of experience in the field and ≥2 years clinical experience with SB ITZ), formed the expert panel. A modified Delphi technique was employed, and a consensus was reached if the concordance in response was >75%. A total of 26 consensus statements were developed. The preferred dose of SB ITZ is 130 mg once daily and if not tolerated, 65 mg twice daily. The preferred duration for treating naïve dermatophytosis is 4-6 weeks and that for recalcitrant dermatophytosis is 6-8 weeks. Moreover, cure rates for dermatophytosis are a little better with SB ITZ than with CITZ with a similar safety profile as of CITZ. Better patient compliance and efficacy are associated with SB ITZ than with CITZ, even in patients with comorbidities and special needs such as patients with diabetes, extensive lesions, corticosteroid abuse, adolescents, and those on multiple drugs. Expert clinicians reported that the overall clinical experience with SB ITZ was better than that with CITZ.

Review of facial acanthosis nigricans: Easy to diagnose and difficult to treat marker of hyperinsulinemia/metabolic syndrome.

Facial acanthosis nigricans (FAN) is an increasingly discussed anatomical variation of acanthosis nigricans (AN). Its presentation as brown to black pigmentation with ill-defined blurred margins with varying degree of textural changes commonly over forehead, temporal, and malar regions of the face predominantly in dark-skinned individuals with a male predilection can be confused with other common facial melanoses. Its pathogenesis, clinical features, and management are in many ways similar to in the commonly described areas like neck and major flexural areas. Understanding of FAN has gained momentum in the past decade with studies highlighting its association with various metabolic abnormalities particularly insulin resistance and obesity. It is now being considered to be a cutaneous marker of metabolic syndrome. While there is uniformity in its clinical description, there appears to be scope for further in depth biochemical and histopathological studies to link the pigmentation, altered texture and microscopic changes in individuals presenting with FAN and hyperinsulinemia with or without other features of metabolic syndrome. It awaits a consensus on grading its severity and correlating it with histological features as patients often hesitate to be subjected to a biopsy of the face. This is a review of current literature pertaining to FAN. Newer clinical, dermoscopic, histopathological, and biochemical insights will help to understand this relatively new entity.

The Emerging Terbinafine-Resistant Trichophyton Epidemic: What Is the Role of Antifungal Susceptibility Testing?

BACKGROUND: Dermatophytosis is commonly encountered in the dermatological clinics. The main aetiological agents in dermatophytosis of skin and nails in humans are Trichophyton (T.) rubrum, T. mentagrophytes and T. interdigitale (former T. mentagrophytes-complex). Terbinafine therapy is usually effective in eradicating infections due to these species by inhibiting their squalene epoxidase (SQLE) enzyme, but increasing numbers of clinically resistant cases and mutations in the SQLE gene have been documented recently. Resistance to antimycotics is phenotypically determined by antifungal susceptibility testing (AFST). However, AFST is not routinely performed for dermatophytes and no breakpoints classifying isolates as susceptible or resistant are available, making it difficult to interpret the clinical impact of a minimal inhibitory concentration (MIC). SUMMARY: PubMed was systematically searched for terbinafine susceptibility testing of dermatophytes on October 20, 2020, by two individual researchers. The inclusion criteria were in vitro terbinafine susceptibility testing of Trichophyton (T.) rubrum, T. mentagrophytes and T. interdigitale with the broth microdilution technique. The exclusion criteria were non-English written papers. Outcomes were reported as MIC range, geometric mean, modal MIC and MIC50 and MIC90 in which 50 or 90% of isolates were inhibited, respectively. The reported MICs ranged from <0.001 to >64 mg/L. The huge variation in MIC is partly explained by the heterogeneity of the Trichophyton isolates, where some originated from routine specimens (wild types) whereas others came from non-responding patients with a known SQLE gene mutation. Another reason for the great variation in MIC is the use of different AFST methods where MIC values are not directly comparable. High MICs were reported particularly in isolates with SQLE gene mutation. The following SQLE alterations were reported: F397L, L393F, L393S, H440Y, F393I, F393V, F415I, F415S, F415V, S443P, A448T, L335F/A448T, S395P/A448T, L393S/A448T, Q408L/A448T, F397L/A448T, I121M/V237I and H440Y/F484Y in terbinafine-resistant isolates.

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 influence of superficial dermatophytoses epidemic in India on patients' quality of life.

INTRODUCTION: Superficial dermatophytoses constitute a common and growing problem in India. However, the associated impact on the affected individuals' quality of life (QoL) has rarely been investigated. AIM: To assess the quality of life of patients with different dermatophytoses. MATERIAL AND METHODS: Among 100 consecutive Indian patients with dermatophytosis, 76% agreed to participate. The diagnosis was established upon the typical clinical manifestation and direct microscopic mycological examination (10% KOH). Dermatology Life Quality Index (DLQI) was utilized to assess QoL impairment. Participants evaluated the presence and intensity of itch during the last 3 days using Numeral Rating Scale (NRS). RESULTS: A combination of tinea corporis and tinea cruris was diagnosed most commonly (52.6%), followed by tinea cruris alone (21%) and tinea corporis alone (13.2%). The mean duration of the disease was assessed as 6.3 ±18.0 months. The mean DLQI score was 8.2 ±5.1 points. A very large and extremely large effect on the DLQI was reported by 26.3% of patients, moderate by 40.8%, whereas small by 29%, with females being more heavily affected than males (9.3 ±5.2 and 7.1 ±4.7 points, respectively) (p = 0.038). Patients with a combination of tinea corporis, tinea cruris and tinea faciei demonstrated the lowest QoL (11.0 ±4.5 points). Additionally, a significant correlation between impairment of QoL and itch intensity (mean NRS score: 6.8 ±1.8 points) (r = 0.37; p < 0.002) was documented. Moreover, there was a trend towards lower QoL in patients who have been previously treated with topical agents containing corticosteroids. CONCLUSIONS: Superficial dermatophytoses are associated with a moderate impact on QoL of the affected subjects.

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.

Epidermoid cysts in kidney transplant patients receiving tacrolimus.

We present a series of three kidney transplant patients developing epidermoid cysts after receiving oral tacrolimus for long-term prevention of rejection of the allograft. Cyclosporin A has been known to show this cutaneous adverse drug reaction, but this is the first series of patients with epidermoid cysts following tacrolimus to the best of our knowledge.

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.

Alarming India-wide phenomenon of antifungal resistance in dermatophytes: A multicentre study.

BACKGROUND: An alarming increase in recalcitrant dermatophytosis has been witnessed in India over the past decade. Drug resistance may play a major role in this scenario. OBJECTIVES: The aim of the present study was to determine the prevalence of in vitro resistance to terbinafine, itraconazole and voriconazole in dermatophytes, and to identify underlying mutations in the fungal squalene epoxidase (SQLE) gene. PATIENTS/METHODS: We analysed skin samples from 402 patients originating from eight locations in India. Fungi were identified by microbiological and molecular methods, tested for antifungal susceptibility (terbinafine, itraconazole, voriconazole), and investigated for missense mutations in SQLE. RESULTS: Trichophyton (T.) mentagrophytes internal transcribed spacer (ITS) Type VIII was found in 314 (78%) samples. Eighteen (5%) samples harboured species identified up to the T interdigitale/mentagrophytes complex, and T rubrum was detected in 19 (5%) samples. 71% of isolates were resistant to terbinafine. The amino acid substitution Phe397Leu in the squalene epoxidase of resistant T mentagrophytes was highly prevalent (91%). Two novel substitutions in resistant Trichophyton strains, Ser395Pro and Ser443Pro, were discovered. The substitution Ala448Thr was found in terbinafine-sensitive and terbinafine-resistant isolates but was associated with increased MICs of itraconazole and voriconazole. CONCLUSIONS: The high frequencies of terbinafine resistance in dermatophytes are worrisome and demand monitoring and further research. Squalene epoxidase substitutions between Leu393 and Ser443 could serve as markers of resistance in the future.

Eczema of recipient and donor skin graft sites: Another example of "Ruocco's immunocompromised district".

A 47-year-old male suffered soft tissue injuries 8 years ago that had been covered by meshed split thickness skin graft. During the last 2 years, he developed a chronic eczema (atopic dermatitis) on both recipient and donor sites on the lower extremities. Eczema on skin graft sites has been described rarely. However, this case is unique since both donor and recipient site were involved. We consider our observation as another example of Ruocco's immunocompromised districts of skin.

A clarion call for preventing taxonomical errors of dermatophytes using the example of the novel Trichophyton mentagrophytes genotype VIII uniformly isolated in the Indian epidemic of superficial dermatophytosis.

An alarming pan Indian increase in the incidence of superficial dermatophytosis has been noticed over the past 5-6 years. Recent studies have demonstrated emerging predominance of Trichophyton (T.) mentagrophytes as the causative organism in such cases. Interestingly, a distinct Indian genotype of T. mentagrophytes has been identified and recognised with the help of sequencing of the ITS region of the rDNA. That has, however, led to a basic confusion owing to the newly introduced taxonomy of dermatophytes in 2017. According to this most recently suggested classification and new taxonomy of dermatophytes, the former "T. mentagrophytes complex" is differentiated into T. mentagrophytes (zoophilic strains) and T. interdigitale (anthropophilic strains). We have noticed that in some recent studies the causative agent of the chronic, relapsing dermatophytosis outbreak in India has been described as T. interdigitale. In our opinion, it is very likely that these T. interdigitale strains isolated in Delhi and Chennai in India are indeed strains more closely related to the neotype of T. mentagrophytes and not strains of T. interdigitale. We therefore want to underscore the importance of a common nomenclature of species in accordance with the new taxonomy of dermatophytes. This would most likely facilitate better understanding of the issue amongst dermatologists and microbiologists in general. Mistaken identification of Trichophyton isolates not limited to India is very likely to occur due to the lack of appropriate molecular diagnosis which in turn is based on the already published data that presumably wrongly identify one species instead of the other.

The current Indian epidemic of superficial dermatophytosis due to Trichophyton mentagrophytes-A molecular study.

The disease burden of chronic-relapsing and therapy-refractory superficial dermatophytosis dramatically increased in India within the past 5-6 years. In order to evaluate the prevalence of this trend, 201 skin scrapings were collected from patients from all parts of India and were tested for dermatophytes using both fungal culture and a PCR-ELISA directly performed with native skin scrapings. Fungal culture material was identified by genomic Sanger sequencing of the internal transcribed spacer (ITS) region and the translation elongation factor (TEF)-1α gene. In total, 149 (74.13%) out of the 201 samples showed a dermatophyte-positive culture result. Out of this, 138 (92.62%) samples were identified as Trichophyton (T.) mentagrophytes and 11 (7.38%) as Trichophyton rubrum. The PCR-ELISA revealed similar results: 162 out of 201 (80.56%) samples were dermatophyte-positive showing 151 (93.21%) T mentagrophytes- and 11 (6.79%) T rubrum-positive samples. In this study, we show for the first time a dramatic Indian-wide switch from T rubrum to T mentagrophytes. Additionally, sequencing revealed a solely occurring T mentagrophytes "Indian ITS genotype" that might be disseminated Indian-wide due to the widespread abuse of topical clobetasol and other steroid molecules mixed with antifungal and antibacterial agents.

Chiari malformation and atlantoaxial instability: problems of co-existence.

BACKGROUND: Association of Chiari malformation and atlantoaxial subluxation varies. There is a complex relationship between the two, bony and soft tissue pathologies. METHODS: This is a review of various articles available from the literature on the management of Chiari and its association with atlantoaxial instability. RESULTS: We have an experience of operating on 86 cases of paediatric atlantoaxial subluxation, of which 12 had Chiari malformation diagnosed preoperatively (13.95%). Of the 76 children with Chiari malformations operated on by us, 11 had associated atlantoaxial subluxation diagnosed on imaging (14.47%). CONCLUSIONS: Re-alignment and reduction with fixation may be effective in achieving decompression in cases where reduction is possible from posterior approach. In these cases, posterior fixation is all that is required. If reduction is not possible from posterior and there is "fixed" ventral compression, anterior decompression needs to be combined with posterior fixation. In most cases, direct posterior decompression is warranted.

[Extensive tinea corporis due to a terbinafine-resistant Trichophyton mentagrophytes isolate of the Indian genotype in a young infant from Bahrain in Germany]. / Ausgeprägte Tinea corporis durch ein Terbinafin-resistentes Trichophyton-mentagrophytes-Isolat vom indischen Genotyp bei einem Säugling aus Bahrain in Deutschland.

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.