Emergence of methicillin resistance predates the clinical use of antibiotics.

The discovery of antibiotics more than 80 years ago has led to considerable improvements in human and animal health. Although antibiotic resistance in environmental bacteria is ancient, resistance in human pathogens is thought to be a modern phenomenon that is driven by the clinical use of antibiotics1. Here we show that particular lineages of methicillin-resistant Staphylococcus aureus-a notorious human pathogen-appeared in European hedgehogs in the pre-antibiotic era. Subsequently, these lineages spread within the local hedgehog populations and between hedgehogs and secondary hosts, including livestock and humans. We also demonstrate that the hedgehog dermatophyte Trichophyton erinacei produces two ß-lactam antibiotics that provide a natural selective environment in which methicillin-resistant S. aureus isolates have an advantage over susceptible isolates. Together, these results suggest that methicillin resistance emerged in the pre-antibiotic era as a co-evolutionary adaptation of S. aureus to the colonization of dermatophyte-infected hedgehogs. The evolution of clinically relevant antibiotic-resistance genes in wild animals and the connectivity of natural, agricultural and human ecosystems demonstrate that the use of a One Health approach is critical for our understanding and management of antibiotic resistance, which is one of the biggest threats to global health, food security and development.

Recognition of Antifungal-Resistant Dermatophytosis by Infectious Diseases Specialists, United States.

Antifungal-resistant dermatophyte infections have recently emerged as a global public health concern. A survey of US infectious diseases specialists found that only 65% had heard of this issue and just 39% knew how to obtain testing to determine resistance. Increased clinician awareness and access to testing for antifungal-resistant dermatophytosis are needed.

The Ptk2-Pma1 pathway enhances tolerance to terbinafine in Trichophyton rubrum.

The increasing prevalence of dermatophyte resistance to terbinafine, a key drug in the treatment of dermatophytosis, represents a significant obstacle to treatment. Trichophyton rubrum is the most commonly isolated fungus in dermatophytosis. In T. rubrum, we identified TERG_07844, a gene encoding a previously uncharacterized putative protein kinase, as an ortholog of budding yeast Saccharomyces cerevisiae polyamine transport kinase 2 (Ptk2), and found that T. rubrum Ptk2 (TrPtk2) is involved in terbinafine tolerance. In both T. rubrum and S. cerevisiae, Ptk2 knockout strains were more sensitive to terbinafine compared with the wild types, suggesting that promotion of terbinafine tolerance is a conserved function of fungal Ptk2. Pma1 is activated through phosphorylation by Ptk2 in S. cerevisiae. Overexpression of T. rubrum Pma1 (TrPma1) in T. rubrum Ptk2 knockout strain (ΔTrPtk2) suppressed terbinafine sensitivity, suggesting that the induction of terbinafine tolerance by TrPtk2 is mediated by TrPma1. Furthermore, omeprazole, an inhibitor of plasma membrane proton pump Pma1, increased the terbinafine sensitivity of clinically isolated terbinafine-resistant strains. These findings suggest that, in dermatophytes, the TrPtk2-TrPma1 pathway plays a key role in promoting intrinsic terbinafine tolerance and may serve as a potential target for combinational antifungal therapy against terbinafine-resistant dermatophytes.

Development of an agar-based screening method for terbinafine, itraconazole, and amorolfine susceptibility testing of Trichophyton spp.

Resistance in dermatophytes is an emerging global public health issue. We, therefore, developed an agar-based method for screening Trichophyton spp. susceptibility to terbinafine (TRB), itraconazole (ITC), and amorolfine (AMF) and validated it using molecularly characterized isolates. Α total of 40 Trichophyton spp. isolates, 28 TRB wild type (WT) (13 T. rubrum, 10 T. mentagrophytes, 5 T. interdigitale) and 12 TRB non-WT (7 T. rubrum, 5 T. indotineae) with different alterations in the squalene epoxidase (SQLE) gene, were used. The optimal test conditions (inoculum and drug concentrations, incubation time, and temperature) and stability over time were evaluated. The method was then applied for 86 WT Trichophyton spp. clinical isolates (68 T. rubrum, 7 T. interdigitale, 6 T. tonsurans, 5 T. mentagrophytes) and 4 non-WT T. indotineae. Optimal growth of drug-free controls was observed using an inoculum of 20 µL 0.5 McFarland after 5-7 days of incubation at 30°C. The optimal concentrations that prevented the growth of WT isolates were 0.016 mg/L of TRB, 1 mg/L of ITC, and 0.25 mg/L of AMF, whereas 0.125 mg/L of TRB was used for the detection of Trichophyton strong SQLE mutants (MIC ≥0.25 mg/L). The agar plates were stable up to 4 months. Inter-observer and inter-experimental agreement were 100%, and the method successfully detected TRB non-WT Trichophyton spp. strains showing 100% agreement with the reference EUCAST methodology. An agar-based method was developed for screening Trichophyton spp. in order to detect TRB non-WT weak and strong mutant isolates facilitating their detection in non-expert routine diagnostic laboratories.

Riparin II-type benzamides as novel antibiofilm agents against dermatophytes: chemical synthesis, in vitro, ex vivo and in silico evaluation.

BACKGROUND: The ability of dermatophytes to develop biofilms in host tissues confers physical and biochemical resistance to antifungal drugs. Therefore, research to find new compounds against dermatophyte biofilm is crucial. OBJECTIVES: To evaluate the antifungal activity of riparin II (RIP2), nor-riparin II (NOR2) and dinor-riparin II (DINOR2) against Trichophyton rubrum, Microsporum canis and Nannizzia gypsea strains. METHODS: Initially, we determined the minimum inhibitory concentration (MIC) and minimum fungicidal concentration (MFC) of benzamides. We evaluated the inhibitory effects on the development of dermatophyte biofilms using in vitro and ex vivo models. Finally, we built three-dimensional models of the sulphite pump Ssu1 to investigate the interactions with the benzamides by molecular docking. RESULTS: RIP2 showed a broad spectrum of activity against T. rubrum, M. canis and N. gypsea, whereas NOR2 and DINOR2 were more selective. Furthermore, the shortening of the carbon chain from RIP2 benzamide to NOR2 and DINOR2 homologs caused a decrease in the MIC values. The benzamides reduced biofilm production and viability in vitro (P < 0.05) at MIC. This result was similar ex vivo in human nail fragments tests, but NOR2 and DINOR2 showed significant results at 2xMIC (P < 0.05). We constructed a model of the Ssu1 protein for each dermatophyte with high similarity. Molecular docking showed that the benzamides obtained higher binding energy values than ciclopirox. CONCLUSIONS: Our study shows the antibiofilm potential for riparin II-type benzamides as new drugs targeting dermatophytes by inhibiting the Ssu1 protein.

Detection of terbinafine-resistant Trichophyton indotineae isolates within the Trichophyton mentagrophytes species complex isolated from patients in Hue City, Vietnam: A comprehensive analysis.

The Trichophyton mentagrophytes complex comprises a group of dermatophyte fungi responsible for various dermatological infections. The increasing drug resistance of this species complex, especially terbinafine resistance of Trichophyton indotineae, is a major concern in dermatologist practice. This study provides a comprehensive analysis of T. mentagrophytes complex strains isolated from patients in Hue City, Vietnam, focusing on their phenotypic and genetic characteristics, antifungal susceptibility profiles, and molecular epidemiology. Keratinophilic fungi from dermatophytosis culture samples were identified morphologically and phenotypically, with species and genotypes confirmed by internal transcribed spacer sequencing and phylogenetic analysis. Antifungal susceptibility testing was carried out to evaluate their susceptibility to itraconazole, voriconazole, and terbinafine. The 24% (n = 27/114) of superficial mycoses were phenotypically attributed to T. mentagrophytes complex isolates. Trichophyton interdigitale, mainly genotype II*, was predominant (44.4%), followed by T. mentagrophytes genotype III* (22.2%), T. indotineae (14.8%), T. tonsurans (11.2%), and T. mentagrophytes (7.4%). While all isolates were susceptible to itraconazole and voriconazole, half of T. indotineae isolates exhibited resistance to terbinafine, linked to the Phe397Leu mutation in the SQLE protein. This study highlighted the presence of terbinafine-resistant T. indotineae isolates in Vietnam, emphasizing the need to investigate dermatophyte drug resistance and implement effective measures in clinical practice.

Species diversity within the Trichophyton mentagrophytes complex isolated from dermatophytosis in Hue City, Vietnam, was observed. Terbinafine-resistant T. indotineae isolates were detected for the first time in Vietnam, emphasizing the importance of implementing antifungal susceptibility testing to effectively manage and prevent the spread of resistant isolates.

Molecular epidemiology and antifungal susceptibility of dermatophytes and Candida isolates in superficial fungal infections at a grade A tertiary hospital in Northern China.

This study analyzed the prevalence and antifungal susceptibility of superficial fungal infections in 295 cases from 2019 to 2020 at a dermatology clinic. Dermatophytes were the predominant pathogens (69.5%), including Trichophytonrubrum, T. interdigitale, Microsporum canis, et al., followed by Candida spp. (29.5%), including Candidaalbicans, Ca. parapsilosis, and Ca. glabrata. The most common infections were onychomycosis (36.3%), tinea cruris (30.5%), and tinea corporis (18.6%). The distribution of SFI types showed variations based on gender, age, and season. Common antifungal agents, including terbinafine, voriconazole, ciclopiroxamine, amphotericin B, itraconazole, and ketoconazole have exhibited low minimum inhibitory concentrations against dermatophytes, especially terbinafine, which has been potent against superficial fungal infections caused by dermatophytes in the local area. Candida spp. strains were generally susceptible or classified as wild-type to 5-flucytosine and amphotericin B, with 92.0% being wild-type for itraconazole. However, resistance to fluconazole and voriconazole was observed in a small percentage of Ca. albicans and Ca. parapsilosis strains. The emergence of drug-resistant Candida underscores the importance of prudent antifungal use and continuous surveillance.

Our study analyzed 295 cases of superficial fungal infections in Taiyuan, located in Northern China. Dermatophytes and Candida spp. were primary pathogens, with varied susceptibilities to antifungals. Results deepen our understanding, emphasizing prudent drug use and surveillance.

Epidemiology and management of tinea capitis in France: A 6-year nationwide retrospective survey.

Tinea capitis (TC) is still a frequent dermatophytosis in France, both autochthonous and imported. A nationwide retrospective survey was performed and a total of 4395 TC cases were recorded within 36 French mycology laboratories during a 6-year period. TC is a disease that occurs in childhood with 85% of the cases occurring before 10 years old and 94% before the age of 15. Anthropophilic origin was predominant with 779 cases of Trichophyton tonsurans (32.6%), 738 cases of Trichophyton soudanense/T. violaceum (31%), and 445 cases of Microsporum audouinii (19.2%). Of note, T. tonsurans represents more than 80% of the cases in the French West Indies (Martinique and Guadeloupe). By contrast, zoophilic species were less prevalent with mainly M. canis (10.3%) confirming the shift from zoophilic to anthropophilic species observed in many centers during the last decades. During this survey, diagnosis methods were also collected. Most labs had a classical process for the diagnosis: microscopic direct examination associated to cultures on Sabouraud and Sabouraud-cycloheximide media (incubated between 25 ± 5°C for at least 3 weeks) in all laboratories. Identification of the causal dermatophyte was performed by microscopic and macroscopic examination of the cultures in 100% of the labs, with various specific culture media available when fructification was insufficient (mainly malt or potato-dextrose agar, or Borelli medium). New techniques were also implemented with the introduction of MALDI-TOF mass spectrometry identification in more than two third of the labs, and molecular identification available if necessary in half of the labs.

A total of 4395 tinea capitis cases were recorded within 36 French mycology laboratories during a 6-year period. An anthropophilic origin was predominant with 33%, 31%, and 18.8% of cases due to Trichophyton tonsurans, T. soudanense/T. violaceum, and Microsporum audouinii, respectively.

Whole genome characterization of Trichophyton indotineae isolated in Singapore.

Complete genome sequences from two Trichophyton indotineae isolates were obtained from a 23-year-old male presenting with tinea cruris after an overseas recreational water exposure and from a 53-year-old female patient with unknown travel history. Analysis of the squalene epoxidase gene and the cyp51 gene family showed an absence of mutations, correlating with phenotypic drug susceptibility. The Single Nucleotide Polymorphisms (SNPs) distance between both isolates was 92. Within the T. indotineae cluster, SNPs ranged from 7 to 182, suggesting a high genetic relatedness with other South Asian isolates. This study suggests that the prevalence of T. indotineae is under-reported and more widespread than previously thought.

Trichophyton indotineae, is a fungus causing difficult to treat ringworm infections. Two isolates were sequenced and their relationship and to other isolates was characterized. We also studied the genes responsible for first-line antifungal treatment.

Molecular Detection of Dermatophytes and Nondermatophytes in Onychomycosis in Antalya, Turkey.

BACKGROUND: Onychomycosis is a chronic nail infection, and dermatophytes, yeasts, and nondermatophytic molds may be the causative agents. This study aimed to determine the etiological agents of onychomycosis by using conventional and molecular methods. METHODS: Between June 2020 and July 2021, 37 patients with a presumptive diagnosis of onychomycosis and mycological evidence (culture and/or EUROArray Dermatomycosis assay) were included in the study. Organisms detected in cultured nail specimens were identified by combined phenotypic characteristics and by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS). An EUROarray Dermatomycosis assay was used for molecular detection of fungal pathogens. RESULTS: The EUROArray Dermatomycosis assay was positive for a single fungal target in 23 samples, and 14 samples were positive by culture. The most common pathogen was Trichophyton rubrum in both methods. Coinfection was detected in 14 samples by using molecular methods, and Trichophyton rubrum and Fusarium solani (9 samples) were the most common pathogens detected together. Trichophyton spp., nondermatophyte molds, and Candida spp. were detected in 33 (89.2%), 16 (43.2%), and 6 (16.2%) samples, respectively, when the two methods were evaluated together. CONCLUSIONS: Our results revealed that fungal culture allows the diagnosis of onychomycosis, but it is not as sensitive as the EUROArray Dermatomycosis test, especially in patients receiving antifungal therapy.

Onychoscopic characteristics of Trichophyton rubrum and Trichophyton interdigitalis fungal infections: A multicentric study.

BACKGROUND: Trichophyton rubrum and Trichophyton mentagrophytes variant interdigitalis are the most frequent etiologic agents of onychomycosis. Diagnosis of certainty requires mycological examination, which often results unfeasible. OBJECTIVES: The aim of our study is to describe pathogen specific dermoscopic features, allowing a differential diagnosis without the need for cultural examination, in order to prescribe the most appropriate treatment anyway. PATIENTS AND METHODS: We conducted an observational retrospective study on 54 patients with a culture proven diagnosis of distal subungual onychomycosis of the toenail, caused by Trichophyton rubrum or Trichophyton mentagrophytes variant interdigitalis. Using a videodermatoscope we collected data on nail colour (white, yellow, orange, brown, dark) and on dermoscopic patterns (aurora, spikes, jagged, ruin, linear edge, dots, striae). RESULTS: Fifty-four patients, with a total of 72 nails, were eligible for this study. Analysing the association between discoloration of the nail plate and type of infection (T. rubrum or T. interdigitalis), no correlation turned out to be statistically significant. Instead, significant associations between spikes and T. rubrum infection and striae and infection from T. interdigitalis were identified. Finally, a 100% specificity was identified for white colour and ruin pattern for T. rubrum infection, and brown colour, jagged border and aurora pattern for T. interdigitalis. CONCLUSIONS: Trying to find relationships between specific pathogens and dermoscopic patterns, we found out an association between spikes and striae and T. rubrum and T. interdigitalis respectively. Further larger studies are however necessary to evaluate our preliminary findings.

Global Insights and Trends in Research on Dermatophytes and Dermatophytosis: A Bibliometric Analysis.

BACKGROUND: Dermatophytosis, caused by dermatophytes, affects up to 25% of people globally, with higher rates observed in Africa and Asia. While these infections are usually superficial, they can become severe in immunocompromised individuals. Despite their high prevalence, scientific research on dermatophytes is limited and the epidemiological data available are insufficient. In addition, diagnostic methods are not standardised and there are challenges with resistance to antifungals. OBJECTIVES: This study aimed to conduct a bibliometric analysis of scientific publications related to dermatophytes and dermatophytosis to assess research output and trends. METHODS: A bibliometric analysis of publications from 2000 to 2023 in Web of Science and Scopus examined trends, citation counts, publication types, key journals, top authors and institutions and funding sources. RESULTS: The analysis revealed a significant increase in dermatophyte-related publications, with 15,868 articles retrieved from the Web of Science and 23,189 from Scopus. Research articles dominated the output, constituting 76.2% in Web of Science and 80% in Scopus. Peak publication years were 2019, 2021 and 2022 in Web of Science, and 2020, 2021 and 2023 in Scopus, with lower output between 2000 and 2002. The United States and India were the leading contributors, followed by Brazil and China, though citation metrics varied. Although there has been a rise in the number of publications, the amount of research conducted on dermatophytes is still very limited in comparison with other types of fungal diseases. CONCLUSIONS: Dermatophyte-related research has increased over the past 2 decades. However, research gaps remain, particularly compared with other fungal diseases. Advances in diagnostics, antifungal testing and taxonomic classification are urgently needed. The study underscores the need for continued research and global collaboration to address these issues.

Tinea faciei clinical characteristics, causative agents, treatments and outcomes; a retrospective study in Thailand.

BACKGROUND: Tinea faciei is a relatively uncommon dermatophyte infection. The studies, which included clinical forms, and isolated species of dermatophytes, are limited. MATERIALS AND METHODS: This retrospective study aims to determine the causative organism, clinical characteristics, treatments and outcomes of patients with tinea faciei attending the dermatologic clinic, Siriraj Hospital, from 1 January 2017 to 30 September 2021. Demographic data, clinical presentations, isolated dermatophyte species, treatments and outcomes were collected and analysed. RESULTS: A total of 151 tinea faciei cases were observed. Trichophyton rubrum (48.6%), Trichophyton mentagrophytes complex (22.2%) and Microsporum canis (18.1%) were common causative agents. Tinea faciei was commonly detected in females (64.9%) with a history of pets (54.6%). Clinical presentations often involved plaques and scales on the cheeks. Among patients with lesions on the cheek, mycological cure was observed significantly less often compared to those without cheek lesions. Patients with other concurrent skin or nail infections, a history of topical steroids and a history of previous fungal infection had a slightly longer duration of mycological cure than those without factors. Recurrent infection was found in 33.3%. Male, history of previous fungal infection, and lesions on the cheeks were significantly associated with recurrent infection. CONCLUSIONS: Fungal infection of the face was commonly found in women and patients with pets. The most common pathogen that caused tinea faciei was T. rubrum. Topical antifungal treatments could be used with favourable outcomes. The history of past infection and lesion on the cheeks should be carefully assessed to be vigilant for recurrent infection.

New Sources of Resistance to Terbinafine Revealed and Squalene Epoxidase Modelled in the Dermatophyte Fungus Trichophyton interdigitale From Australia.

BACKGROUND: Terbinafine is widely used to treat onychomycosis caused by dermatophyte fungi. Terbinafine resistance in recent years is causing concern. Resistance has so far been associated with single-nucleotide substitutions in the DNA sequence of the enzyme squalene epoxidase (SQLE) but how this affects SQLE functionality is not understood. OBJECTIVES: The aim of this study was to understand newly discovered resistance in two Australian strains of Trichophyton interdigitale. PATIENTS/METHODS: Resistance to terbinafine was tested in four newly isolated strains. Three-dimensional SQLE models were prepared to investigate how the structure of their SQLE affected the binding of terbinafine. RESULTS: This study found the first Australian occurrences of terbinafine resistance in two T. interdigitale strains. Both strains had novel deletion mutations in erg1 and frameshifts during translation. Three-dimensional models had smaller SQLE proteins and open reading frames as well as fewer C-terminal α-helices than susceptible strains. In susceptible strains, the lipophilic tail of terbinafine was predicted to dock stably into a hydrophobic pocket in SQLE lined by over 20 hydrophobic amino acids. In resistant strains, molecular dynamics simulations showed that terbinafine docking was unstable and so terbinafine did not block squalene metabolism and ultimately ergosterol production. The resistant reference strain ATCC MYA-4438 T. rubrum showed a single erg1 mutation that resulted in frameshift during translation, leading to C-terminal helix deletion. CONCLUSIONS: Modelling their effects on their SQLE proteins will aid in the design of potential new treatments for these novel resistant strains, which pose clinical problems in treating dermatophyte infections with terbinafine.

Terbinafine resistance in Trichophyton mentagrophytes and Trichophyton rubrum in the Czech Republic: A prospective multicentric study.

BACKGROUND: Terbinafine, an allylamine antifungal, is crucial for treating dermatophytosis by inhibiting squalene epoxidase (SQLE) in the ergosterol biosynthetic pathway. However, resistance is emerging, particularly in India and Southeast Asia, but reports of resistance spread worldwide. Despite this, comprehensive studies on terbinafine resistance in Trichophyton are still limited. OBJECTIVES: This research aimed to determine the prevalence of terbinafine resistance in the Czech Republic, with a focus on Trichophyton rubrum and Trichophyton mentagrophytes, and investigate the underlying molecular mechanisms. PATIENTS/METHODS: A total of 514 clinical strains of T. rubrum and 240 T. mentagrophytes collected from four Czech clinical institutions were screened for terbinafine resistance. Molecular investigations included DNA sequencing, specifically the ITS rDNA region and SQLE gene, as well as antifungal susceptibility testing following EUCAST guidelines. RESULTS: While no resistance was observed in T. rubrum, 2.5% of T. mentagrophytes strains exhibited resistance, marked by the F397L mutation in SQLE. Notably, resistance surged from 1.2% in 2019 to 9.3% in 2020 but reverted to 0% in 2021. All resistant strains were identified as T. mentagrophytes var. indotineae. Resistant strains exhibited high MICs for terbinafine (≥4 mg L-1 ) but low MICs to the other seven antifungals tested except for fluconazole. CONCLUSIONS: This study highlights the emergence of terbinafine-resistant T. mentagrophytes strains in the Czech Republic, with the F397L mutation being pivotal. Due to the relatively low resistance level, the current guidelines for dermatomycosis treatment in the Czech Republic remain effective, but ongoing surveillance is essential for timely adaptations if resistance patterns change.

A survey of 701 cases of tinea faciei in Hangzhou, southeastern China, from 2018 to 2023.

BACKGROUND: Tinea faciei, a specific dermatophytosis that affects the glabrous skin of the face, not only causes physical discomfort but also leads to greater psychological distress. Tinea faciei is a public health concern. OBJECTIVES: To analyse the epidemiological characteristics, responsible dermatophyte species and clinical features of tinea faciei in Hangzhou. METHODS: Data were obtained from the Laboratory Information System of the Mycology Laboratory and Medical Information System at a hospital in Hangzhou. Isolates were identified based on their macroscopic appearance and microscopic morphology. RESULTS: Tinea faciei was diagnosed in 701 patients, involving 359 males and 342 females, aged between 2 months and 97 years. In total, 499 isolates (71.18%) were identified as Trichophyton rubrum. Anthropophilic isolates were identified in 297 (82.73%) males and 207 (60.53%) females (p < .01). Among patients with anthropophilic dermatophytes infection, 447 (88.69%) were adults. Zoophilic dermatophytes were isolated in 57 (15.88%) males and 130 (38.01%) females (p < .01), among whom 108 (57.75%) were children. CONCLUSIONS: Anthropophilic dermatophytes, especially T. rubrum, were the predominant cause of tinea faciei, while zoophilic dermatophytes were the most prevalent in children. Compared with men, women may be more susceptible to zoophilic dermatophytes.

Understanding Global Access to Topical Onychomycosis Therapy: A Systematic Review and Meta-Analysis.

INTRODUCTION: Equal access to medicines is crucial to ensuring public health, but access is difficult to measure, especially for infections where changes in infective species make treatment choices highly dynamic. This study investigated if the combination of infection prevalence with medicine efficacy and regulatory availability could access medicines access of topical onychomycosis medicines. METHODS: Two databases, PubMed and Web of Science, were used to identify relevant information published between 1990 and 2019. For the meta-analysis, human onychomycosis investigations using PCR analysis were included. Reviewers independently selected eligible articles, extracted data and assessed the study quality. A random-effects meta-analysis model with a Freeman-Tukey transformation was employed to the PCR data. For the meta-analysis, the global infection trends and regional differences in the infective organisms were determined. RESULTS: Of the 26 studies analysed, the PCR analysis in 18 studies confirmed onychomycosis in about half of the visually suspected cases (55%, CI 43%-67%). Across all 26 studies dermatophytes were the most prevalent infective organism (57%, CI 37%-76%), but a sub-group analysis showed yeasts predominated in females (31%, CI 0%-84%) (p < 0.0001), in fingernail infections (42%, CI 21%-65%) (p < 0.0001) and in arid countries (p < 0.0001). Combining these results with medicine efficacy data showed that residents from 83 of the 92 countries assessed (90%) could not access the most efficacious topical product, and 22% could not access any broad-spectrum agents. Countries in Africa had the poorest access to topical onychomycosis medicines. CONCLUSION: This study identified that access to effective topical products for onychomycosis is a global problem. This issue appeared to be due to under-representation of candida infections in pivotal clinical studies of topical onychomycosis products. A head-to-head multicentre study for topical efinaconazole or a novel broad spectrum topical agent is needed to help resolve these access problems. PROTOCOL REGISTRATION: PROSPERO-CRD42023464744.

Identification of primary metabolites in fungal species of Trichophyton mentagrophyte and Trichophyton rubrum by NMR spectroscopy.

BACKGROUND: Superficial mycoses are fungal infections limited to the outermost layers of the skin and its appendages. The chief causative agents of these mycoses are dermatophytes and yeasts. The diagnosis of dermatophytosis can be made by direct mycological examination with potassium hydroxide (10%-30%) of biological material obtained from patients with suspected mycosis, providing results more rapid than fungal cultures, which may take days or weeks. This information, together with clinical history and laboratory diagnosis, ensures that the appropriate treatment is initiated promptly. However, false negative results are obtained in 5%-15%, by conventional methods of diagnosis of dermatophytosis. OBJECTIVES: To study the metabolic profiles of the commonly occurring dermatophytes by NMR spectroscopy. PATIENTS/MATERIALS: We have used 1D and 2D Nuclear Magnetic Resonance (NMR) experiments along with Human Metabolome Database (HMDB) and Chenomx database search for identification of primary metabolites in the methanol extract of two fungal species: Trichophyton mentagrophyte (T. mentagrophyte) and Trichophyton rubrum (T. rubrum). Both standard strains and representative number of clinical isolates of these two species were investigated. Further, metabolic profiles obtained were analysed using multivariate analysis. RESULTS: We have identified 23 metabolites in the T. mentagrophyte and another 23 metabolites in T. rubrum. Many important metabolites like trehalose, proline, mannitol, acetate, GABA and several other amino acids were detected, which provide the necessary components for fungal growth and metabolism. Altered metabolites were defined between Trichophyton mentagrophyte and T. rubrum strains. CONCLUSION: We have detected many metabolites in the two fungal species T. mentagrophyte and T. rubrum by using NMR spectroscopy. NMR spectroscopy provides a holistic snapshot of the metabolome of an organism. Key metabolic differences were identified between the two fungal strains. We need to perform more studies on metabolite profiling of the samples from these species for their rapid diagnosis and prompt treatment.

Molecular typing of a collection of Iranian clinical Trichophyton tonsurans isolates based on the non-transcribed spacer region of rDNA and antifungal susceptibility testing of the species.

INTRODUCTION: Wrestling, considered the national sport of Iran, has gained immense popularity among Iranians. Wrestlers frequently encounter skin conditions, with dermatophyte fungal infections, particularly tinea gladiatorum (TG), being a common issue. TG, caused by the Trichophyton genus, has emerged as a major health concern for wrestlers and other contact sport athletes worldwide. This study aimed to assess the genotypic diversity and antifungal susceptibility of Trichophyton tonsurans isolates responsible for TG in Iranian wrestlers from Mazandaran province, northern Iran. MATERIALS AND METHODS: A total of 60 clinical T. tonsurans isolates collected from various cities in Mazandaran, were included in the study. The isolates were identified through PCR-restriction fragment length polymorphism and sequencing methods. Genomic DNA was extracted from these isolates, and the non-transcribed spacer (NTS) region of ribosomal RNA (rRNA) was targeted for genotyping using newly designed primers. Haplotype analysis was performed to explore genetic diversity, and antifungal susceptibility to terbinafine (TRB) and itraconazole (ITC) was assessed. RESULTS: The results revealed five distinct NTS types: NTS-I, NTS-II, NTS-III, NTS-IV and NTS-V, with NTS-IV being the most prevalent. The distribution of NTS types varied across different cities, suggesting potential transmission patterns among wrestlers. Antifungal susceptibility testing showed that all isolates were susceptible to TRB, while one isolate demonstrated resistance to ITC. Genotypic diversity was not correlated with antifungal susceptibility, emphasising the importance of monitoring susceptibility to ensure effective treatment. Haplotype analysis highlighted significant genetic diversity among the T. tonsurans isolates. This diversity may be attributed to factors such as human-to-human transmission, geographic location and lifestyle changes. The study's findings underscore the need for comprehensive genotypic analysis to understand the epidemiology and evolution of T. tonsurans infections in athletes. CONCLUSION: In conclusion, this study provides valuable insights into the genotypic diversity and antifungal susceptibility of T. tonsurans isolates causing TG in Iranian wrestlers. The presence of multiple NTS types and varying susceptibility patterns highlights the complexity of T. tonsurans infections in this population. Further research is warranted to track the transmission routes and genetic evolution of T. tonsurans strains among wrestlers and develop effective control measures.

Potential emergence of terbinafine resistance by squalene epoxidase gene mutations: An 18-month cohort study of onychomycosis patients in the United States.

BACKGROUND: There is a concerning rise in antifungal-resistant dermatophytosis globally, with resistance to terbinafine conferred by point mutations in the squalene epoxidase (SQLE) gene. OBJECTIVES: Report changes in the prevalence and profile of SQLE mutations in onychomycosis patients in the United States. METHODS: A longitudinal cohort study of toenail samples was collected from suspected onychomycosis patients over an 18-month period from 2022 to 2023. Samples were submitted from across the United States and subjected to multiplex real-time polymerase chain reactions for dermatophyte detection, with further screening of SQLE mutations at four known hotspots (393Leu, 397Phe, 415Phe and 440His). RESULTS: A total of 62,056 samples were submitted (mean age: 57.5 years; female: 60.4%). Dermatophytes were detected in 38.5% of samples, primarily Trichophyton rubrum complex (83.6%) and T. mentagrophytes complex (10.7%). A survey of SQLE mutations was carried out in 22,610 dermatophyte samples; there was a significant increase in the prevalence of SQLE mutations between the first quarter of 2022 and the second quarter of 2023 (29.0 to 61.9 per 1000 persons). The Phe397Leu substitution was the predominant mutation; Phe415Ser and His440Tyr have also emerged which were previously reported as minor mutations in skin samples. The temporal change in mutation rates can be primarily attributed to the Phe415Ser substitution. Samples from elderly patients (>70 years) are more likely to be infected with the T. mentagrophytes complex including strains harbouring the Phe415Ser substitution. CONCLUSION: The prevalence of SQLE mutations among onychomycosis patients with Trichophyton infections may be underestimated. Older individuals may have a higher risk.