Mapping the Global Spread of T. indotineae: An Update on Antifungal Resistance, Mutations, and Strategies for Effective Management.

INTRODUCTION: The global spread of Trichophyton indotineae presents a pressing challenge in dermatophytosis management. This systematic review explores the current landscape of T. indotineae infections, emphasizing resistance patterns, susceptibility testing, mutational analysis, and management strategies. METHODS: A literature search was conducted in November 2023 using Embase, PubMed, Scopus, and Web of Science databases. Inclusion criteria covered clinical trials, observational studies, case series, or case reports with T. indotineae diagnosis through molecular methods. Reports on resistance mechanisms, antifungal susceptibility testing, and management were used for data extraction. RESULTS AND DISCUSSION: A total of 1148 articles were identified through the systematic search process, with 45 meeting the inclusion criteria. The global spread of T. indotineae is evident, with cases reported in numerous new countries in 2023. Tentative epidemiological cut-off values (ECOFFs) suggested by several groups provide insights into the likelihood of clinical resistance. The presence of specific mutations, particularly Phe397Leu, correlate with higher minimum inhibitory concentrations (MICs), indicating potential clinical resistance. Azole resistance has also been reported and investigated in T. indotineae, and is a growing concern. Nevertheless, itraconazole continues to be an alternative therapy. Recommendations for management include oral or combination therapies and individualized approaches based on mutational analysis and susceptibility testing. CONCLUSION: Trichophyton indotineae poses a complex clinical scenario, necessitating enhanced surveillance, improved diagnostics, and cautious antifungal use. The absence of established clinical breakpoints for dermatophytes underscores the need for further research in this challenging field.

An update on antifungal resistance in dermatophytosis.

INTRODUCTION: The reports of resistance to antifungal agents used for treating onychomycosis and other superficial fungal infections are increasing. This rise in antifungal resistance poses a public health challenge that requires attention. AREAS COVERED: This review explores the prevalence of dermatophytes and the current relationship between dermatophyte species, their minimum inhibitory concentrations (MICs) for terbinafine (an allylamine) and itraconazole (an azole), and various mutations prevalent in these species. The most frequently isolated dermatophyte associated with resistance in patients with onychomycosis and dermatophytosis was T. mentagrophytes. However, T. indotineae emerged as the most prevalent isolate with mutations in the SQLE gene, exhibiting the highest MIC of 8 µg/ml for terbinafine and MICs of 8 µg/ml and ≥ 32 µg/ml for itraconazole.Overall, the most prevalent SQLE mutations were Phe397Leu, Leu393Phe, Ala448Thr, Phe397Leu/Ala448Thr, and Lys276Asn/Leu415Phe (relatively recent). EXPERT OPINION: Managing dermatophyte infections requires a personalized approach. A detailed history should be obtained including details of travel, home and occupational exposure, and clinical examination of the skin, nails and other body systems. Relevant testing includes mycological examination (traditional and molecular). Additional testing, where available, includes MIC evaluation and detection of SQLE mutations. In case of suspected terbinafine resistance, itraconazole or voriconazole (less commonly) should be considered.

Global prevalence of onychomycosis in general and special populations: An updated perspective.

BACKGROUND: Onychomycosis is a chronic nail disorder commonly seen by healthcare providers; toenail involvement in particular presents a treatment challenge. OBJECTIVE: To provide an updated estimate on the prevalence of toenail onychomycosis. METHODS: We conducted a literature search using PubMed, Embase and Web of Science. Studies reporting mycology-confirmed diagnoses were included and stratified into (a) populations-based studies, and studies that included (b) clinically un-suspected and (c) clinically suspected patients. RESULTS: A total of 108 studies were included. Based on studies that examined clinically un-suspected patients (i.e., with or without clinical features suggestive of onychomycosis), the pooled prevalence rate of toenail onychomycosis caused by dermatophytes was 4% (95% CI: 3-5) among the general population; special populations with a heightened risk include knee osteoarthritis patients (RR: 14.6 [95% CI: 13.0-16.5]), chronic venous disease patients (RR: 5.6 [95% CI: 3.7-8.1]), renal transplant patients (RR: 4.7 [95% CI: 3.3-6.5]), geriatric patients (RR: 4.7 [95% CI: 4.4-4.9]), HIV-positive patients (RR: 3.7 [95% CI: 2.9-4.7]), lupus erythematosus patients (RR: 3.1 [95% CI: 1.2-6.3]), diabetic patients (RR: 2.8 [95% CI: 2.4-3.3]) and hemodialysis patients (RR: 2.8 [95% CI: 1.9-4.0]). The prevalence of onychomycosis in clinically suspected patients was significantly higher likely due to sampling bias. A high degree of variability was found in a limited number of population-based studies indicating that certain pockets of the population may be more predisposed to onychomycosis. The diagnosis of non-dermatophyte mould onychomycosis requires repeat sampling to rule out contaminants or commensal organisms; a significant difference was found between studies that performed single sampling versus repeat sampling. The advent of PCR diagnosis results in improved detection rates for dermatophytes compared to culture. CONCLUSION: Onychomycosis is an underrecognized healthcare burden. Further population-based studies using standardized PCR methods are warranted.

Effectiveness and safety of oral terbinafine for dermatophyte distal subungual onychomycosis.

INTRODUCTION: Terbinafine has been a cornerstone in dermatophyte infection treatment. Despite its global efficacy, the emergence of terbinafine resistance raises concerns, requiring ongoing vigilance. AREAS COVERED: This paper focuses on evaluating the efficacy and safety of terbinafine in treating dermatophyte toenail infections. Continuous and pulse therapies, with a 24-week continuous regimen and a higher dosage of 500 mg/day have demonstrated superior efficacy to the FDA approved regimen of 250 mg/day x 12 weeks. Pulse therapies, though showing comparable effectiveness, present debates with regards to their efficacy as conflicting findings have been reported. Safety concerns encompass hepatotoxicity, gastrointestinal, cutaneous, neurologic, hematologic and immune adverse-effects, and possible drug interactions, suggesting the need for ongoing monitoring. EXPERT OPINION: Terbinafine efficacy depends on dosage, duration, and resistance patterns. Continuous therapy for 24 weeks and a dosage of 500 mg/day may enhance outcomes, but safety considerations and resistance necessitate individualized approaches. Alternatives, including topical agents and alternative antifungals, are to be considered for resistant cases. Understanding the interplay between treatment parameters, adverse effects, and resistance mechanisms is critical for optimizing therapeutic efficacy while mitigating resistance risks. Patient education and adherence are vital for early detection and management of adverse effects and resistance, contributing to tailored and effective treatments.

Concepts, Terminology, and Innovations in Follicular Unit Excision Hair Restoration Surgery.

Follicular unit excision (FUE) has emerged as the preferred method for hair transplants. Standardized terms and definitions established by members of the International Society of Hair Restoration Surgery and prominent hair restoration surgeons have become the standard, enabling effective knowledge sharing. This chapter provides an overview of the terminology relating to the field.The historical evolution of FUE and its pivotal role in modern hair transplantation is summarized. Anatomical terminology and graft-related definitions follow, providing insights into the scalp's complex structures and graft characteristics. The subsequent sections detail the terminology associated with graft excision and extraction, shedding light on the precise techniques and procedures employed. An exploration of various FUE techniques and the evolving landscape of FUE devices underscores the continual refinement of hair restoration practices. The chapter proceeds to discuss the "safe'" scalp donor zones, donor assessment terminology, and elements in identifying the optimal donor area for a successful FUE procedure. Additionally, punch dynamics and technique characteristics are examined, emphasizing their pivotal role in achieving superior FUE outcomes. The chapter concludes by discussing the classification of punches and graft evaluation terms, offering insights into the tools, and criteria used to assess graft quality and viability.

Navigating fungal infections and antifungal stewardship: drug resistance, susceptibility testing, therapeutic drug monitoring and future directions.

Antifungal stewardship refers to the rational use of antifungal agents. Historically, in some instances, the misuse or overuse of antifungal agents has predisposed patients to an elevated risk of systemic side-effects and treatment resistance, as well as increased healthcare costs. Superficial mycoses, such as onychomycosis, are sometimes treated without any diagnostic testing and is associated with a high likelihood of self-diagnosis and self-treatment, potentially leading to the emergence of resistance against commonly used antifungals like terbinafine. Practitioners need to ensure that a proper clinical diagnosis is backed up by appropriate testing. This may include the traditional light microscopy and culture; additionally, molecular techniques (such as polymerase chain reaction, terbinafine gene mutational analysis) and antifungal susceptibility testing are considerations as appropriate. The choice of antifungal agent should be guided by what is the standard of care in the location where the clinician practices as well as more broadly state and national prescription patterns. Recently, reports of treatment resistance concerning both superficial and deep fungal infections have added another layer of difficulty to clinical practice. This review aims to explore the phenomenon of antifungal drug resistance, and highlights the importance of adopting antifungal stewardship programs. We provide an overview of treatment resistance and mechanisms of resistance reported thus far in dermatophytes. Challenges of performing antifungal susceptibility testing and therapeutic drug monitoring are discussed, as well as principles, recommendations and future directions of antifungal stewardship programs.

Relative Effects of Minoxidil 5%, Platelet-Rich Plasma, and Microneedling in Pattern Hair Loss: A Systematic Review and Network Meta-Analysis.

Background: Combination treatments may improve the utility of approved agents for the treatment of pattern hair loss (PHL); however, head-to-head comparisons are lacking. Objective: The aim of the study was to compare the efficacy of 5% minoxidil, platelet-rich plasma (PRP), and microneedling across adults with PHL insofar as change in total hair density at 24 weeks. Methods: We conducted a literature search in July 2022. Through our Bayesian network meta-analysis, we estimated treatments' surface under the cumulative ranking distribution (SUCRA) values and relative effects - in terms of mean difference (MD). Results: Data from 27 trials, totaling 1,110 patients, were extracted. Interventions were ranked based on the probability of inducing hair density improvements: 5% minoxidil plus microneedling (SUCRA = 95.8%), 5% minoxidil plus PRP (SUCRA = 64.7%), 5% minoxidil (SUCRA = 53.9%), PRP (SUCRA = 34.9%), microneedling (SUCRA = 27.8%), and PRP with microneedling (SUCRA = 22.9%). The efficacy of 5% minoxidil plus microneedling in improving total hair density was significantly greater (p < 0.05) than 5% minoxidil monotherapy (MD = 13 hairs/cm2), PRP monotherapy (MD = 16 hairs/cm2), and microneedling monotherapy (MD = 17 hairs/cm2). Conclusion: Five percent minoxidil plus microneedling is an effective treatment option for improving hair density at 6 months in adult PHL patients.

Utility of devices for onychomycosis: a review.

Onychomycosis is difficult to treat due to long treatment durations, poor efficacy rates of treatments, high relapse rates, and safety issues when using systemic antifungal agents. Device-based treatments are targeted to specific regions of the nail, have favorable safely profiles, and do not interfere with systemic agents. They may be an effective alternative therapy for onychomycosis especially with increasing reports of squalene epoxidase gene mutations and potential resistance to terbinafine therapy. In this review, we discuss four devices used as antifungal treatments and three devices used as penetration enhancers for topical agents. Lasers, photodynamic therapy, microwaves, and non-thermal plasma have the capacity to inactivate fungal pathogens demonstrated through in vivo studies. Efficacy rates for these devices, however, remain relatively low pointing toward the need to further optimize device or usage parameters. Ultrasound, nail drilling, and iontophoresis aid in improving the permeability of topical agents through the nail and have been investigated as adjunctive therapies. Due to the paucity in clinical data, their efficacy in treating onychomycosis has not yet been established. While the results of clinical studies point toward the potential utility of devices for onychomycosis, further large-scale randomized clinical trials following regulatory guidelines are required to confirm current results.

Systematic review of mesotherapy: a novel avenue for the treatment of hair loss.

Mesotherapy is a technique by which lower doses of therapeutic agents and bioactive substances are administered by intradermal injections to the skin. Through intradermal injections, mesotherapy can increase the residence time of therapeutic agents in the affected area, thus allowing for the use of lower doses and longer intervals between sessions which may in turn improve the treatment outcome and patient compliance. This systematic review aims to summarize the current literature that evaluates the efficacy of this technique for the treatment of hair loss and provides an overview of the results observed. Of the 416 records identified, 27 articles met the inclusion criteria. To date, mesotherapy using 6 classes of agents and their combinations have been studied; this includes dutasteride, minoxidil, growth factors or autologous suspension, botulinum toxin A, stem cells, and mesh solutions/multivitamins. While several studies report statistically significant improvements in hair growth after treatment, there is currently a lack of standardized regimens. The emergence of adverse effects after mesotherapy has been reported. Further large-scale and controlled clinical trials are warranted to evaluate the utility of mesotherapy for hair loss disorders.

Antifungal Resistance, Susceptibility Testing and Treatment of Recalcitrant Dermatophytosis Caused by Trichophyton indotineae: A North American Perspective on Management.

There is an ongoing epidemic of chronic, relapsing dermatophytoses caused by Trichophyton indotineae that are unresponsive to one or multiple antifungal agents. Although this new species may have originated from the Indian subcontinent, there has been a notable increase of its reporting in other countries. Based on current literature, antifungal susceptibility testing (AFST) showed a large variation of terbinafine minimum inhibitory concentrations (MICs) (0.04 to ≥ 32 µg/ml). Elevated terbinafine MICs can be attributed to mutations in the squalene epoxidase gene (single mutations: Leu393Phe, Leu393Ser, Phe397Leu, and double mutations: Leu393Phe/Ala448Thr, Phe397Leu/Ala448Thr). Itraconazole MICs had a lower range when compared with that of terbinafine (0.008-16 µg/ml, with most MICs falling between 0.008 µg/ml and < 1 µg/ml). The interpretation of AFST results remains challenging due to protocol variations and a lack of established breakpoints. Adoption of molecular methods for resistance detection, coupled with AFST, may provide a better evaluation of the in vitro resistance status of T. indotineae. There is limited information on treatment options for patients with confirmed T. indotineae infections by molecular diagnosis; preliminary evidence generated from case reports and case series points to itraconazole as an effective treatment modality, while terbinafine and griseofulvin are generally not effective. For physicians working outside of endemic regions, there is currently an unmet need for standardized clinical trials to establish treatment guidelines; in particular, combination therapy of oral and topical agents (e.g., itraconazole and ciclopirox), as well as with other azoles (i.e., fluconazole, voriconazole, ketoconazole), warrants further investigation as multidrug resistance is a possibility for T. indotineae.

Detection of Squalene Epoxidase Mutations in United States Patients with Onychomycosis: Implications for Management.

Resistance to oral terbinafine, the most commonly used antifungal to treat dermatophytosis and onychomycosis worldwide, is being increasingly reported. In this study, we aimed to investigate the species distribution and prevalence of squalene epoxidase mutations among toenail dermatophyte isolates. Samples from 15,683 patients suspected of onychomycosis visiting the offices of dermatologists and podiatrists in the United States were analyzed. Clinical information was reviewed, and dermatophyte species with or without squalene epoxidase mutations were detected using multiplex real-time PCRs. The frequency of dermatophytes was 37.6%; of isolates belonging to the Trichophyton genus, 88.3% were the T. rubrum complex, and 11.2% were the T. mentagrophytes complex. Individuals aged >70 years exhibited higher infection rates for the T. mentagrophytes complex. The overall mutation rate among Trichophyton spp. was 3.7%, with a higher mutation rate detected in the T. mentagrophytes complex (4.3 vs. 3.6%). Commonly detected mutations were T1189C/Phe397Leu (34.5%), T1306C/Phe415Ser (16.0%), and C1191A/Phe397Leu (11.0%). Squalene epoxidase gene mutations associated with decreased terbinafine susceptibility have been identified in United States patients with toenail onychomycosis. Physicians should be aware of the risk factors for resistance development and engage in antifungal stewardship practices such as directed diagnosis and treatment of dermatophytosis and onychomycosis.

Factors Associated With Musculoskeletal Pain Among Hair Transplant Surgeons: Analyses of Survey Data and Review of the Literature.

BACKGROUND: The prevalence of work-related musculoskeletal disorders (WRMD) is increasing among all surgical specialties. OBJECTIVE: Results of a cross-sectional survey of hair transplant surgeons were analyzed, with the aims to (1) determine the prevalence of WRMD, (2) assess risk factors associated with musculoskeletal (MSK) symptoms, and (3) identify mitigation measures. MATERIALS AND METHODS: A survey pertaining to demographics, MSK-related symptoms and its impacts, and pain mitigation measures taken, if any, were distributed to 834 hair transplant surgeons. Risk factors associated with pain severity were assessed using linear regression. RESULTS: Overall, 78.5% (73 of 93) respondents had experienced pain when performing surgery. Musculoskeletal symptoms were most severe in the neck, followed by upper/lower back, and extremities. Number of grafts performed per session of follicular unit extraction positively correlated with pain severity; female surgeons and surgeons aged >71 years were at higher risk. A majority expressed concern that WRMD may limit their career and agreed to a need for improved workplace education. Strength training and ergonomic improvements of surgical procedure were not commonly adopted. CONCLUSION: In sum, WRMD can be debilitating in health care professionals. Workplace ergonomic adjustments and physical exercise programs may be warranted to better mitigate MSK symptoms.

Alopecia areata and pattern hair loss (androgenetic alopecia) on social media - Current public interest trends and cross-sectional analysis of YouTube and TikTok contents.

BACKGROUND: With an ever-growing influence of social media in healthcare, concurrent with increased emphasis on patient autonomy and shared decision-making, dermatologists treating hair loss need to be cognizant of online interest trends and the types of information disseminated across popular platforms. OBJECTIVES: To evaluate recent health-related interest trends and assess engagement, quality, and accuracy of alopecia areata (AA) and pattern hair loss (PHL, androgenetic alopecia) contents on social media. METHODS: Relative search volumes (RSVs) were extracted from Google Trends using the search category 'alopecia areata' and 'pattern hair loss'. Eighty matching videos on TikTok and YouTube were also extracted and characterized. Viewer engagement was estimated using the engagement ratio, and quality and accuracy were assessed using DISCERN and Dy et al. Accuracy Scale (DAS). CONCLUSIONS: AA-related contents on TikTok discussing personal experiences of female subjects were significantly more engaging. DISCERN and DAS scoring showed significantly higher quality and accuracy in videos created by healthcare providers on YouTube, but not TikTok, which could in part be related to YouTube videos being longer. RSV fluctuations corresponding to news in popular culture had high impact. Sponsorship disclosures were generally not reported in product promotional videos.

Systematic review of newer agents for the management of alopecia areata in adults: Janus kinase inhibitors, biologics and phosphodiesterase-4 inhibitors.

Management options for moderate-to-severe alopecia areata (AA) are limited owing to a lack of safe and effective treatments suitable for long-term use. However, newer agents have the potential to induce and maintain hair regrowth in patients with a better side-effects profile compared to systemic steroids or conventional systemic agents. In this article, we conducted a systematic review of newer agents, including Janus kinase (JAK) inhibitors, biologics and phosphodiesterase-4 (PDE-4) inhibitors, for the treatment of AA in adult patients evaluated in randomized controlled trials (RCTs) using the Severity of Alopecia Tool score. A literature search was performed on PubMed and ClinicalTrials.gov, which identified 106 items with 12 RCTs eligible for review. Information regarding the treatment regimen, duration, endpoints, efficacy and adverse events were extracted; product monograph information was also summarized for approved agents with or without indications for AA. Overall, current data suggest the oral JAK inhibitors (baricitinib, ritlecitinib, deuruxolitinib, brepocitinib) as a promising new class of agents that can induce significant hair regrowth, with mild to moderate adverse effects. Baricitinib recently received US FDA approval for the treatment of severe AA, while ritlecitinib and deuruxolitinib have received the breakthrough therapy designation for AA. In contrast, PDE-4 inhibitors (apremilast) and the biologics (dupilumab, secukinumab and aldesleukin) appear to have limited efficacy thus far. Results from ongoing and future long-term studies could shed light on the utility of the newer agents in altering the progression of AA.

Strategies for the enhancement of nail plate permeation of drugs to treat onychomycosis.

Onychomycosis is caused by dermatophytes, non-dermatophytes and yeasts. It has a global prevalence of 5.5%, requires long treatment periods, and has high relapse rates following therapy. Oral antifungals are generally the most common treatment. While effective, they have limitations such as drug-drug interactions, hepatotoxicity and adverse side effects; thus, they cannot be used in several populations. Topical antifungals do not have the safety limitations but are typically not as effective. The primary challenge of topical treatment is the permeation of drug molecules across the nail plate barrier, which is a highly cross-linked keratin network. The use of drugs and formulations with favourable characteristics such as small size, absence of lipophilicity, hydrophilic nature, hydrating properties and appropriate pH can greatly improve permeation. Here, we review physical, nanoparticle-based, formulation-based, mechanical and chemical drug delivery strategies to improve the permeation of drugs across the nail plate.

Biomaterials, biological molecules, and polymers in developing vaccines.

Vaccines have been used to train the immune system to recognize pathogens, and prevent and treat diseases, such as cancer, for decades. However, there are continuing challenges in their manufacturing, large-scale production, and storage. Some of them also show suboptimal immunogenicity, requiring additional adjuvants and booster doses. As an alternate vaccination strategy, a new class of biomimetic materials with unique functionalities has emerged in recent years. Here, we explore the current bioengineering techniques that make use of hydrogels, modified polymers, cell membranes, self-assembled proteins, virus-like particles (VLPs), and nucleic acids to deliver and develop biomaterial-based vaccines. We also review design principles and key regulatory issues associated with their development. Finally, we critically assess their limitations, explore approaches to overcome these limitations, and discuss potential future applications for clinical translation.