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.

Comparison of dermoscopic characteristics on toenail onychomycosis in psoriatic and non-psoriatic patients: A prospective study.

BACKGROUND: Psoriatic patients may experience the coexistence of onychomycosis (OM). However, the evaluation of OM in psoriatics has been hindered by potential clinical differences from OM in non-psoriatics. OBJECTIVE: To assess and compare dermoscopic features between toenail OM in psoriatic and in non-psoriatic patients. PATIENTS AND METHODS: Between September 2020 and September 2023, dermoscopy was conducted on 183 affected toenails by OM in psoriatics and 232 affected toenails by OM in non-psoriatics in two centres. The dermoscopic characteristics were compared using the Chi-squared test. RESULTS: Among toenail OM cases in psoriatic subjects, the most prevalent dermoscopic features included pitting (147/183, 80.33%) and subungual hyperkeratosis (118/183, 64.48%). Conversely, toenail OM in non-psoriatics was characterized by subungual hyperkeratosis (175/232, 75.43%) and nail spikes (139/232, 59.91%). Comparative analysis revealed a significantly higher occurrence of pitting (80.33% vs. 15.96%, p < .001), periungual telangiectasis (22.40% vs. 4.74%, p < .001), oil patches (12.57% vs. 0.43%,p < .001) and transverse grooves (43.72% vs. 28.45%,p < .01) in toenail OM in psoriatics. Furthermore, toenail OM in psoriatics exhibited a significantly lower frequency of yellow structureless area (13.11% vs. 42.67%, p < .001), nail spikes (43.17% vs. 59.91%, p < .01), ruin appearance of sulphur nugget (8.20% vs. 31.03%, p < .001), dotted/blocky haemorrhage (6.01% vs. 20.69%,p < .001) and partial onycholysis (32.79% vs. 46.98%, p < .01). CONCLUSIONS: Dermoscopic features of toenail OM in psoriatic and non-psoriatic patients exhibit notable differences. OM in psoriatics shows a higher frequency of pitting and periungual telangiectasis, while a lower frequency of yellow structureless areas and nail spikes under dermoscopy.

Validation of the Onychomycosis Severity Index in a Brazilian population.

Onychomycosis is the most frequent nail disorder, but unfortunately, curative treatment is still a challenge, and commonly the infection recurs. A widely disseminated system to accurately assess and classify the severity of this disease, such as the MASI score for melasma or PASI for psoriasis, is lacking in the literature. In 2011, Carney et al. established and successfully validated the Onychomycosis Severity Index (OSI), proving it to be a simple and reproducible tool. To validate the Onychomycosis Severity Index in a Brazilian population. Four experienced dermatologists were taught how to use the OSI system, and then evaluated photographs of 24 nails. There was no consultation between the dermatologists, and the results were evaluated by an impartial third party. A statistically significant (p<0.001) high degree of agreement was observed between the evaluators and overall OSI score (mild, moderate or severe) as well as its subcategories (area of involvement, proximity to the nail matrix and presence of dermatophytoma or hyperkeratosis). OSI is a very useful tool to improve the clinical assessment of onychomycosis and support clinical trial inclusion criteria (p<0.001). It also provides important prognostic data and allows for a better follow-up of treatment efficacy.

Activity of amorolfine or ciclopirox in combination with terbinafine against pathogenic fungi in onychomycosis-Results of an in vitro investigation.

BACKGROUND: Onychomycoses are difficult-to-treat fungal infections with high relapse rates. Combining oral and topical antifungal drugs is associated with higher success rates. Additive or synergistic modes of action are expected to enhance treatment success rates. OBJECTIVES: Investigation of the combined effects of antifungal drugs in vitro with different modes of action and application on clinical isolates from mycotic nails. METHODS: Isolates of Trichophyton rubrum, Trichophyton interdigitale and Scopulariopsis brevicaulis were collected from infected toenail specimens of patients with onychomycosis. Susceptibility testing was performed in 96-well polystyrene plates using a standard stepwise microdilution protocol. Additive or synergistic activity at varying concentrations was investigated by the checkerboard method. RESULTS: Combining terbinafine with amorolfine tended to be more effective than terbinafine in conjunction with ciclopirox. In most combinations, additive effects were observed. Synergy was detected in combinations with involving amorolfine in S. brevicaulis. These additive and synergistic interactions indicate that combined therapy with topical amorolfine and oral terbinafine is justified. Sublimation of amorolfine (and terbinafine) may enhance the penetration in and through the nail plate, and support treatment efficacy. CONCLUSIONS: These in vitro results support the notion that combining oral terbinafine and topical amorolfine is beneficial to patients with onychomycosis, particularly if the pathogen is a non-dermatophyte fungus such as S. brevicaulis.

Safety assessment for nail cosmetics: Framework for the estimation of systemic exposure through the nail plate.

All cosmetics products, including nail care products, must be evaluated for their safety. The assessment of systemic exposure is a key component of the safety assessment. However, data on the exposure, especially via ungual route (nail plate) are limited. Based on the physicochemical properties of human nails and permeability data of topical onychomycosis drugs, the nail plate is considered a good barrier to chemicals. We examine factors impacting penetration of nail care ingredients through the nail plate, including properties of the nails of the ingredients and formulations. The molecular weight, vapor pressure, logP, water solubility, and keratin binding, as well as formulations properties e.g., polymerization of acrylate monomers are considered important factors affecting penetration. To estimate systemic exposure of nail care ingredients through the nail plate, a standardized framework is applied that quantifies the impacts of these properties on penetration with an adjustment factor for each of these influencing properties. All the adjustment factors are then consolidated to derive an integrated adjustment factor which can be used for calculation of the systemic exposure dose for the ingredient. Several case studies are presented to reflect how this framework can be used in the exposure assessment for nail cosmetic products.

Number of Affected Nails Is the Primary Determinant of Efinaconazole 10% Solution Usage for Onychomycosis.

Good adherence to treatment is necessary for the successful treatment of onychomycosis and requires that an appropriate amount of medication be prescribed. Most prescriptions for efinaconazole 10% solution, a topical azole antifungal, are for 4 mL per month but there are no data on patient factors or disease characteristics that impact how much medication is needed. Data from two phase 3 studies of efinaconazole 10% solution for the treatment of toenail onychomycosis were pooled and analyzed to determine monthly medication usage based on the number of affected toenails, percent involvement of the target toenail, body mass index (BMI), and sex. Participants with two or more affected nails required, on average, >4 mL of efinaconazole per month, with increasing amounts needed based on the number of nails with onychomycosis (mean: 4.39 mL for 2 nails; 6.36 mL for 6 nails). In contrast, usage was not greatly impacted by target toenail involvement, BMI, or sex. Together, these data indicate that the number of affected nails should be the major consideration when determining the monthly efinaconazole quantity to prescribe. J Drugs Dermatol. 2024;23(2):110-112.    doi:10.36849/JDD.7676.

In vitro determination of the combination of ciclopirox and terbinafine in the treatment of dermatophytosis.

INTRODUCTION: The cases of dermatophytosis are increasing and they are associated with a higher number of therapeutic failures leading the doctor to prescribe combinations of antifungals as therapy. The objective was to evaluate the interaction of terbinafine and ciclopirox, the most commonly antifungals used in the clinic, in dermatophyte isolates. METHODOLOGY: The minimum inhibitory concentrations (MIC) of ciclopirox and terbinafine were determined by the broth microdilution method according CLSI and the checkerboard assay was used to evaluate the interaction between the antifungal agents. RESULTS: For terbinafine the mic50 was 0.125 ug/mL and mic90 was 0.250 ug/mL. For ciclopirox the values were 2.0 ug/mL for mic50 and 4.0 ug/mL for mic90. No synergistic interaction was observed for the dermatophyte isolates tested. CONCLUSION: These results suggest that the use of terbinafine in combination with ciclopirox, which is widely used in the clinic, may not be a good choice for the treatment of onychomycosis.

[Trichophyton mentagrophytes genotype VII increasingly causes anogenital infections]. / Trichophyton mentagrophytes Genotyp VII als zunehmender Auslöser anogenitaler Infektionen.

In the course of globalization, migration and global warming, we are increasingly confronted with pathogens that do not occur naturally in our latitudes or appear in a different form. We know keratinophilic dermatophytes as the cause of tinea pedis, onychomycosis and also tinea corporis and capitis. Transmission usually occurs via domestic or farm animals and via autoinoculation. In recent years dermatophytes have gained additional importance as a possible sexually transmitted disease between immunocompetent persons. For the first time, dermatophytosis was described as a sexually transmitted infection in travelers who developed pronounced pubogenital or anogenital tinea after travelling in Southeast Asia, including Thailand, mostly after intensive sexual contact. Molecular and cultural analyses have identified Trichophyton (T.) mentagrophytes ITS (internal transcribed spacer) genotype VII as the main pathogen. Although this dermatophyte genotypically belongs to the zoophilic complex, direct (sexual) and occasionally indirect human-to-human contact with infected persons is suspected to be the current route of transmission. The infection can lead to inflammatory and purulent dermatophytosis, causing a high level of suffering. In this respect, a rapid and reliable diagnosis is essential in order to be able to initiate targeted treatment. The discovery of infection pathways and the awareness of the need to take rare diseases into account in our everyday lives will increasingly accompany us over the next few years and present us with new challenges, particularly in terms of prevention and treatment.

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.

Line-field confocal optical coherence tomography, a novel non-invasive tool for the diagnosis of onychomycosis.

BACKGROUND AND OBJECTIVES: Onychomycosis is common and important to distinguish from other nail diseases. Rapid and accurate diagnosis is necessary for optimal patient treatment and outcome. Non-invasive diagnostic tools have increasing potential for nail diseases including onychomycosis. This study evaluated line-field confocal optical coherence tomography (LC-OCT) as a rapid non-invasive tool for diagnosing onychomycosis as compared to confocal laser scanning microscopy (CLSM), optical coherence tomography (OCT), and conventional methods. PATIENTS AND METHODS: In this prospective study 86 patients with clinically suspected onychomycosis and 14 controls were examined using LC-OCT, OCT, and CLSM. KOH-preparation, fungal culture, PCR, and histopathology were used as comparative conventional methods. RESULTS: LC-OCT had the highest sensitivity and negative predictive value of all methods used, closely followed by PCR and OCT. Specificity and positive predictive value of LC-OCT were as high as with CLSM, while OCT scored much lower. The gold standard technique, fungal culture, showed the lowest sensitivity and negative predictive value. Only PCR and culture allowed species differentiation. CONCLUSIONS: LC-OCT enables quick and non-invasive detection of onychomycosis, with advantages over CLSM and OCT, and similar diagnostic accuracy to PCR but lacking species differentiation. For accurate nail examination, LC-OCT requires well-trained and experienced operators.

Expression Profiles of Protease in Onychomycosis-Related Pathogenic Trichophyton rubrum and Tinea Capitis-Related Pathogenic Trichophyton violaceum.

The two fungal species Trichophyton rubrum and Trichophyton violaceum are common pathogens on human, infecting keratinized tissue of the outer body parts. Both species are belonging to the "Trichophyton rubrum complex" and share very high similarity in the genome. Secreted proteinases, key factors for keratin degradation, are nearly identical. Contrary, the ecological niches are differing. Trichophyton rubrum preferably infects skin and nails, whereas T. violaceum preferably infects the scalp. We postulate, that differences in the protease expression contribute to differences in ecological preferences. We analyzed the expression profiles of all 22 endoprotease genes, 12 subtilisins (S8A), 5 deuterolysins (M35) and 5 fungalysins (M36), for both species. To compare the influence of the keratin source, we designed experiments with human nail keratin, sheep wool keratin and keratin free cultivation media. Samples were taken at 12 h, 24 h, 48 h and 96 h post incubation in keratin medium. The expression of the proteases is higher in wool-keratin medium compared to human nail medium, with the exception of MEP4 and SUB6. Expression in the keratin-free medium is lowest. The expression profiles of the two species are remarkable different. The expression of MEP1, MEP3, SUB5, SUB11 and SUB12 are higher in T. rubrum compared to T. violaceum. MEP2, NpIIc, NpIIe, SUB1, SUB3, SUB4, SUB7 and SUB8 are higher expressed in T. violaceum compared to T. rubrum. The differences of the protease expression in the two species may expalin the differences in the ecological niches. Further analysis are necessary to verify the hypothesis.Please check and conform the edit made in title.Here I thinke the species of strains shouldnt be capital， and the right expression should be,  "Expression Profiles of Protease in Onychomycosis-Related Pathogenic Trichophyton rubrum and Tinea Capitis-Related Pathogenic Trichophyton violaceum"Author names: Please confirm if the author names are presented accurately and in the correct se-quence (given name, middle name/initial, family name). Author 1 Given name: [Jingjing] Last name [Chen], Author 2 Given name: [Yangmin] Last name [Gao], Author 3 Given name: [Shuzhen] Last name [Xiong], Author 4 Given name: [Ping] Last name [Zhan]. Also, kindly confirm the details in the metadata are correct.YesPlease check and confirm the inserted city and country are correctly identified for affiliation 3.Please change the affiliations, Affiliation 2: ²Jiangxi Provincial Clinical Research Center for Skin Diseases, Dermatology Hospital of Jiangxi Province,The Affiliated Dermatology Hospital of Nanchang University, Nanchang, 330200, Jiangxi; Affiliation 3: 3Institute of Clinical Medicine, Jiangxi Provincial People's Hospital, The First Affiliated Hospital of Nanchang Medical College,Nanchang 330001, Jiangxi. Thanks a lot!

Development of microemulgel formulations with varied permeation enhancers for transungual delivery of luliconazole in onychomycosis management.

Luliconazole-loaded microemulgels containing different permeation enhancers were formulated for transungual drug delivery for the management of onychomycosis, onychomycosis, which affects nails. The physicochemical properties like droplet size, zeta potential, pH, viscosity, spreadability, extrudability, oil binding capacity, drug content, and microscopic study were evaluated. The Pseudo-ternary phase diagram was constructed for the formulation of microemulsions (MEs) by keeping the Km ratio constant at 3:1 and characterized for clarity, mean droplet size, zeta potential, viscosity, pH, transmittance, refractive index, and stability. The ME mean droplet size and zeta potential were found in the range of 38.78 to 171.4 nm, and 0.00 to - 6.6 mV, respectively. Prepared MEs were converted into microemulgel by adding a 2.5% gelling agent (Carbapol 934) in the external phase, and a drug release study was conducted. Formulation E3 showed better drug release and was chosen as the control. Four different penetration enhancers were added separately within E3 and further evaluated for pH, viscosity, spreadability, extrudability, oil binding capacity, drug content, microscopic study, Compatibility study, XRD, and DSC. A favorable docking score was observed between luliconazole and Lanosterol 14-alpha-demethylase. In-vitro cumulative drug release at the end of 24 h from E3-SS, containing sodium sulfide as a penetration enhancer, was found to be 94.70% and was 2 times more than the control formulation. Ex-vivo transungual permeation studies through cutting nail clippings were found to be in the range of 28.18 - 36.52 µg/mm2. The microemulgels tagged as E3, E3-SS, and E3-SL showed a significant zone of inhibition against Candida albicans and Aspergillus fumigatus as compared to the marketed formulation.

Efficacy of topical trichloroacetic acid 100% either alone or combined with topical tioconazole 28% versus systemic itraconazole in the treatment of onychomycosis.

BACKGROUND: Treatment of onychomycosis is still challenging and warrants the development of new treatment strategies. Different trials were conducted to increase the penetration and efficacy of topical antifungals aiming at finding an alternative treatment especially when systemic antifungals are contraindicated. OBJECTIVES: To evaluate the efficacy of trichloroacetic acid (TCA) 100% either alone or combined with topical tioconazole 28% versus itraconazole pulse therapy in the treatment of onychomycosis. PATIENTS/METHODS: Forty-five patients with onychomycosis were divided into three groups: group (A) treated by topical TCA 100% for 12 sessions, group (B) treated by TCA 100% for 12 sessions combined with topical tioconazole 28% for 18 weeks and group (C) treated by itraconazole (400 mg/day for 1 week/month for 4 months). RESULTS: TCA 100% combined with topical tioconazole 28% showed the highest therapeutic response; however, the difference between the groups was statistically insignificant. Mycological cure (negative culture) was reported in 66.7% of group B versus 60% of group A and 40% of group C at the 20 week. CONCLUSIONS: TCA 100% is an effective and safe treatment option for onychomycosis especially when combined with antifungals. This modality is promising in the treatment of onychomycosis especially with the increased resistance to different antifungals.

Inter-observer reliability of the Onychomycosis Severity Index depending on clinical experience: A review of 50 cases.

BACKGROUND: Onychomycosis (ONM) is the most prevalent nail unit pathology, and its severity and monitoring are often based on the visual judgement of clinicians. OBJECTIVE: The objective of this study is to assess the reliability of the Onychomycosis Severity Index (OSI) classification when utilized by three clinicians with varying levels of clinical experience: an experienced podiatrist (with 5 years of experience), a moderately experienced podiatrist (with 2 years of experience) and an inexperienced podiatrist (a recent graduate familiar with the OSI classification but lacking clinical experience). Additionally, we compared the severity assessments made through visual inspection with those determined using the OSI by different clinicians. METHODS: We evaluated reliability using the intraclass correlation index (ICC), analysing 50 images of ONM. RESULTS: The OSI demonstrated a very high level of reliability (ICC: 0.889) across clinicians, irrespective of their experience levels. Conversely, a statistically significant increase in severity was observed when comparing visual assessments with the OSI (p < .001) for ONM severity evaluation. CONCLUSION: The OSI proves to be a reproducible classification system, regardless of the clinical experience of the practitioner employing it.

Treatment of onychomycosis in an era of antifungal resistance: Role for antifungal stewardship and topical antifungal agents.

A growing body of literature has marked the emergence and spread of antifungal resistance among species of Trichophyton, the most prevalent cause of toenail and fingernail onychomycosis in the United States and Europe. We review published data on rates of oral antifungal resistance among Trichophyton species; causes of antifungal resistance and methods to counteract it; and in vitro data on the role of topical antifungals in the treatment of onychomycosis. Antifungal resistance among species of Trichophyton against terbinafine and itraconazole-the two most common oral treatments for onychomycosis and other superficial fungal infections caused by dermatophytes-has been detected around the globe. Fungal adaptations, patient characteristics (e.g., immunocompromised status; drug-drug interactions), and empirical diagnostic and treatment patterns may contribute to reduced antifungal efficacy and the development of antifungal resistance. Antifungal stewardship efforts aim to ensure proper antifungal use to limit antifungal resistance and improve clinical outcomes. In the treatment of onychomycosis, critical aspects of antifungal stewardship include proper identification of the fungal infection prior to initiation of treatment and improvements in physician and patient education. Topical ciclopirox, efinaconazole and tavaborole, delivered either alone or in combination with oral antifungals, have demonstrated efficacy in vitro against susceptible and/or resistant isolates of Trichophyton species, with low potential for development of antifungal resistance. Additional real-world long-term data are needed to monitor global rates of antifungal resistance and assess the efficacy of oral and topical antifungals, alone or in combination, in counteracting antifungal resistance in the treatment of onychomycosis.