Safety and efficacy of new generation azole antifungals in the management of recalcitrant superficial fungal infections and onychomycosis.

INTRODUCTION: Terbinafine is considered the gold standard for treating skin fungal infections and onychomycosis. However, recent reports suggest that dermatophytes are developing resistance to terbinafine and the other traditional antifungal agents, itraconazole and fluconazole. When there is resistance to terbinafine, itraconazole or fluconazole, or when these agents cannot used, for example, due to potential drug interactions with the patient's current medications, clinicians may need to consider off-label use of new generation azoles, such as voriconazole, posaconazole, fosravuconazole, or oteseconazole. It is essential to emphasize that we do not advocate the use of newer generation azoles unless traditional agents such as terbinafine, itraconazole, or fluconazole have been thoroughly evaluated as first-line therapies. AREAS COVERED: This article reviews the clinical evidence, safety, dosage regimens, pharmacokinetics, and management algorithm of new-generation azole antifungals. EXPERT OPINION: Antifungal stewardship should be the top priority when prescribing new-generation azoles. First-line antifungal therapy is terbinafine and itraconazole. Fluconazole is a consideration but is generally less effective and its use may be off-label in many countries. For difficult-to-treat skin fungal infections and onychomycosis, that have failed terbinafine, itraconazole and fluconazole, we propose consideration of off-label voriconazole or posaconazole.

Patient-physician perception gaps in setting treatment goals and communication including shared decision making: Results from the survey illuminating dialogues and insights in onychomycosis management (IDIOM survey).

Onychomycosis, an infectious disease affecting the nails, can spread within oneself and to others, potentially leading to functional disabilities, therefore achieving a complete cure is necessary. Additionally, shared decision making (SDM) has been gaining attention in the treatment of various diseases in recent years. This study aimed to uncover the realities of patient-physician communication and perception in onychomycosis treatment, particularly in setting treatment goals and the SDM process for selecting therapeutic agents. We conducted a web-based survey of both patients and dermatologists to identify issues in the decision-making process for onychomycosis treatment. The survey revealed several communication challenges between patients and dermatologists regarding onychomycosis treatment. First, a notable percentage of dermatologists do not prioritize a complete cure for onychomycosis in their treatment goals. Second, the dermatologists' treatment explanations tended to emphasize risks, information necessary for appropriate decision-making was not adequately conveyed to patients, and SDM practice was insufficient (the mean scores of SDM-Q-9 and SDM-Q-Doc were 49.0 and 70.9, respectively). Third, dermatologists overestimated the reluctance of older patients to take oral medications. Dermatologists should recognize their patients' expectations for a complete cure for onychomycosis and choose a therapeutic agent that meets patients' needs. Furthermore, dermatologists should explain the benefits and risks of treatment options in a balanced manner, strive for improved patient-physician communication, and aim for a complete cure by administering suitable treatment.

Mendelian Randomization Analysis Supports Causal Effect of Type II Diabetes Mellitus on Onychomycosis.

Introduction: Onychomycosis is common among adults with diabetes mellitus (DM). We used two-sample Mendelian randomization to estimate the causal effect of genetic risk for DM on onychomycosis and tinea skin infections in the All of Us Research Program. Methods: Onychomycosis and tinea corporis, pedis, manus, and cruris cases were identified using electronic health record data, and genetic instrument variables and summary statistics were collected from a type II DM (T2DM) genome-wide association study (GWAS) meta-analysis. Results: Inverse variance weighted regression showed positive effect of T2DM genetic risk on onychomycosis (beta = 0.135, p = 1.86E-2), and weighted median regression produced a comparable estimate of effect size (beta = 0.148). There was no significant effect of T2DM on skin dermatophytosis. Conclusions: Our results suggest that T2DM has a positive causal effect on onychomycosis but not tinea skin infection risk. As onychomycosis may impair occupational function and increase risk for secondary soft tissue infections, patients with diabetes should be screened for onychomycosis and counseled on mitigating infection risk.

CO2 Laser-Assisted Nail Sampling for Mycological Testing in Onychomycosis.

Introduction: Onychomycosis is the most common nail infection, predominantly caused by Trichophyton spp., and is divided into four main types. Confirmatory testing is crucial, but obtaining an adequate sample may be challenging. We suggest the use of carbon dioxide (CO2) laser for painlessly detaching the nail plate during mycological examination and ensuring a sufficient specimen. Methods: We retrospectively enrolled 25 patients with distolateral onychomycosis, treated according to the following protocol: (1) multiple passes of CO2 laser at 10 W in continuous mode along the proximal border of the affected nail plate; (2) the nail plate was gently cut; (3) the nail bed was curetted; (4) subungual debris and plate fragments were collected for KOH test and culture. Results: The mean visual analog score (VAS) for pain experienced during the procedure was 0.7 (SD: 2.1), indicating that the sampling was relatively painless for the majority of patients. There were no permanent changes observed in the nail unit of any patients during the follow-up visits as a result of using the CO2 laser. Conclusion: We firmly believe that the use of lasers offers numerous advantages, including ease of use, reduced pain perception, and the ability to target the proximal margin of fungal infections where viable hyphae are significantly represented.

Efficacy of Laser Therapy in Comparison With Other Methods for the Treatment of Onychomycosis: A Systematic Review and Meta-Analysis.

Onychomycosis, a fungal infection of the nails, presents a significant challenge in clinical management due to its chronic nature and resistance to conventional therapies. This study aims to evaluate the efficacy of laser therapy in treating onychomycosis compared to traditional methods such as terbinafine. A systematic review and meta-analysis were conducted to analyze existing literature on the subject. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) diagram illustrates the selection process of studies. Findings suggest that laser therapy demonstrates promising results in the treatment of onychomycosis, with comparable efficacy to terbinafine and fewer adverse effects. Further large-scale randomized controlled trials are warranted to validate these findings and establish laser therapy as a standard treatment option for onychomycosis.

Onychomycosis in Foot and Toe Malformations.

Introduction: It has long been accepted that trauma is one of the most important and frequent predisposing factors for onychomycoses. However, the role of direct trauma in the pathogenesis of fungal nail infections has only recently been elucidated in a series of 32 cases of post-traumatic single-digit onychomycosis. The importance of repeated trauma due to foot and toe abnormalities was rarely investigated. Aimof the study: This is a multicenter single-author observational study over a period of 6 years performed at specialized nail clinics in three countries. All patient photographs taken by the author during this period were screened for toenail alterations, and all toe onychomycosis cases were checked for whether they contained enough information to evaluate potential foot and toe abnormalities. Particular attention was paid to the presence of hallux valgus, hallux valgus interphalangeus, hallux erectus, inward rotation of the big toe, and outward rotation of the little toe, as well as splay foot. Only cases with unequivocal proof of fungal nail infection by either histopathology, mycologic culture, or polymerase chain reaction (PCR) were accepted. Results: Of 1653 cases, 185 were onychomycoses, proven by mycologic culture, PCR, or histopathology. Of these, 179 involved at least one big toenail, and 6 affected one or more lesser toenails. Three patients consulted us for another toenail disease, and onychomycosis was diagnosed as a second disease. Eight patients had a pronounced tinea pedum. Relatively few patients had a normal big toe position (n = 9). Most of the cases had a mild to marked hallux valgus (HV) (105) and a hallux valgus interphalangeus (HVI) (143), while hallux erectus was observed in 43 patients, and the combination of HV and HVI was observed 83 times. Discussion: The very high percentage of foot and toe deformations was surprising. It may be hypothesized that this is not only a pathogenetically important factor but may also play an important role in the localization of the fungal infection, as no marked hallux deviation was noted in onychomycoses that affected the lesser toes only. As the management of onychomycoses is a complex procedure involving the exact diagnosis with a determination of the pathogenic fungus, the nail growth rate, the type of onychomycosis, its duration, and predisposing factors, anomalies of the toe position may be important. Among the most commonly mentioned predisposing factors are peripheral circulatory insufficiency, venous stasis, peripheral neuropathy, immune deficiency, and iatrogenic immunosuppression, whereas foot problems are not given enough attention. Unfortunately, many of these predisposing and aggravating factors are difficult to treat or correct. Generally, when explaining the treatment of onychomycoses to patients, the importance of these orthopedic alterations is not or only insufficiently discussed. In view of the problems encountered with the treatment of toenail mycoses, this attitude should be changed in order to make the patient understand why there is such a low cure rate despite excellent minimal inhibitory drug concentrations in the laboratory.

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.

Penetration Profiles of Four Topical Antifungals in Mycotic Human Toenails Quantified by Matrix-Assisted Laser Desorption Ionization-Fourier Transform Ion Cyclotron Resonance Imaging.

INTRODUCTION: Onychomycosis is a fungal infection of the nails that can be challenging to treat. Here, matrix-assisted laser desorption ionization-Fourier transform ion cyclotron resonance (MALDI-FTICR) imaging was applied to the quantitative analysis of the penetration profile of the antifungal compound, amorolfine, in human mycotic toenails. The amorolfine profile was compared with those of three other antifungals, ciclopirox, naftifine, and tioconazole. METHODS: Antifungal compounds (amorolfine 5% lacquer, ciclopirox 8% lacquer, naftifine 1% solution, and tioconazole 28% solution) were applied to mycotic nails (n = 42). Nail sections were prepared, and MALDI-FTICR analysis was performed on the sections at a spatial resolution of 70 µm to compare the distribution profiles. Based on the minimum inhibitory concentrations of the four test compounds needed to kill 90% (MIC90) of the fungal organism, Trichophyton rubrum, the fold differences between the MIC90 and the antifungal concentrations in the nails (termed the multiplicity of the MIC90) were calculated for each. RESULTS: The penetration profiles indicated higher concentrations of amorolfine and ciclopirox in the deeper layers of the nails 3 h after treatment, compared with naftifine and tioconazole. The mean concentrations across the entire nail sections at 3 h were significantly different among the four antifungals: amorolfine, 2.46 mM; ciclopirox, 0.95 mM; naftifine, 0.63 mM; and tioconazole, 1.36 mM (p = 0.016; n = 8 per compound). The median multiplicity of the MIC90 at 3 h was 191-fold for amorolfine, tenfold for ciclopirox, 52-fold for naftifine, and 208-fold for tioconazole. CONCLUSION: In this study, MALDI-FTICR was successfully applied to the quantitative analysis of antifungal distribution in human mycotic nails. The findings suggest that amorolfine penetrates deeper layers of the nail and accumulates at concentrations far exceeding the MIC needed to exert antimycotic activity.

Penetration Profile of Terbinafine Compared to Amorolfine in Mycotic Human Toenails Quantified by Matrix-Assisted Laser Desorption Ionization-Fourier Transform Ion Cyclotron Resonance Imaging.

INTRODUCTION: Amorolfine 5% lacquer is an established topical treatment for fungal infection of the nails. The success of topical therapy for onychomycosis depends on whether the permeated drug concentration in the deep nail bed is retained above the effective antifungal minimum inhibitory concentration (MIC). We compared the penetration profile of amorolfine and a new topical formula of terbinafine in human mycotic toenails using matrix-assisted laser desorption ionization mass spectrometry imaging-Fourier transform ion cyclotron resonance (MALDI-FTICR) imaging. METHODS: Amorolfine 5% lacquer and terbinafine 7.8% lacquer were applied to mycotic nails (n = 17); nail sections were prepared, and MALDI-FTICR analysis was performed. Based on the MICs of amorolfine and terbinafine needed to kill 90% (MIC90) of Trichophyton rubrum, the fold differences between the MIC90 and the antifungal concentrations in the nails (the multiplicity of the MIC90) were calculated overall and for the keratin-unbound fractions. RESULTS: Both amorolfine and terbinafine penetrated the entire thickness of the nail. The mean concentration across the entire nail section 3 h following terbinafine treatment was 1414 µg/g of tissue (equivalent to 4.9 mM) compared with 780 µg/g (2.5 mM) following amorolfine treatment (not significantly different; p = 0.878). The median multiplicity of the MIC90 was significantly higher in amorolfine- than terbinafine-treated nails overall (191 vs. 48; p = 0.010) and for the keratin-unbound fractions only (7.4 vs. 0.8; p = 0.002). CONCLUSION: In this ex vivo study, MALDI-FTICR demonstrated that, although amorolfine 5% and terbinafine 7.8% had similar distribution profiles, both penetrating from the surface to the nail bed, the concentration of amorolfine in the nail was significantly higher than that of terbinafine relative to their respective MIC90 values. Clinical studies are required to determine whether these effects translate to a clinical difference in treatment success.

Long-term follow-up study of the efficacy of fosravuconazole in the treatment of onychomycosis in elderly patients.

Onychomycosis is a chronic and intractable disease whose prevalence increases during aging. In elderly patients, if onychomycosis is left untreated and progresses to a severe stage it may cause functional decline of the lower limbs due to foot pain. This could lead to a decline in activities of daily living and secondary impairment such as cognitive decline. Thus, the treatment of onychomycosis in elderly patients is important. We have previously shown that fosravuconazole is relatively safe and effective for onychomycosis in elderly patients. In the present study, we continued the follow-up study and investigated the efficacy of re-administration of fosravuconazole in patients with recurrent onychomycosis. One hundred and twenty-five patients aged ≥65 years who had been initially diagnosed with onychomycosis at our hospital's dermatology department, and who had responded well to fosravuconazole at 48 weeks after the initial treatment, were followed up until 144 weeks after the start of the initial treatment. Patients who experienced a recurrence within 24 weeks after the start of the follow-up were assigned to the short-term recurrence group, and those who experienced a recurrence after 24 weeks were assigned to the long-term recurrence group. All patients in both groups were re-treated with fosravuconazole to evaluate its efficacy. The short-term and long-term recurrence groups consisted of 17 (14.3%) and 10 (8.4%) patients, respectively. There were no significant differences in mean age and sex ratio between the two groups. There were no serious adverse effects in either group, and the toenail opacity ratio was significantly reduced after 12 weeks of re-treatment in both groups. The short-term and long-term recurrence groups were significantly more likely to have wedge-shaped onychomycosis and total dystrophic onychomycosis, respectively. The results suggest that re-administration of fosravuconazole is safe and as effective as the first administration for elderly patients with recurrent onychomycosis. This study was registered at UMIN-CTR (UMIN000053516).

Awareness of people using municipal swimming pools about the prevention, symptoms, and treatment of athlete's foot and onychomycosis before COVID-19.

Introduction: Superficial mycosis is one of the most common diseases worldwide; however, its epidemiology is changing over time. Aim: To present the awareness of people using swimming pools about athlete's foot and onychomycosis. Material and methods: A total of 690 participants were subjected to an extensive survey administered via Google Documents. The questionnaire consisted of 30 online polling items and aimed to evaluate respondents' knowledge pertaining to fungal infections, encompassing aspects such as prevention strategies, disease trajectory, and therapeutic modalities. The survey sample specifically encompassed students and sports enthusiasts associated with 33 Internet groups, and data collection transpired during the period spanning 12 January to 15 March, 2018, predating the advent of the COVID-19 pandemic. Results: In the study, 85.2% of participants regularly inspected their feet, with 4.8% seeking podiatric services. While 75.2% demonstrated hygienic behaviour by changing towels after each pool visit, 41.4% acknowledged sharing nail tools. Notably, 75.7% preferred professional assistance for symptoms, with 24.3% opting for home remedies. Gender disparities were evident, with women showing significantly better hygiene practices and pool usage than men (p < 0.001). Women also exhibited a stronger tendency to disinfect grooming tools and prioritise sterility during beautician services (p < 0.001). These findings emphasise the importance of gender-specific health behaviour analysis in promoting preventive measures. Conclusions: The study highlights onychomycosis as a significant societal concern. Pre-COVID-19, awareness among municipal swimming pool users regarding prevention, symptoms, and treatment of athlete's foot and onychomycosis was insufficient.

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.

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.

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.

Natural Treatment Options for Nail Disorders.

The growing demand for natural treatments has raised concerns among clinicians due to limited scientific evidence supporting their use. This review article addresses the issue by assisting dermatologists and general practitioners in recommending natural treatments for the following common nail disorders: nail brittleness, onychomycosis, periungual verrucae, paronychia, chloronychia, nail psoriasis, nail lichen planus, onychocryptosis, onycholysis, and congenital malalignment of the great toenail. One limitation is the scarcity of existing reviews on natural treatment options for nail disorders in the literature. Through a comprehensive review of existing literature, this article consolidates the available evidence on natural treatment options for these conditions. Although some natural treatments for nail disorders are supported by scientific evidence, the indiscriminate use of such remedies may lead to severe poisoning and health problems. Given the widespread and increasing use of natural treatments, clinicians play a pivotal role in educating patients about evidence-based remedies and debunking misleading claims. By doing so, clinicians can enhance patient safety and improve treatment outcomes. It is essential for healthcare professionals to be well-informed and equipped with the knowledge to differentiate between effective natural treatments and unverified claims, ensuring that patients receive appropriate care.

Prevalence and risk factors for onychomycosis in acute care dermatology wards.

We conducted a cross-sectional study on the clinical and mycological features of onychomycosis in patients in the dermatology ward of Iwate Medical University Hospital, an acute care hospital. Of the 226 hospitalized patients, 73 (32.3%) had onychomycosis and 61 (26.9%) were diagnosed after admission. The toenail was the most common site of onychomycosis (94.5%), while toenail plus fingernail and fingernail only sites were 4.1% and 1.4%, respectively. The most common clinical form of onychomycosis was distal and lateral subungual onychomycosis (79%) with Trichophyton rubrum (66.7%) and T. interdigitale (27.8%) as the main causative species. Patients who were older, or had neurological diseases, or needed stretcher transfer had onychomycosis significantly more frequently than those who were obese, had diabetes, cancer, needed an escort for moving, or could move independently. Our study suggests that there is likely to be a significant number of untreated and undiagnosed patients with onychomycosis in acute care hospitals. Therefore, it is necessary to increase awareness of onychomycosis in hospitals.