On the Basis of Sex: Impact and Treatment of Toenail Onychomycosis in Female Patients.

Onychomycosis is a fungal infection of the nail unit affecting approximately five percent of the global population and representing 50 percent of all nail dystrophies seen in clinical practice. Patients with onychomycosis can suffer significant pain in addition to physical and psychological distress, which may seriously impair their quality of life (QoL). It is well established that onychomycosis prevalence is impacted by patient characteristics, including age and systemic comorbidities. However, the impact of patient sex on onychomycosis occurrence and treatment is not well characterized. This narrative review of the literature was conducted to address a dearth of published information on epidemiology, QoL, clinical trial participation, and treatment success specifically in female patients with onychomycosis. Additionally, an analysis of real-world treatment of onychomycosis in female patients is reported, including prescription patterns and the impact of toenail polish on topical treatments for onychomycosis. Understanding sex as a clinically relevant variable may inform onychomycosis treatment strategies and improve treatment outcomes.

Design, Development, and Evaluation of Constant Voltage Iontophoresis for the Transungual Delivery of Efinaconazole.

The efficacy of topical antifungal therapy in onychomycosis has been hindered by the failure of the antimycotic to permeate the nail plate. This research aims to design and develop a transungual system for the effective delivery of efinaconazole utilizing constant voltage iontophoresis. Seven prototype drug-loaded hydrogel formulations (E1-E7) were prepared to assess the influence of solvent (ethanol) and cosolvent (Labrasol®) on transungual delivery. Optimization was performed to evaluate the effect of three independent variables; voltage, solvent-to-cosolvent ratio, and penetration enhancer (PEG 400) concentration on critical quality attributes (CQAs), such as drug permeation and loading into the nail. The selected hydrogel product was characterized for pharmaceutical properties, efinaconazole release from the nail, and antifungal activity. Preliminary data indicates ethanol, Labrasol®, and voltage influence the transungual delivery of efinaconazole. Optimization design indicates a significant impact by applied voltage (p-0.0001) and enhancer concentration (p-0.0004) on the CQAs. Excellent correlation between selected independent variables and CQAs was confirmed by the high desirability value (0.9427). A significant (p < 0.0001) enhancement in the permeation (~78.59 µg/cm2) and drug loading (3.24 µg/mg) was noticed in the optimized transungual delivery with 10.5 V. FTIR spectral data indicates no interaction between the drug and excipients, while the DSC thermograms confirmed the amorphous state of the drug in the formulation. Iontophoresis produces a drug depot in the nail that releases above the minimum inhibitory concentration level for an extended period, potentially reducing the need for frequent topical treatment. Antifungal studies further substantiate the release data and have shown remarkable inhibition of Trichophyton mentagrophyte. Overall, the promising results obtained here demonstrate the prospective of this non-invasive method for the effective transungual delivery of efinaconazole, which could improve the treatment of onychomycosis.

Antifungal Activity of Efinaconazole Compared to Fluconazole, Itraconazole, and Terbinafine against Terbinafine- and Itraconazole-Resistant and -Susceptible Clinical Isolates of Dermatophytes, Candida, and Mold.

BACKGROUND: Recently, an increasing number of resistant-to-terbinafine dermatophytosis cases have been reported. Thus, identifying an alternative antifungal agent that possesses a broad-spectrum activity, including against resistant strains, is needed. METHODS: In this study, we compared the antifungal activity of efinaconazole to fluconazole, itraconazole, and terbinafine against clinical isolates of dermatophyte, Candida, and molds using in vitro assays. The minimum inhibitory concentration (MIC) and minimum fungicidal concentration (MFC) of each antifungal was quantified and compared. Both susceptible and resistant clinical isolates of Trichophyton mentagrophytes (n=16), T. rubrum (n=43), T. tonsurans (n=18), T. violaceum (n=4), Candida albicans (n=55), C. auris (n=30), Fusarium sp., Scedosporium sp., and Scopulariopsis sp. (n=15 for each) were tested. RESULTS: Our data shows that efinaconazole was the most active antifungal, compared to the other agents tested, against dermatophytes with MIC50 and MIC90 (Concentration that inhibited 50% and 90% of strains tested, respectively) values of 0.002 and 0.03 µg/ml, respectively. Fluconazole, itraconazole and terbinafine showed MIC50 and MIC90 values of 1 and 8 µg/ml, 0.03 and 0.25 µg/ml, and 0.031 and 16 µg/ml, respectively. Against Candida isolates, efinaconazole MIC50 and MIC90 values were 0.016 and 0.25 µg/ml, respectively, whereas fluconazole, itraconazole and terbinafine had MIC50 and the MIC90 values of 1 and 16 µg/ml, 0.25 and 0.5 µg/ml, and 2 and 8 µg/ml, respectively. Against various mold species, efinaconazole MIC values ranged from 0.016 and 2 µg/ml, compared to 0.5 to greater than 64 µg/ml for the comparators. CONCLUSIONS: efinaconazole showed superior potent activity against a broad panel of susceptible and resistant dermatophyte, Candida, and mold isolates.

Drug Susceptibility Profiling of Prototheca Species Isolated from Cases of Human Protothecosis.

Prototheca are unicellular, achlorophyllous, yeast-like microalgae that occur in a wide range of natural habitats. At least five species have been implicated as the causative agents of opportunistic infections of men. Human protothecosis typically manifests as cutaneous, articular, or systemic disease. Treatment is largely empirical with poorly predictable and often unsuccessful outcomes. This is largely due to the frequently observed resistance of Prototheca species to conventional antimicrobial agents. This work is the first to perform drug susceptibility profiling exclusively on isolates from human cases of protothecosis. A total of 23 such isolates were tested against amphotericin B and 9 azoles, including efinaconazole and luliconazole, whose activities against Prototheca have never been studied before. Efinaconazole was the most active, with median minimum inhibitory concentration (MIC) and minimum algicidal concentration (MAC) values of 0.031 mg/L and 0.063 mg/L, respectively. Fluconazole and luliconazole had the lowest activity, with median MIC and MAC values of 128 mg/L. To conclude, amphotericin B and most of the azoles showed in vitro activity, with an algicidal rather than algistatic effect, against Prototheca. Still, the activity of individual drugs differed significantly between the species and even between strains of the same species. These differences can be attributed to a species-specific potential for acquiring drug resistance, which, in turn, might be linked to the treatment history of the patient from whom the strain was recovered. The results of this study underscore the potential clinical utility of efinaconazole as a promising therapeutic agent for the treatment of human protothecosis.

In vitro antifungal susceptibility profile of Iranian Fusarium isolates: Emphasising on the potent inhibitory effect of efinaconazole compared to other drugs.

BACKGROUND: Fusarium species are opportunistic human pathogens that remarkably cause fungal infections ranging from superficial to fatal invasive disseminated infections. Fusarium species are notoriously resistant to the majority of antifungal agents. OBJECTIVES: Therefore, detailed studies regarding in vitro susceptibility are required and may lead to a better prognosis of severe infections. METHODS: We evaluated 25 antifungal drugs in vitro against 282 clinical and environmental Fusarium isolates. RESULTS: Fusarium species demonstrated high MICs/MECs values to the most commonly used antifungal drugs in clinical practice. The geometric mean (GM) MICs for luliconazole (0.004 µg/ml) and lanoconazole (0.012 µg/ml) were the lowest, followed by efinaconazole (0.98 µg/ml) and amphotericin B (1.04 µg/ml). CONCLUSIONS: Efinaconazole, a novel triazole, may be a promising candidate for the treatment of superficial Fusarium infections. Furthermore, the development of systemic formulations of these drugs as well as further in vitro and in vivo investigations could aid in the treatment of systemic fusariosis.

Novel and Investigational Treatments for Onychomycosis.

Onychomycosis is a common nail disease caused by fungi. The primary pathogens are dermatophytes; however, yeasts, non-dermatophyte moulds, and mixed fungal populations may also contribute to the development of a recalcitrant condition, usually accompanied by difficulties in everyday life and severe emotional stress. Treatment failure and relapse of the infection are the most frequent problems, though new issues have become the new challenges in the therapeutic approach to onychomycosis. Resistance to antifungals, an increasing number of comorbidities, and polydrug use among the ageing population are imperatives that impose a shift to safer drugs. Topical antifungals are considered less toxic and minimally interact with other drugs. The development of new topical drugs for onychomycosis is driven by the unmet need for effective agents with prolonged post-treatment disease-free time and a lack of systemic impact on the patients' health. Efinaconazole, Tavaborole, and Luliconazole have been added to physicians' weaponry during the last decade, though launched on the market of a limited number of countries. The pipeline is either developing new products (e.g., ME-1111 and NP213) with an appealing combination of pharmacokinetic, efficacy, and safety properties or reformulating old, well-known drugs (Terbinafine and Amphotericin B) by using new excipients as penetration enhancers.

Treatment of Fingernail Onychomycosis with Efinaconazole 10% Solution in a Patient with Scleroderma: A Case Report.

Introduction: Oral antifungals are typically preferred over topicals for moderate to severe onychomycosis due to efficacy and shorter treatment courses. However, systemics are contraindicated or cautioned in patients with liver dysfunction and with some autoimmune diseases, and in those taking interacting medications. Efinaconazole 10% solution is a topical antifungal therapy, but application for fingernail onychomycosis has not been adequately studied. Case Presentation: We present a case of a 78-year-old female with scleroderma and moderate onychomycosis of the right 4th fingernail successfully treated with topical efinaconazole 10% solution. Conclusion: We review the literature on contraindications to oral antifungals for onychomycosis, precautions with terbinafine in patients with some autoimmune diseases, and topical onychomycosis therapies. Topical efinaconazole may represent an effective alternative for patients with fingernail onychomycosis who have contraindications to oral medications.

Formulation-by-Design of Efinaconazole Spanlastic Nanovesicles for Transungual Delivery Using Statistical Risk Management and Multivariate Analytical Techniques.

As regulatory and technical landscapes for pharmaceutical formulation development are rapidly evolving, a risk-management approach using multivariate analysis is highly essential for designing a product with requisite critical quality attributes (CQA). Efinaconazole, a newly approved poorly water-soluble antifungal triazole drug has poor permeability. Spanlastics, new-generation surfactant nanovesicles, being fluidic, help improve the permeability of drugs. Therefore, we optimized efinaconazole spanlastics using the concepts of Formulation-by-Design (FbD) and explored the feasibility of transungual delivery for the management of onychomycosis. Using the Ishikawa fishbone diagram, the risk factors that may have an impact on the CQA of efinaconazole spanlastic vesicles were identified. Application of the Plackett-Burman experimental design facilitated the screening of eight different formulation and process parameters influencing particle size, transmittance, relative deformability, zeta potential, entrapment efficiency, and dissolution efficiency. With the help of Pareto charts, the three most significant factors were identified, viz., vesicle builder (Span), edge activator (Tween), and mixing time. The levels of these three critical variables were optimized by FbD to reduce the particle size and maximize the transparency, relative deformability, encapsulation efficiency, and dissolution efficiency of efinaconazole spanlastic nanovesicles. Bayesian and Lenth's analysis and mathematical modeling of the experimental data helped to quantify the critical formulation attributes required for getting the formulation with optimum quality features. The optimized efinaconazole-loaded spanlastic vesicles had a particle size of 197 nm, transparency of 91%, relative deformability of 12.5 min, and dissolution efficiency of 81.23%. The spanlastic formulation was incorporated into a gel and explored ex vivo for transungual delivery. This explorative study provides an example of the application of principles of risk management, statistical multivariate analysis, and the FbD approach in developing efinaconazole spanlastic nanovesicles.

[ANALYSIS OF PATCH TEST RESULTS FOR INDIVIDUAL INGREDIENTS IN PATIENTS WITH ALLERGIC CONTACT DERMATITIS CAUSED BY 10% EFINACONAZOLE NAIL SOLUTION].

BACKGROUND: Ten percent efinaconazole nail solution (EFCZ solution) is a new topical triazole antifungal drug, and we sometimes encounter patients with allergic contact dermatitis (ACD) caused by EFCZ solution in our outpatient clinic. However, no previous reports have summarized the patch test (PT) results obtained for individual ingredients in several patients with EFCZ solution-induced ACD. OBJECTIVES: This study aimed to 1) confirm the causative agent of EFCZ solution-induced ACD based on PT of individual ingredients and 2) analyze the optimal concentration and vehicle for such PT on the basis of previous studies. PATIENTS AND METHODS: We clinically diagnosed eight patients with EFCZ solution-induced ACD from Sep. 2014 to Aug. 2021, and performed 48-hour closed PT using EFCZ solution and its ingredients. Readings were done on days (D) 2, 3, and 7 according to the International Contact Dermatitis Research Group criteria. RESULTS: Six of the 8 patients underwent PT with EFCZ solution, and all showed + to +++ reactions on D3. The results for the main component, EFCZ, were + to +++ on D3 in all patients. Two patients were patch tested with both 10% EFCZ in ethanol and 10% EFCZ in petrolatum, which produced similar reactions. One patient had an allergic reaction to ethanol. CONCLUSIONS: The causative agent of EFCZ solution-induced ACD was EFCZ in all patients. For PT, we recommend EFCZ solution as is, its 10-fold dilution and 1% and 0.1% EFCZ in petrolatum.

Development and Validation of HPLC Method for Efinaconazole: Application to Human Nail Permeation Studies.

Efinaconazole is the first azole derivative approved by FDA for the topical treatment of onychomycosis. The objective of present study was to develop and validate HPLC method for estimation of efinaconazole in ex vivo human nail permeation study samples. The chromatographic analysis was performed on a HPLC system equipped with diode array detector. The efinaconazole and internal standard (IS) were extracted from the human nail samples by using the protein precipitation method. The samples were injected on to 5 µm Polar C18 100Å, 4.6 mm × 150 mm column. The mobile phase consisted of 0.01 M potassium dihydrogen phosphate: acetonitrile (36:64) and eluent was monitored at 205 nm. The chromatographic separation of drug and analyte was achieved using isocratic elution at flow rate of 1 mL/min with a total run time of 15 min. The efinaconazole and IS were eluted at 6.4 ± 0.5 and 8.3 ± 0.5 min, respectively. The developed method was validated as per FDA guidelines, and the results met with acceptance criteria. The method developed was specific, and the analyte concentrations were linear at range of 50 to 10000 ng/mL (R2 ≥ 0.9981). The validated HPLC method was applied for quantifying efinaconazole in human nail permeation study samples. The permeation of efinaconazole was increased by twofolds with Labarfac CC (15135.4 ± 2233.9 ng/cm2) compared to formulations containing Transcutol P (6892.0 ± 557.6 ng/cm2) and Labrasol (7266.1 ± 790.6 ng/cm2). The study results demonstrate that developed efinaconazole HPLC method can be employed for formulation evaluation and clinical studies.

In vitro activities of 8 antifungal agents against geophilic dermatophyte isolates.

BACKGROUND: Members of the Nannizzia gypsea complex are globally the most common geophilic dermatophytes which cause infection in animals and human. Although the susceptibility patterns of anthropophilic or zoophilic dermatophyte species to antifungal agents are well documented, the effectiveness of such drugs against geophilic species have rarely been explored. OBJECTIVES: This study was aimed to evaluate the in vitro antifungal activity of common and new antifungals against a set of environmental and clinical geophilic dermatophyte isolates. METHODS: 108 soil and clinical geophilic isolates from two genera Nannizzia (N. fulva n = 59; N. gypsea n = 43) and Arthroderma (A. quadrifidum n = 4; A. gertleri n = 1; A. tuberculatum n = 1) were included in the study. The in vitro antifungal susceptibility patterns of eight common and new antifungals against the isolates were determined according to broth microdilution method and by CLSI M38-A3 (3rd edition) protocol. RESULTS: MIC values across all isolates from five species ranged as: luliconazole: 0.0002-0.002 µg/ml, terbinafine: 0.008-0.125 µg/ml, efinaconazole: 0.008-0.125 µg/ml, ciclopirox olamine: 0.03-0.5 µg/ml, itraconazole: 0.125-1 µg/ml, amorolfine hydrochloride: 0.125-4 µg/ml, griseofulvin: 0.25-2 µg/ml and tavaborole: 1-8 µg/ml, respectively. CONCLUSION: Luliconazole, terbinafine and efinaconazole exhibited the highest in vitro efficacy, regardless of the dermatophyte species. Further surveillance studies are recommended to confirm the implication of such in vitro data for the clinical recovery rate of dermatophytosis with geophilic species following antifungal therapy.

Onychomycosis in children - review on treatment and management strategies.

BACKGROUND: Onychomycosis is an uncommon condition in children with increasing global prevalence. Health practitioners should confirm the diagnosis through mycology examination and examine family members of affected individuals for onychomycosis and tinea pedis. OBJECTIVE: To comprehensively summarize the treatment and management strategies for pediatric onychomycosis. METHODS: We performed a comprehensive literature search in the PubMed database to identify clinical studies on treatment for mycologically-confirmed dermatophyte onychomycosis in children <18 years. The exclusion criteria were combination therapy, case reports, reviews, systematic reviews and duplicate studies. RESULTS: Per-weight dosing regimens of systemic antifungal agents such as terbinafine, itraconazole, and fluconazole are found to be safe in children and are used off-label for the treatment of pediatric onychomycosis with high efficacy. Topical antifungal agents such as ciclopirox, efinaconazole, and tavaborole have established safety and efficacy in children. Children respond better than adults to topical therapy due to their thinner, faster growing nails. There is no data on the efficacy of medical devices for onychomycosis in children. CONCLUSION: Efinaconazole topical solution 10% and tavaborole topical solution 5% are FDA approved for the treatment of onychomycosis in children ≥6 years; ciclopirox topical solution 8% nail lacquer is approved in children ≥12 years.

Efinaconazole topical solution (10%) for the treatment of onychomycosis in adult and pediatric patients.

INTRODUCTION: Onychomycosis, a common nail disorder caused by fungal infection, can be managed pharmaceutically with oral or topical treatments. While oral treatments are often used first-line to treat nail infections, these systemic antifungals are not appropriate for all patients, and no oral treatments are approved for use in children in the USA. Given this need, topical antifungals were developed, which can be used as monotherapy or in combination with oral drugs. AREAS COVERED: Efinaconazole 10% solution is an azole antifungal indicated for topical treatment of toenail onychomycosis in pediatric and adult patients. This qualitative literature review summarizes available chemical, pharmacological, efficacy, safety, and post-marketing surveillance data of efinaconazole 10% topical solution. Efinaconazole 10% has been shown to be safe and efficacious regardless of disease severity/duration at baseline; patient gender, ethnicity, or age (including pediatrics); or comorbidities such as diabetes or tinea pedis. Overall, efinaconazole is a safe and effective clinical option for the treatment and management of onychomycosis. EXPERT OPINION: Efinaconazole is the first new antifungal approved for onychomycosis in 10 years in the USA. It has comparable efficacy to systemic antifungal agents such as itraconazole, and a favorable adverse events profile with minimal systemic exposure and no drug-drug interactions.

Chronological evaluation of treatment effect for tinea unguium with efinaconazole: Possibility of an early estimation of treatment effects.

The topical antifungal efinaconazole was applied to 27 nails (17 patients), and the treatment effects were monitored over a stipulated period (after 3, 6, and 12 months). Fourteen nails were observed for 18 months. Effects of the treatment were determined on the basis of the improvement rate of the turbidity ratio compared with that before treatment. After 12 months, five nails were cured and marked improvement was noted, whereas moderate and marked improvements were noted in 11 and six nails, respectively. The cured patients exhibited a significantly better improvement rate at 6 months (68.8%) than the other groups. Only 10.6% improvement was observed at the same point in time for the mild improvement group. Thus, in cases where the improvement rate after 6 months of treatment was 10% or less, it was judged that oral treatment should be considered. Furthermore, of the nails monitored for 18 months, those that exhibited further growth in improvement rates at 12 months was 51.6%, suggesting that an improvement rate of 50% at 12 months after starting treatment could be used as an indicator to determine switching to oral treatment.

Nitric Oxide-Releasing Nanoparticles Are Similar to Efinaconazole in Their Capacity to Eradicate Trichophyton rubrum Biofilms.

Filamentous fungi such as Trichophyton rubrum and T. mentagrophytes, the main causative agents of onychomycosis, have been recognized as biofilm-forming microorganisms. Nitric oxide-releasing nanoparticles (NO-np) are currently in development for the management of superficial and deep bacterial and fungal infections, with documented activity against biofilms. In this context, this work aimed to evaluate, for the first time, the in vitro anti-T. rubrum biofilm potential of NO-np using standard ATCC MYA-4438 and clinical BR1A strains and compare it to commonly used antifungal drugs including fluconazole, terbinafine and efinaconazole. The biofilms formed by the standard strain produced more biomass than those from the clinical strain. NO-np, fluconazole, terbinafine, and efinaconazole inhibited the in vitro growth of planktonic T. rubrum cells. Similarly, NO-np reduced the metabolic activities of clinical strain BR1A preformed biofilms at the highest concentration tested (SMIC50 = 40 mg/mL). Scanning electron and confocal microscopy revealed that NO-np and efinaconazole severely damaged established biofilms for both strains, resulting in collapse of hyphal cell walls and reduced the density, extracellular matrix and thickness of the biofilms. These findings suggest that biofilms should be considered when developing and testing new drugs for the treatment of dermatophytosis. Development of a biofilm phenotype by these fungi may explain the resistance of dermatophytes to some antifungals and why prolonged treatment is usually required for onychomycosis.

Clinical effectiveness of efinaconazole 10% solution for treatment of onychomycosis with longitudinal spikes.

Onychomycosis with longitudinal spikes in the nail plate has been reported to be refractory to oral drugs as with dermatophytoma. We evaluated the efficacy of 10% efinaconazole solution in the treatment of onychomycosis with longitudinal spikes. Of the 223 subjects who were enrolled in a previous study, a post-hoc analysis of 82 subjects with longitudinal spikes was performed in this study. The opacity ratio of longitudinal spikes was decreased over time from 8.1 to 0.9 at the final assessment. In addition, the longitudinal spike disappearance rate increased early after the application to 81.7% at the final assessment. Therefore, 10% efinaconazole solution can be a first-line drug for longitudinal spikes, which have been regarded as refractory to oral drugs.

More than Nail Deep: The Effect of Efinaconazole 10% Treatment on the Quality of Life in Patients with Onychomycosis: A post hoc Study.

INTRODUCTION: Onychomycosis is a common, difficult-to-treat fungal nail infection. Clinical signs include nail discoloration and thickening, which patients often find embarrassing, causing a negative impact on their quality of life (QOL). METHODS: In this post hoc study, we analyze the effect of efinaconazole 10% solution on a patient's QOL using patient-reported scores from the OnyCOE-t™ questionnaire (appearance, stigma, physical problems, symptom frequency, symptom bothersomeness, treatment satisfaction, and overall problem). Higher scores corresponded to better functioning, thus higher QOL. RESULTS: Efinaconazole 10% treatment and clinical efficacy were positively correlated with improved QOL in all domains for all groups, except with symptom bothersomeness (how much the onychomycosis symptoms worried or concerned the patient) for female patients <40 years. While still showing improvement in most domains during efficacious treatment, female and younger patients reported lower QOL scores than their male and older counterparts, despite having better clinical outcomes at follow-ups. DISCUSSION: Female and younger patients appear to be more emotionally bothered by their symptoms, regardless of treatment success or improvement of their nail's appearance, suggesting that onychomycosis is more than nail deep and has a greater psychological effect on these patients. Therefore, younger female patients may require more assurance and mental support.

Topical efinaconazole: A sequential combination therapy with oral terbinafine for refractory tinea unguium.

Efinaconazole is a topical antifungal drug approved in Japan for tinea unguium. Although topical treatments generally have low cure rates with a prolonged therapy period, a Cochrane review confirmed that high-quality evidence supports the effectiveness of efinaconazole for the complete cure of tinea unguium. Combination therapy is a way to improve the cure rate of onychomycosis. In this study, topical efinaconazole was administrated to 12 patients who had been treated with oral terbinafine (125 mg daily) for more than 20 weeks with little expected effect. Because terbinafine accumulates for a long time in the nail, treatment immediately followed by other drugs can be considered sequential combination therapy. During terbinafine monotherapy, the percentage involvement decreased from 53.5% to 44.0% after 37.4 weeks and the effective and cure rates were 16.7% and 0%, respectively. During sequential topical efinaconazole therapy combined with lasting terbinafine in the nail, the percentage involvement decreased from 44.0% to 18.7% after 28.4 weeks, and the effective and cure rates were 66.7% and 16.7%, respectively. The improvement rate per month of combination therapy (12.6%) was higher than that with monotherapy (2.1%) (p = 0.002). There were no serious side-effects. This sequential combination therapy with efinaconazole was effective in poor terbinafine responders, making it a promising regimen for improving the cure rate of tinea unguium.