Onychomycotic Nails Research Articles

Extended Use of Topical Efinaconazole Remains Safe and Can Provide Continuing Benefits for Dermatophyte Toenail Onychomycosis.

Efinaconazole 10% topical solution labeling for onychomycosis describes phase III trials of 12 months of treatment; the slow growth of onychomycotic nails suggests a longer treatment period may increase efficacy. We present here the first evaluation of extended use of efinaconazole 10% topical solution for up to 24 months. Enrolled patients (n = 101) had one target great toenail with mild to moderate distal lateral subungual onychomycosis and applied efinaconazole 10% topical solution to all affected toenails once daily for 18 months (EFN18) or 24 months (EFN24). Efficacy and safety were evaluated at each visit by visual review and mycology sampling. Regarding the target toenail for patients treated for 24 months (EFN24), mycological cure (negative microscopy and culture) was 66.0% at Month 12, increasing to 71.7% at Month 24; effective cure (mycological cure and ≤10% affected nail) was 13.2% at Month 12, rising to 22.6% at Month 24. Mild to moderate application site reactions (symptoms of erythema/scaling) were the only efinaconazole-related reactions, in eight patients (7.9%). No systemic efinaconazole events or drug interactions were found. Patients aged 70 years or more had similar efficacy to younger patients at all time periods and did not show any increased treatment risks. Thinner nails exhibited better clearance versus thicker nails. A higher proportion of patients with Trichophyton mentagrophytes complex infection experienced application site reactions (35.7%), and a higher effective cure was found at Month 24 versus T. rubrum patients. There is a trend of increasing mycological cure and effective cure beyond Month 12 to Month 24, without an increased safety risk. The enrolled population in this trial was significantly older than in the phase III trials, with a greater degree of onychomycosis severity; however, increased age did not appear to reduce the chance of efficacy to Month 24 in this study. Our data suggest that lack of ability to clear nail dystrophy remains a significant problem for patients, rather than any lack of efinaconazole action over long-term treatment periods.

Antifungal Nail Lacquer for Enhanced Transungual Delivery of Econazole Nitrate.

The fungal disease of the nail, onychomycosis, which is also the most prevalent nail disturbance, demands effective topical treatment options considering the possible adverse effects of systemic antifungal therapy. The current work is focused on development of an adhesive and resistant, drug-delivering and permeation-enhancing polymeric film containing econazole nitrate (ECN) for topical antifungal treatment. The development of the lacquer formulation was guided by the Quality by Design approach to achieve the critical quality attributes needed to obtain the product of desired quality. Eudragit RSPO at 10% w/w was found to be the ideal adhesive polymer for the application and an optimal permeation-enhancing lacquer formulation was achieved by the optimization of other formulation excipients, such as plasticizer and the solvent system. Additionally, novel experimental enhancements introduced to the research included refined D50 drying time and drying rate tests for lacquer characterization as well as a multi-mechanism permeation-enhancing pre-treatment. Moreover, a practical implication was provided by a handwashing simulation designed to test the performance of the lacquer during actual use. In vitro drug release testing and ex vivo nail permeation testing demonstrated that the optimized nail lacquer performed better than control lacquer lacking the permeation enhancer by achieving a faster and sustained delivery of ECN. It can be concluded that this is a promising drug delivery system for topical antifungal treatment of onychomycotic nails, and the novel characterization techniques may be adapted for similar formulations in the future.

Consistency of histologic fungal burden in onychomycotic nails regardless of clinical severity: A retrospective case series of 79 patients

To the Editor: Onychomycosis is a fungal nail infection. Although classifications of the clinical and histologic severities of onychomycosis exist,1 the information on whether clinical severity (CS) correlates with histologic fungal burden (HFB) is limited.

27602 Long-term efficacy and safety of once-daily topical efinaconazole 10% topical solution (Jublia) for dermatophyte toenail onychomycosis: An interim analysis

Introduction: Efinaconazole 10% topical solution (efinaconazole) labeling for onychomycosis describes 12-month phase III trials; the slow growth of onychomycotic nails suggests a longer treatment period may increase efficacy. We present here for the first time an interim evaluation of once-daily efinaconazole over 24 months.

1540 nm LIBS Investigation of Healthy and Pathological Human Nails

The paper discusses the possibility of using laser-induced breakdown spectroscopy (LIBS) as a method for the diagnosis of human nail onychomycosis. LIBS spectra obtained with excitation of plasma on the surface of healthy and onychomycotic nails by pulses of Q switched Yb, Er: Glass laser radiation with a wavelength of 1540 nm were compared for the first time. The spectrum of onychomycotic nail contained unique lines additional to characteristic spectral lines of healthy nails. These additional lines disappeared after 90 days of sample storage in air at room temperature 20 ± 3 °C.

Efficacy of laser treatment for onychomycotic nails: a systematic review and meta-analysis of prospective clinical trials.

Laser therapy for onychomycosis is emerging but its efficacy remains unestablished. To examine current evidence on efficacy of laser treatment of onychomycosis. A systematic review and one-arm meta-analysis, including all prospective clinical trials, identified on PubMed, Cochrane Library, and EMBASE databases. Trials with participants as unit of analysis (UOA), n = 13, were analyzed separately from trials with nails as UOA, n = 7. Summary proportions and 95% confidence intervals (95% CI) were calculated. Outcomes were mycological cure, clinical improvement, or complete cure. Twenty-two prospective trials (four randomized controlled trials and 18 uncontrolled trials) with a total of 755 participants were analyzed. Summary proportions with 95% CI for participants as UOA were mycological cure 70.4%, 95% CI 52.2-83.8%; clinical improvement 67.2%, 95% CI 43.2-84.7%; and complete cure 7.2%, 95% CI 1.9-23.5%. High statistical heterogeneity was detected (mycological cure I2 = 88%, P < 0.01; clinical improvement I2 = 69%, P < 0.01; complete cure I2= 60%, P = 0.11). The current level of evidence is limited and with high heterogeneity, making it difficult to assess the true efficacy of laser treatment for onychomycosis. Larger randomized controlled trials with well-defined methodology are warranted.

Microstructural alterations in the onychomycotic and psoriatic nail: Relevance in drug delivery

Despite the important nail alterations caused by onychomycosis and psoriasis few studies have characterized the microstructure of the diseased nail plate and the diffusion and penetration of drugs through this altered structure. This work aimed to characterize the microstructure of the healthy, onychomycotic and psoriatic human nail using Raman spectroscopy, scanning electron microscopy, optical microscope profilometry and mercury intrusion porosimetry followed by analysis of the structure with PoreCor® software. The results showed that onychomycotic nails have higher porosity and lower amounts of disulphide bonds compared to healthy nails. This suggests that the presence and action of fungi on the nail plate makes this structure more permeable to water and drugs. Psoriatic nails had increased porosity compared to healthy nails but lower than fungal infected specimens. In vitro permeation studies showed that diseased nails were more permeable to ciclopirox (onychomycosis) and clobetasol (psoriasis) although drug permeation was highly variable and likely to be influenced by the degree of alteration of the nail structure. On the whole, this work provides new and valuable information about the microstructure and porosity of diseased nails and a plausible explanation of the increased drug permeability observed in this work and elsewhere.

Expression of innate immune defence genes in healthy and onychomycotic nail and stratum corneum

Onychomycosis, a fungal infection of the nail, is predominantly caused by dermatophytes1. Our understanding of the pathogenic response to these fungi and their ability to establish chronic infection and evade immune clearance remains limited2. Evidence suggests an association between onychomycosis and immunosuppression3 but the nail plate represents a site of infection with negligible adaptive immune cell presence; the host response here led largely by components of the innate immune system4 including antimicrobial peptides (AMP). AMP are a cornerstone of innate host defence4, but their role in onychomycosis, is poorly understood. This study is the first detailed investigation of associations between innate immune defence gene expression and onychomycosis. This article is protected by copyright. All rights reserved.

A critical review of improvement rates for laser therapy used to treat toenail onychomycosis.

Onychomycosis is a nail infection that is primary caused by dermatophytes. Alternative treatments are needed as current therapies (oral and topical antifungals) have limited effectiveness. Lasers are currently approved by the FDA to temporarily increase the amount of clear nail in onychomycosis patients. Lasers can theoretically elicit fungicidal effects but in practice produce mixed results. This review compared laser-induced improvement rates to FDA-approved indications and traditional onychomycosis treatments. A review of the literature (PubMed, Clinicaltrials.gov, Medline and Embase) was used to locate articles for this review. RCTs, non-randomized, uncontrolled and retrospective studies that included at least one of the following measures were eligible; complete cure, mycological cure, clinical improvement and clinical cure. Mycological cure (negative culture and negative microscopy) was evaluated in two studies using patients as the unit of analysis with an average rate of 11%, increasing to 63% when nails were used as the unit of analysis (three studies). Clinical cure (100% clear nail) was evaluated in six studies with a rate of 13% using nails as the unit of analysis and 13% when patients were used as the unit of analysis (two studies). Clinical improvement (at any time point) was found in 36% of patients (five studies) and 67% of nails (nine studies). Nail clarity as measured by clear nail growth and/or nail plate/bed clearance at 12 weeks was found to be 2.6 mm across onychomycotic nails. Laser studies, to date, provide preliminary evidence of clinical improvement and clear nail growth in toenail onychomycosis, consistent with the FDA clearance for aesthetic endpoints. Laser studies however do not provide efficacy rates for medical endpoints that equate or exceed those found with traditional therapies (oral and topical treatments).

A painless, minimally invasive technique for debulking onychomycotic nails

A painless, minimally invasive technique for debulking onychomycotic nails

Fractional carbon-dioxide (CO2) laser-assisted topical therapy for the treatment of onychomycosis

Inability of topical medications to penetrate via nail plate brings a great challenge to clinicians in treating onychomycosis. Furthermore, oral medications are not appropriate for all patients because of drug interactions, adverse effects, and contraindications. We sought to evaluate the clinical efficacy of fractional carbon-dioxide laser-assisted topical therapy for onychomycosis. In total, 75 patients with 356 onychomycotic nails confirmed by mycologic examination were included in this study. All the affected nails received 3 sessions of laser therapy at 4-week intervals and once-daily application of terbinafine cream for 3 months. In all, 94.66% and 92% of the treated patients were potassium hydroxide and culture negative, respectively, after 3 months of treatment. However, only 84% and 80% were potassium hydroxide and culture negative, respectively, at 6 months of follow-up. Using Scoring Clinical Index for Onychomycosis electronic calculator, 73.33% of the patients scored higher than 6 and 26.66% of the patients scored 6 or less. Those who scored more than 6 were evaluated clinically and 98.18% of them showed response to treatment at 3 months and 78.18% of them at 6 months of follow-up. Lack of control group and short duration of follow-up are limitations. Fractional carbon-dioxide laser therapy combined with topical antifungal was found to be effective in the treatment of onychomycosis. However, randomized clinical studies are needed before it can be widely used in clinics.

Ultrasonographic characterization of the nails in patients with psoriasis and onychomycosis

ObjectiveThe study aimed at assessment of ultrasound (US) in diagnosing nail psoriasis and onychomycosis. MethodsOne hundred subjects were included: the psoriatic patients group (n=25), the onychomycosis patients group (n=25) and the control group (n=50). Nail psoriasis severity index (NAPSI) score and onychomycosis severity index were used to assess the patients, in addition to performing nail culture. The thickness of right index and thumb nail plate (NP) and nail bed (NB) was measured by US. The following parameters were also assessed: contour and echogenicity of the NP, NB focal lesions, interpolate space, distal interphalangeal joint (DIJ) changes, proximal nail fold (PNF) changes and distance between proximal NP and DIJ. ResultsThumb NP thickness in psoriasis, onychomycosis and control groups was 0.80±0.14mm and 0.77±0.21mm, and 0.61±0.09mm respectively. The thumb NB thickness in psoriasis, onychomycosis and control groups was 2.05±0.32mm, 2.13±0.32mm, and 1.79±0.23mm respectively. Psoriatic nails show preserved interplate space and DIJ changes. Onychomycotic nails show loss of interplate space proximally, swollen PNF and decreased Plate/DIJ distance. ConclusionUS nail measurements and characters can differentiate between psoriasis and onychomycosis.

Efficacy and safety of 1064-nm Nd:YAG laser in treatment of onychomycosis

Background: Onychomycosis is a common nail disease, especially in older patients. Various treatment options are currently available for onychomycosis; however, their limitations include high failure rates, time-consuming nature, high cost and high risk of drug interactions. Previous studies on the treatment of dermatophyte onychomycosis with a long-pulsed 1064-nm Nd:YAG laser demonstrated excellent outcomes without severe side effects. Objective: To evaluate the efficacy and side effects of onychomycosis treatment with a long-pulsed 1064-nm Nd:YAG laser. Methods: Sixty-four onychomycotic nails (35 patients) were evaluated. The first treatment cycle involved treatment with a long-pulsed 1064-nm Nd:YAG laser in four sessions at 1-week intervals. A potassium hydroxide examination and fungal culture were performed every week during this treatment course and then at a 1-month follow-up visit. If either test was positive for a pathogenic organism, a second treatment cycle was performed. If the two tests produced negative results, each affected nail was followed up at 3- and 6-month visits after completion of the second treatment protocol. In cases of resistance (positive for a pathogenic organism after completion of the second treatment cycle), the onychomycotic nails were excluded from the study and treated by standard methods. Results: Of all 64 nails evaluated, 59 completed the first cycle of treatment and 24 (40.7%) demonstrated mycological clearance at the 1-month follow up. Thirty-five of the 59 nails (59.3%) were positive for a pathogenic organism and underwent a second treatment cycle. Upon completion of the second treatment cycle, 28 nails remained enrolled in the study, and the mycological test results were negative in nine of these (31.2%). For all nails that completed the first or second treatment cycle, the overall cure rates at the 1-, 3- and 6-month follow-up visits were 63.5, 57.7 and 51.9%, respectively. Side effects were mild and limited to erythema and swelling after the laser procedure. Conclusions: Long-pulsed 1064-nm Nd:YAG laser therapy is safe and effective for the treatment of onychomycosis. However, a larger sample and longer follow-up period are needed to confirm our findings.

Does Laser Work for Treating Onychomycosis? Maybe, Sometimes

Two new studies examine different laser approaches to treating onychomycotic nails. Hollmig and colleagues enrolled 27 patients with a total of 125 nails needing treatment to evaluate the effectiveness of 1064-nm Nd:YAG laser for mycologic cure and clinical improvement (defined as proximal nail-plate clearance). Patients randomized to treatment received two laser treatments, 2 weeks apart. Among the 22 study completers, treatment recipients and untreated control patients had no statistically significant differences in mycologic cure (33% and 20%, …

Treatment of onychomycosis using the 1 064 nm Nd:YAG laser: a clinical pilot study

Nd:YAG lasers could be a safe and effective treatment modality for onychomycosis, without the side effects of drugs. Long and short-pulsed Nd:YAG lasers were used in this clinical study in a side-comparison manner without removal of onychomycotic nail material before treatment. Big toenails of 10 patients were treated twice in a side-comparison manner with the short-pulsed Nd:YAG laser. Fungal cultures were taken and a histological examination was performed before treatment and after 9 months. Two independent investigators rated clearance using the "Onychomycosis Severity Index (OSI)" and standardized photographs at 3-month intervals. OSI-Scores decreased for 3.8 (15 %; p = 0.006), 4.8 (19 %; p = 0.0002) and 2.9 points (12 %; p = 0.04) within 3, 6 and 9 months. The positive culture rate at 9 months was significantly reduced to 35 % (p = 0.0003). Classification of severity of onychomycosis showed no change. The difference between the treatment regimens was not significant. These results suggest that treatment of onychomycosis with the Nd:YAG laser without removing mycotic nail material can lead to a temporary clinical improvement, a reduction of positive fungal cultures and an improvement of the Onychomycosis Severity Index. The treatment regimen should be optimized to be used as an effective antimycotic monotherapy.

Drug delivery to the nail: therapeutic options and challenges for onychomycosis.

Onychomycosis is one of the most common nail disorders. It affects 10-30% of the world population and is caused by dermatophytes, non-dermatophytes, molds, and yeasts. Present treatment methods of onychomycosis include oral therapy, topical therapy, and a combination of both; they have mild-to-moderate efficacy, with a relapse and reinfection rate of 20-25%. For oral therapy, newer antifungal compounds (azole class and allylamine class) are being investigated to increase efficacy and minimize side effects. Oral therapy with antifungal agents have severe side effects, with lesser bioavailability and longer duration of treatment. By contrast, topical therapy of onychomycosis is associated with greater patient compliance and fewer systemic side effects and drug interactions. Current topical treatment options of onychomycosis are nail lacquers, ointments, lotions, solutions, and gels, but these formulations have been unsuccessful due to poor penetration and distribution of drugs at the infected site. Therefore, novel therapeutic options are constantly being researched to improve the efficacy of onychomycosis treatment by enhancing the permeation of the drug across the nail to reach the infected site. Various physical and chemical enhancement methods have been studied to increase the permeation of drugs across the nail plate to the nail bed. Device-based therapeutic options have also been investigated to increase the antifungal drug concentration and its effects in the onychomycotic nail. Randomized clinical trials of these novel therapies have demonstrated better efficacy. The present review discusses the anatomy of the human nail, onychomycosis and its types, onycholysis, and conventional and novel therapies. We also review patents granted as well as design challenges facing optimal drug formulation for onychomycosis treatment.

Transungual delivery of terbinafine by iontophoresis in onychomycotic nails

Trans-nail permeability is limited due to the innate nature of the nail plate and the recent investigations indicated the potential of iontophoresis in enhancing the transungual drug delivery in normal nails. However, the onychomycotic nails differ from the normal nails with respect to the anatomical and biological features. The current study investigated the effect of iontophoresis (0.5 mA/cm2 for 1 h) on the transungual delivery of terbinafine in onychomycotic finger and toe nails. The presence of fungi in the onychomycotic nails was diagnosed by potassium hydroxide (KOH) microscopy. Passive and iontophoretic delivery of terbinafine across the infected nail was studied in Franz diffusion cell. Further, the release profile of terbinafine from the drug-loaded nails was investigated by agar diffusion method. KOH microscopy confirmed the presence of fungi in all the nails used. The amount of drug permeated across the nail plate was enhanced significantly during iontophoresis over passive delivery, that is, by 21-fold in case of finger and 37-fold in case of toe nails. Further, the total drug load in the onychomycotic nail was enhanced by ~12-fold (in both finger and toe nails) due to iontophoresis. Release of terbinafine from the iontophoresis-loaded nails into agar plates exhibited two phases, a rapid phase followed by a steady release, which extended >2 months. This study concluded that the drug delivery in onychomycotic nails did not differ significantly when compared with normal nails, although the extent of drug permeation and drug load differs between finger and toe nails.

The diabetic foot

It is estimated that currently 60 million individuals worldwide have diabetes mellitus, and it is projected by the World Health Organization that this number will more than double to 200 million by the year 2010. The “diabetic foot” is characterized by neuropathy, ischemia (peripheral vascular disease) and immunologic impairment. Peripheral neuropathy may be present in up to 55% of diabetics, with an increased incidence as the duration of diabetes increases. When peripheral neuropathy is present there is an increased insensitivity to stimuli and this reduces the likelihood that the diabetic will be able to recognize and react to injury and foot trauma. Ischemia has been found in up to 60% of diabetics with non-healing ulcers and in 46% of diabetics undergoing major amputation. Peripheral neuropathy and ischemia are associated with 60% and 20% of foot ulcers, respectively. Impaired healing ability of the foot may increase morbidity and the potential for future amputation. In severe cases it may be necessary to conduct amputation of the limb in order to control infection and other complications. Ulceration, onychomycosis and tinea pedis may predispose the diabetic to infections of the feet. Repetitive stress to certain sites of the foot in a diabetic may result in the development of ‘hot spots’, callous formation, pressure necrosis, and subsequently development of ulcers. Although an ulcer may appear to be superficial at the surface it may actually be much deeper than anticipated. Chronic ulcers can lead to osteomyelitis, with 64% of chronic benign plantar ulcers being associated with osteomyelitis. Eighty-four percent of persistent and untreated ulcers result in lower limb amputations. Diabetics afflicted with ulcers must “off load”, that is, allow the injured part of the foot to rest and not to bear weight. Relapses and recurrences of infection are not uncommon and may be associated with poor peripheral perfusion, impaired immune response and slow outgrowth of the onychomycotic nail. Diabetes mellitus is increasing in incidence to the point that it is one of the most common diseases in the world. It is important to be cognizant of the factors that may lead to the breakdown of the skin in the diabetic foot.

Pseudomonas surgical-site infections linked to a healthcare worker with onychomycosis.

To determine the etiology of Pseudomonas aeruginosa surgical-site infections following cardiac surgery. University teaching hospital. Those with wound cultures that grew P. aeruginosa after cardiac surgery performed from 1999 to 2001. Medical records and operating room (OR) records of patients with P. aeruginosa cardiac surgical-site infections from 1999 to 2001 were reviewed. Healthcare workers involved with two or more cases were interviewed and examined. Specimens for environmental cultures were obtained from the ORs and cardiac surgical equipment. Cardiac surgery cases were observed and postoperative care and the cleaning of surgical instruments were investigated. OR air handling system records during the epidemic period were reviewed. Molecular fingerprinting of available P. aeruginosa isolates from infected patients and a healthcare worker was done. There were five P. aeruginosa cardiac surgical-site infections from January to August 2001, compared with no such infections from 1999 to 2000. All were adult patients. One cardiac surgeon with onychomycosis operated on all five cases. He did not routinely double glove. The involved fingernail grew P. aeruginosa. Three P. aeruginosa patient isolates were available for pulsed-field gel electrophoresis; two were identical to the isolate from the involved surgeon's onychomycotic nail. No environmental OR cultures grew P. aeruginosa. The surgeon's culture-positive nail was completely removed. There have been no P. aeruginosa surgical-site infections among cardiac surgery patients since this intervention. At least two cases of a cluster of P. aeruginosa surgical-site infections resulted from colonization of a cardiac surgeon's onychomycotic nail.

Hipersensibilidad a los antígenos del Trichophyton rubrum en podólogos atópicos y no atópicos

Podiatrists as well as manicurists are exposed to inhale nail dust contaminated with mycotic particles when filing and burring the onychomycotic nails of their patients. As some of them with atopic background suffered worsening of their symptoms we decided to study the immune response to the fungus Trichophyton rubrum (Tr) that was isolated from the nail dust obtained from the podiatrists office. A detailed clinical record, intracutaneous skin tests with a extract of Tr and the serum levels of total and specific IgE were performed in rhinitis-asthma as well as control patients. As the asthmatic group refused to perform the challenge bronchial test with Tr we developed a guinea pig experimental model with daily aerosolization of Tr during 12 weeks studying the levels of specific IgE and IgG as well as the lung's histopathology. Atopic patients showed positive immediate skin tests with Tr and both groups revealed delayed hypersensitivity to the antigen.RAST-IgE-anti-Tr and RAST-inhibition confirmed the specificity of the antibodies. Guinea pigs also synthetized IgG and IgE anti-Tr and suffered different degrees of lung lesions similar to those of hypersensitivity pneumonitis. Atopic podiatrists are exposed to fungal allergens that may participate or aggravate their previous respiratory conditions.