Kaushik Venkatesh1; Jaggi Rao, MD, FRCPC2
1Medical Student, University of Pittsburgh, Pennsylvania, USA
2Board Certified Dermatologist & Clinical Professor, University of Alberta, Alberta, Canada
Onychomycosis, also known as tinea unguium, is a progressive fungal infection of the nails resulting in discoloration, nail plate thickening, and onycholysis. This infection is caused by dermatophytes, nondermatophyte molds, and yeasts. It accounts for up to 90% of toenail and 50% of fingernail infections in North America.1 Onychomycosis afflicts 10% of the general population, 20% of those older than 60 years, and 50% of those older than 70 years. Risk factors include peripheral vascular disease, diabetes mellitus, immunologic disorders, hyperhidrosis, obesity, concurrent fungal infections, and nail trauma.2,3 As per the Canadian clinical pathway, treatment of onychomycosis needs to start as soon as the infection is diagnosed.4,5 Especially in diabetic and immunocompromised patients, treatment of onychomycosis is medically indicated, as untreated onychomycosis affects quality of life and often leads to secondary infections as abrasions or ulcerations created by sharp onychomycotic nails allow bacterial and fungal entry.6 Efinaconazole is a novel topical azole that has shown promising and superior activity against dermatophytes, non-dermatophytes, and yeasts causing onychomycosis.7-9
Diagnostic and Clinical Features
- Onychomycosis has several different clinical presentations including distal lateral subungual, proximal subungual, superficial white, and total dystrophic forms.3 Although onychomycosis accounts for about 50% of the nail abnormalities, establishing a differential diagnosis is important to rule out other nail pathologies.10 Differential diagnoses include other infections (both fungal and bacterial), primary cutaneous dermatoses (such as psoriasis, lichen planus or dermatitis), trauma, and tumors such as melanomas, fibromas, and carcinomas.3,12
- Accurate diagnosis requires visual identification of physical changes as well as positive laboratory analysis of nail clippings and subungual debris. Laboratory analysis includes microscopy using KOH (potassium hydroxide) and then subsequent culture and/or histological evaluations of negative microscopy results.3 As per product monographs of the approved medications for onychomycosis in Canada, positive laboratory analysis are required prior to starting an oral treatment, though it is not required before starting a topical treatment.
Background on Efinaconazole 10% (w/w) Solution
- Efinaconazole is a topical triazole that has been shown to have superior antifungal potency in vitro and in vivo, when compared to the other commonly used onychomycosis topical therapies such as ciclopirox nail lacquer.7,8
- The treatment inhibits fungal lanosterol 14α-demethylase in the ergosterol biosynthesis pathway, which is a structural component in fungal cell membranes. The accumulation of 14α-methyl sterols and subsequent loss of ergosterol in the fungi cell wall may be responsible for the fungistatic and fungicidal activity of efinaconazole. This activity has been shown to be effective against dermatophytes, non-dermatophytes and yeasts.8,13
- Efinaconazole 10% w/w topical solution grants easier and more convenient administration, which is important for compliance with its daily application regimen.
- Its low molecular weight allows it to penetrate easily through the nail plate and even through nail polish.14
- Its non-lacquer profile avoids buildup and does not require nail debridement7, an added benefit when compared to other topical treatments, e.g. Ciclopirox lacquer.15
- It is also easy to administer by patients simply by gently squeezing the bottle in upside-down position to wet the flowthrough applicator brush attached to the bottle and spreading the solution to the affected region.16 One application on each affected toenail and 2 applications on the big toenail, once daily.
- Its low surface tension and low keratin affinity allows it to permeate through the nail plate more efficiently than Ciclopirox, contributing to higher fungicidal activity underneath and within the nail plate.17
- The recommended treatment regimen is once daily topical application for 48 weeks to the nail plate surface, lateral and proximal nailfolds, hyponychium, underside of nail plate, and surrounding skin.7,16 A complete cure may be seen some months after mycological cure is achieved.
Several studies have found that combining different modalities of treatment with topical Efinaconazole may provide a synergism that increases fungicidal efficacy and cure rates. Faster visible results and increased efficacy may enhance compliance by inspiring patients to adhere to the combination regimen.
- Fungal infections of the skin surrounding the toenail can often lead to or perpetuate onychomycosis.18 In a survey of 2761 patient with toenail onychomycosis, 42.8% had some other concomitant fungal infection. Of these, tinea pedis was the most common and accounted for 80% of concomitant infections.19
- Several studies have documented higher onychomycosis cure rates with the treatment of concomitant tinea pedis. For example, one study found that treatment of concomitant tinea pedis resulted in a complete cure of 29.4% and mycological cure of 56.2% compared to a complete cure of 16.1% and mycological cure of 45.2% in the control of no concomitant tinea pedis treatment.20,21
- Oral therapies have been recorded to have high cure rates for onychomycosis. However, hepatotoxicity, adverse effects, drug interactions and the need for bloodwork monitoring may limit the viable population while also incurring greater burdens on the patient to comply with regular monitoring practices.7
- A systematic review of 26 studies found that combined systemic and topical treatment regimens resulted in a higher complete cure rate of 80.8% compared to the 70.8% complete cure rate in systemic treatment alone.22
- Laser treatments for onychomycosis are currently approved by the FDA only as a temporary solution to increase the clear nail surface area. Currently, laser studies primarily provide evidence for aesthetic endpoints rather than medical endpoints.23
- However, some studies have found that combined use of laser treatments with topical therapy have high cure rates, with clinical efficacy rates ranging from 70% – 90% and mycological cure rates ranging from 57% – 70%.24-28
- Others have also found that this combined modality has decreased rate of reinfection.28
Managing Patient Expectations
Efinaconazole treatment, given its relatively high efficacy, has been documented to have positive impact on patient satisfaction and quality of life measures. Importantly, this impact was greatest in patients who were considered clinically improved and correlated inversely with percent of nail affected.29 It is important to adequately manage patient expectations in the treatment of onychomycosis, and the following suggestions may help physicians to accomplish this goal:
- While Efinaconazole has been shown to be a superior topical treatment, physicians should clearly convey to patients the mycological and complete cure rates so that patients can have realistic expectations for treatment outcome. In two Phase III studies conducted on 1655 patients, at the end of the study at week 52, they found:7
- Mycological cure rates: 55.2% and 53.4%
- Complete cure rates: 17.8% and 15.2%
Explain Prognostic Factors
- Physicians should educate patients on factors that affect response
to treatment and prognosis.13 These include:
- Patient demographics:
- Gender30, advancing age, and history of nail trauma
- Diabetes mellitus, liver or kidney transplantation, immunosuppression, cancer, neutrophil defects, chronic steroid therapy, and peripheral vascular disease
- Nail characteristics and disease severity:
- Distal lateral subungual onychomycosis, proximal subungual onychomycosis, total dystrophic onychomycosis, dermatophytoma, severe onycholysis, two feet-one hand syndrome, slow nail growth, and lengthy disease duration
- Co-infection with other pathogenic organisms:
- Mixed bacterial and fungal infections, yeasts, and nondermatophytes
- Patient demographics:
Detail Recurrence Rates
Physicians should also educate patients on the recalcitrant nature of the disease and high rates of recurrence. Indeed, recurrence rates vary from 20% to 25%.31,32
Preparation for Appropriate Therapy Duration
- Physicians should also explain the long duration of treatment for the topical solution, i.e. at least 48 weeks. It may work well to justify this lengthier treatment by explaining the limitations of oral treatments. That is, although generally efficacious, systemic medications are limited by drug interactions and potential hepatotoxicity which may require regular monitoring.7
- The rate of nail clearance is dependent on slow toenail regrowth in healthy subjects. With a growth rate of 1 to 2 mm per month, it may take up to 4-6 months for fingernail clearance and 12-18 months for toenail clearance. Slower growth occurs in patients with comorbidities and older patients.33
Patient compliance is essential to positive treatment outcomes and is consistently a struggle with a variety of therapies. It has been shown that up to 80% of patients are non-adherent to drug treatments independent of diagnosis or prognosis.34 One study found that up to 95% of dermatology patients underdose on topical treatments.35 Nonadherence is particularly concerning with onychomycosis treatment. The following suggestions may assist physicians to improve compliance in their onychomycosis patients:
Remind Patients of the Consequences of Noncompliance
- Issues with medical adherence such as early termination, incorrect or irregular dosing, and missed dosing are serious risk factors in poor response to treatment.3
- Afflicted nails, if left unattended, can become increasingly discolored, thickened, flaky, separated from the nail bed, and painful. Severe onychomycosis can also hinder mobility and thus occupational functions, as well as lead to cellulitis in older adults and foot ulcers in diabetics.3,36 Moreover, serious cases might require surgery.37
Use Visual Aids to Demonstrate the Potential for Treatment Success
- Visual aids can significantly increase comprehension of treatment schedules and improve patient compliance.38 Physicians should consider using a “before-and-after” set of pictures taken at intermittent intervals in the treatment process (e.g. baseline, 6 months and 1 year) (see Figure 1). This discussion can be paired with charts showing Efinaconazole cure rates and nail clearance over time (see Figures 2 & 3). Showing patients pictures of positive results, while still managing expectations, can help them visualize potential success with compliance to proper treatment.
- Additionally, physicians can utilize visual aids to help patients better understand the pathology of onychomycosis (see Figure 4), which has similarly been shown to increase compliance.38
- A patient toolkit may be beneficial in packaging together a comprehensive and encouraging onychomycosis treatment plan, with explanations and visualizations of disease pathology, treatment mechanism, and treatment regimen and trajectories.
- Efinaconazole 10% solution is an effective and convenient topical antifungal treatment for onychomycosis, with toenail mycological cure rates between 53.4% and 55.2% and complete cure rates between 15.2% and 17.8%.
- Treatment may be more effective when combining Efinaconazole with other modalities such as topical antifungals for the management of tinea pedis on adjacent skin, oral antifungals, and laser treatment.
- Patient adherence is the cornerstone of treatment success. It is crucial that patients adhere to daily application of efinaconazole throughout the treatment course. Compliance should be encouraged by emphasizing the consequences of nonadherence, using visual guides to aid in understanding of disease pathology and treatment mechanisms, and inspiring a motivated outlook on treatment trajectory.
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- Bausch Pharmaceuticals. Jubilia (efinaconazole) topical solution, 10% [package
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