Perspectives on the diagnosis & management of onychomycosis | CCID - Dove Medical Press
Introduction
Onychomycosis is a fungal infection of the nail unit caused by dermatophytes, non-dermatophyte molds (NDM) and yeast.1,2 It is the most common nail infection encountered in clinical practice,3 with a worldwide prevalence of 5.5%, and an estimated prevalence of 2% to 14% in the United States (US),4 and 0.5% to 24% in Europe.5–8 Risk factors include prior dermatologic conditions, such as hyperhidrosis, tinea pedis, and psoriasis, as well as exogenous factors, including occlusive shoes, trauma, and poor nail grooming. Comorbidities, such as diabetes mellitus, immunosuppression, malignancy, venous insufficiency, peripheral arterial disease, obesity, and inflammatory bowel disease also increase risk.4 Altered foot biomechanics due to biomechanical malignments, congenital deformities, or neurological deficits can result in repetitive microtrauma during walking and increase the risk of infection and recurrence.9,10 Genetics may predispose to developing infection11,12 and transmission risk increases when members of the same household are infected.13 Onychomycosis may occur at any age, however prevalence increases with age,14,15 affecting roughly 50% of patients greater than 70 years old,16 and is rather rare in the pediatric population, with increased risk seen in children with Down's syndrome or immunodeficiency.17
Onychomycosis, especially with secondary bacterial infections, can result in local pain and paresthesia, which pose significant psychosocial consequences. Limited dexterity and ambulation and difficulty finding comfortable fitting footwear can lead to social embarrassment and decreased self-esteem, which can be largely distressing, even when the infection is not severe.1,4 Patients also report stigmatization and dissatisfaction with the aesthetic appearance of their nails, and thus may avoid social interactions.18 In a systematic review of 30 studies evaluating the effect of onychomycosis and treatment on quality of life (QoL),19 women and patients with fingernail involvement had the poorest QoL scores. There were greater improvements in QoL with oral treatments versus topical therapies. Therefore, onychomycosis is more than just a cosmetic concern, and dermatologists and podiatrists should inquire about nail concerns during routine office visits in addition to evaluating all 20 nail units.1 In an analysis of the top 51 search engine hits for onychomycosis,20 overall readability was poor, with only one-third of websites meeting the acceptable seventh grade reading level for patients. Therefore, internet-based information about onychomycosis is lacking, highlighting the need for proper in-office patient education and counseling for this chronic and recurrent disease.
Pathogenic Organisms
The majority of onychomycosis cases are due to dermatophytes (60–90%), most commonly Trichophyton rubrum and T. mentagrophytes. Less common dermatophytes include T. verrucosum, T. violaceum, T. krajdenii, Epidermophyton floccosum, and Arthroderma spp., with infection due to Microsporum spp. being very rare. Cases secondary to dermatophyte infections are specifically referred to as tinea unguium.1,4,13 Infection with NDMs account for about 10% of cases worldwide, with the most common organisms being, Aspergillus spp., Fusarium spp., Acremonium spp., Scopulariopsis brevicaulis, Alternaria alternata, and Neoscytalidium spp.21–24 Yeast infections account for up to 10–20% of cases, with the most common pathogen being Candida spp., including C. albicans, C. krusei, C. parapsilosis, C. glabrata and C. tropicalis. Yeast infections are more frequent in the fingernails, especially if the hands are routinely submerged in water.4,25–27 Onychomycosis due to the yeast Kloeckera apiculata is uncommon but has been isolated in select cases.28,29 In children, infection with T. tonsurans may occur.13 Infections with two or more organisms can occur, and mixed dermatophyte-NDM infections account for estimated 3–11% of onychomycosis cases, which may potentially be more difficult to treat and more prone to recurrences.1,4 Importantly, prevalence and infecting pathogen can vary according to the population studied1 due to differences in geographic location, climates, and daily activities, including professions and personal habits. Specifically, prevalence in North America ranges from 8.7% to 13.8%14,25 and is predominately caused by dermatophytes due to immigration of dermatophytes from other parts of the world.30 Prevalence in Europe is broader at about 0.5–24%.5–8 In tropical and warmer climates, infection with NDM and yeasts are more common.31–33 Additionally, instead of acting planktonically (in suspension, independent, and free-floating), pathogens may merge into groups and form biofilms.4,34 Biofilms attach to surfaces, such as the nail plate, via an extracellular matrix,35 which protect fungi from host immune responses and give them increased virulence36 (Figure 1). Resultantly, biofilms may contribute to treatment resistance and difficulty controlling chronic infections.37,38
 | Figure 1 Scanning electron microscopy demonstrating mature fungal biofilms that were formed in 24-well plates. White arrows depict extracellular matrix covering and connecting the hyphae. (A) Trichophyton rubrum ATCC 28189. (B) Trichophyton mentagrophytes ATCC 11481. Reprinted from J Am Acad Dermatol, 1;80(4), Lipner SR, Scher RK, Onychomycosis: Clinical overview and diagnosis, 835–851, Copyright (2019), with permission from Elsevier.4 |
Clinical Presentation
History
Patients may fail to disclose nail conditions to their dermatologists or podiatrists due to the apprehension of discussing something that may seem trivial. Therefore, dermatologists and podiatrists must routinely inquire about nail problems as part of a complete history.1 Patients with onychomycosis typically complain of nail discoloration (most commonly yellow, white, or brown if the fungus is dense), nail separation, brittleness, and thickening.39 Symptoms may worsen progressively until the nail crumbles away,1 and in untreated cases, the skin may become sore and inflamed.40 Patients may report local pain and paresthesia in affected nails, trouble fitting into shoes, difficulty with ambulation, and social embarrassment.1,41 Medication use, including oral, topical, and over-the-counter therapies, should also be thoroughly reviewed with the patient, as diagnostic testing and treatment regimens can be impacted by current use of antifungals.4,42
Physical Examination
Onychomycosis may affect either fingernails or toenails or both,43 however, toenail involvement is much more common than fingernail involvement. For toenails, the great or second toenail is most frequently affected.44 Unless there has been antecedent trauma or the patient is immunosuppressed, it is unusual for a fingernail to be involved without concomitant toenail infection.1 Regardless, all 20 nails should be examined in clinical practice.24 Since it is common to have accompanying scale in the web spaces and/or plantar feet, dermatologists and podiatrists should perform a comprehensive physical examination including the hands and feet in addition to the nail units.4
Common physical examination findings include yellow nail plate discoloration and thickening and subungual hyperkeratosis, which may cause nail plate onycholysis (Figure 2). In severe cases, there may be onychodystrophy with nail plate ridging, thickening, and crumbling, onychocryptosis, and nail loss. Trauma may result in red, black, or brown nail plate discoloration (hematoma).1,4 Dermatophytomas are fungal abscesses that present as orange and brown or white and yellow longitudinal streaks or patches in the subungual space. NDM infections can also result in nail matrix involvement, causing periungual inflammation and tenderness.24 A standardized composite score, such as The Scoring Clinical Index for Onychomycosis, can be used to assess overall disease severity and aid in the development of an individualized treatment plan.45
 | Figure 2 Patient with laboratory confirmed onychomycosis. (A) Clinical appearance of toenails with onycholysis, nail plate thickening and subungual debris. (B) Dermoscopy showing ruin-like appearance and streaks of various colors. |
Dermoscopy
Dermoscopy can aid in differentiating between other nail diseases, including onychomycosis (Figure 2), psoriasis, pseudomonas colonization, and traumatic onycholysis.1,46 Typical dermatoscopic findings of onychomycosis are a jagged proximal margin of onycholysis and longitudinal striae, with vertical streaks of differing colors in the onycholytic area that resemble an aurora borealis.4,47 The subungual area may have a ruin-like appearance, representing hyperkeratosis and debris.48,49 Linear bands, multicolored or yellow/white patterns or streaks, subungual keratosis, reverse triangular or nonlongitudinal homogenous patterns, nail plate scales,50 and rarely, pseudo-Hutchinson sign or longitudinal patterns51 may be seen in fungal melanonychia. Importantly, dermoscopy should be used only as an aid and not for definitive diagnosis. Confirmatory testing should be performed prior to initiating both oral and topical treatments and is especially important considering that different nail pathologies can have similar clinical presentations.
Diagnostic Testing
History, clinical examination, and dermoscopy alone are not sufficient to make a definitive diagnosis of onychomycosis. Mycologic laboratory testing is necessary for diagnosis and is cost-effective.52 Laboratory confirmation is quick, easy to perform, and prevents treatment failures, inaccurate diagnoses, avoidable adverse effects, and possible drug–drug interactions.53,54 In 2013, the American Academy of Dermatology, as part of the ABIM Foundation's Choosing Wisely campaign, recommended that confirmatory testing of onychomycosis be performed before prescribing oral antifungal therapy.55 In a retrospective analysis of 1774 patients with a diagnosis of onychomycosis, 2002–2018,56 only 39.3% underwent diagnostic testing, with a steady decrease in testing from 2007 onwards, except for an isolated spike in 2014. Therefore, diagnostic testing for onychomycosis is underperformed, with a need for increased physician education regarding the importance of confirmatory testing. Prior to any diagnostic testing, a three-to-six-month washout period of antifungal therapies, including all oral, topical, and over-the-counter medications, should be performed. Antifungals may be retained in the subungual debris and nail plate, which may be transported to culture media and can impede fungal growth for culture as well as affecting other diagnostic tests.4,57
There are multiple techniques available for diagnosing onychomycosis (Table 1). The specific method should be chosen after careful consideration of patient characteristics, clinician expertise, and cost, sensitivity, specificity, and turnaround time for the result.4 For potassium hydroxide (KOH) and microscopy, fungal culture, and polymerase chain reaction (PCR), the nail is cleaned with 70% isopropyl alcohol and soap and water to prevent contamination of the sample with the skin flora and/or environment. The affected nail plate is then clipped1,39 (Figure 3), with the precise location of sample collection determined by the clinical presentation.4 The subungual debris can be scraped onto a paper with a contrasting background to better visualize the quantity collected.58 Histopathology does not require similar preparation of the sample. Sampling the nail is a specialized technique learned and perfected during residency training and physician experience is an integral component of this process. Patient performed clippings are not appropriate for diagnostic testing.59
 | Table 1 Summary of the Diagnostic Testing Methods |
 | Figure 3 A nail clipper is used to clip the most proximal area of onycholysis. |
KOH and Microscopy
Fungal elements can be visualized with microscopic examination (positive direct microscopy) of nail scrapings treated with 5–40% KOH.40,53 The addition of KOH aids in dissolving larger keratinocytes, making them flatter and limiting reflection of cell borders. Light microscopy is used to look for the presence or absence of fungal elements.39,60 Although KOH is the most frequently used reagent, alternative reagents include sodium sulfide, sodium hydroxide, Parker blue black ink, or calcofluor white. Calcofluor white requires use of a fluorescent microscope for visualization.4,40 Enhancement of KOH with chlorazol black E can increase sensitivity and cost-effectiveness.61 Light microscopy with staining can be performed in the clinic in a matter of minutes; however, it lacks sensitivity, especially for detection of NDMs, cannot determine fungal viability or provide precise fungal identification, and is dependent on clinician expertise.4,62
Fungal Culture
Fungal culture is the only technique that can identify both the organism and determine its viability. In the laboratory, sabouraud dextrose agar with cycloheximide (to encourage dermatophyte growth) or without cycloheximide (to culture NDMs) is used.63 Chloramphenicol and gentamicin can be added to the agar to inhibit growth of bacterial contaminants.40 The culture is grown at 25–30°C for up to a month. Alternatively, dermatophyte test medium is a simple and rapid method that can be utilized to culture dermatophytes. Alkaline metabolites are released upon growth of dermatophytes, with the increase in pH resulting in a color change from yellow to red approximately 10 to 14 days later.64 There are high rates of false-negatives (up to 40%) with fungal cultures, which can be even lower when there is residual antifungal medication and/or partial treatments.1,40 Insufficient incubation time or temperature as well as the presence of more than one species in a sample may also contribute.64,65 There is higher culture yield when there is adequate quantity of subungual debris for evaluation.66
Histopathology
Histopathology is performed on nail plate clippings in 10% buffered formalin,4,53 with turnaround time for results within days, and is more sensitive than both KOH and fungal culture.67 It may also be more reliable in ascertaining whether the pathogen is permeating the nail plate or merely colonizing the nail.52 Hematoxylin and eosin staining is used to visualize fungal elements. Periodic acid-Schiff (PAS) or Grocott methenamine-silver staining enhance visualization of the hyphae,1 which are the preferred staining methods.68 Immunofluorescence, Fontana-Masson, and Mayer mucicarmine stains can also be used.69 Histopathology can identify yeast, spores, hyphae, and pseudohyphae,4 but cannot identify or determine viability of the causative organism.1 Histopathology can also differentiate between other nail conditions, such as nail psoriasis.
PCR
PCR is a newer technique that uses specific primers to amplify DNA segments in order to identify dermatophytes, NDMs and Candida spp.1,40,70 Common targets include a gene fragment of the fungal small ribosomal subunit 18s rRNA, the chitin synthase I gene, the topoisomerase II gene, or the internal transcribed spacer region of ribosomal DNA.70,71 Distinction between yeasts, dermatophytes, and molds is possible by using ≥2 restriction enzymes to digest amplicons.72 Results are available within 24 to 48 hours40 and PCR is three to four times less likely than fungal culture to yield false-negatives.73 Potential false-positive results with PCR are due to the stability of fungal DNA and possible contaminants.40 The test is expensive compared to culture or microscopy,1 however it is becoming more widely available and is covered by many insurance plans.4 A similar technique is real-time PCR, which quantitates relative transcript amounts40 and provides indirect information on fungal viability.74 A commercial PCR kit is another alternative, which is more accessible than regular PCR, is cost-effective, has high sensitivity and specificity for diagnosing onychomycosis, can reduce delays in diagnoses, and may be more accurate than fungal culture, especially in cases of NDM infections.75–77
Artificial Intelligence (AI)
A convolutional neural network is a type of deep-learning algorithm that resembles the organization of the visual cortex78 and has been used to diagnose a variety of dermatologic conditions, including psoriasis, melanoma, non-melanoma skin cancer, rosacea, and atopic dermatitis.79–84
AI has also been applied for diagnosis of onychomycosis.78,85,86 In a prospective study of 90 patients with onychodystrophy of the toenails,78 clinical photographs of the nails were taken by nonphysicians and evaluated clinically by five board-certified dermatologists (mean 5.6 years of experience), as well as by two board-certified dermatologists using dermoscopy and compared to AI to diagnose onychomycosis. KOH microscopy or fungal culture was used to confirm the diagnosis in all cases. The area under the curve (AUC) value of the AI [0.751; 95% confidence interval (CI), 0.646–0.856] was comparable to dermoscopy (0.755; 95% CI, 0.654–0.855) (Delong's test; p = 0.952). The Youden index score (sensitivity+specificity-100%) of the AI (0.429) was also comparable to the mean Youden index score of the five board-certified dermatologists (0.230±0.176) (Wilcoxon rank-sum test; p = 0.667). In a study evaluating 1155 dermoscopic images (603 onychomycosis, 227 normal nails, 221 nail psoriasis, 104 traumatic onychodystrophy),85 the diagnostic performances between the AI and 54 dermatologists were compared. There was high specificity (>82%) of diagnosing onychomycosis for five dermoscopic nail plate patterns, including jagged edge, longitudinal striae, marble-like turbid areas, distal irregular termination, and cone-shaped keratosis. The Youden index of the AI (0.715) was significantly higher than mean Youden index of 54 dermatologists (0.427±0.188, 0.444±0.172) (p < 0.05). Not all diagnoses were confirmed by histology and the study included resident physicians. In a study comparing the diagnostic accuracy of AI to four dermatopathologists,87 199 PAS-stained nail tissue samples were evaluated, with 101 positive and 98 negative for onychomycosis, respectively. The AUC of the AI was 98.1% (CI 96.1–99.8%), with two senior dermatopathologists having higher AUC and specificity and two junior dermatopathologists having lower AUC and specificity than the AI. All dermatopathologists had higher sensitivity than the AI. Therefore, the use of AI on whole-slide images is statistically non-inferior regarding AUC and specificity compared with dermatopathologists using a conventional analogous setting with a microscope. Together, these studies show that AI may be an emerging tool that can be used to diagnose onychomycosis effectively and objectively. Prior to widespread adoption of new AI tools for onychomycosis diagnosis, more prospective studies incorporating AI into routine clinical workflow are necessary.
Treatment
Treatment for onychomycosis should be aimed at eliminating the fungal pathogen and restoring the normal state of the nail. This process can be quite slow, given that toenails and fingernails grow approximately 1 to 2 mm and 2 to 3 mm per month, respectively.88 It is important to educate patients that confirmation of the diagnosis is relatively quick compared to the amount of time that they had the condition, and that it is necessary to make sure of the diagnosis before starting treatment rather than treating empirically.53 Onychomycosis can mimic other benign conditions, including trauma, nail psoriasis, nail lichen planus, subungual exostosis, verruca, onychomatricoma, and bacterial infections, as well as malignant conditions, including squamous cell carcinoma and amelanotic melanoma.39 Empiric antifungal treatment in these cases increases the risk of unnecessary side effects, would not improve, and may even worsen, benign conditions, and may increase morbidity and mortality in cases of malignant conditions.53
There are several treatment options available for onychomycosis, including oral and topical antifungals, device-based therapies (ie, lasers), surgical nail avulsion, nail debridement, and combination therapies.40,88,89 Oral antifungals are generally recommended for moderate to severe onychomycosis and topical antifungals for mild to moderate disease2 (Tables 2 and 3). Nail debridement can decrease fungal load and can be used as an adjunct with topical therapies,40 while nail avulsion has limited use, primarily for cases of a painful and/or nongrowing single nail.90 Laser therapies are United States (US) Food and Drug Administration (FDA) approved for temporary increases in clear nail; however, cure rates are lower than for oral and topical antifungals with less rigorous endpoints required by the FDA for approval and definitive guidelines for use are currently lacking.1,2,88 Regardless, treatment plans should be individualized, with consideration of disease severity, infecting pathogen, medication cost, and patient comorbidities, medication history, and likelihood of compliance.88,89 Combination therapy should not be considered first-line treatment and should be reserved for patients with poor prognostic factors (ie, older age, immunosuppression, mixed infections) or for those who have failed monotherapy for onychomycosis.91 In a systematic review of race reporting in onychomycosis clinical trials, less than a fifth (17.5%; 32/182) of trials reported on race and/or ethnicity, with only one trial comparing treatment efficacy in different subgroups.92 Therefore, treatment recommendations garnered from these trials should be interpreted with caution in patients of color.
 | Table 2 Summary of Commonly Used Oral Onychomycosis Medications |
 | Table 3 Summary of FDA-Approved Topical Onychomycosis Medications |
Oral Therapies
Systemic medications are widely used for the treatment of onychomycosis due to their accessibility, high efficacy, and comparatively low cost.1,88 Oral medications reach the nail bed systemically and must penetrate the ventral nail plate.1,93 The amount of drug that can reach the infected site is therefore limited by low blood circulation to the nail bed.94 Oral medications may have poor penetration of biofilms95 and there is increased risk of serious side effects and drug–drug interactions.96
Currently, terbinafine, itraconazole, and griseofulvin are US FDA approved for onychomycosis treatment.88 Griseofulvin is rarely used because it requires longer treatment durations, with lower efficacy and higher risk of adverse events and recurrence compared to other oral antifungals.90 It is dosed at 375 up to 750 mg once daily for at least six months for toenails.2,97 Fluconazole is not US FDA approved of onychomycosis treatment but is frequently used off-label.40
Terbinafine
Terbinafine is an allylamine that inhibits squalene epoxidase, with broad-spectrum activity against dermatophytes and some activity against NDMs and Candida spp.98 It is dosed at 250 mg daily for 6 and 12 weeks for fingernails and toenail infections, respectively.88 The complete cure rates are 59% and 38% and the mycologic cure rates are 79% and 70% for fingernails and toenails, respectively.1 Potential side effects are mild and include headaches, rashes, and gastrointestinal symptoms. Rarely, hepatotoxicity and taste disturbances can occur.88,99 Although terbinafine-related hepatotoxicity is rare, patients are often hesitant to start terbinafine in fear of developing liver injury.100 In an analysis of 35 websites with information on terbinafine,100 only 51.4% provided accurate information on terbinafine-related hepatotoxicity and less than a quarter (20.0%) stated that hepatoxicity was rare. Few websites (11.4%) were authored by board-certified dermatologists. Therefore, accurate information regarding terbinafine-associated hepatotoxicity must be disseminated online in order to ease terbinafine fears and increase the likelihood of non-dermatologist providers and patients prescribing and accepting efficacious onychomycosis therapy, respectively.
According to the package insert, laboratory evaluation of liver function is recommended for all patients prior to initiating terbinafine therapy.101 Periodic laboratory monitoring during terbinafine treatment for adults is controversial.102 In a retrospective analysis of 944 adult patients taking a 12-week course of oral terbinafine for onychomycosis,103 only 2.4% and 2.8% of patients had abnormal monitoring liver function tests (LFT) and complete blood count (CBC) results, respectively, and were threefold more likely to be ≥65 years old versus the overall study population. In a retrospective analysis of 4309 adults and children taking terbinafine for dermatophyte infections, 2006–2016,104 grade 2 or higher monitoring ALT and AST elevations were found in only 0.2% and 0.07% of patients, respectively. Six patients (0.14%) discontinued treatment due to grade 1 to 3 terbinafine associated LFT abnormalities. In a retrospective review of the Taiwanese Longitudinal Health Insurance Database,105 12,376 patients took oral terbinafine with only two cases (0.016%) of drug-induced liver injury. Therefore, interval monitoring is unnecessary in healthy adults without preexisting hematologic and hepatic abnormalities but may be considered in older patients with comorbidities. There are fewer risk factors for terbinafine-induced hepatotoxicity in children, with no consensus regarding laboratory surveillance during treatment. In a retrospective analysis of 134 children prescribed terbinafine (average treatment course 8.2 weeks) for superficial fungal infections,106 0% and 1.7% had baseline and monitoring LFT elevations, respectively, and 3.9% and 4.4% had baseline and monitoring CBC elevations, respectively. All abnormal laboratory results were mild and resolved with treatment discontinuation or completion. In a retrospective review of 269 children prescribed terbinafine for onychomycosis,107 53.5% had laboratory monitoring of LFTs and/or CBC, with 23.6% before treatment and 70.8% before treatment and at 6 weeks. Most patients (87.5%) had normal laboratory results. Grade 1 abnormalities were noted in 8.3% and 4.2% of patients before or during therapy, respectively, with three patients discontinuing treatment. Therefore, monitoring tests in healthy children are also unnecessary. Baseline tests should be performed in both adults and pediatric patients to rule out pre-existing liver or hematologic diseases prior to initiating terbinafine treatment.
Terbinafine can be administered as pulse therapy as an off-label treatment option for onychomycosis and may be cost-effective and improve patient compliance.42,108 These pulse-dosed regimens have been studied in clinical trials but are not US FDA approved.88 In a meta-analysis evaluating different terbinafine treatment regimens for onychomycosis,109 a pulsed regimen of two cycles of 250 mg/day for four weeks on and four weeks off had similar mycologic cure rates to continuous terbinafine [risk ratio (RR) for intention to treat: 0.94 (95% CI: 0.74–1.19, p = 0.6, n = 2); RR for evaluable patients: 1.01 (95% CI: 0.84–1.22, p = 0.92, n = 2)]. Complete cure was also comparable to that of 12 weeks of continuous therapy (250 mg/day). In a systematic review of 30 studies comparing continuous and pulsed terbinafine regimens for treatment of onychomycosis,110 there were no significant differences in mycologic cure or likelihood of experiencing adverse events for terbinafine administered continuously (250 mg for 12 weeks) or pulsed (500 mg daily for one week per month, pulsed 3 times). Therefore, for patients that are hesitant to accept treatment with terbinafine, pulse treatment regimens can be considered since safety and efficacy are comparable to continuous treatments.
Itraconazole
Itraconazole is a triazole that inhibits lanosterol 14a-demethylase and is efficacious against dermatophytes, Candida spp. and NDMs.111,112 The dosing for toenails is 200 mg daily for 12 weeks and for fingernails is 200 mg twice daily for 1 week separated by 3 weeks of washout for 2 treatment pulses.88 The complete cure rates are 47% and 14% and the mycologic cure rates are 61% and 54% for fingernails and toenails, respectively. Potential side effects include headaches, upper respiratory tract infections, gastrointestinal symptoms, hypertriglyceridemia, elevated transaminases, and rarely, peripheral neuropathy and hepatitis.1,88 Drug–drug interactions are common and a thorough medication history should be performed prior to treatment initiation. Ventricular dysfunction, including congestive heart failure, is a contraindication to use.113
Booster Therapy
Additional doses of terbinafine or itraconazole can be used as booster or supplemental therapy after completion of the original full antifungal course.1,88 It may improve cure rates in onychomycosis patients with specific nail plate characteristics (lateral involvement, >2mm in thickness, >75% surface area involvement), slow growing nails, immunosuppression, and matrix involvement.114,115 The suggested dose is an additional four weeks of terbinafine or itraconazole six to nine months after the original initiation of antifungal treatment.116,117 However, booster therapy has not been studied in clinical trials, but given the low risk of additional oral therapy, it may be warranted in challenging cases.
Fluconazole
Fluconazole is a triazole that inhibits lanosterol 14a-demethylase. It is approved for onychomycosis treatment in Europe and China and is used off-label in the US, with efficacy against dermatophytes, Candida spp., and some NDMs.1,88 Due to a short residual concentration in the nails, longer treatment courses are necessary. Dosing for fingernails and toenails are 150 mg weekly for 6–9 months and 12–18 months, respectively.118,119 It may be challenging to remember to take fluconazole on a weekly rather than daily basis; therefore, patients can implement a reminder text or alarm notification system on their mobile devices to increase medication compliance.120 In a double blind, randomized study in 362 patients receiving fluconazole 150, 300, or 450 mg once weekly, complete cure rates were 37%, 46%, and 48%, respectively, for toenails at 12 months, with a low (4%) recurrence rate 6 months after treatment.121 The most common side effects include nausea, rash, headache, abdominal pain, and elevated LFTs. Rarely, liver injury or failure can occur, but is more common in immunosuppressed patients.122 Drug–drug interactions are also common, especially with warfarin and hypoglycemic agents.99 Fluconazole has advantages over itraconazole, including absorption that is non-dependent on gastric pH or food, once-weekly dosing, and ability to use in patients with comorbidities, including cardiac dysfunction.123 Prescribing patterns amongst dermatologists for fluconazole have trended upwards in recent years.124
In a 2017 Cochrane Review of 48 studies (10,200 participants) examining oral antifungal therapies for the treatment of toenail onychomycosis,125 terbinafine and the azoles were more effective in achieving clinical cure (RR 6.00, 95% CI 3.96–9.08; RR 22.18, 95% CI 12.63–38.95, respectively) and mycologic cure (RR 4.53, 95% CI 2.47–8.33; RR 5.86, 95% CI 3.23–10.62, respectively) compared to placebo. There was moderate quality evidence that terbinafine was likely more effective than the azoles for achieving clinical cure (RR 0.82, 95% CI 0.72–0.95) and mycologic cure (RR 0.77, 95% CI 0.68–0.88). There were no differences in recurrence rates (RR 1.11, 95% CI 0.68–1.79) or the risk of adverse events (RR 1.00, 95% CI 0.86–1.1) between terbinafine and the azoles, with the most common adverse events being headache, nausea, and viral infection in both groups.
Novel Oral Therapies
Recent attention has been given to novel oral therapies for use in onychomycosis treatment. Posaconazole is an extended-spectrum triazole that is approved in the US and Europe for oropharyngeal candidiasis and for prophylaxis of invasive fungal infections.126 In a phase IIb, randomized, multicenter study,126 218 adult patients with toenail onychomycosis received posaconazole (oral suspension) 100, 200, or 400 mg once daily for 24 weeks, posaconazole 400 mg once daily for 12 weeks, oral terbinafine 250 mg once daily for 12 weeks, or placebo for 24 weeks. All posaconazole groups had significantly greater proportions of patients achieving complete cure vs placebo at 48 weeks (p ≤ 0.012). Patients receiving posaconazole 200 or 400 mg for 24 weeks had higher complete cure rates (54.1%, 45.5%, respectively) vs terbinafine (37%), while complete cure was lower for patients taking posaconazole 400 mg for 12 weeks (20%) (p > 0.05, all). Mycologic cure at week 48 for patients taking posaconazole 200 mg and 400 mg for 24 weeks (70.3%, 78.8%, respectively) was similar to terbinafine (71.4%), while mycologic cure was lower for patients taking posaconazole 100 or 400 mg for 24 weeks (37.1%, 42.9% respectively). Posaconazole was well tolerated, with only 3.8% (7/182) of patients withdrawing from the study due to asymptomatic elevations in transaminases.
Fosravuconazole L-lysine ethanolate (F-RVCZ) is an azole prodrug of ravuconazole with improved bioavailability and hydrophilicity that is approved in Japan (100 mg/day for 3 months) for onychomycosis treatment.127 In a phase-III, multicenter, randomized, double-blind study,128 153 Japanese patients with toenail onychomycosis received either 100 mg F-RVCZ or placebo once daily for 12 weeks. At 48 weeks, the complete and mycologic cure rates were significantly higher in the F-RVCZ group (59.4%, 82.0%, respectively) vs placebo (5.8%, 20.0%, respectively) (p < 0.001, both). Adverse drug reactions were mild and reported in 23.8% of patients taking F-RVCZ.
Otesesconazole is a tetrazole that inhibits the lanosterol demethylase (CYP51) enzyme, which is required to produce the membrane lipid ergosterol necessary for fungal survival. It is not yet US FDA approved for onychomycosis treatment, but has been studied in recent clinical trials.129 In a phase II, multicenter, randomized, placebo-controlled, double-blind study,130 259 patients with toenail onychomycosis received either oteseconazole 300 mg or 600 mg once daily for 14 days, followed by a once-weekly dose for 10 or 22 weeks. At week 60, complete and mycologic cure rates were higher in the oteseconazole groups (41–45%, 65–75%, respectively) vs placebo (0%, 13%, respectively) (p < 0.001, all). All of these novel agents show promise as well-tolerated and efficacious onychomycosis treatment options but must be validated in phase III studies before widespread treatment recommendations can be made.
Topical Therapies
Topical medications for onychomycosis treatment are becoming increasingly popular because they may penetrate biofilms, have lower risks of drug–drug interactions given there is little to no systemic absorption of the medication, and do not require laboratory monitoring.88,96,131,132 Topical therapies must penetrate the nail plate to reach the transungual space where the fungus resides and applied concentrations must therefore be adequate to retain the minimal inhibitory concentration.1,93 There are barriers to penetration, including slow growth and thickness of the nail, a hard nail plate that functions as a concentrated hydrogel, an impermeable dense network of keratin fibers, and nails in diseased states (ie, thickened nail or nail plates that are detached from the nail bed). Nail keratin can also adversely affect antifungal activity.93,133–136 The newer topicals are costly and compliance may pose an issue due to lengthy treatment requirements (ie, 48 weeks for the toenails) and for patients with limited mobility and/or dexterity.1,88 Clear instructions outlining medication usage should be disseminated to patients in addition to counseling about common adverse effects.137 In a retrospective review of adverse events reported to the United States Food and Drug Administration Adverse Event Reporting database,137 the most common adverse reactions reported with ciclopirox 8% nail lacquer, efinaconazole 10% solution, and tavaborole 5% solution were drug ineffectiveness, with nail discoloration and application site erythema reported with all three drugs. Currently, ciclopirox 8% nail lacquer is US FDA approved for the treatment of fingernail and toenail onychomycosis and efinaconazole 10% solution and tavaborole 5% solution are approved for toenail onychomycosis.40 Amorolfine 5% nail lacquer is approved in Europe for onychomycosis treatment but is not available in the US.138
Ciclopirox
Ciclopirox 8% nail lacquer is a hydroxypyridone that chelates trivalent cations, resulting in inhibition of metal-dependent enzymes.139 It is effective against dermatophytes, Candida spp., and some NDMs and gram-positive and gram–negative bacteria.140 In two double-blind, placebo-controlled studies of 460 patients with onychomycosis of the great toenails without lunula involvement treated with ciclopirox 8% nail lacquer for 48 weeks, complete cure rates were between 5.5–8.5% and mycologic cure rates were between 29%-36%.141 A 2020 Cochrane Review found that ciclopirox 8% lacquer may be more effective than vehicle in achieving complete cure (RR 9.29, 95% CI 1.72–50.14) and mycologic cure (RR 3.15, 95% CI 1.93–5.12) based on two studies. There were little to no differences in adverse events observed (RR 1.61, 95% CI 0.89–2.9).142 Efficacy is increased with weekly nail clippings and monthly office debridement.143 Patients should be instructed to remove the lacquer with alcohol on a weekly basis.144 Side effects are localized and include periungual erythema, burning, and application site reactions.88
Efinaconazole
Efinaconazole 10% solution is a triazole that inhibits lanosterol 14a-demethylase, thereby disrupting ergosterol synthesis in the fungal cell membrane. It has activity against dermatophytes, Candida spp., and NDMs1 and is the preferred treatment in cases of dermatophytoma.2,145 In two multicenter, double-blind, randomized, vehicle-controlled phase III trials in 1665 patients (study 1: n = 870; study 2: n = 785) with DLSO of the toenail with 20–50% nail involvement,146 patients received efinaconazole or vehicle once daily for 48 weeks without debridement. Mycologic and complete cure rates were greater in efinaconazole (53.4–55.2%, 15.2–17.8%, respectively) vs vehicle (16.8–16.9%, 3.3–5.5%, respectively) groups (both p < 0.001). Adverse events were application site reactions and ingrown toenails, which were similar to vehicle treated patients. A 2020 Cochrane Review found that efinaconazole was more effective vs vehicle in achieving clinical cure (RR 3.07, 95% CI 2.08–4.53, 2 studies), complete cure (RR 3.54, 95% CI 2.24–5.60, 3 studies) and likely mycologic cure (RR 2.31, 95% CI 1.08–4.94, 3 studies). There was a slightly higher risk of adverse events with efinaconazole compared to placebo (RR 1.10, 95% CI 1.01–1.20, 3 studies).142
Efinaconazole should be applied to the affected toenails once daily for 48 weeks, including the skin around the nails (nail folds, hyponychium, and ventral surface of the nail plate) to increase medication delivery.147 In a study on human cadaver thumbnails painted with two coats of nail polish (three different brands),148 permeation of efinaconazole was 0.56% of the applied dose on day seven, with cumulative concentrations of efinaconazole in the receptor using Franz diffusion cells ranging from 13.6–16.1 μg/cm2 for polished nails versus 17.6 μg/cm2 for unpolished nails. There were no significant differences in efinaconazole levels between polished and unpolished nails at all time points. Therefore, removal of nail polish prior to application is unnecessary since it can penetrate nails coated with polish.148 However, the current formulation degrades nail polish.149,150 In a study on 13 female patients with distal lateral subungual onychomycosis (DLSO) of at least 1 great toenail (thickness ≤3 mm) treated with daily topical efinaconazole 10% solution for 52 weeks,151 average OSI scores in patients with concurrent nail polish use did not differ significantly from patients without nail polish use. Daily treatment with concurrent nail polish use was associated with diminished nail polish quality on average 60% of the time.
Tavaborole
Tavaborole 5% solution is a benzoxaborole that inhibits fungal aminoacyl transfer RNA synthetase and therefore protein synthesis,152 with broad-spectrum activity against dermatophytes, yeasts, and NDMs.1,88 In two multicenter, randomized, double-blind, vehicle-controlled trials, 1194 patients with onychomycosis affecting 20–60% of the toenail without dermatophytoma or lunula involvement were treated with tavaborole or vehicle once daily for 48 weeks, with mycologic and complete cure rates between 31.1–35.9% and 6.5–9.1%, respectively.153 A 2020 Cochrane review found that tavaborole is more effective than vehicle in achieving mycologic cure (RR 3.40, 95% CI 2.34–4.93) and likely complete cure (RR 7.40, 95% CI 2.71–20.24), but has a likely higher risk of adverse events (RR 3.82, 95% CI 1.65–8.85) based on two studies.142
Nail penetration of tavaborole is good due to its small size and hydrophilicity.154 In a prospective study,155 nails from cadaver donors were treated with 1, 2, or 4 coats of over-the-counter (OTC) or salon nail polish followed by tavaborole 5% topical solution applied to each nail once daily for 14 or 20 consecutive days. Tavaborole penetration through the nail was quantified using qualified liquid chromatography-tandem mass spectrometry and was compared to unpolished control nails. Mean cumulative tavaborole penetration on day 21 was higher for nails treated with 1 coat of OTC nail polish and tavaborole for 20 days (3526±1433 μg/cm2) vs unpolished nails (2661±1319 μg/cm2) (p > 0.05). Mean cumulative tavaborole penetration on day 15 for nails treated with tavaborole and 1 or 4 coats of salon nail polish (1227±974 μg/cm2, 1179 ± 554 μg/cm2, respectively) or 1 or 2 coats of OTC nail polish (1428±841 μg/cm2, 1493±1322 μg/cm2, respectively) for 14 days was higher vs control nails (566±318 μg/cm2), although significance was not assessed. Therefore, penetration is not significantly influenced by the application of cosmetic nail polish. Patients should be instructed to apply tavaborole daily for 48 weeks for toenail infections.40 Side effects are local and include erythema, dermatitis, and exfoliation.156
Amorolfine
Amorolfine 5% nail lacquer is a morpholine derivative that inhibits fungal enzymes 14-α reductase and 7,8 isomerase, thereby disrupting fungal sterol synthesis.157 It has activity against dermatophytes, molds, and some yeasts.158 In an open, randomized study of 456 patients with onychomycosis of the fingernails and/or toenails treated with amorolfine once or twice weekly for up to 6 months,159 complete cure was 46.0% and 54.2%, respectively, and mycologic cure was 70.6% and 76.1%, respectively, after three months of treatment. Mild local irritation occurred in 0.9% of patients. In a randomized, double-blind study of 80 patients with toenail onychomycosis applying daily 5% amorolfine,160 mycologic and complete cure rates were 60% and 38%, respectively. One patient reported mild burning sensation under the toenails. Amorolfine should be applied once or twice weekly to a cleaned nail plate and left for 3–5 minutes until dry. Organic solvents should be avoided when removing the lacquer.161 Since it penetrates the nail bed through the nail plate, concentrations remain for at least 14 days after application.162
Novel Topical Therapies
Novel topical formulations for onychomycosis as alternatives to traditional topical treatments have been of recent interest. In a phase III, multicenter, randomized, double-blind study,163 365 patients (ages 12–74) with 20–60% distal and lateral subungual onychomycosis of at least one toenail received a once daily application of topical terbinafine (MOB-015 formulation) or matching vehicle for 48 weeks. At week 52, mycologic and complete cure were higher in the MOB-015 (69.9%, 4.5%, respectively) vs vehicle (27.7%, 0%, respectively) groups (p < 0.001, p = 0.0195, respectively). Adverse events were mild to moderate and led to treatment discontinuation in 2.8% of patients in the MOB-015 group and 4.2% in the vehicle group. The formulation of the MOB-015 vehicle (urea, propylene glycol, lactic acid) may increase the opaqueness of the nail plate. These aesthetic color changes may interfere with analysis of complete cure and result in rates that were lower than expected.
Several other topical terbinafine formulations are still under investigation.1 Ciclopirox hydrolacquer (P-3051) is another novel topical therapy that is not approved for onychomycosis treatment in the US, but is approved and marketed in more t...
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