Onychomycosis: Management

INTRODUCTION — Onychomycosis, fungal infection of the nail, can cause disfigurement of the nail, pain, and may increase risk for soft tissue bacterial infection in immunocompromised patients. Dermatophytes, particularly Trichophyton rubrum, are the most common causes of onychomycosis. Yeast (eg, Candida albicans) and nondermatophyte molds can also cause onychomycosis. (See "Onychomycosis: Epidemiology, clinical features, and diagnosis".)

Therapeutic options for onychomycosis include oral antifungal medications, topical antifungal medications, and physical interventions. Factors such as the causative organism, severity of nail involvement, treatment side effects, and patient preference influence treatment selection.

The management of onychomycosis will be reviewed here. The clinical features and diagnosis of onychomycosis are reviewed separately. (See "Onychomycosis: Epidemiology, clinical features, and diagnosis".)

APPROACH TO TREATMENT

Patient selection — Treatment of onychomycosis is not mandatory in all patients. We suggest treating onychomycosis in:

●Patients with a history of cellulitis of the lower extremity, especially if repeated, who have ipsilateral toenail onychomycosis

●Patients with diabetes and toenail onychomycosis who have additional risk factors for cellulitis (ie, prior cellulitis, venous insufficiency, edema) [1] (see "Cellulitis and skin abscess: Epidemiology, microbiology, clinical manifestations, and diagnosis", section on 'Cellulitis and erysipelas')

●Patients who are experiencing discomfort or pain associated with infected nails [2-4]

●Immunosuppressed patients

●Patients who desire treatment for cosmetic reasons

Treatment options — Treatment options for onychomycosis include topical and systemic antifungal drugs, laser treatment, photodynamic therapy (PDT), and surgery. In addition, patients with symptomatic onychomycosis may benefit from measures to reduce discomfort regardless of whether they proceed with curative treatments. (See 'Symptom relief' below.)

Topical and systemic antifungal drugs are the mainstays of therapy. Factors that may influence the selection of topical versus systemic therapy include the clinical subtype, causative organism, disease severity, treatment side effects, feasibility of monitoring for side effects, treatment availability, and cost. The major advantage of topical therapy is the negligible risk for serious adverse effects and drug interactions compared with systemic antifungal therapy. However, topical therapy typically requires longer treatment courses than systemic therapy and may be less effective, particularly for disease that is extensive or associated with involvement of the nail matrix and lunula. (See "Onychomycosis: Epidemiology, clinical features, and diagnosis", section on 'Clinical features' and "Onychomycosis: Epidemiology, clinical features, and diagnosis", section on 'Additional findings'.)

Despite the availability of multiple therapies, onychomycosis can be challenging to treat. Treatment failure and disease recurrence are common. (See 'Treatment failure' below and 'Recurrence' below.)

Pretreatment diagnostic testing — Given the broad differential diagnosis of nail dystrophy, we prefer to confirm the presence of fungi prior to treatment.

Tests typically used to confirm onychomycosis in the clinical setting include potassium hydroxide (KOH) preparations, fungal cultures, histopathologic examination with a periodic acid-Schiff (PAS) stain, and polymerase chain reaction (PCR) [5]. In addition, fungal cultures and PCR can identify the type of fungus present, and fungal culture can confirm fungal viability, supporting the presence of active infection. The approach to diagnosis of onychomycosis is reviewed separately (algorithm 1). (See "Onychomycosis: Epidemiology, clinical features, and diagnosis", section on 'Diagnosis' and "Onychomycosis: Epidemiology, clinical features, and diagnosis", section on 'Differential diagnosis'.)

If the initial test that supports fungal infection of the nail does not identify the causative organism (eg, KOH preparation or PAS stain) and testing to confirm the causative organism will have delayed results (eg, fungal culture) or cannot be performed, patients can be treated empirically for dermatophyte infection (the most common cause of onychomycosis) unless the clinical scenario suggests another etiology. As an example, fingernail onychomycosis occurring in association with chronic paronychia is suggestive of Candida infection. Later, if culture results support a yeast or nondermatophyte mold infection, therapy can be adjusted appropriately. (See 'Dermatophyte onychomycosis' below and 'Yeast and nondermatophyte mold onychomycosis' below.)

However, the cost-effectiveness of diagnostic testing prior to treatment has been questioned. An analysis of published study data that compared costs of immediate terbinafine treatment, treatment after a positive KOH preparation (or after a positive PAS stain in patients with KOH-negative results), and treatment after PAS testing in patients with suspected onychomycosis in the United States found that empirical terbinafine treatment was associated with reduced cost (per-patient cost savings of $47 and $135 for KOH screening and PAS testing models, respectively) and minimal impact on patient safety [6]. This finding is not applicable to all therapies and all locales and may change over time. Empirical treatment with topical efinaconazole did not appear to be cost-effective [6].

DERMATOPHYTE ONYCHOMYCOSIS — Disease severity influences the therapeutic options for dermatophyte onychomycosis. For mild to moderate known or suspected dermatophyte onychomycosis (eg, distal lateral subungual onychomycosis involving ≤50 percent of the nail and sparing the matrix/lunula), both systemic and topical therapies are options, whereas systemic therapy is the treatment of choice for more severe disease (eg, distal lateral subungual onychomycosis with involvement of >50 percent of the nail or involvement of the matrix/lunula, proximal subungual onychomycosis, or total dystrophic onychomycosis). Local treatment is often sufficient for white superficial onychomycosis because of the superficial location of infection. (See "Onychomycosis: Epidemiology, clinical features, and diagnosis", section on 'Clinical features' and 'Mild to moderate dermatophyte onychomycosis' below and 'Moderate to severe dermatophyte onychomycosis' below and 'White superficial onychomycosis' below.)

Mild to moderate dermatophyte onychomycosis

Treatment selection — First-line treatment options for mild to moderate onychomycosis (eg, distal lateral subungual onychomycosis involving ≤50 percent involvement of the nail and sparing the matrix/lunula) include oral terbinafine and several topical agents including efinaconazole, amorolfine, tavaborole, and ciclopirox.

Although oral antifungal therapy is considered the gold standard treatment for onychomycosis because of higher complete cure rates and shorter courses of treatment when compared with topical therapy, the clinical scenario determines whether oral therapy is the most appropriate first-line treatment for mild to moderate onychomycosis. Examples of scenarios in which topical therapy may be preferred include:

●Patients with contraindications to systemic antifungal therapy

●Patients at risk for drug-drug interactions with systemic antifungal drugs

●Patients who prefer to avoid systemic treatment (especially with three or fewer nails involved)

Children may be more favorable candidates for topical therapy than adults because of a thinner nail plate and potentially faster nail growth rate. A small randomized trial suggested that the likelihood of response to topical ciclopirox is higher in children [7]. (See "Ciclopirox: Drug information".)

The cost of therapies for onychomycosis varies widely and may influence treatment selection. In 2015, a course of oral terbinafine could be obtained for as low as $10 in the United States. In contrast the cost of a course of treatment with efinaconazole was greater than $2000 [6].

Oral terbinafine — Terbinafine is the first-line oral agent for mild to moderate dermatophyte onychomycosis. Treatment is given in the same manner as terbinafine therapy for more severe disease. Itraconazole is an alternative systemic treatment for patients who cannot tolerate terbinafine or fail to respond to terbinafine. (See 'Moderate to severe dermatophyte onychomycosis' below.)

Topical therapy — First-line topical therapies include efinaconazole, amorolfine, tavaborole, and ciclopirox. High-quality, head-to-head trials are lacking, leaving insufficient data for definitive conclusions on the comparative efficacy of these therapies.

Topical treatment is limited to agents specifically indicated for nail disease. Topical antifungal agents developed for cutaneous fungal infections generally are poorly effective for onychomycosis because of poor penetration of the nail plate [8-10].

Efinaconazole — Efinaconazole is a topical triazole antifungal agent. The efficacy of efinaconazole for onychomycosis was demonstrated in two phase III multicenter randomized trials (n = 870 and n = 785) in which patients with dermatophytic or dermatophytic and candidal distal lateral subungual onychomycosis involving 20 to 50 percent of the target toenail and sparing the matrix and lunula were randomized in a 3 to 1 ratio to treatment with efinaconazole 10% solution or vehicle once daily for 48 weeks [11]. Four weeks after the end of treatment, complete cure (0 percent clinical involvement of the target nail and mycologic cure) was achieved by 18 and 15 percent of patients treated with efinaconazole compared with only 3 and 6 percent of patients treated with vehicle. Evaluation of the secondary endpoint of complete or almost complete cure (≤5 percent clinical involvement of the target toenail and mycologic cure) yielded response rates of 26 and 23 percent with efinaconazole and 7 and 8 percent for placebo.

Efinaconazole 10% solution is applied directly to the nails once daily for 48 weeks. One drop is applied to the surface of each affected nail; for the great toenail, an additional drop should be applied at the end of the toenail. The application brush is used to spread the solution to the toenail bed, adjacent nail folds, hyponychium, and undersurface of the nail plate. Avoidance of pedicures, nail polish, or cosmetic nail products is recommended during treatment.

Efinaconazole is well tolerated. Ingrown toenails and local skin irritation or discomfort occur infrequently.

Amorolfine — Amorolfine is a topical antifungal agent with activity against dermatophytes, yeasts, dimorphic fungi, and a variety of filamentous and dematiaceous fungi [12]. The drug is not available in the United States.

In two dose-comparison randomized trials, once-weekly application of amorolfine 5% nail lacquer for six months to onychomycosis involving less than 80 percent of the nail surface and lacking involvement of the nail matrix and lunula led to both clinical cure and mycologic cure in 38 and 46 percent of patients [13,14]. Of note, clinical cure was defined as complete clearance or ≤10 percent of nail remaining affected in one trial [14] and was not clearly defined in the other trial [13].

In addition, there is evidence that amorolfine may increase cure rates when used in combination with oral antifungals [15]. In a randomized, open-label trial comparing terbinafine (250 mg per day for three months) plus amorolfine (once weekly for 12 months) versus terbinafine alone, patients who received combination therapy were more likely to achieve both clinical and mycologic cure (59 versus 45 percent) [16]. Further studies are necessary to determine which patients should be treated with combination therapy.

Amorolfine is applied once weekly after the surface of the nail is filed with a disposable file and wiped with alcohol. Fingernails are generally treated for six months; toenails are treated for 9 to 12 months. Local skin irritation is an uncommon side effect [14]. The lower frequency of application (once weekly) compared with therapies requiring daily application may facilitate adherence to therapy [17].

Tavaborole — Tavaborole 5% solution is an oxaborole antifungal agent. Tavaborole was evaluated in two multicenter randomized trials in which a total of 1194 patients with onychomycosis applied tavaborole 5% solution or vehicle once daily for 48 weeks. Patients in the trials had 20 to 60 percent involvement of the target toenail and lacked both clinical evidence of a dermatophytoma and involvement of the lunula [18]. In one trial, 7 percent of patients treated with tavaborole achieved both clinical cure (no clinical evidence of onychomycosis) and mycologic cure after treatment compared with only 1 percent of patients in the vehicle group. In the second trial, these rates were 9 and 2 percent, respectively. Rates of completely or almost clear nail (<10 percent of the distal nail dystrophic or discolored and minimal onycholysis or subungual hyperkeratosis) plus negative mycology in the two trials were 15 and 18 percent for tavaborole versus 2 and 4 percent for vehicle.

Tavaborole 5% solution is applied to the surface and under the distal tip of infected toenails once daily for 48 weeks. Potential side effects include ingrown toenail and local skin exfoliation or irritation.

Ciclopirox — Ciclopirox is a hydroxypyridone derivative with activity against dermatophytes, yeasts, and molds [19]. Combined results from two randomized, controlled trials (n = 223 and n = 237) that included patients with distal subungual onychomycosis involving 20 to 65 percent of the target nail suggest that complete resolution occurs in approximately 7 percent of patients treated with ciclopirox 8% nail lacquer daily for 48 weeks compared with 0.4 percent using placebo [20]. A small randomized trial suggested that the likelihood of response to topical ciclopirox may be better in children; however, additional studies are necessary to confirm this finding [7].

Randomized trials have also evaluated the efficacy of ciclopirox in combination with oral terbinafine [21,22]. No greater clinical efficacy was found than with terbinafine alone. The studies reported higher rates of mycologic cure with combination therapy; however, this was assessed while the patients were still being treated with topical ciclopirox, which may have affected the ability to detect persistent fungal infection.

Ciclopirox 8% nail lacquer is applied once daily to the affected nail, 5 mm of surrounding skin, and to the nail bed, hyponychium, and undersurface of the nail plate if possible. The nail is wiped clean with alcohol once weekly, and the unattached infected part of the nail is removed periodically. Treatment is continued until nail clearance or up to 48 weeks [8].

Ciclopirox is a well-tolerated treatment [23]. Potential side effects include temporary nail changes and local skin irritation.

Moderate to severe dermatophyte onychomycosis — Oral terbinafine is the first-line treatment for moderate to severe dermatophyte onychomycosis (eg, dermatophyte onychomycosis involving >50 percent of the nail or involving the matrix or lunula, proximal subungual onychomycosis, or total dystrophic onychomycosis). Itraconazole is an alternative systemic treatment for patients who cannot tolerate terbinafine or fail to respond to terbinafine.

Oral terbinafine — Terbinafine is an allylamine antifungal drug with fungicidal activity:

●Efficacy – Randomized trial data support the efficacy of oral terbinafine for onychomycosis [24,25]. A systematic review and meta-analysis of randomized trials evaluating oral antifungal therapy for toenail onychomycosis found high-quality evidence for superiority of terbinafine over placebo for achieving clinical and mycologic cure (risk ratio [RR] 6.00, 95% CI 3.96-9.08 and 4.53, 95% CI 2.47-8.33, respectively) [26].

Terbinafine may have advantages over itraconazole and other azoles. The systematic review and meta-analysis found moderate-quality evidence for superiority of terbinafine over azoles (itraconazole, fluconazole, albaconazole, posaconazole, ravuconazole) in achievement of clinical or mycologic cure (RR 0.82, 95% CI 0.72-0.95 and 0.77, 95% CI 0.68-0.88, respectively) with similar rates of adverse effects.

There is low-quality evidence from randomized trials suggesting similar recurrence rates following terbinafine and azole therapy [26]. However, specifically for itraconazole, a randomized, double-blind trial found terbinafine more effective than itraconazole pulse therapy on measures of long-term clinical outcomes [27]. In addition, long-term cure rates appear to be better with terbinafine than with a continuous itraconazole regimen [28,29].

●Administration – Terbinafine is administered daily [30]. The following regimen is used for adults:

•Fingernail onychomycosis – 250 mg per day for 6 weeks

•Toenail onychomycosis – 250 mg per day for 12 weeks

Weight-based pediatric dose regimens include [31]:

•Terbinafine (6 weeks for fingernails; 12 weeks for toenails):

-10 to 20 kg – 62.5 mg daily

-20 to 40 kg – 125 mg daily

-Above 40 kg – 250 mg daily

We typically use the continuous treatment regimens described above; however, pulse dosing of terbinafine has been advocated by some clinicians as a potential way to reduce risk for side effects, reduce cost, and improve patient compliance during treatment. These benefits have not been confirmed in clinical trials.

Pulse regimens vary in dose, duration, and frequency of drug administration [32,33]. A 2013 meta-analysis of studies that compared cure rates for continuous treatment with one of four pulsed treatment regimens found that overall, continuous treatment was superior to pulsed treatment for achieving mycologic cure and had similar efficacy as pulsed treatment for achieving complete (both clinical and mycologic) cure [32]. Of the pulsed regimens evaluated, only a two-pulse regimen consisting of 250 mg per day for four weeks, then four weeks off, then an additional four weeks of treatment yielded mycologic cure rates similar to continuous therapy.

In patients receiving continuous therapy, monitoring of transaminase levels is typically performed at baseline and repeated at six weeks if therapy will continue beyond six weeks. However, the need for repetition of transaminase levels after baseline testing has been questioned [34-36]. A retrospective study that included laboratory data from 4985 children and adults treated with terbinafine or griseofulvin for dermatophyte infections found rates of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) elevations, anemia, lymphopenia, and neutropenia during 4309 courses of terbinafine therapy were low and similar to baseline rates [36]. Another retrospective study found a low incidence of laboratory abnormalities among 144 children treated with terbinafine for onychomycosis who had laboratory monitoring [34]. Only six children developed liver function test or complete blood count abnormalities during treatment, all of which were grade 1 events (table 1). These findings suggest transaminase monitoring after baseline testing may be unnecessary in patients without underlying hepatic diseases.

The need for baseline laboratory monitoring in children also has been questioned based upon a low likelihood for the detection of clinically significant abnormalities and an unclear relationship between baseline transaminase abnormalities and risk for terbinafine-induced liver injury [35]. Additional study is necessary to clarify the best approach to laboratory monitoring in adults and children treated with terbinafine.

●Adverse effects – Examples of side effects of oral terbinafine include headache, dermatitis, gastrointestinal distress, taste disturbances, and liver enzyme abnormalities. Rare serious drug eruptions such as Stevens-Johnson syndrome may occur. Severe hepatic toxicity and thrombotic microangiopathy (including thrombotic thrombocytopenic purpura and hemolytic uremic syndrome) are rare, potentially fatal side effects [37].

Terbinafine is an inhibitor of CYP2D6. Clinicians should be aware of the potential for drug-drug interactions.

Itraconazole — Itraconazole, a triazole antifungal drug that is primarily fungistatic, is a second-line systemic antifungal therapy for dermatophyte onychomycosis primarily used for patients who cannot tolerate oral terbinafine or fail to respond to oral terbinafine. The potential for drug-drug interactions is higher for itraconazole than terbinafine (see "Pharmacology of azoles", section on 'Drug interactions'):

●Efficacy – Use of itraconazole for onychomycosis stems from efficacy demonstrated in randomized trials [24-26]. A systematic review of randomized trials evaluating systemic antifungal drugs for toenail dermatophyte onychomycosis found mycologic cure rates of 63±7 percent for pulsed itraconazole and 59±5 percent for continuous itraconazole therapy [24]. Pooled rates of clinical response (clinical cure or marked improvement) were 70±11 percent and 70±5 percent, respectively.

●Administration – Both continuous and pulse therapy are accepted oral regimens for onychomycosis. Standard regimens for adults are:

•Pulse therapy:

-Fingernail onychomycosis – 200 mg twice daily for one week per month for two months

-Toenail onychomycosis – 200 mg twice daily for one week per month for three months

•Continuous therapy:

-Fingernail onychomycosis – 200 mg per day for 6 weeks

-Toenail onychomycosis – 200 mg per day for 12 weeks

Children can be treated with the following regimen:

•Itraconazole daily for one week per month (two months of therapy for fingernails; three months of therapy for toenails):

-Less than 20 kg – 5 mg/kg per day

-20 to 40 kg – 100 mg per day

-40 to 50 kg – 200 mg per day

-More than 50 kg – 200 mg twice daily

Liver function tests should be monitored in patients with preexisting liver disease and in all patients receiving treatment for more than one month.

●Adverse effects – Itraconazole therapy may lead to side effects, such as headache, gastrointestinal effects, and liver function abnormalities. Severe hepatotoxicity is an uncommon side effect. Itraconazole is contraindicated in patients with ventricular dysfunction (eg, congestive heart failure). Adverse effects are reviewed in greater detail separately. (See "Pharmacology of azoles", section on 'Adverse effects'.)

Itraconazole is a strong inhibitor of CYP3A4, which places patients at risk for multiple drug-drug interactions. (See "Pharmacology of azoles", section on 'Drug interactions'.)

White superficial onychomycosis — White superficial onychomycosis (WSO) usually can be treated by mechanical removal of the involved area (ie, scraping the superficial nail plate) followed by use of a topical antifungal agent for onychomycosis [38,39]. The duration of topical antifungal treatment is dependent on the clinical response. Up to several months of topical treatment may be required [39]. (See 'Topical therapy' above.)

Clinical experience suggests that systemic therapy (with or without concomitant topical antifungal therapy) may be the treatment of choice for WSO that occurs in association with other clinical subtypes of onychomycosis or that appears to originate from the proximal nail fold [38]. The approach to systemic therapy is similar to that used for other forms of onychomycosis and is dependent on the causative organism. Dermatophytes are responsible for most cases of WSO. Occasionally, WSO is caused by yeast or nondermatophyte molds. (See 'Moderate to severe dermatophyte onychomycosis' above and 'Yeast and nondermatophyte mold onychomycosis' below.)

YEAST AND NONDERMATOPHYTE MOLD ONYCHOMYCOSIS — Data on the comparative efficacy of therapies for onychomycosis caused by yeast (mainly C. albicans) or nondermatophyte molds are limited. Itraconazole is considered the treatment of choice for these patients [40-43]. The dose used is the same as the dose regimen for dermatophyte onychomycosis. Oral terbinafine may also be effective in some cases [44,45].

The topical therapies (efinaconazole, amorolfine, tavaborole, and ciclopirox) have some activity against yeasts and nondermatophyte molds [46,47]. Further study is necessary to clarify the efficacy of these agents as monotherapy for nondermatophyte onychomycosis. (See 'Topical therapy' above.)

The treatment of Fusarium onychomycosis in immunocompromised patients is reviewed separately. (See "Treatment and prevention of Fusarium infection", section on 'Onychomycosis'.)

SYMPTOM RELIEF — Thick, dystrophic nails can make it difficult for patients to trim nails and may lead to pain during ambulation. The removal of hyperkeratotic nail debris may help to ameliorate these symptoms.

Topical urea is a keratolytic agent that we have found useful for this purpose in patients who forgo antifungal treatment and as an adjunctive measure in those who proceed with treatment [48-50]. For patients with very thick, dystrophic nails, we utilize the following nighttime regimen:

●Apply a generous, protective layer of petrolatum to the periungual skin

●Apply a thick layer of topical urea 40% cream or ointment to the nail

●Occlude the nail with a bandage or tape and leave on overnight

●Wash the topical urea off with soap and water in the morning

●Repeat this procedure nightly until the nail softens and can be easily clipped or debrided

Reapplication of topical urea without occlusion on an as-needed basis can be used to maintain improvement. Treatment without occlusion also is often sufficient for reducing nail hyperkeratosis in patients with less severe nail thickening.

OTHER THERAPIES — Less common therapeutic interventions for onychomycosis include oral antifungal agents other than terbinafine and itraconazole, laser therapy, photodynamic therapy, and surgical nail removal.

Alternative oral antifungal drugs — Fluconazole, 150 to 450 mg once weekly for adults, has been effective for onychomycosis and may be useful in patients with complicated medication regimens [26,51,52]. However, head-to-head comparisons have not found once weekly fluconazole to be as effective or as cost-effective as itraconazole and terbinafine [53-55]. In addition, longer treatment courses (ie, three months for fingernail onychomycosis and at least six months for toenail infection) are generally needed [52].

Griseofulvin has been used for the treatment of onychomycosis. A systematic review and meta-analysis of randomized trials found moderate-quality evidence in support of similar efficacy of azoles and griseofulvin for achieving clinical and mycologic cure (risk ratio [RR] 0.94, 95% CI 0.45-1.96 and 0.87, 95% CI 0.50-1.51, respectively) and low-quality evidence in support of greater efficacy of terbinafine over griseofulvin for these endpoints (RR 0.32, 95% CI 0.14-0.72 and 0.64, 95% CI 0.46-0.90, respectively) [26]. A disadvantage of griseofulvin is the need for prolonged courses of treatment (four to six months or longer). Compared with terbinafine and azoles, griseofulvin may also be associated with increased risk for adverse effects (eg, gastrointestinal distress) [26].

Posaconazole, a newer oral broad spectrum antifungal agent, may be effective for onychomycosis. In a phase II randomized trial (n = 218), posaconazole oral suspension (100 mg, 200 mg, or 400 mg daily for 24 weeks or 400 mg once daily for 12 weeks) was compared with terbinafine (250 mg daily for 12 weeks) and placebo [56]. At the 48-week assessment, all dose regimens of posaconazole were superior to placebo. The best results with posaconazole were obtained when patients were given 200 mg or 400 mg daily for 24 weeks (54 and 46 percent complete cured, respectively); the cure rates in these groups did not differ significantly from the terbinafine group (37 percent cured). Adverse event rates were similar among the groups. The high cost of posaconazole favors the preferred use of other systemic therapies. (See 'Oral terbinafine' above and 'Itraconazole' above.)

Albaconazole is a broad spectrum oral antifungal agent that is not commercially available. A phase II randomized trial that found that albaconazole was more effective than placebo for distal subungual onychomycosis suggests that this drug may be a future treatment option for onychomycosis [57]. Other antifungal agents that may be useful for onychomycosis are in development, including VT-1161, a new generation (tetrazole antifungal) inhibitor of lanosterol 14-alpha demethylase (CYP 51) [58].

Oral ketoconazole should not be used for the treatment of onychomycosis. The drug is an unfavorable choice because of risk for life-threatening hepatotoxicity, adrenal insufficiency, and multiple drug-drug interactions [59]. (See "Tinea versicolor (pityriasis versicolor)", section on 'Other therapies'.)

Lasers — Although neodymium-doped:yttrium aluminum garnet (Nd:YAG) and diode lasers have emerged as treatment options for onychomycosis, data on the efficacy of these interventions are limited, and the mechanisms of action and optimal regimens for these treatments remain unclear [60-62]. Until more robust data supporting the efficacy of laser therapy for onychomycosis are available, we cannot recommend the routine use of this modality.

Support for the efficacy of such laser devices is primarily limited to uncontrolled studies that document clinical improvement in varying proportions of patients [63-68]. One small randomized trial found improvement in onychomycosis following the use of a dual wavelength near-infrared diode laser [69].

Randomized trials of Nd:YAG lasers in onychomycosis have yielded poor results [70,71]. A randomized trial in which 27 patients with onychomycosis involving 125 nails were randomly assigned to two treatments with a 1064 nm Nd:YAG laser (17 patients) or no treatment (10 patients) did not find a statistical difference in the proportion of patients with mycologic clearance of all affected nails after three months [70]. In addition, a nonsignificant trend towards greater proximal nail clearance in the active treatment group detected at the three-month time point dissipated by 12 months. Of note, responses could not be assessed in 5 of the 17 patients in the laser treatment group because of a failure to return for follow-up. Moreover, a separate randomized trial compared a series of four treatments with a short-pulsed 1064 nm Nd:YAG laser to no laser treatment in 20 patients with 82 onychomycotic nails [71]. The trial found laser treatment ineffective for achieving mycologic remission or clinical improvement.

Proposed mechanisms of action for laser therapy for onychomycosis include direct fungicidal effects, inhibition of fungus by laser-induced changes in the tissue environment, and laser-induced immunologic effects [72], though an in vitro study evaluating the effects of a submillisecond Nd:YAG laser on fungal nail pathogens did not find support for a laser-induced direct fungicidal effect [63]. Further study with randomized trials that compare laser devices with placebo and other onychomycosis treatments as well as long-term, follow-up studies will be useful for clarifying the efficacy, mechanisms, optimal regimens, and indications for laser therapy.

Additional study will also be useful for determining whether combination therapy with an ablative fractional laser and a topical antifungal agent is effective for onychomycosis. In an uncontrolled study in which 24 patients with onychomycosis underwent three treatment sessions with an ablative fractional carbon dioxide (CO₂) laser and once-daily application of topical amorolfine for 12 weeks, complete responses (normal-appearing nail and negative microscopic examination for fungus) were documented in 50 percent of patients after 12 weeks [73]. This included all four patients with superficial white onychomycosis, 8 of 14 patients with distolateral subungual onychomycosis (57 percent), and none of six patients with total dystrophic onychomycosis. The authors of the study postulated that ablative fractional laser therapy might induce direct fungicidal effects, and the numerous vertical columns of tissue damage created by these lasers might increase penetration of a topical antifungal agent. Topical amorolfine is not available in the United States. (See "Ablative laser resurfacing for skin rejuvenation", section on 'Mechanism'.)

Photodynamic therapy — Photodynamic therapy has been studied for the treatment of onychomycosis [60]. The procedure involves the application of a topical photosensitizer followed by irradiation of the treatment site with an appropriate light source. Successful treatment with this modality was reported in case reports and a small, open-label study [74-77].

Surgery — Surgical removal of the nail (nail avulsion) is typically reserved for patients who cannot be successfully treated with pharmacologic therapy alone [78]. Topical or systemic antifungal therapy is usually initiated after surgery. Recurrences are common in the absence of subsequent systemic or topical treatment. (See "Nail avulsion and chemical matricectomy", section on 'Nail avulsion'.)

Efficacy data on nail avulsion followed by antifungal therapy are limited. In a randomized trial comparing the results of four different topical ketoconazole or oxiconazole regimens after nail avulsion in 40 patients with onychomycosis, approximately one-third of patients failed to complete therapy and among patients who completed therapy, mycologic cure rates were between 33 and 75 percent [79]. Patients with total dystrophic onychomycosis were least likely to benefit from treatment.

Other — Iontophoretic drug delivery, in which a low electrical current is used to enhance the absorption of topical medications, may have promise for improving the efficacy of topical antifungal treatment [80-82]. In a small, unblinded, randomized trial that compared treatment of toenail onychomycosis with topical terbinafine plus iontophoresis with topical terbinafine alone, combination therapy appeared to increase the likelihood for new healthy nail growth [80]. Additional studies are necessary to determine the role of iontophoresis in the treatment of onychomycosis.

There are few data on the efficacy of a medicated chest rub containing eucalyptus oil, camphor, menthol, thymol, oil of turpentine, oil of nutmeg, and oil of cedar leaf (eg, Vicks VapoRub) in the treatment of onychomycosis. In a series of 18 patients who were instructed to apply this type of medicated chest rub to affected nails daily for 48 weeks, four patients (22 percent) achieved both clinical and mycologic cure [83]. Improvement in a minority of patients was also reported in a retrospective chart review; clinical clearance of onychomycosis was documented within 5 to 16 months in 32 out of 85 patients (38 percent) who agreed to apply a generic formulation of a medicated chest rub to the nails daily [84]. Although use of medicated chest rubs and similar products is unlikely to be harmful, additional studies that support their efficacy in onychomycosis are necessary before treatment with these agents can be recommended.

The recognition of in vitro antifungal properties of resin from the Norway spruce (Picea abies) led to a randomized trial (n = 73) comparing 30% resin lacquer (once daily for nine months), amorolfine 5% lacquer (once daily for nine months), and oral terbinafine (250 mg daily for three months) for toenail onychomycosis [85]. At 10 months, the resin lacquer and amorolfine demonstrated similar efficacy, and both were less effective than terbinafine (complete mycologic cure rates with resin, amorolfine, and terbinafine of 13 percent [95% CI 0-28], 8 percent [95% CI 0-19], and 56 percent [95% CI 35-77], respectively).

Data on the efficacy of acetic acid, a major component of vinegar, for onychomycosis are limited. Similar efficacy of weekly application of amorolfine 5% nail lacquer and daily application of a nail polish containing acetic acid were reported in a trial in which 102 adults with onychomycosis were randomly assigned to either of these treatments. After 180 days, the increase in healthy surface of the great toenail for the amorolfine group and acetic acid group was 13 and 12 percent, respectively. Additional study is necessary to confirm benefit of acetic acid [86].

TREATMENT FAILURE — All treatments for onychomycosis have relatively high rates of failure. Potential causes of treatment failure include:

●Inaccurate diagnosis (eg, disease is psoriasis rather than onychomycosis) (see "Onychomycosis: Epidemiology, clinical features, and diagnosis", section on 'Differential diagnosis' and "Overview of nail disorders")

●Inadequate adherence to a full course of therapy

●Concomitant tinea pedis (particularly for patients who fail to respond to topical therapy)

●Drug resistance (rare)

The best approach to patients with confirmed onychomycosis who fail to respond to an appropriate course of systemic antifungal therapy is unclear. Combining systemic therapy with topical therapy or referral to a dermatologist are common next steps. Other options include extending the treatment course of a topical or oral agent, adding a topical retinoid or topical keratolytic as an adjunctive therapeutic agent, and trials of surgical nail avulsion or other physical interventions. (See 'Other therapies' above.)

RECURRENCE — Long-term recurrence rates of onychomycosis range from approximately 20 to 50 percent [27,87,88]. Methods that are sometimes tried in an attempt to prevent recurrence include intermittent oral antifungal therapy and the application of topical antifungal creams, powders, or ciclopirox to affected nails after clinical cure is attained. There is little objective evidence to support these attempts at prophylaxis [89].

There is some evidence supporting the use of amorolfine following successful treatment of onychomycosis. In a randomized trial (n = 52), more patients treated with amorolfine remained disease free three years after initial cure than patients who received no prophylactic therapy (70 versus 50 percent) [90]. However, a separate prospective study reported no significant difference in the rate of recurrence of onychomycosis with or without amorolfine prophylaxis [29]. Amorolfine is not available in the United States. (See 'Amorolfine' above.)

We typically do not prescribe prophylactic therapy after successful treatment of onychomycosis. However, we suggest that patients who develop tinea pedis after resolution of onychomycosis should be treated for this disorder in the hope that this might reduce the risk of recurrent onychomycosis. (See "Onychomycosis: Epidemiology, clinical features, and diagnosis", section on 'Additional findings'.)

Behavioral measures that may help to reduce risk for recurrence include [91]:

●Regular inspection of feet for signs of tinea pedis

●Avoidance of cutting cuticles

●Keeping feet cool and dry (ie, changing socks and shoes if they become moist from perspiration)

●Wearing shoes in public areas (eg, public showers, gyms)

●Avoidance of shared, unsterilized nail manicure equipment

Patients who develop recurrent onychomycosis can generally be retreated with success rates similar to those seen for primary treatment [27].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Dermatophyte infections".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topic (see "Patient education: Fungal nail infections (The Basics)")

SUMMARY AND RECOMMENDATIONS

●Overview – Onychomycosis is an infection of the nail caused by dermatophytes, yeast, or nondermatophyte molds. (See 'Introduction' above.)

●Whom to treat – Treatment of onychomycosis is not mandatory in all patients. Indications for treatment include a history of repeated lower extremity cellulitis, diabetes plus risk factors for cellulitis, immunosuppression, and nail pain or discomfort. The patient's desire for treatment because of cosmetic concerns is another common reason for treatment. (See 'Approach to treatment' above.)

●Pretreatment assessment – Because of the broad differential of nail dystrophy, we prefer to confirm fungal infection prior to treatment (algorithm 1). If the initial test that confirms fungal infection does not identify the causative organism (eg, potassium hydroxide [KOH] preparation or periodic acid-Schiff [PAS] stain) and testing to confirm the causative organism will have delayed results (eg, fungal culture) or cannot be performed, patients can be treated empirically for dermatophyte infection (the most common cause of onychomycosis) unless the clinical scenario suggests another etiology. (See 'Pretreatment diagnostic testing' above.)

●Antifungal treatment:

•Mild to moderate dermatophyte onychomycosis – For patients with mild to moderate dermatophyte onychomycosis (eg, distal lateral subungual onychomycosis involving ≤50 percent involvement of the nail and sparing the matrix/lunula), we suggest treatment with oral terbinafine (Grade 2B). Patients who have contraindications to systemic antifungal therapy, who are at risk for drug-drug interactions with systemic antifungal drugs, or who prefer to avoid systemic treatment can be treated with topical therapy. (See 'Mild to moderate dermatophyte onychomycosis' above.)

•Moderate to severe dermatophyte onychomycosis – For patients with moderate to severe dermatophyte onychomycosis (eg, dermatophyte onychomycosis involving >50 percent of the nail or involving the matrix or lunula, proximal subungual onychomycosis, or total dystrophic onychomycosis), we suggest treatment with oral terbinafine (picture 1A-C) (Grade 2B). Oral itraconazole is an alternative treatment for patients who cannot tolerate terbinafine or for patients who fail to respond to terbinafine. (See 'Moderate to severe dermatophyte onychomycosis' above.)

•Yeast and nondermatophyte mold onychomycosis – Data are limited on the treatment of yeast and nondermatophyte mold onychomycosis. Itraconazole is the mainstay of treatment for these variants. Oral terbinafine may also be effective for some patients. (See 'Yeast and nondermatophyte mold onychomycosis' above.)

●Management of symptoms – Patients with pain or discomfort from onychomycotic nails may benefit from removal of hyperkeratotic nail debris. Application of topical urea under occlusion can help with debridement of the nail and symptom improvement. (See 'Symptom relief' above.)

●Prevention of recurrence – Recurrence after treatment of onychomycosis is common. Aggressive treatment of tinea pedis after resolution of onychomycosis may be beneficial for reducing risk for recurrence. The role of prophylactic antifungal therapy for onychomycosis is uncertain. (See 'Recurrence' above.)