Treatments
Topical Treatment
The hard keratin and compact structure of the dorsal nail plate act as a barrier to topical drug diffusion into and through the nail plate. The concentration of topically applied drug can drop by 1000 times from the outer to inner surface. The hydrophilic nature of the nail plate also precludes absorption of most lipophilic molecules with high molecular weights. The role of monotherapy with topical antifungals is limited to SWO (except in transverse or striate infections), early DLSO (except in the presence of longitudinal streaks) when < 80% of the nail plate is affected with lack of involvement of the lunula, or when systemic antifungals are contraindicated. Studies comparing the efficacy of topical treatments in onychomycosis are rare. Technologies that enhance the penetration of topical antifungals into the nail plate are a matter of current research.
Amorolfine (Strength of Recommendation D; Level of Evidence 3; SeeAppendices 1andAppendices 2). Amorolfine (Loceryl®; Galderma, Amersham, U.K.) belongs to the morpholine group of synthetic antifungal drugs and exhibits broad-spectrum fungistatic and fungicidal activity. It inhibits the delta 14 reductase and delta 8 and delta 7 isomerase enzymes in the ergosterol biosynthetic pathway and is fungicidal against C. albicans and T. mentagrophytes. It is available as a 5% lacquer and is applied to the affected nail once or twice weekly for 6–12 months, after removal of as much of the diseased areas of the nail as possible by gentle filing. It persists in the nail for 14 days after treatment is completed. Amorolfine nail lacquer has been shown to be effective in around 50% of cases of distal fingernail and toenail onychomycosis. Similar results have been obtained in other studies that have confirmed the greater efficacy of amorolfine 5% vs. the 2% concentration. Once-weekly application is as effective as twice-weekly application. An important observation is that the clinical improvement obtained with amorolfine and other topical antifungals may not be synonymous with mycological cure, which has invariably lower rates, often by 30%. Amorolfine has also been found to be effective as a prophylactic treatment for recurrence of onychomycosis. Side-effects following amorolfine lacquer treatment are rare and are limited to local burning, pruritus and erythema.
Ciclopirox (Strength of Recommendation D; Level of Evidence 3). Ciclopirox is a hydroxypyridone derivative with broad-spectrum antifungal activity against T. rubrum,S. brevicaulis and Candida species. Ciclopirox inhibits metal-dependent enzymatic processes including nutrient uptake, cellular energy production and degradation of toxic intracellular peroxide. It is available as an 8% lacquer applied once daily for up to 48 weeks. Ciclopirox lacquer once daily was shown to be more effective than placebo in the treatment of toenail onychomycosis (34% mycological cure vs. 10% with placebo, and a clinical cure of 8% vs. 1% with placebo). The recommended duration of treatment is up to 24 weeks on the fingernails and up to 48 weeks on the toenails. There are no head-to-head trials comparing amorolfine with ciclopirox in the treatment of onychomycosis; however, cure rates are usually lower with ciclopirox. Periungual and nail fold erythema are the most common side-effects.
Tioconazole (Strength of Recommendation D; Level of Evidence 3). Tioconazole is an imidazole antifungal available as a 28% solution (Trosyl®; Pfizer, Sandwich, U.K.). In an open-ended study of 27 patients with onychomycosis treated with tioconazole, mycological and clinical cure was achieved in 22% of patients. Allergic contact dermatitis to tioconazole is not uncommon.
Other Topical Treatments (Strength of Recommendation D; Level of Evidence 3). Once-daily application of topical 10% efinaconazole, a new triazole antifungal agent, has recently been found to be more effective than vehicle in the treatment of onychomycosis, with mycological cure rates approaching 50% and complete cure (defined as mycological and clinical cure) in 15% of patients after 48 weeks of application.
New topical formulations of terbinafine are being investigated, with early data showing promising clinical and mycological results.
Butenafine, bifonazole, salicylic acid, over-the-counter mentholated ointment, ozonized sunflower oil and undecenoates have been used, but there are limited data to support their use as monotherapy for onychomycosis. A 40% urea ointment is now available as an over-the-counter preparation for the treatment of onychomycosis.
Systemic Therapy
The main systemic drugs approved and widely used for the treatment of onychomycosis are the allylamine terbinafine and the triazole itraconazole. Griseofulvin is also licensed for treating onychomycosis but is much less commonly used now given the higher efficacy and compliance rates and lower relapse rates of the other systemic agents. Fluconazole is not licensed for the treatment of onychomycosis, but may represent a useful third-line therapy. Ketoconazole also demonstrates efficacy but the risk of hepatotoxicity with long-term therapy limits its use. In the U.S.A. and Europe, including the U.K., it has been removed from the market for the treatment of superficial mycoses. The rate of treatment failure with standard antifungal drugs is in the range of 25–40%, and this failure has been attributed to poor patient compliance, low bioavailability, lack of drug penetration into the nail, drug resistance and drug interactions. The new second-generation triazoles represent a further group of therapeutic agents that may have a role in the treatment of refractory cases of onychomycosis.
Griseofulvin (Strength of Recommendation C; Level of Evidence 2+). Griseofulvin (Fulcin®; Grisovin®; GlaxoSmithKline, Uxbridge, U.K.) is weakly fungistatic, and acts by inhibiting nucleic acid synthesis, arresting cell division and inhibiting fungal cell wall synthesis. It is the only antifungal agent licensed for use in children with onychomycosis, with a recommended dose for the age group of 1 month and above of 10 mg kg per day. It should be taken with fatty food to increase absorption and aid bioavailability. In adults the recommended dose is 500–1000 mg per day for 6–9 months in fingernail infection and 12–18 months in toenail infection. Mycological cure rates for toenail infection are only 30–40%. Side-effects include nausea and rashes in 8–15% of patients. In adults, it is contraindicated in pregnancy and the manufacturers caution against men fathering a child for 6 months after therapy. Studies comparing griseofulvin therapy with terbinafine and itraconazole have demonstrated lower cure rates for griseofulvin. Griseofulvin has several limitations including lower efficacy, long treatment duration, risk of greater drug interactions and the availability of newer antifungal agents. For these reasons it is no longer a treatment of choice for onychomycosis unless other drugs are unavailable or contraindicated.
Terbinafine (Strength of Recommendation A; Level of Evidence 1+). Terbinafine (Lamisil®; Novartis, Camberley, U.K.) acts by inhibiting squalene epoxidase, which is essential for the biosynthesis of ergosterol, an integral component of the fungal cell wall. Its action results in both a depletion of ergosterol, which has a fungistatic effect, and an accumulation of squalene, which appears to be directly fungicidal. It is presently the only oral fungicidal antimycotic. More than 70% of terbinafine is absorbed when taken orally, and absorption is not affected by food intake; 99% of oral terbinafine binds to plasma proteins, and it is cleared mostly by the kidney and excreted in urine. Terbinafine clearance is decreased when patients have severe liver or kidney disease. Terbinafine is strongly lipophilic and therefore distributes well in skin and nails. It is detected in the nail within 1 week of starting therapy and persists for 6 months after the completion of treatment, as it has a long half-life. Terbinafine has broad and potent fungicidal effects against dermatophytes, particularly T. rubrum and T. mentagrophytes, but has lower fungistatic activity against Candida species than the azoles. Oral terbinafine is generally well tolerated but there have been rare reports of serious adverse reactions, including Stevens–Johnson syndrome and toxic epidermal necrolysis. A postmarketing surveillance study revealed that the most common side-effects were gastrointestinal (4·9%), such as nausea, diarrhoea or taste disturbance, and dermatological events (2·3%) such as rash, pruritus, urticaria or eczema. The incidence of serious adverse events was 0·04%. Although studies have demonstrated that terbinafine is associated with only minimal hepatic toxicity, there have been rare reports of serious hepatic toxicity, which occurred usually in patients with pre-existing liver disease. Therefore, systemic terbinafine is not recommended in patients with active or chronic liver disease. Baseline liver function tests and a complete full blood count are recommended in patients with a history of heavy alcohol consumption, hepatitis or haematological abnormalities. Baseline monitoring should also be considered for children, as terbinafine is not licensed for use in treating paediatric onychomycosis. Oral terbinafine has minimal drug–drug interactions. The only potentially significant drug interaction with terbinafine is with drugs metabolized by the cytochrome P450 2D6 isoenzyme. Taste disturbance is a very rarely reported adverse effect, but it can be permanent and patients should be warned of this.
Itraconazole (Strength of Recommendation A; Level of Evidence 1+). Itraconazole (Sporonox®; Janssen-Cilag, High Wycombe, U.K.) is active against a range of fungi including yeasts, dermatophytes and some nondermatophyte moulds. It is not as active in vitro against dermatophytes as terbinafine, its minimum inhibitory concentration (MIC) being 10 times greater. Although it is generally felt to be a fungistatic agent, it can achieve fungicidal concentrations, although its minimum fungicidal concentration is about 10 times higher than its MIC. The mechanism of action of itraconazole is the same as that of the other azole antifungals: it inhibits the fungal cytochrome P450 oxidase-mediated synthesis of ergosterol, which is required for fungal cell walls. Itraconazole is optimally absorbed with food and an acidic pH. It is highly lipophilic and is metabolized in the liver by the cytochrome P450 3A4 system, which increases the risk of it interacting with other drugs metabolized by this route. Like terbinafine, it also penetrates the nail quickly and is detectable in the nail as early as 7 days after starting therapy, and persists in the nails for up to 6–9 months after therapy discontinuation. The rapid detection, concentration and persistence of itraconazole in the nail plate make the intermittent dosing regimen as efficacious as daily dosing.
The most common adverse reactions to itraconazole include headache and gastrointestinal upset. Adverse effects are lower if itraconazole is given as pulse therapy. Asymptomatic liver function abnormalities occur in 1·9% of patients treated with pulse itraconazole and in 3% of those treated with continuous itraconazole. Hepatitis tends to occur with continuous therapy usually after 4 weeks. Monitoring hepatic function tests is recommended in patients with pre-existing deranged results, those receiving continuous therapy for more than a month, and with concomitant use of hepatotoxic drugs. Itraconazole is contraindicated in patients with congestive cardiac failure due to the increased risk of negative inotropic effects. Itraconazole may also prolong the QT interval, and therefore coadministration with other drugs that also increase the QT interval is contraindicated.
Terbinafine vs. Itraconazole in Dermatophyte Onychomycosis. Both of these drugs have been shown to be more effective than griseofulvin in dermatophyte onychomycosis, and therefore the optimum choice of treatment lies between terbinafine and itraconazole. As both terbinafine and itraconazole persist in the nail for a considerable period after elimination from the plasma, intermittent or 'pulse' treatment regimens have been developed. Unless there are contraindications, terbinafine should be considered as the first choice based on its higher efficacy and tolerability.
Terbinafine is licensed at a dose of 250 mg per day for 6 weeks in fingernail and 12–16 weeks in toenail infection. Patients should be re-evaluated 3–6 months after treatment initiation and further treatment should be given if the disease persists. Itraconazole is licensed at a dose of 200 mg per day for 12 weeks continuously, or alternatively as pulse therapy at a dose of 400 mg per day for 1 week per month. Two pulses are recommended for fingernail onychomycosis and three pulses for toenail onychomycosis.
Several large studies demonstrate higher efficacy rates for terbinafine in comparison with itraconazole. A multicentre, randomized trial involving 508 subjects demonstrated complete cure (defined as negative mycological analysis and a normal nail) in 55% or 26% of patients receiving 16 weeks of continuous terbinafine or pulsed itraconazole, respectively, at follow-up at 72 weeks (strength of recommendation A; level of evidence 1). The 151 patients in the Icelandic arm of this study were further studied for the long-term effectiveness of treatment during a 5-year blinded prospective follow-up study. At the end of the study mycological cure without a second therapeutic intervention was found in 46% and 13% of the terbinafine- and itraconazole-treated patients, respectively. Mycological and clinical relapse was significantly higher in the itraconazole group (53% and 48%, respectively) than in the terbinafine group (23% and 21%) (strength of recommendation A; level of evidence 1). Other subsequent studies have reported similar cure rates for terbinafine and itraconazole. Terbinafine and itraconazole have also been used to treat onychomycosis effectively and safely in special patient populations, such as children, the elderly, immunocompromised patients, diabetics and those with Down syndrome. However, efficacy appears to be lower in patients over the age of 65 years, with one study demonstrating complete cure with terbinafine in only 15% of patients. In patients with psoriasis, too, it has been demonstrated that response to treatment of onychomycosis with itraconazole is lower.
Since the publication of the last guidelines there have been trials investigating the efficacy and tolerability of pulse terbinafine treatment for onychomycosis (500 mg per day for 1 week per month for 3 months). Results have been conflicting, with smaller studies suggesting comparable efficacy between pulse and continuous terbinafine (250 mg per day for 3 months). However, a larger randomized trial demonstrated a mycological cure rate of 70·9% vs. 58·7% at follow-up at 18 months for continuous vs. pulse terbinafine, respectively. Other regimens using 'intermittent' as opposed to pulse terbinafine therapy have also been trialled, again with variable success. A recent meta-analysis of the efficacy of continuous and intermittent terbinafine regimens for toenail onychomycosis concluded that although continuous terbinafine is generally more effective than a pulse regimen for mycological cure, both are equally effective for complete clinical cure.
In theory, it should be possible to offer an effective pulse terbinafine treatment regimen, given that terbinafine persists in nails for at least as long as itraconazole following treatment discontinuation, and it represents an attractive option as it can reduce the costs of treatment as well as drug-associated adverse effects.
Hyphanox™ (Stiefel; a GSK Company, Research Triangle Park, NC, U.S.A.) is a patented formulation of itraconazole with higher bioavailability. Stiefel completed a phase III randomized controlled trial for onychomycosis comparing a dose of 200 mg per day of Hyphanox with itraconazole 100 mg twice daily for 3 months. Although Hyphanox demonstrated no significant advantage over itraconazole (44% vs. 37% mycological cure rate, respectively) this was the largest ever clinical trial for onychomycosis, enrolling 1381 patients and demonstrating good tolerability with both formulations of itraconazole.
In a meta-analysis of systemic antifungals for the treatment of onychomycosis, adverse effects led to treatment discontinuation in 3·4% of patients receiving continuous terbinafine, 2·1% of patients receiving pulse terbinafine, 4·2% of patients receiving continuous itraconazole and 2·6% of patients receiving pulsed itraconazole. A recent meta-analysis comparing long-term mycological recurrences of toenail onychomycosis after successful treatment with terbinafine vs. itraconazole demonstrated a significantly lower mycological recurrence rate with terbinafine compared with itraconazole. The authors suggest that the reason for this is the fungicidal action of terbinafine compared with the fungistatic action of itraconazole. Terbinafine, in comparison with itraconazole, is also associated with a lower risk of drug interactions. In conclusion, terbinafine is superior to itraconazole both in vitro and in vivo for dermatophyte onychomycosis and should be considered the first-line treatment, with itraconazole as the next best alternative.
Fluconazole (Strength of Recommendation B; Level of Evidence 2++). Fluconazole has a long half-life, allowing once-daily dosing. It is excreted predominantly in the urine and therefore the dose needs to be adjusted depending on the creatinine clearance. It remains detectable in toenails for up to 6 months after therapy discontinuation. It has some activity against dermatophytes and some Candida species. Although it is currently not licensed for use in onychomycosis, attention has been focused on using it in a once-weekly dosing (450 mg) regimen. This is possible because of its pharmacokinetic properties, and it offers the advantage of improving compliance and reducing treatment costs.
Seven studies have evaluated fluconazole for the treatment of onychomycosis. However, only three of these were randomized, double-blind placebo-controlled trials, which evaluated different weekly dosages of fluconazole (150–450 mg) and different treatment durations (4, 6, 9 or 12 months). Mycological cure rates ranged from 47% to 62% in toenail infections and from 89% to 100% in fingernail infections. Clinical cure rates were lower (28–36% for toenail infections and 76–90% for fingernail infections). Higher doses (450 mg per week) and longer treatment duration (9 and 12 months) were associated with higher cure rates. There are few comparative trials, but fluconazole appears to be less effective than itraconazole or terbinafine. However, fluconazole 450 mg per week for 3 months in fingernail infections, and for at least 6 months in toenail infections, may be a useful alternative in patients unable to tolerate terbinafine or itraconazole, and its once-weekly dosing regimen may improve compliance in some patients compared with daily terbinafine or itraconazole.
The common adverse effects of fluconazole include headache, skin rash, gastrointestinal complaints and insomnia. Adverse effects leading to treatment discontinuation occur in 2·0% of patients receiving fluconazole 150 mg per week, which increases to 5·8% for higher weekly doses (300–450 mg). Fluconazole is a weaker inhibitor of the cytochrome P450 enzymes than itraconazole, and therefore may have fewer drug interactions.
Second-generation Triazoles (New Triazoles). The second-generation triazoles have broad-spectrum antifungal activity, particularly to yeasts and nondermatophyte moulds. They have an improved safety profile and fewer drug interactions than the first-generation triazoles. Clinical trials assessing their efficacy for onychomycosis are presently limited or ongoing. Their utility is restricted by their high cost, and to date they have been reserved primarily for the treatment of invasive opportunistic fungal infections, particularly in the immunocompromised.
Voriconazole has demonstrated high in vitro activity against onychomycosis-causing dermatophytes, as well as Candida species, Scopulariopsis,Neoscytalidium and Fusarium species. It may therefore represent a useful alternative therapeutic option for recalcitrant nail infections.
Posaconazole (strength of recommendation C; level of evidence 2++) has broad-spectrum activity and high efficacy against yeasts and moulds. It exhibits MICs comparable with terbinafine against dermatophytes. A recently completed phase II multicentre randomized double-blinded, placebo-controlled, dose-ranging study compared the efficacy of posaconazole (100, 200 or 400 mg per day for 24 weeks, or 400 mg per day for 12 weeks) with terbinafine (250 mg per day for 12 weeks) for DLSO in 218 patients. Complete cure at 48 weeks was significantly higher for posaconazole 200 mg per day for 24 weeks (54·1%) and 400 mg per day for 24 weeks (45·5%), but lower for 200 mg per day for 12 weeks (20%) compared with terbinafine (37%). Treatment was generally well tolerated. The most commonly reported adverse effects were headaches (6%), diarrhoea (5%), nausea (4%) and fatigue (4%). Seven patients receiving posaconazole had to withdraw from the study because of asymptomatic liver enzyme increases, as dictated by protocol. The authors suggest that the failure to demonstrate a higher cure rate with the higher dose of posaconazole may be due to small sample sizes, or because the absorption of posaconazole into the toenail does not increase in a dose-proportional manner.
Ravuconazole (strength of recommendation D; level of evidence 2+) has been investigated for the treatment of distal subungual toenail onychomycosis. A phase I/II randomized, double-blind, placebo-controlled, dose-ranging study demonstrated high tolerability and mycological cure in 59% of subjects treated with oral ravuconazole 200 mg per day for 12 weeks. The drug has not yet undergone phase III trials.
Albaconazole has broad-spectrum antifungal activity and good pharmacokinetic and bioavailability properties. It has already demonstrated potent activity against Candida and Aspergillus species. Its long half-life allows for weekly dosing schedules. A recent phase II double-blind, placebo-controlled study enrolled 584 patients with distal subungual toenail onychomycosis, who were randomized to receive albaconazole 100, 200 or 400 mg or placebo weekly for 24 or 36 weeks. Cure rates of 21–54% were demonstrated in the treatment groups at week 52. Efficacy was dose dependent and was highest in the group treated with 400 mg weekly for 36 weeks. Cure rates increased until week 52, and so it is possible that they might have been higher with longer follow-up periods. Treatment-related adverse effects occurred in < 3% of patients and were mild to moderate. The most common adverse effects were headache, nausea, diarrhoea and a transient and mild increase in liver enzymes. The weekly dosing schedule of albaconazole has the potential to improve compliance, particularly as longer courses of antifungal therapy may be required for some patients.
Pramiconazole was developed with the objective of treating superficial infections of the skin, mucosae and nails. It has broad-spectrum action, with preclinical studies demonstrating similar or superior antifungal activity to itraconazole and ketoconazole. It has excellent bioavailability and a long half-life, permitting once-daily dosing. Encouraging results from phase II clinical trials against cutaneous dermatophyte and yeast infections warrant further development and trials of this drug for onychomycosis.
In conclusion, the new triazoles may play a useful role in onychomycosis that is resistant to standard antifungal agents, for the treatment of nondermatophyte moulds that have traditionally responded poorly to established antifungal therapies, and for treating special patient populations such as the immunocompromised.
Echinocandins
The echinocandins are a new class of antifungal drugs that inhibit the synthesis of glucan, an essential component of fungal cell walls. They have broad range and potent fungicidal effects against yeasts, and are used as salvage therapy for invasive candidosis and aspergillosis. They are available only as intravenous formulations and therefore are unlikely to be used for the treatment of onychomycosis.
Candida
Clinical studies have demonstrated that itraconazole has significantly greater efficacy than terbinafine for the treatment of onychomycosis. However, studies to date are limited by relatively small patient numbers, and they do not always define the clinical subtype (DLSO, TDO or onychomycosis associated with paronychia). A study conducted in India demonstrated cure rates of 92% (12/13) vs. 40% (four of 10) for 4-month courses of pulse itraconazole (400 mg per day for 1 week each month) and pulse terbinafine (250 mg per day for 1 week each month), respectively, in the treatment of Candida onychomycosis. A higher cure rate of 60% was achieved when Candida onychomycosis was treated with terbinafine 250 mg per day for 4 months. Cure rates are reported to be even higher with long treatment schedules of terbinafine: mycological cure rates of 70% and 85% were demonstrated for C. albicans and C. parapsilosis, respectively, after 48 weeks of terbinafine 250 mg per day. These studies suggest that terbinafine is effective, but only when given for long treatment periods. Itraconazole and fluconazole are believed to be equally effective in the treatment of Candida onychomycosis and should be given for a minimum of 4 weeks for fingernail and 12 weeks for toenail onychomycosis. Itraconazole can be given at a dose of 200 mg per day or as pulse therapy (400 mg per day for 1 week each month), and fluconazole can be given either as 50 mg per day or 300 mg per week.
In summary, unless there are contraindications against its use, itraconazole should be considered the first-line treatment for Candida onychomycosis, given its shorter treatment duration. This also means that itraconazole is more cost–effective and more likely to be associated with greater compliance. Fluconazole can be used as an alternative if there are contraindications to using itraconazole.
Chronic mucocutaneous candidosis is characterized by frequent relapses, and patients with chronic mucocutaneous candidosis often fail to respond to normal drug dosages. Therefore, it is recommended that high-dose therapy is given for long periods. However, this can lead to the development of drug-resistant strains. Therefore, for this reason, other antifungals such as flucytosine, amphotericin, the new azoles such as voriconazole and posaconazole, and echinocandins have sometimes been used. Some patients with chronic mucocutaneous candidiasis also develop dermatophyte onychomycosis, which can also respond poorly to treatment.
There is a distinction between the treatment of someone with a local reason for having Candida in the nail (e.g. Raynaud phenomenon or occupational disease) and someone with immune suppression or mucocutaneous disease. The former will also benefit from local measures, such as warm hands and work practices, both in eradication and prevention of relapse.
Nondermatophyte Moulds
Onychomycosis caused by nondermatophyte moulds is often difficult to eradicate. Although clinical studies have shown that terbinafine is more efficacious than itraconazole for onychomycosis caused by dermatophytes, itraconazole has broader antimicrobial coverage for Candida and nondermatophyte moulds.In vitro susceptibility testing of the common antifungals against nondermatophyte moulds has demonstrated that Aspergillus has excellent susceptibility to itraconazole, followed by miconazole, ketoconazole and terbinafine. Scopulariopsis had wide MIC ranges for nearly all antifungal drugs including terbinafine. Fusarium and Acremonium were the agents with reduced susceptibility to nearly all of the antifungal drugs tested. Of the antifungal drugs, terbinafine demonstrated the lowest activity against the majority of the nondermatophyte moulds. Despite these results, it is often apparent that the clinical efficacy of drug therapy does not always correlate with the in vitro activity.
There are far fewer trial data of the treatment of nondermatophyte onychomycosis, perhaps because it is less common, particularly in temperate climates. The following studies, unless otherwise indicated, have used standard 3-month courses of pulse itraconazole 200–400 mg per day for 1 week each month, or terbinafine 250 mg per day. In a study of 59 cases of Scopulariopsis onychomycosis treated with different antifungals, there was no efficacy with griseofulvin (600 mg twice daily for 12 months), low efficacy with fluconazole (150 mg per day for 12 weeks) and ketoconazole (200 mg per day for 4 months), but high and comparable efficacy with itraconazole and terbinafine. Treatment of 36 cases in Belgium, the majority of which had infection with Scopulariopsis (64%) followed by Aspergillus (22%), also demonstrated a high cure rate of 88% with itraconazole. A study from India demonstrated clinical and mycological cure rates of 62% (five of eight) and 44% (four of nine) with itraconazole and terbinafine, respectively, in the treatment of nondermatophyte onychomycosis. Another small study comparing itraconazole with terbinafine demonstrated higher cure rates with pulse itraconazole in the treatment of Scopulariopsis or Fusarium species responsible for onychomycosis. However, terbinafine does demonstrate high efficacy against Aspergillus onychomycosis: pulse therapy with 500 mg per day of terbinafine for 1 week each month for 3 months led to an 88% (30/34) clinical and mycological cure rate after 1 year.
In conclusion, the clinical data show that cases of onychomycosis caused by Aspergillus in particular, as well as Scopulariopsis, are generally easier to eradicate by drug therapy than other agents causing nondermatophyte mould onychomycosis. Tosti et al. recommend either terbinafine (250 mg per day) or pulse itraconazole (400 mg per day for 1 week per month) for 2–3 months for the treatment of Aspergillus species distal lateral subungual onychomycosis. For the more difficult-to-treat nondermatophyte moulds, recommended treatment should involve a combination of approaches such as systemic antifungal therapy combined with topical nail lacquers, or surgical or chemical avulsion combined with topical therapy. In a trial of 59 cases of nondermatophyte onychomycosis, a significantly higher cure rate (approximately 60%) was seen with a combination of topical treatment with surgical avulsion compared with monotherapy with either terbinafine or itraconazole, which demonstrated cure rates of approximately only 20–40%, depending on species. In a recent review it was concluded that systemic and/or topical therapy combined with periodic chemical or surgical nail debridement/avulsion may be the best option in the management of nondermatophyte mould onychomycosis.
The new azoles may have a role in the future management of nondermatophyte mould onychomycosis, but at present there are limited clinical data. A single case report of Neoscytalidium onychomycosis showed good response to pulse posaconazole therapy (400 mg twice daily for 5 days each month for 3 months), but there was subsequent relapse. Voriconazole was more successful in the treatment of Neoscytalidium onychomycosis.
Treatment of Paediatric Onychomycosis
Onychomycosis is less common in children, with an approximate worldwide prevalence of < 0·5%. However, as in adults, the toenails are more commonly affected, and DLSO is the most common presentation. The dominant aetiological agents in childhood cases of onychomycosis are T. rubrum,T. mentagrophytes and Candida species. Children with onychomycosis should be examined carefully for concomitant tinea capitis and tinea pedis. Their parents and siblings should also be checked for onychomycosis and tinea pedis.
As the nail plate in children is thin and grows faster than in adults, topical treatment is often advocated. However, there are no clinical trials demonstrating the efficacy of topical therapies for onychomycosis in paediatric populations. In addition, some experts believe that, as in adult onychomycosis, topical therapies alone are generally ineffective, particularly when there is significant nail plate disease or nail matrix involvement.
There are clinical trial data demonstrating the efficacy and safety of systemic treatment for paediatric onychomycosis. A systematic review of all data was recently published by Gupta and Paquet, and describes five clinical trials, three retrospective analyses and a number of case reports. The following two studies demonstrated efficacy for both itraconazole and terbinafine. A study of only 17 cases (age 3–14 years, mean 8·5) treated with pulse itraconazole (5 mg kg per day for 1 week each month) for 3–5 months demonstrated a high clinical cure rate of 94% with no relapse for 1–4·25 years after therapy initiation. A more recent study of 36 cases (age 4–17 years) of onychomycosis treated with either a 12-week course of itraconazole 200 mg per day, or daily terbinafine at a dose determined by body weight, demonstrated clinical cure in 100% of cases treated with itraconazole and in 88% of cases treated with terbinafine. Treatment with both drugs is well tolerated in paediatric populations. These studies demonstrate higher cure rates for paediatric onychomycosis than adult onychomycosis and also a faster response to treatment in paediatric populations.
In summary, the three drugs that are proposed for use in the systemic management of paediatric onychomycosis are terbinafine, itraconazole and fluconazole. The azoles are advocated when onychomycosis is caused by Candida species. Griseofulvin is no longer recommended as the first line of treatment for paediatric onychomycosis, because of long treatment duration and low efficacy. Pulse itraconazole therapy (5 mg kg per day for 1 week every month) is recommended for 2 months for fingernail infection and 3 months for toenail infection. Fluconazole is recommended at 3–6 mg kg once weekly for 12–16 weeks for fingernail infection and 18–26 weeks for toenail infection. Daily terbinafine is recommended for 6 weeks for fingernail and 12 weeks for toenail infection at 62·5 mg per day if weight is < 20 kg, 125 mg per day for 20–40 kg weight, and 250 mg per day if weight exceeds 40 kg.
Griseofulvin is the only systemic antifungal drug licensed for use in children. Although terbinafine is presently not licensed for use in children under the age of 12 years, it is now accepted as being recommended by consensus for the treatment of paediatric onychomycosis. It is helpful that the safety of systemic terbinafine for the treatment of tinea capitis in children has been established, although the duration of drug therapy required for tinea capitis is usually not as long as for onychomycosis.
Combination Treatment (Strength of Recommendation D; Level of Evidence 3)
Slow nail growth and suboptimal concentration in the affected nail may explain failure of topical antifungal monotherapy in many cases of onychomycosis. It has been suggested that a combination of topical and systemic antifungal treatments for onychomycosis provides antimicrobial synergy, wider antifungal spectrum with improved fungicidal activity, increased cure rates, suppression of resistant mutants and enhancement of tolerability and safety. Topical imidazoles, ciclopirox and amorolfine have all been used in combination with systemic antifungal agents.
Tioconazole 28% solution combined with 1 g oral griseofulvin for 1 year resulted in 69% clinical and mycological cure, compared with 41% in a griseofulvin-only group.
Amorolfine 5% nail lacquer in association with two pulses of itraconazole therapy was at least as effective as three pulses of itraconazole alone in moderate-to-severe fingernail onychomycosis caused by Candida. The combination was also shown to be more effective in severe toenail onychomycosis. A multicentre randomized controlled study showed that in the treatment of dermatophytic toenail onychomycosis with matrix involvement, amorolfine 5% nail lacquer once weekly for 12 months in combination with oral terbinafine 250 mg per day for 3 months was more effective than oral terbinafine alone for 3 months. Similarly, combination therapy with topical ciclopirox and oral terbinafine has been suggested to improve cure rates when compared with systemic treatment alone.
However, another study found that combination of amorolfine or ciclopirox nail lacquers with oral terbinafine pulse therapy did not offer any advantage over oral terbinafine pulse monotherapy in the treatment of onychomycosis caused by dermatophytes, yeasts and nondermatophyte moulds.
There is sufficient evidence to recommend combination therapy if response to topical monotherapy is likely to be poor, such as may be the case in proximal nail disease.
Onychomycosis in Special Groups
Diabetics. Up to one-third of diabetics may have onychomyosis. This high prevalence of onychomycosis in diabetics is attributed to a combination of host factors including impaired glycaemic index, ischaemia, neuropathy and local immunosuppression. Onychomycosis is a significant predictor for the development of foot ulcers in diabetes. Low risk of drug interactions and hypoglycaemia makes terbinafine the oral antifungal agent of choice in the treatment of onychomycosis in diabetics. Itraconazole is contraindicated in congestive heart failure due to increased risk of negative ionotropic effect. As there is increased prevalence of cardiac disease in diabetics, terbinafine is preferred over itraconazole in the treatment of onychomycosis in this population. Topical treatments may be appropriate for mild-to-moderate infections and where risk of drug interaction is considered high.
Immunosuppression. The prevalence of onychomycosis in HIV-positive patients is approximately 30%, and correlates with CD4 counts of 450 mm. While PSO was over-represented in patients with AIDS in the 1990s, introduction of highly active antiretroviral treatments and fluconazole treatment of oropharyngeal candidosis may explain the reduction in incidence of PSO in this patient population. Iatrogenic immunosuppression also increases the risk of onychomycosis. Most cases of onychomycosis in immunosuppressed patients are due to T. rubrum. Nondermatophytes account for only a small proportion of the cases of onychomycosis in immunosuppressed patients. Griseofulvin is the least effective oral antifungal in the treatment of onychomycosis in patients with HIV. As there is an increased risk of interaction of itraconazole and ketoconazole with antiretrovirals, terbinafine and fluconazole are preferred for the treatment of onychomycosis in this patient population.
Surgery, Lights and Lasers (Level of Evidence 1−)
Surgical avulsion followed by topical antifungal therapy would seem a logical approach for single-nail onychomycosis, but results from a randomized controlled trial were disappointing. Further studies are needed in this area, and at present this treatment is not recommended based on the evidence available.
Debridement alone cannot be recommended as a treatment for onychomycosis. Mechanical intervention may be necessary to remove the dermatophytomas within the nail plate or nail bed.
In a single-centre open trial, photodynamic therapy (PDT) has recently been reported to achieve cure rates of 44·3% at 12 months, reducing to 36·6% at 18 months.
Based on the paucity of available evidence, PDT cannot currently be recommended for the treatment of onychomycosis (strength of recommendation D; level of evidence 3).
Newer devices such as near infrared diode at 870 and 930 nm, and millisecond 1064-nm neodymium-doped yttrium aluminium garnet lasers are showing promising results in the treatment of onychomycosis, but recommendations cannot be made at this stage.