Consultant dermatologist Dr Alexis Granite discusses the different options for treating fungal nail infections
Onychomycosis is a nail infection that is typically caused by dermatophytes and, less often, by yeast and non-dermatophyte moulds.1,2 Onychomycosis is the most common nail condition and accounts for approximately half of all diseased nails. It is prevalent in around 2-10% of the general population., Patients often present to clinic with concerns regarding the appearance of their nails. However, I have found that it is a common misconception amongst some healthcare professionals that onychomycosis is merely a cosmetic problem. When left untreated, onychomycosis may cause significant morbidity, resulting not only in an unsightly nail appearance, but also nail pain and functional impairment.3,4
Onychomycosis can compromise skin integrity, serving as a potential entry point for other skin infections, especially in patients with diabetes.5 Fungal infections are contagious,6 and may spread to other areas of the body as well as to family members and other contacts. Sensitising fungal antigens may also predispose patients to conditions such as asthma, atopic dermatitis and urticaria. The psychosocial impact of onychomycosis may be significant as well, with affected patients experiencing embarrassment and social withdrawal for fear of looking unclean or transmitting their nail infection to others.7 All of these potential issues underscore the rationale for treatment of onychomycosis.
Dermatophytes, including Trichophyton rubrum, Trichophyton mentagrophytes, Epidermophyton floccosum, and Microsporum spp, are the most common pathogens responsible for onychomycosis (80-90% of cases).8 Non-dermatophyte moulds such as Acremonium, Alternaria and Aspergillus spp., as well as yeasts such as Candida spp., account for the remainder of infections. Concomitant tinea pedis (fungal skin infection of the skin) may be associated with onychomycosis in up to half of cases.9
Advanced age, male gender (although there is no clear reason why), physical activity such as running and the use of community bathing and swimming facilities all increase the risk of onychomycosis.10,11,12 Genetic factors and underlying medical conditions including immunosuppression, diabetes and peripheral vascular disease also predispose patients to the development of fungal nail infections.13,14
Toenails are much more commonly affected (20-25x) than fingernails in onychomycosis, with the first and fifth toenails being most often affected, likely due to repetitive trauma to these nails from footwear. Toenails tend to be more difficult to treat as they are thicker than finger nails. There are five main subtypes of onychomycosis based on their clinical presentation: distal lateral subungual (DLSO), proximal subungual, superficial white (SWO), endonyx (milky white discolouration of the nail plate), and total dystrophic.15
It is important to exclude other potential causes of nail dystrophy prior to initiating antifungal therapy. The differential diagnosis of onychomycosis includes chronic nail trauma, bacterial infection, psoriasis, lichen planus, Darier’s disease, eczema, and tumours such as squamous cell carcinoma and melanoma.16,17
Diagnosis of onychomycosis is best made by clipping affected nails as far back as possible and obtaining a full thickness sample from any dystrophic, discoloured, or crumbly/brittle areas. Nail curettage may be useful in cases of SWO as it is superficial. If in-office direct microscopy is available, samples can be dissolved with 10-20% potassium hydroxide (KOH) and examined for fungal hyphae, pseudohyphae and spores. Samples may also be sent for histologic evaluation with periodic acid-Schiff (PAS) and methenamine silver stains.18
These methods confirm the presence of fungus, but culture is necessary for identification of the particular causative organism. Nail clippings should be sent to the laboratory for culture in a sterile container and results may take up to six weeks. Polymerase chain reaction (PCR) shows to be promising as a rapid, sensitive diagnostic technology for onychomycosis, but is not widely available at present as it is seen to be too expensive and is not commercially available.20,21
Spontaneous remission of onychomycosis is rare and given the hard and impermeable nature of nail keratin as well as the high frequency of recurrence, this condition may represent a clinical challenge for both practitioner and patient.22,23 Randomised, controlled clinical trials comparing different treatment options are lacking in this area; however, below is a summary of the therapeutic options currently available for onychomycosis.
Amorolfine is a morpholine derivative with broad-spectrum fungistatic and fungicidal activity. It interferes with the ergosterol biosynthetic pathway via inhibition of delta 14 reductase and delta 7-8 isomerase enzymes.24 Amorolfine is available as a 5% nail lacquer. When applied to affected nails, after filing once-twice weekly for six to 12 months, amorolfine has shown to be effective in approximately 50% of cases of distal onychomycosis.25,26,27 Its effectiveness has also been shown for prevention of onychomycosis recurrence.28 Side effects of amorolfine are rare, but may include localised burning, pruritus and erythema.29
Ciclopirox is a synthetic hydroxypyridone derivative with broad-spectrum fungistatic and fungicidal activity.28 Ciclopirox inhibits metal dependent enzymes (cytochromes) that are involved in the breakdown of toxic peroxides within fungal cells, nutrient uptake and cellular energy production.30 It is available as an 8% nail lacquer. The recommended treatment protocol is one daily application after gentle nail debridement for up to 24 weeks on the fingernails and up to 48 weeks on the toenails.31 Mycological cure rates with ciclopirox (29%-36%) have been demonstrated to be higher when compared to placebo (10%).31 Reported side effects include irritation, erythema and burning.32
Tioconazole is an imidazole antifungal and is available as a 28% topical solution in the UK.33 Tioconazole inhibits lanosterol 14 alpha-demethylase, which are involved in the ergosterol biosynthesis pathway within fungal cell walls, thereby increasing cell permeability.34 Mycologic and clinical cure were reported in 22% of patients in one open ended study on its effectiveness.35 Allergic contact dermatitis to tioconazole has been reported, although there are no exact estimates.36
Two newer topical antifungals, efinaconazole and tavaborole, have been found to be more effective than vehicle groups in the treatment of onychomycosis. 10% efinaconazole was approved by the FDA in 2014 for the treatment of onychomycosis.37 Efinaconazole is a triazole antifungal that, similar to tioconazole, inhibits lanosterol 14 alpha-demethylase. Efficacy of once daily application of 10% efinaconazole solution in the treatment of DSLO was evaluated in two phase-III trials. Once daily application over 48 weeks without prior debridement was found to be more effective than vehicle in achieving mycologic cure (55.2%-53.4% vs 16.8%-16.9%).38,39,40 Reported side effects included local dermatitis and localised pain.41
Tavaborole, a class of antifungal, exhibits broad-spectrum antifungal activity by binding to fungal transfer ribonucleic acid synthetase (tRNA), leading to inhibition of protein synthesis.42 5% tavaborole topical solution was also approved by the FDA in 2014 for the treatment of onychomycosis.43 In two phase-III trials, tavaborole was shown to be significantly more effective than vehicle (31.1%-35.9% vs 7.2%-12.2%) when applied once daily for 48 weeks. Reported side effects included local exfoliation, erythema and dermatitis.44,45
The two main systemic drugs used in the treatment of onychomycosis are terbinafine and itraconazole. Reported treatment failures with these two medications range from 25-40%.46 Fluconazole is not licensed in the UK, or anywhere else, for the treatment of onychomycosis, but may be considered as third-line therapy.47 Griseofulvin is less commonly prescribed now, given the higher efficacy and lower relapse rates associated with other oral therapies. Ketoconazole has been removed from the market in the US, Europe and the UK for treatment of superficial mycoses due to the risk of hepatotoxicity associated with long-term use.47
Terbinafine is a fungicidal/fungistatic allylamine that works via the inhibition of squalene epoxidase, an enzyme essential for the production of ergosterol within fungal cell walls.48 Given its strong lipophilic qualities, terbinafine is well absorbed in the skin and nails, with detection in the nail plate as early as one week after initiating therapy and it can persist for as long as six months after discontinuation.49 The recommended dose is 250mg daily (with or without food) for six weeks in fingernail infections and six to 12 weeks in toenail infections.50 If infection persists after three to six months, re-treatment may be necessary.
Terbinafine is generally well tolerated, with the most common side effects being nausea, diarrhoea and rashes.51 There have been rare reports of persistent taste disturbance and more serious side effects including hepatotoxicity, Stevens-Johnson syndrome and toxic epidermal necrolysis (TEN).52 Acute or chronic liver disease is a relative contraindication to treatment with terbinafine, and there is potential for interaction with other medications metabolised by the cytochrome P450 2D6 isoenzyme.53 In my practice, I do a blood test to check baseline liver enzymes prior to initiating therapy with terbinafine, and I re-check after six weeks of treatment, although some practitioners may choose to monitor only in higher risk patients.
Itraconazole is a predominantly fungistatic triazole with a similar mechanism of action as previously described. Similar to terbinafine, itraconazole is rapidly absorbed within nails and persists for months once treatment has finished.54 Itraconazole may be taken as 200mg daily or as pulse dosing (giving medication in bursts rather than continuously), 400mg daily for one week per month. The recommended treatment duration is at least six weeks, or two pulses for fingernails, and 12 weeks, or three pulses for toenails.50 Itraconazole is best absorbed when taken with food.55
The most common side effects are gastrointestinal upset and headache.51 Itraconazole is metabolised by the cytochrome P450 3A4 system and may interact with certain medications.56 I check baseline liver enzymes prior to starting treatment with itraconazole for all patients. Continued monitoring of liver enzymes is recommended for patients with abnormal baseline results, those receiving continuous treatment over four weeks and/or concomitant use of hepatotoxic medications. Itraconazole is contraindicated in patients with congestive heart failure and has potential to prolong the QT interval, which is a measurement on an electrocardiogram, therefore it cannot be given with other medications that may have this effect.57,58,59
Fluconazole is an oral azole with the benefit of a long half-life, allowing for one weekly dosing. Several randomised, controlled trials examined the efficacy of different weekly doses (150-450mg) for various durations (four to 12 months) and have reported clinical cure rates of 76%-90% for fingernails and 28%-36% for toenail infections.60,61,62 Common side effects of fluconazole include headache, rash and gastrointestinal upset.63 Fluconazole has less potential drug interactions than itraconazole due to its relatively weaker inhibition of the cytochrome P450 enzyme system.64 In my practice, I consider fluconazole for patients with onychomycosis unable to tolerate terbinafine or itraconazole due to side effects or potential drug interactions.
Griseofulvin is a weakly fungistatic oral agent that works by inhibiting nucleic acid synthesis, interfering with fungal cell division and cell wall synthesis.65 Cure rates with this medication are lower compared to terbinafine and itraconazole, however it is the only antifungal licensed for the treatment of onychomycosis in children over one month of age (10mg/kg per day). In adults, the recommended dose is 500-1,000mg daily with fatty food for six to nine months in fingernail infections and for 12-18 months in toenail infections. The most frequently reported side effects are nausea and rashes.67 I generally reserve the use of griseofulvin for fungal infections in children, which isn’t very often, as children tend to go through the NHS for fungal treatment.
Clinical phase II trials examining the efficacy of newer, second-generation triazoles have been carried out or are currently ongoing. These include albaconazole, posaconazole and ravuconazole, among others.68,69,70 Results in the treatment of onychomycosis are promising, and further studies are needed to determine whether these agents should be made more widely available for clinical use.
Surgical avulsion followed by topical antifungal therapy and debridement alone have been studied in a small number of randomised, controlled trials with limited success for onychomycosis. Therefore, at this time, these procedures are not recommended as stand-alone treatments.71 There is some evidence that debridement combined with topical or oral antifungal therapies may offer an added benefit.72
Lasers have potential in the treatment of onychomycosis as an alternative to more traditional oral therapies that may be associated with an increased risk of systemic side effects and poor patient compliance. The mechanism of action for laser therapy in onychomycosis has yet to be elucidated. It has been postulated that destruction of fungal elements occurs by selective photothermolysis.73 Another theory suggests that free radicals are formed via laser energy and light absorption by the fungal pigment xanthomegnin.73 The lasers currently FDA cleared for treatment of onychomycosis utilise Nd:YAG technology.
A number of small studies have been carried out that examine the efficacy of long and short pulse and Q-switched Nd:YAG, as well as dual wavelength diode, erbium, titanium sapphire and fractional CO2 lasers in the treatment of fungal nail infections.74,75 While results have been promising, there are many limitations to these investigations as standardised treatment protocols, objective methods for defining clinical and mycological cures, long-term follow up, and randomised controlled comparisons are lacking.76
I find that many patients are interested in laser treatment as they are looking to avoid oral therapies. I discuss with patients the limited robust data for laser treatment of onychomycosis, but offer it when other therapies are contraindicated or when a laser-based treatment option is preferred. Combination therapy using laser with topical antifungals may be more efficacious than either option alone, however, again, more studies are needed in this area.77
Photodynamic therapy (PDT) incorporates the use of a photosensitiser and illumination with visible light. As the photosensitiser accumulates in the target and is illuminated, reactive oxygen species are produced, leading to target destruction.78 Fungi are selectively targeted by four chemical photosensitisers: phenothiazine dyes, porphyrins, phthalocyanines, and protoporphyrin IX via aminolevulinic acid, all of which are highly sensitive and require much lower light doses than required for destruction of keratinocytes.79
Several case reports and one prospective trial have examined the efficacy of aminolevulinic acid (ALA) or methyl aminolevulinate (MAL) PDT following application of topical urea as treatment for onychomycosis. Results are limited, but promising with negative cultures sustained for up to 12 months following therapy. Adverse effects included pain, burning, erythema and blistering.80,81 As in the case with lasers, larger scale, randomised controlled trials are needed before a recommendation can definitively be made regarding the use of PDT for onychomycosis.
Terbinafine is generally regarded as the most efficacious treatment for dermatophyte onychomycosis and is my preferred option in patients with more than 50-60% nail plate involvement.82 Itraconazole and fluconazole may be slightly more effective with shorter treatment courses than terbinafine in the treatment of Candida nail infections.83
There are several studies suggesting that systemic treatment with terbinafine or itraconazole combined with nail debridement and/or topical therapy may be more effective than either medication alone in the treatment of onychomycosis caused by non-dermatophyte moulds.84,85 Given their limited absorption, monotherapy with topical antifungals is often reserved only for cases of SWO, early DSLO (<20% involvement of nail plate, spared lunula), or when systemic antifungal therapy is contraindicated.86
Increasingly, I have tried combination therapy (such as Terbinafine and Ciclopirox) in my practice, as several studies,87,88,89 have also shown combined topical and oral agents may be more effective than single treatments for all types of onychomycosis. The regular use of topical antifungals to the feet and toenails may also be helpful as prophylaxis following a course of treatment with a systemic antifungal medication.90,91,92
As practitioners, we can help educate patients regarding prevention of onychomycosis. Tips include keeping nails short and clean, wearing comfortable shoes and avoiding nail trauma as well as the use of protective footwear in damp areas such as pools and gyms. Antifungal powders and sprays may also be helpful, and remind patients to launder socks in hot water and discard of older ‘infected’ shoes to avoid recurrence.93,94
A multitude of treatment options are available for onychomycosis, however there still exists a high rate of relapse and recurrence amongst patients with this condition. The antifungal therapy selected should be guided by several factors including identification of the infectious organism, severity of affected nails and patient comorbidities, concomitant medications and preference. In general, data comparing treatment methods for onychomycosis are lacking. Oral therapies continue to be the mainstay for most fungal nail infections. Topical antifungals are useful mainly as monotherapy in very early, limited cases of onychomycosis or as adjuvant or prophylactic treatment. Laser, PDT, as well as combined treatment modalities (such as oral and topical therapy or topical therapy and laser or PDT), show promise in the treatment of onychomycosis, but more rigorous studies are needed.
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