Tinea unguium

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Tinea unguium

Antonella Tosti and Bianca Maria Piraccini

Evidence Levels:  A Double-blind study  B Clinical trial ≥ 20 subjects  C Clinical trial < 20 subjects  D Series ≥ 5 subjects  E Anecdotal case reports

image

Onychomycosis accounts for about half of all nail abnormalities and a third of all fungal infections of the skin. It affects about 10% of the general population, with figures that vary in different areas of the world. About 85% of cases of onychomycosis are due to dermatophytes, the most common being Trichophyton rubrum, followed by Trichophyton interdigitale. The prevalence of onychomycosis increases with age, and the toenails are most frequently affected. Tinea pedis is associated with onychomycosis in most patients. Predisposing factors for onychomycosis include old age, diabetes, HIV infection, peripheral vascular impairment and peripheral neuropathies, podiatric abnormalities, sports activities, and traumatic nail disorders.

Management Strategy

Different clinical patterns of nail infection result from the way in which fungi colonize the nail. In distal subungual onychomycosis (DSO), the most common type, fungi reach the nail from the hyponychium and colonize the nail bed, producing onycholysis and subungual hyperkeratosis. In proximal subungual onychomycosis (PSO), fungi penetrate the nail matrix via the proximal nail fold and colonize the deep portion of proximal nail plate, resulting in a subungual white patch located in the lunula area. In white superficial onychomycosis (WSO), fungi are localized on the nail plate surface and produce whitish opaque, friable areas on the nail plate. The type of nail invasion depends on both the causative fungus and host susceptibility.

The goals for antifungal therapy are mycological cure and a normal-looking nail. Clinical cure, which requires several months owing to slow nail growth, can be impossible to achieve when onychomycosis is associated with traumatic nail dystrophies. Immediately after treatment with systemic agents, which usually lasts 3 months, it is common to observe a still abnormal nail: signs of a good response are no proximal progression and a proximal area of normal-appearing nail.

Treatment of onychomycosis depends on the clinical type of the onychomycosis, the number of affected nails, and the severity of involvement. A systemic treatment with either terbinafine, itraconazole or fluconazole is always required in PSO and in DSO involving the lunula region. WSO and DSO limited to the distal nail can be treated with a topical agent such as amorolfine or ciclopirox. Combined systemic and topical treatment increases the cure rate.

In recent years, the number of patients with AIDS-related or iatrogenic immunosuppresion has substantially increased, leading to the appearance of new patterns of nail invasion by fungi. There is now evidence that some clinical varieties of superficial onychomycosis (i.e., in transverse lines) may be due to fungal invasion of the nail plate under the ventral nail fold: this substantially changes treatment options, since topical therapy does not cure these cases. New types of PSO have also been described. These include non-dermatophyte PSO, usually due to Fusarium or Aspergillus species, which is typically associated with acute periungual inflammation.

Terbinafine is an allylamine with fungicidal properties. Interactions of terbinafine with other drugs are extremely rare. Adverse effects may involve gastrointestinal function and the skin. Patients with known lupus erythematosus or photosensitivity are predisposed to drug-induced or drug-exacerbated disease. Liver toxicity can occasionally occur. Terbinafine is administered at a dose of 250 mg daily; treatment duration is 6 weeks for fingernails and 12 weeks for toenails. Clinical trials have repeatedly demonstrated a higher efficacy of terbinafine compared to other antifungal treatments. A meta-analysis of 18 studies on terbinafine for onychomycosis showed a mycological cure rate of 76%.

Terbinafine persists in the nail for at least 30 weeks after the completion of treatment, and is effective also when administered as pulse regimen at a dose of 250 mg for 1 week per month every 2 or 3 months.

Itraconazole is a synthetic triazole with fungistatic activity and a broad spectrum of action. It can be administered as a daily 200 mg dose or as pulse therapy at a dose of 400 mg daily for 1 week a month. Treatment duration is 6 weeks for fingernails and 12 weeks for toenails. The drug should be administered with a high-fat meal and/or an acidic beverage to improve its absorption. Agents that increase gastric alkalinity reduce absorption. With itraconazole the basis of some drug interactions is the inhibition/induction of the cytochrome P450-linked enzyme 3A4 (CYP 3A4). Adverse effects may involve gastrointestinal symptoms. The use of itraconazole may be associated with congestive heart failure. A meta-analysis of six studies on pulse itraconazole for onychomycosis showed a mycological cure rate of 63%.

Fluconazole is a bis-triazole broad-spectrum fungistatic drug with high oral bioavailability. It is administered as pulse treatment, with regimens ranging from 150 to 450 mg once a week for 6 (fingernails) to 9 (toenails) months. Fluconazole inhibits cytochrome P450-linked enzymes (CYP 3A4 and CYP 2C9), intensifying the action of many other drugs. Adverse effects may involve gastrointestinal symptoms. A meta-analysis of three studies on fluconazole for onychomycosis showed a mycological cure rate of 48%.

Posaconazole is a new azole that has been evaluated in onychomycosis and its use is likely to be limited to second-line treatment in terbinafine-refractory infections, those with non-dermatophyte mould infections or those sensitive to or intolerant of terbinafine. It showed a mycological cure rate of 48%.

Two transungual delivery systems are currently marketed: amorolfine 5% nail lacquer (not approved in the USA) and ciclopiroxolamine 8% nail lacquer. Amorolfine is applied once a week, whereas ciclopiroxolamine is applied daily. Long-term (6–12 months) monotherapy has been used in the treatment of white superficial onychomycosis and distal subungual onychomycosis limited to the distal nail of a few digits. The clinical efficacy of monotherapy with nail lacquers is low. Nail lacquers combined with oral treatment may increase cure rates. Numerous new topical formulations are currently being evaluated. Several studies are also testing the efficacy of new systemic antifungals with few good results so far.

Surgical or chemical debulking of the thickened nail plate increases cure rate. Photodynamic therapy after application of a solution of ALA methyl ester in aqueous cream on the nails has recently been reported to be effective in T. rubrum onychomycosis. Several laser devices have been marketed to treat onychomycosis, including Nd:YAG lasers and diode lasers. Evidence-based data on efficacy of these different lasers are still poor.

Poor prognostic factors of onychomycosis include areas of nail involvement >50%, involvement of the lateral portion of the nail, subungual hyperkeratosis thicker than 2 mm, white/yellow or orange/brown streaks in the nail (including dermatophytoma), diffuse nail involvement that includes the matrix, and immunosuppression.

Recurrence (relapse or re-infection) of onychomycosis is not uncommon, with reported rates ranging from 10% to 53%.

Specific investigations

The diagnosis of onychomycosis always requires laboratory confirmation, as differential diagnosis from psoriasis or traumatic onychodystrophy is often impossible on a clinical basis.

Fungal elements in the affected nails can be detected using KOH preparations of the nail samples or histopathology of PAS-stained nail clippings.

Cost-effectiveness of diagnostic tests for toenail onychomycosis: a repeated-measure, single-blinded, cross-sectional evaluation of 7 diagnostic tests.

Lilly KK, Koshnick RL, Grill JP, Khalil ZM, Nelson DB, Warshaw EM. J Am Acad Dermatol 2006; 55: 620–6.

This study compared the cost-effectiveness of diagnostic tests for onychomycosis. KOH and PAS were equally sensitive. Identification of the responsible fungus can, however, only be done using cultures. A negative mycological result does not rule out onychomycosis, as direct microscopy is negative in up to 10% of cases and culture in up to 30%.

Correct sampling of nail debris is mandatory for obtaining reliable mycological results. In the most common variety of onychomycosis, the distal subungual type (DSO), culture sensitivity improves the more proximal the location of the sample.

A new classification system for grading the severity of onychomycosis: Onychomycosis Severity Index.

Carney C, Tosti A, Daniel R, Scher R, Rich P, DeCoster J, et al. Arch Dermatol 2011; 147: 1277–82.

The onychomycosis severity index (OSI) has recently been proposed to grade the severity of DSO. The OSI score is obtained by multiplying the score for the area of involvement (range, 0–5) by the score for the proximity of disease to the matrix (range, 1–5). Ten points are added for the presence of a longitudinal streaking or a patch (dermatophytoma) or for greater than 2 mm of subungual hyperkeratosis. Mild onychomycosis corresponds to a score of 1–5; moderate, 6–15; and severe, 16–35.

Although several recent reports underline the high sensitivity and rapidity of polymerase chain reaction (PCR) assays, cultures remain the best and most cost-effective technique for laboratory identification of fungi.

First-line therapies – SYSTEMIC

Second-line therapies

A randomized, placebo- and active-controlled, parallel-group, multicentre, investigator-blinded study of four treatment regimens of posaconazole in adults with toenail onychomycosis.

Elewski B, Pollak R, Ashton S, Rich P, Schlessinger J, Tavakkol A. Br J Dermatol 2011.

This study evaluated the efficacy of oral administration of four posaconazole doses compared with placebo and terbinafine in the treatment of dermatophyte onychomycosis of one great toenail (nail involvement ranging from 25–75%) in 218 patients. Treatments were the following: posaconazole 100 mg once daily for 24 weeks; posaconazole 200 mg once daily for 24 weeks; posaconazole 400 mg once daily for 24 weeks; posaconazole 400 mg once daily for 12 weeks; terbinafine (tablets) 250 mg daily for 12 weeks; placebo (matched to posaconazole) for 24 weeks. Only 178 patients concluded the study. At 48 weeks, treatment success was similar for posaconazole 200 mg and 400 mg for 24 weeks and terbinafine 250 mg for 12 weeks. The authors conclude that ‘Use of posoconazole is likely to be limited to second-line treatment in terbinafine-refractory infections, those with non-dermatophyte mould infections or those sensitive to or intolerant of terbinafine.’

Third-line therapies

A multicentre, randomized, controlled study of the efficacy, safety and cost-effectiveness of a combination therapy with amorolfine nail lacquer and oral terbinafine compared with oral terbinafine alone for the treatment of onychomycosis with matrix involvement.

Baran R, Sigurgeirsson B, de Berker D, Kaufmann R, Lecha M, Faergemann J, et al. Br J Dermatol 2007; 157: 149–57.

This randomized study evaluated clinical cure and negative mycology at 18 months in patients with dermatophyte toenail onychomycosis and matrix involvement undergoing treatment with either a combination of amorolfine 5% nail lacquer once weekly for 12 months plus terbinafine 250 mg once daily for 3 months, or terbinafine alone once daily for 3 months. The results showed a significantly higher success rate in patients treated with the combination (59.2% vs 45.0%).

Topical Therapies

imageTopical amorolfine A
imageTopical ciclopiroxolamine A
imageTopical terbinafine B

Two transungual delivery systems are currently marketed: amorolfine 5% nail lacquer (not approved in the USA), and ciclopiroxolamine 8% nail lacquer. Amorolfine is applied once a week, whereas ciclopiroxolamine is applied daily. Long-term (6–12 months) monotherapy has been used in the treatment of WSO and DSO limited to the distal nail of a few digits. The clinical efficacy of monotherapy with nail lacquers is low. Nail lacquers in association with oral treatment may increase cure rates. Numerous new topical formulations are currently being evaluated. Several studies are also testing the efficacy of new systemic antifungals with few good results so far.

[/level-membership-for-dermatology-category][not-level-membership-for-dermatology-category]

Tinea unguium

Antonella Tosti and Bianca Maria Piraccini

Evidence Levels:  A Double-blind study  B Clinical trial ≥ 20 subjects  C Clinical trial < 20 subjects  D Series ≥ 5 subjects  E Anecdotal case reports

image

Onychomycosis accounts for about half of all nail abnormalities and a third of all fungal infections of the skin. It affects about 10% of the general population, with figures that vary in different areas of the world. About 85% of cases of onychomycosis are due to dermatophytes, the most common being Trichophyton rubrum, followed by Trichophyton interdigitale. The prevalence of onychomycosis increases with age, and the toenails are most frequently affected. Tinea pedis is associated with onychomycosis in most patients. Predisposing factors for onychomycosis include old age, diabetes, HIV infection, peripheral vascular impairment and peripheral neuropathies, podiatric abnormalities, sports activities, and traumatic nail disorders.

Management Strategy

Different clinical patterns of nail infection result from the way in which fungi colonize the nail. In distal subungual onychomycosis (DSO), the most common type, fungi reach the nail from the hyponychium and colonize the nail bed, producing onycholysis and subungual hyperkeratosis. In proximal subungual onychomycosis (PSO), fungi penetrate the nail matrix via the proximal nail fold and colonize the deep portion of proximal nail plate, resulting in a subungual white patch located in the lunula area. In white superficial onychomycosis (WSO), fungi are localized on the nail plate surface and produce whitish opaque, friable areas on the nail plate. The type of nail invasion depends on both the causative fungus and host susceptibility.

The goals for antifungal therapy are mycological cure and a normal-looking nail. Clinical cure, which requires several months owing to slow nail growth, can be impossible to achieve when onychomycosis is associated with traumatic nail dystrophies. Immediately after treatment with systemic agents, which usually lasts 3 months, it is common to observe a still abnormal nail: signs of a good response are no proximal progression and a proximal area of normal-appearing nail.

Treatment of onychomycosis depends on the clinical type of the onychomycosis, the number of affected nails, and the severity of involvement. A systemic treatment with either terbinafine, itraconazole or fluconazole is always required in PSO and in DSO involving the lunula region. WSO and DSO limited to the distal nail can be treated with a topical agent such as amorolfine or ciclopirox. Combined systemic and topical treatment increases the cure rate.

In recent years, the number of patients with AIDS-related or iatrogenic immunosuppresion has substantially increased, leading to the appearance of new patterns of nail invasion by fungi. There is now evidence that some clinical varieties of superficial onychomycosis (i.e., in transverse lines) may be due to fungal invasion of the nail plate under the ventral nail fold: this substantially changes treatment options, since topical therapy does not cure these cases. New types of PSO have also been described. These include non-dermatophyte PSO, usually due to Fusarium or Aspergillus species, which is typically associated with acute periungual inflammation.

Terbinafine is an allylamine with fungicidal properties. Interactions of terbinafine with other drugs are extremely rare. Adverse effects may involve gastrointestinal function and the skin. Patients with known lupus erythematosus or photosensitivity are predisposed to drug-induced or drug-exacerbated disease. Liver toxicity can occasionally occur. Terbinafine is administered at a dose of 250 mg daily; treatment duration is 6 weeks for fingernails and 12 weeks for toenails. Clinical trials have repeatedly demonstrated a higher efficacy of terbinafine compared to other antifungal treatments. A meta-analysis of 18 studies on terbinafine for onychomycosis showed a mycological cure rate of 76%.

Terbinafine persists in the nail for at least 30 weeks after the completion of treatment, and is effective also when administered as pulse regimen at a dose of 250 mg for 1 week per month every 2 or 3 months.

Itraconazole is a synthetic triazole with fungistatic activity and a broad spectrum of action. It can be administered as a daily 200 mg dose or as pulse therapy at a dose of 400 mg daily for 1 week a month. Treatment duration is 6 weeks for fingernails and 12 weeks for toenails. The drug should be administered with a high-fat meal and/or an acidic beverage to improve its absorption. Agents that increase gastric alkalinity reduce absorption. With itraconazole the basis of some drug interactions is the inhibition/induction of the cytochrome P450-linked enzyme 3A4 (CYP 3A4). Adverse effects may involve gastrointestinal symptoms. The use of itraconazole may be associated with congestive heart failure. A meta-analysis of six studies on pulse itraconazole for onychomycosis showed a mycological cure rate of 63%.

Fluconazole is a bis-triazole broad-spectrum fungistatic drug with high oral bioavailability. It is administered as pulse treatment, with regimens ranging from 150 to 450 mg once a week for 6 (fingernails) to 9 (toenails) months. Fluconazole inhibits cytochrome P450-linked enzymes (CYP 3A4 and CYP 2C9), intensifying the action of many other drugs. Adverse effects may involve gastrointestinal symptoms. A meta-analysis of three studies on fluconazole for onychomycosis showed a mycological cure rate of 48%.

Posaconazole is a new azole that has been evaluated in onychomycosis and its use is likely to be limited to second-line treatment in terbinafine-refractory infections, those with non-dermatophyte mould infections or those sensitive to or intolerant of terbinafine. It showed a mycological cure rate of 48%.

Two transungual delivery systems are currently marketed: amorolfine 5% nail lacquer (not approved in the USA) and ciclopiroxolamine 8% nail lacquer. Amorolfine is applied once a week, whereas ciclopiroxolamine is applied daily. Long-term (6–12 months) monotherapy has been used in the treatment of white superficial onychomycosis and distal subungual onychomycosis limited to the distal nail of a few digits. The clinical efficacy of monotherapy with nail lacquers is low. Nail lacquers combined with oral treatment may increase cure rates. Numerous new topical formulations are currently being evaluated. Several studies are also testing the efficacy of new systemic antifungals with few good results so far.

Surgical or chemical debulking of the thickened nail plate increases cure rate. Photodynamic therapy after application of a solution of ALA methyl ester in aqueous cream on the nails has recently been reported to be effective in T. rubrum onychomycosis. Several laser devices have been marketed to treat onychomycosis, including Nd:YAG lasers and diode lasers. Evidence-based data on efficacy of these different lasers are still poor.

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