NIHR Signal Terbinafine is probably first choice oral drug for fungal toenail infection

Published on 24 October 2017

The oral antifungal drug terbinafine appears to be slightly better than alternative ‘azole’ drugs for treating fungal toenail infection. Fifty-eight percent of people had a normal nail appearance after a treatment course compared with 47% taking ‘azoles’. Both drug classes were more effective than placebo and had similar side effects.

Current guidelines recommend terbinafine or itraconazole as first-choice treatments, but consider terbinafine more effective. However, systematic reviews on the topic were outdated. This Cochrane review updates the evidence, pooling the findings from 43 trials comparing oral antifungals with each other or placebo.

The results support guidelines recommending terbinafine as the first choice for treatment unless contraindicated.

Antifungals are available in oral and topical forms (applied to the nail). Topical antifungals have long been thought less effective, but the review did not gather evidence to confirm this.

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Why was this study needed?

Fungal nail infection is thought to affect somewhere between two and 14% of the adult population. It is most common in older people and those with diabetes.

Most cases of toenail infections (about 80%) are due to dermatophyte fungi such as Trichophyton; other fungi include Aspergillus, Scopulariopsis, Fusarium and Alternaria. Some are highly resistant to treatments.

Toenail infections have a low complication rate, but they may affect the function of the nail and quality of life. Topical treatments are commonly used, but they have a low success rate. The most common oral antifungal treatments are terbinafine and itraconazole (an azole drug). Drug treatment can be costly to the NHS as a standard course of oral treatment is three months, and it may take as long as six months to a year to treat infection successfully.

Though oral antifungal drugs are thought to be effective, systematic review evidence is outdated. The researchers wanted to perform an up-to-date review to find out which oral antifungal was most effective for toenail infections to help guide evidence-based treatment.

What did this study do?

This systematic review pooled 43 randomised controlled trials including 9,730 people and comparing oral antifungal treatment with another active treatment or placebo.

Seven trials compared terbinafine with placebo, nine compared itraconazole with placebo and 17 compared these two drugs with each other. Other studies assessed griseofulvin and other ‘azole’ drugs. Treatment duration ranged from four months to two years.

Lack of blinding of researchers and/or participants and potential for biased allocation to treatment group were common across studies. Over half the trials were published before the year 2000. Most were carried out in outpatient dermatology settings in Western countries, but only three were conducted in the UK. However, the evidence was assessed as high quality for most outcomes.

What did it find?

  • Terbinafine was more effective than azoles. Forty-seven percent of people who took azoles were cured, based on normal nail appearance, compared with 58% who took terbinafine (relative risk [RR] 0.82, 95% confidence interval [CI] 0.72 to 0.95; 15 studies, 2,168 people). People taking azoles were similarly less likely to achieve a mycological cure as defined by negative results on microscopy or culture: 53% vs 68% with terbinafine (RR 0.77, 95% CI 0.68 to 0.88; 17 studies, 2,544 people). Adverse effects and recurrence rates were similar between the two drugs.
  • In placebo comparisons, terbinafine was more effective. Forty-eight percent achieved a clinical cure compared with only 6% of the placebo group (RR 6.00, 95% CI 3.96 to 9.08; 8 studies, 1,006 people). The mycological cure rate was 59% vs 17% with placebo (RR 4.53, 95% CI 2.47 to 8.33) though there was high variability between individual studies for this outcome. Gastrointestinal symptoms and respiratory infections were among side effects reported with terbinafine, but these were still not significantly more common than with placebo.
  • Azoles were also more effective than placebo with 31% achieving a clinical cure vs 14% in the placebo group (RR 22.18, 95% CI 12.63 to 38.95; 9 studies, 3,440 people). They were also more likely to achieve mycological cure (35% vs 7%; RR 5.86, 95% CI 3.23 to 10.62), but as with terbinafine, there was high variability between studies for this outcome.
  • There was low-quality evidence that griseofulvin was less effective than terbinafine regarding clinical cure (RR 0.32, 95% CI 0.14 to 0.72; four studies, 270 people) and mycological cure (RR 0.64, 95% CI 0.46 to 0.90; five studies, 465 people). There was no statistically significant difference in the likelihood of achieving clinical or mycological cure with griseofulvin compared with an azole.
  • There was very low-quality evidence from a single study (176 people) that the combination of terbinafine plus an azole was more effective than terbinafine alone (clinical cure: RR 1.41, 95% CI 1.01 to 1.97; mycological cure: RR 1.41, 95% CI 1.08 to 1.83).

What does current guidance say on this issue?

The British Association of Dermatologists (2014) suggests either terbinafine or itraconazole as first options for the treatment of fungal nail infection in both adults and children. However, they say that unless there are contraindications terbinafine is preferred based on its higher efficacy and tolerability.

Griseofulvin has lower efficacy, higher relapse rates and more side effects than terbinafine or itraconazole but remains an option if these drugs are ineffective or not tolerated.

What are the implications?

These results support guideline recommendations that terbinafine is the most effective oral drug and should be considered the first-choice in fungal nail infection.

Topical treatments may still be in widespread use, particularly when purchased over-the-counter. This study was not able to assess or confirm their comparative lack of efficacy when compared with oral treatment.

Nail infection may recur after stopping treatment, so prevention is important. Healthcare professionals should advise people to wear protective shoes in public changing rooms (e.g. swimming pools or gyms), keep their nails short, avoid sharing nail clippers and wear shoes that fit properly.

Citation and Funding

Kreijkamp-Kaspers S, Hawke K, Guo L, et al. Oral antifungal medication for toenail onychomycosis. Cochrane Database Syst Rev. 2017;(7): CD010031.

Cochrane UK and the Cochrane Skin Group are supported by the National Institute for Health research via Cochrane Infrastructure funding.

Bibliography

Ameen M, Lear JT, Madan V, et al. British Association of Dermatologists' guidelines for the management of onychomycosis 2014. Br J Dermatol. 2014;171(5):937-58.

NHS Choices. Fungal nail infections. London: Department of Health; 2015.

Why was this study needed?

Fungal nail infection is thought to affect somewhere between two and 14% of the adult population. It is most common in older people and those with diabetes.

Most cases of toenail infections (about 80%) are due to dermatophyte fungi such as Trichophyton; other fungi include Aspergillus, Scopulariopsis, Fusarium and Alternaria. Some are highly resistant to treatments.

Toenail infections have a low complication rate, but they may affect the function of the nail and quality of life. Topical treatments are commonly used, but they have a low success rate. The most common oral antifungal treatments are terbinafine and itraconazole (an azole drug). Drug treatment can be costly to the NHS as a standard course of oral treatment is three months, and it may take as long as six months to a year to treat infection successfully.

Though oral antifungal drugs are thought to be effective, systematic review evidence is outdated. The researchers wanted to perform an up-to-date review to find out which oral antifungal was most effective for toenail infections to help guide evidence-based treatment.

What did this study do?

This systematic review pooled 43 randomised controlled trials including 9,730 people and comparing oral antifungal treatment with another active treatment or placebo.

Seven trials compared terbinafine with placebo, nine compared itraconazole with placebo and 17 compared these two drugs with each other. Other studies assessed griseofulvin and other ‘azole’ drugs. Treatment duration ranged from four months to two years.

Lack of blinding of researchers and/or participants and potential for biased allocation to treatment group were common across studies. Over half the trials were published before the year 2000. Most were carried out in outpatient dermatology settings in Western countries, but only three were conducted in the UK. However, the evidence was assessed as high quality for most outcomes.

What did it find?

  • Terbinafine was more effective than azoles. Forty-seven percent of people who took azoles were cured, based on normal nail appearance, compared with 58% who took terbinafine (relative risk [RR] 0.82, 95% confidence interval [CI] 0.72 to 0.95; 15 studies, 2,168 people). People taking azoles were similarly less likely to achieve a mycological cure as defined by negative results on microscopy or culture: 53% vs 68% with terbinafine (RR 0.77, 95% CI 0.68 to 0.88; 17 studies, 2,544 people). Adverse effects and recurrence rates were similar between the two drugs.
  • In placebo comparisons, terbinafine was more effective. Forty-eight percent achieved a clinical cure compared with only 6% of the placebo group (RR 6.00, 95% CI 3.96 to 9.08; 8 studies, 1,006 people). The mycological cure rate was 59% vs 17% with placebo (RR 4.53, 95% CI 2.47 to 8.33) though there was high variability between individual studies for this outcome. Gastrointestinal symptoms and respiratory infections were among side effects reported with terbinafine, but these were still not significantly more common than with placebo.
  • Azoles were also more effective than placebo with 31% achieving a clinical cure vs 14% in the placebo group (RR 22.18, 95% CI 12.63 to 38.95; 9 studies, 3,440 people). They were also more likely to achieve mycological cure (35% vs 7%; RR 5.86, 95% CI 3.23 to 10.62), but as with terbinafine, there was high variability between studies for this outcome.
  • There was low-quality evidence that griseofulvin was less effective than terbinafine regarding clinical cure (RR 0.32, 95% CI 0.14 to 0.72; four studies, 270 people) and mycological cure (RR 0.64, 95% CI 0.46 to 0.90; five studies, 465 people). There was no statistically significant difference in the likelihood of achieving clinical or mycological cure with griseofulvin compared with an azole.
  • There was very low-quality evidence from a single study (176 people) that the combination of terbinafine plus an azole was more effective than terbinafine alone (clinical cure: RR 1.41, 95% CI 1.01 to 1.97; mycological cure: RR 1.41, 95% CI 1.08 to 1.83).

What does current guidance say on this issue?

The British Association of Dermatologists (2014) suggests either terbinafine or itraconazole as first options for the treatment of fungal nail infection in both adults and children. However, they say that unless there are contraindications terbinafine is preferred based on its higher efficacy and tolerability.

Griseofulvin has lower efficacy, higher relapse rates and more side effects than terbinafine or itraconazole but remains an option if these drugs are ineffective or not tolerated.

What are the implications?

These results support guideline recommendations that terbinafine is the most effective oral drug and should be considered the first-choice in fungal nail infection.

Topical treatments may still be in widespread use, particularly when purchased over-the-counter. This study was not able to assess or confirm their comparative lack of efficacy when compared with oral treatment.

Nail infection may recur after stopping treatment, so prevention is important. Healthcare professionals should advise people to wear protective shoes in public changing rooms (e.g. swimming pools or gyms), keep their nails short, avoid sharing nail clippers and wear shoes that fit properly.

Citation and Funding

Kreijkamp-Kaspers S, Hawke K, Guo L, et al. Oral antifungal medication for toenail onychomycosis. Cochrane Database Syst Rev. 2017;(7): CD010031.

Cochrane UK and the Cochrane Skin Group are supported by the National Institute for Health research via Cochrane Infrastructure funding.

Bibliography

Ameen M, Lear JT, Madan V, et al. British Association of Dermatologists' guidelines for the management of onychomycosis 2014. Br J Dermatol. 2014;171(5):937-58.

NHS Choices. Fungal nail infections. London: Department of Health; 2015.

Oral antifungal medication for toenail onychomycosis

Published on 15 July 2017

Kreijkamp-Kaspers, S.,Hawke, K.,Guo, L.,Kerin, G.,Bell-Syer, S. E.,Magin, P.,Bell-Syer, S. V.,van Driel, M. L.

Cochrane Database Syst Rev Volume 7 , 2017

BACKGROUND: Fungal infection of the toenails, also called onychomycosis, is a common problem that causes damage to the nail's structure and physical appearance. For those severely affected, it can interfere with normal daily activities. Treatment is taken orally or applied topically; however, traditionally topical treatments have low success rates due to the nail's physical properties. Oral treatments also appear to have shorter treatment times and better cure rates. Our review will assist those needing to make an evidence-based choice for treatment. OBJECTIVES: To assess the effects of oral antifungal treatments for toenail onychomycosis. SEARCH METHODS: We searched the following databases up to October 2016: the Cochrane Skin Group Specialised Register, CENTRAL, MEDLINE, Embase, and LILACS. We also searched five trials registers and checked the reference lists of included and excluded studies for further references to relevant randomised controlled trials (RCTs). We sought to identify unpublished and ongoing trials by correspondence with authors and by contacting relevant pharmaceutical companies. SELECTION CRITERIA: RCTs comparing oral antifungal treatment to placebo or another oral antifungal treatment in participants with toenail onychomycosis, confirmed by one or more positive cultures, direct microscopy of fungal elements, or histological examination of the nail. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. MAIN RESULTS: We included 48 studies involving 10,200 participants. Half the studies took place in more than one centre and were conducted in outpatient dermatology settings. The participants mainly had subungual fungal infection of the toenails. Study duration ranged from 4 months to 2 years.We assessed one study as being at low risk of bias in all domains and 18 studies as being at high risk of bias in at least one domain. The most common high-risk domain was 'blinding of personnel and participants'.We found high-quality evidence that terbinafine is more effective than placebo for achieving clinical cure (risk ratio (RR) 6.00, 95% confidence interval (CI) 3.96 to 9.08, 8 studies, 1006 participants) and mycological cure (RR 4.53, 95% CI 2.47 to 8.33, 8 studies, 1006 participants). Adverse events amongst terbinafine-treated participants included gastrointestinal symptoms, infections, and headache, but there was probably no significant difference in their risk between the groups (RR 1.13, 95% CI 0.87 to 1.47, 4 studies, 399 participants, moderate-quality evidence).There was high-quality evidence that azoles were more effective than placebo for achieving clinical cure (RR 22.18, 95% CI 12.63 to 38.95, 9 studies, 3440 participants) and mycological cure (RR 5.86, 95% CI 3.23 to 10.62, 9 studies, 3440 participants). There were slightly more adverse events in the azole group (the most common being headache, flu-like symptoms, and nausea), but the difference was probably not significant (RR 1.04, 95% CI 0.97 to 1.12; 9 studies, 3441 participants, moderate-quality evidence).Terbinafine and azoles may lower the recurrence rate when compared, individually, to placebo (RR 0.05, 95% CI 0.01 to 0.38, 1 study, 35 participants; RR 0.55, 95% CI 0.29 to 1.07, 1 study, 26 participants, respectively; both low-quality evidence).There is moderate-quality evidence that terbinafine was probably more effective than azoles for achieving clinical cure (RR 0.82, 95% CI 0.72 to 0.95, 15 studies, 2168 participants) and mycological cure (RR 0.77, 95% CI 0.68 to 0.88, 17 studies, 2544 participants). There was probably no difference in the risk of adverse events (RR 1.00, 95% CI 0.86 to 1.17; 9 studies, 1762 participants, moderate-quality evidence) between the two groups, and there may be no difference in recurrence rate (RR 1.11, 95% CI 0.68 to 1.79, 5 studies, 282 participants, low-quality evidence). Common adverse events in both groups included headache, viral infection, and nausea.Moderate-quality evidence shows that azoles and griseofulvin probably had similar efficacy for achieving clinical cure (RR 0.94, 95% CI 0.45 to 1.96, 5 studies, 222 participants) and mycological cure (RR 0.87, 95% CI 0.50 to 1.51, 5 studies, 222 participants). However, the risk of adverse events was probably higher in the griseofulvin group (RR 2.41, 95% CI 1.56 to 3.73, 2 studies, 143 participants, moderate-quality evidence), with the most common being gastrointestinal disturbance and allergic reaction (in griseofulvin-treated participants) along with nausea and vomiting (in azole-treated participants). Very low-quality evidence means we are uncertain about this comparison's impact on recurrence rate (RR 4.00, 0.26 to 61.76, 1 study, 7 participants).There is low-quality evidence that terbinafine may be more effective than griseofulvin in terms of clinical cure (RR 0.32, 95% CI 0.14 to 0.72, 4 studies, 270 participants) and mycological cure (RR 0.64, 95% CI 0.46 to 0.90, 5 studies, 465 participants), and griseofulvin was associated with a higher risk of adverse events, although this was based on low-quality evidence (RR 2.09, 95% CI 1.15 to 3.82, 2 studies, 100 participants). Common adverse events included headache and stomach problems (in griseofulvin-treated participants) as well as taste loss and nausea (in terbinafine-treated participants). No studies addressed recurrence rate for this comparison.No study addressed quality of life. AUTHORS' CONCLUSIONS: We found high-quality evidence that compared to placebo, terbinafine and azoles are effective treatments for the mycological and clinical cure of onychomycosis, with moderate-quality evidence of excess harm. However, terbinafine probably leads to better cure rates than azoles with the same risk of adverse events (moderate-quality evidence).Azole and griseofulvin were shown to probably have a similar effect on cure, but more adverse events appeared to occur with the latter (moderate-quality evidence). Terbinafine may improve cure and be associated with fewer adverse effects when compared to griseofulvin (low-quality evidence).Only four comparisons assessed recurrence rate: low-quality evidence found that terbinafine or azoles may lower the recurrence rate when compared to placebo, but there may be no difference between them.Only a limited number of studies reported adverse events, and the severity of the events was not taken into account.Overall, the quality of the evidence varied widely from high to very low depending on the outcome and comparison. The main reasons to downgrade evidence were limitations in study design, such as unclear allocation concealment and randomisation as well as lack of blinding.

Expert commentary

Based on 48 randomised therapy studies in 10,200 people, the cure rate was much higher with terbinafine and azoles compared to placebo. Some differences were seen between terbinafine and the azoles for similar adverse events. Overall cure rates were possibly higher with terbinafine.

Most itraconazole dosing was pulse therapy (one week in four) and fluconazole once weekly, which may be sub-therapeutic for some infections. Griseofulvin has more side effects.

David W. Denning, Professor of Infectious Diseases in Global Health; President, Global Action Fund for Fungal Infections; Director, National Aspergillosis Centre Education and Research Centre, University Hospital of South Manchester (Wythenshawe Hospital)

Categories

  •   Infections, Medicines, Skin conditions, Primary care