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BMJ Clin Evid. 2008; 2008: 1715.
Published online 2008 December 15.
PMCID: PMC2907960

Fungal toenail infections

Jill Ferrari, Senior Lecturer

Abstract

Introduction

Fungal infections are reported to cause 23% of foot diseases and 50% of nail conditions in people seen by dermatologists, but are less common in the general population, affecting 3-5% of people.

Methods and outcomes

We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of oral treatments for fungal toenail infections? What are the effects of topical treatments for fungal toenail infections? We searched: Medline, Embase, The Cochrane Library, and other important databases up to May 2008 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).

Results

We found 11 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.

Conclusions

In this systematic review we present information relating to the effectiveness and safety of the following interventions: amorolfine, butenafine, ciclopirox, fluconazole, griseofulvin, itraconazole, ketoconazole, mechanical debridement, terbinafine, and tioconazole.

Key Points

Fungal toenail infection (onychomycosis) is characterised as infection of part or all of the toenail unit, which includes the nail plate, the nail bed, and the nail matrix. Over time, the infection causes discoloration and distortion of part or all of the nail unit.

  • Fungal infections are reported to cause 23% of foot diseases and 50% of nail conditions in people seen by dermatologists, but are less common in the general population, affecting 3-5% of people.
  • Infection can cause discomfort in walking, pain, or limitation of activities.

People taking oral antifungal drugs reported greater satisfaction, and fewer onychomycoses-related problems, such as embarrassment, self-consciousness, and being perceived as unclean by others, compared with people using topical antifungals.

  • Oral antifungals have general adverse effects including gastrointestinal complaints (such as diarrhoea), rash, and respiratory complaints. It was rare for people to withdraw from an RCT because of adverse effects.

Both oral itraconazole and oral terbinafine effectively increase cure rates of fungal toenail infection; terbinafine seems slightly more effective.

  • Adverse effects unique to terbinafine include sensory loss, such as taste, smell, or hearing disturbance.

Alternative oral antifungal treatments include fluconazole, which seems to modestly improve cure rates, and ketoconazole and griseofulvin, which may be effective; but the evidence is insufficient to allow us to say for certain.

Topical ciclopirox seems to modestly improve symptoms of fungal toenail infection compared with placebo.

About this condition

Definition

Fungal toenail infection (onychomycosis) is characterised as infection of part or all of the nail unit, which includes the nail plate, the nail bed, and the nail matrix. Over time, the infection causes discoloration and distortion of part or all of the nail unit. The tissue under and around the nail may also thicken. This review deals exclusively with dermatophyte toenail infections (see aetiology) and excludes candidal or yeast infections.

Incidence/ Prevalence

Fungal infections are reported to cause 23% of foot diseases and 50% of nail conditions in people seen by dermatologists, but are less common in the general population, affecting 3-5% of people. The prevalence varies among populations, which may be due to differences in screening techniques. In a large European project (13,695 people with a range of foot conditions), 35% had a fungal infection diagnosed by microscopy/culture. One prospective study in Spain (1000 adults aged over 20 years) reported a prevalence of fungal toenail infection as 2.7% (infection defined as clinically abnormal nails with positive microscopy and culture). In Denmark, one study (5755 adults aged over 18 years) reported the prevalence of fungal toenail infection as 4.0% (determined by positive fungal cultures). The incidence of mycotic nail infections may have increased over the past few years, perhaps because of increasing use of systemic antibiotics, immunosuppressive treatment, more advanced surgical techniques, and the increasing incidence of HIV infection. However, this was contradicted by a study in an outpatient department in Eastern Croatia, which compared the prevalence of fungal infections between two periods (1986-1988, 47,832 people; 1997-2001, 75,691 people). It found that the prevalence of fungal infection overall had increased greatly over the 10 years, but that the percentage of fungal infections affecting the nails had decreased by 1% (fungal infections overall: 0.26% in 1986-1988 v 0.73% in 1997-2001; nail: 10.31% in 1986-1988 v 9.31% in 1997-2001).

Aetiology/ Risk factors

Fungal nail infections are most commonly caused by anthropophilic fungi called dermatophytes. The genera Trichophyton, Epidermophyton, and Microsporum are typically involved, specifically T rubrum, T mentagrophytes var interdigitale, and E floccosum. Other fungi, moulds, or yeasts may be isolated, such as Scopulariopsis brevicaulis, Aspergillus, Fusarium, and Candida albicans. T rubrum is now regarded as the most common cause of onychomycosis worldwide. Several factors that increase the risk of developing a fungal nail infection have been identified. One survey found that 26% of people with diabetes had onychomycosis, and that diabetes increased the risk of infection, but the type and severity of diabetes was not correlated with infection (OR 2.77, 95% CI 2.15 to 3.57). Another survey found that peripheral vascular disease (OR 1.78, 95% CI 1.68 to 1.88) and immunosuppression (OR 1.19, 95% CI 1.01 to 1.40) increased the risk of infection. These factors may explain the general increase in prevalence of onychomycosis in the elderly population. Environmental exposures such as occlusive footwear or warm, damp conditions have been cited as risk factors, as has trauma. Fungal skin infection has been proposed as a risk factor. However, one large observational study, which included 5413 people with positive mycology, found that only a small proportion (21.3%) had both skin and toenail infections.

Prognosis

Onychomycosis does not have serious consequences in otherwise healthy people. However, the Achilles project (846 people with fungal toenail infection) found that many people complain of discomfort in walking (51%), pain (33%), or limitation of their work or other activities (13%). Gross distortion and dystrophy of the nail may cause trauma to the adjacent skin, and may lead to secondary bacterial infection. In immunocompromised people, there is a risk that this infection will disseminate. Quality-of-life measures specific to onychomycosis have recently been developed. Studies using these indicators suggest that onychomycosis has negative physical and psychosocial effects.

Aims of intervention

To eradicate fungal spores from the nail unit (nail bed, matrix, or plate); to allow a normal nail to regrow if permanent damage to the nail matrix has not occurred.

Outcomes

Negative microscopy and culture; satisfaction with treatment; adverse effects of treatment, especially liver failure.

Methods

Clinical Evidence search and appraisal May 2008. The following databases were used to identify studies for this review: Medline 1966 to May 2008, Embase 1980 to May 2008, and The Cochrane Library, Issue 2, 2008. Additional searches were carried out using these websites: NHS Centre for Reviews and Dissemination (CRD), Database of Abstracts of Reviews of Effects (DARE), Health Technology Assessment (HTA), Turning Research into Practice (TRIP), and NICE clinical guidelines. Abstracts of the studies retrieved were assessed independently by two information specialists using predetermined criteria to identify relevant studies. Study design criteria for inclusion in this review were: published systematic reviews and RCTs in any language, at least single blinded, and containing more than 20 people of whom more than 80% were followed up. The minimum length of follow-up required was 3 months to include studies. We excluded all studies described as "open", "open label", or not blinded unless the interventions could not be blinded. RCTs of treatment in fingernails and of infections related to candidal and yeast infections were also excluded. We considered systematic reviews, RCTs, and observational studies for the harms because of the potentially serious nature of the harms (liver failure). In addition, we use a regular surveillance protocol to capture harms alerts from organisations such as the FDA and the UK Medicines and Healthcare products Regulatory Agency (MHRA), which are continually added to the review as required. We have performed a GRADE evaluation of the quality of evidence for interventions included in this review (see table ). To aid readability of the numerical data in our reviews, we round many percentages to the nearest whole number. Readers should be aware of this when relating percentages to summary statistics such as RRs and ORs.

Table
GRADE evaluation of interventions for fungal toenail infections

Glossary

High-quality evidence
Further research is very unlikely to change our confidence in the estimate of effect.
Low-quality evidence
Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Moderate-quality evidence
Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Very low-quality evidence
Any estimate of effect is very uncertain.

Notes

Disclaimer

The information contained in this publication is intended for medical professionals. Categories presented in Clinical Evidence indicate a judgement about the strength of the evidence available to our contributors prior to publication and the relevant importance of benefit and harms. We rely on our contributors to confirm the accuracy of the information presented and to adhere to describe accepted practices. Readers should be aware that professionals in the field may have different opinions. Because of this and regular advances in medical research we strongly recommend that readers' independently verify specified treatments and drugs including manufacturers' guidance. Also, the categories do not indicate whether a particular treatment is generally appropriate or whether it is suitable for a particular individual. Ultimately it is the readers' responsibility to make their own professional judgements, so to appropriately advise and treat their patients.To the fullest extent permitted by law, BMJ Publishing Group Limited and its editors are not responsible for any losses, injury or damage caused to any person or property (including under contract, by negligence, products liability or otherwise) whether they be direct or indirect, special, incidental or consequential, resulting from the application of the information in this publication.

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2008; 2008: 1715.
Published online 2008 December 15.

Itraconazole (oral)

Summary

CURE RATE Compared with placebo: Oral itraconazole may be more effective at curing fungal toenail infection ( very low-quality evidence ). Compared with oral griseofulvin: Oral itraconazole and oral griseofulvin may be equally effective at curing fungal toenail infection after 24–72 weeks (very low-quality evidence). Compared with oral terbinafine: Oral itraconazole may be less effective at curing fungal toenail infection after 12–16 weeks' treatment (very low-quality evidence). Pulsed oral itraconazole compared with continuous oral itraconazole: Pulsed oral itraconazole for 3–4 months and continuous oral itraconazole may be equally effective at curing fungal toenail infection ( low-quality evidence ). Compared with topical treatments: Oral antifungal treatment may lead to greater patient satisfaction after 9 months (very low-quality evidence). NOTE We found no clinically important results about the effects of oral itraconazole compared with oral ketoconazole or oral fluconazole.

Benefits

Oral itraconazole versus placebo:

We found one systematic review (search date 2000). It found that 12 weeks of itraconazole 200 mg daily significantly increased cure rates at the end of treatment compared with placebo (3 RCTs, 433 people with fungal toenail infection; AR: 63% with itraconazole v 4% with placebo; ARI 60%, 95% CI 54% to 67%).

Oral itraconazole versus oral griseofulvin:

See benefits of oral griseofulvin.

Oral itraconazole versus oral terbinafine:

We found one systematic review (search date 2000, 4 RCTs)and one subsequenl RCT. The first and second RCTs identified by the review found that 12 weeks of itraconazole 200 mg daily produced significantly lower cure rates compared with 12 weeks of terbinafine 250 mg daily at about 1 year (501 people with fungal toenail infection; AR: 69% with terbinafine v 48% with itraconazole; ARR 21%, 95% CI 13% to 29%). The third RCT identified by the review compared three treatments given for 16 weeks: pulsed itraconazole (400 mg/day for 1 week in every 4 weeks); pulsed terbinafine (500 mg/day for 1 week in every 4 weeks); and continuous terbinafine 250 mg daily. It found no significant difference in cure rates between pulsed itraconazole and continuous terbinafine at 43 weeks (60 people with fungal toenail infection; AR: 75% with itraconazole v 84% with continuous terbinafine; ARR +9%, 95% CI –34% to +16%). The fourth RCT identified by the review compared four treatments: pulsed itraconazole for 12 weeks (400 mg/day for 1 week in every 4 weeks); pulsed itraconazole for 16 weeks (regimen as for 12-week treatment); continuous terbinafine for 12 weeks 250 mg daily; and continuous terbinafine 250 mg daily for 16 weeks. It found that pulsed itraconazole produced significantly lower cure rates compared with continuous terbinafine, regardless of duration, at 72 weeks (250 people with fungal toenail infection; AR after 12 weeks' treatment: 33% with itraconazole v 65% with terbinafine; ARR 33%, 95% CI 21% to 44%; 246 people with fungal toenail infection; AR after 16 weeks' treatment: 42% with itraconazole v 67% with terbinafine; ARR 25%, 95% CI 13% to 37%).

The subsequent RCT (70 people with diabetes and dermatophyte toenail distal and lateral subungual onychomycosis) compared oral pulsed itraconazole (200 mg twice daily, 1 week on/3 weeks off for 12 weeks) versus oral terbinafine (250 mg/day for 12 weeks). The RCT found no significant difference in cure rates between groups at 48 weeks (30/35 [88%] with pulsed itraconazole v 23/29 [77%] with continuous terbinafine; ARR 11.5%, 95% CI –5.2% to 28.2%).

Oral itraconazole versus oral ketoconazole:

We found one systematic review (search date 2000), which found no RCTs.

Oral itraconazole versus oral fluconazole:

We found one systematic review (search date 2000), which found no RCTs.

Pulsed versus continuous oral itraconazole:

We found one systematic review (search date 2000, 3 RCTs). The first RCT identified by the review found no significant difference in cure rates between 12 weeks of continuous itraconazole (200 mg/day) and 12 weeks of pulsed itraconazole (400 mg/day for 1 week in every 4 weeks) at 52 weeks (121 people with fungal toenail infection; AR: 66% with continuous itraconazole v 69% with pulsed itraconazole; ARR +3%, 95% CI –10% to +20%). The second RCT identified by the review found no significant difference in cure rates between 3 and 4 months of pulsed itraconazole (400 mg/day for 1 week in every 4 weeks) at 24 weeks (50 people with fungal toenail infection; AR: 64% with 3 months and 72% with 4 months; ARR +8%, 95% CI –20% to +30%). The third RCT identified by the review found no significant difference in cure rates between 12 or 16 weeks of continuous itraconazole (200 mg/day) and 12 or 16 weeks of pulsed itraconazole (200 mg/day for 1 week in every 4 weeks) at 48 weeks (64 people with fungal toenail infection; AR after 12 weeks' treatment: 68% with continuous itraconazole v 50% with pulsed itraconazole; ARI +18%, 95% CI –50% to +40%; AR after 16 weeks' treatment: 64% with continuous itraconazole v 64% with pulsed itraconazole; ARR 0%, 95% CI –34% to +34%).

Oral itraconazole versus topical treatments:

We found no systematic review or RCTs. We found one longitudinal study comparing oral antifungals versus topical treatments (see comment on oral griseofulvin).

Harms

Oral itraconazole versus oral griseofulvin:

See harms of oral griseofulvin.

Oral itraconazole versus oral terbinafine:

The RCT of pulsed itraconazole versus continuous terbinafine in people with diabetes mellitus reported that only one person in the itraconazole group withdrew due to gastic pain. There were no other serious adverse events or interactions with normal medications.

Re-infection rates:

One open-label RCT comparing oral itraconazole (400 mg/day for 1 week in every 4 for 12 weeks) versus oral terbinfine (250 mg/day for 12 weeks) recorded the number of people initially considered cured (mycological cure) and who then became re-infected with either the same or a different fungal species during the course of the study (relapsed). At the final follow-up (96 weeks), 21% of people in the itroconazole group versus 14% of the terbinafine group were found to have a further infection. This was reported to be non-significant (P greater than 0.05).

Comment

See comment on oral griseofulvin.

Oral itraconazole versus placebo:

Outcomes were measured at 12 weeks. It is more clinically relevant to measure outcomes after at least 9 months, because it takes at least 6 months for the toenail to regrow completely.

Substantive changes

Itraconazole (oral) One RCT added to the benefits section comparing oral pulsed itraconazole versus oral terbinafine. The RCT found no significant difference in cure rates between groups at 48 weeks. One open-label RCT added to the harms section comparing oral itraconazole versus oral terbinfine. It found no significant difference in the rate of relapse between groups. Categorisation unchanged (Beneficial).

2008; 2008: 1715.
Published online 2008 December 15.

Oral terbinafine (oral)

Summary

CURE RATE Compared with placebo: Oral terbinafine for 12–24 weeks may be more effective at curing fungal toenail infection ( very low-quality evidence ). Compared with oral itraconazole: Oral terbinafine may be more effective at curing fungal toenail infection after 12–16 weeks' treatment (very low-quality evidence). Compared with oral griseofulvin: Oral terbinafine may be more effective at curing fungal toenail infection after 24–52 weeks' treatment ( low-quality evidence ). Compared with oral terbinafine plus topical ciclopirox: Continuous terbinafine alone for 12 weeks and pulsed or continuous terbinafine for 12 weeks plus topical ciclopirox for 48 weeks may be equally effective at curing fungal toenail infection ( moderate-quality evidence ). ADVERSE EFFECTS Terbinafine has been associated with hepatotoxicity, but serious adverse effects are rare. NOTE We found no clinically important results about the effects of oral terbinafine compared with ketoconazole or fluconazole.

Benefits

Oral terbinafine versus placebo:

We found one systematic review (search date 2000, 5 RCTs). The review found that 12 weeks of terbinafine 250 mg daily significantly increased cure rates at the end of treatment compared with placebo (3 RCTs, 337 people with fungal toenail infection; AR: 63% with terbinafine v 20% with placebo; ARI 43%, 95% CI 34% to 53%). The review identified two further RCTs, which could not be included in the meta-analysis because they examined different terbinafine regimens. The first of these RCTs found that 12 and 24 weeks of terbinafine 250 mg daily significantly increased cure rates at 48 weeks compared with placebo (353 people with fungal toenail infection; AR after 12 weeks' treatment: 70% with terbinafine v 8% with placebo; ARI 62%, 95% CI 52% to 72%; AR after 24 weeks' treatment: 87% with terbinafine v 8% with placebo; ARI 79%, 95% CI 70% to 87%). The second of these RCTs found that 12, 16, and 24 weeks of terbinafine 250 mg daily significantly increased cure rates at 72 weeks compared with placebo (109 people with fungal toenail infection; AR after 12 weeks' treatment: 38% with terbinafine v 0% with placebo; ARI 38%, 95% CI 20% to 50%; AR after 16 weeks' treatment: 37% with terbinafine v 0% with placebo; ARI 37%, 95% CI 21% to 56%; AR after 24 weeks' treatment: 65% with terbinafine v 0% with placebo; ARR 65%, 95% CI 46% to 81%).

Oral terbinafine versus oral griseofulvin:

See benefits of oral griseofulvin.

Oral terbinafine versus oral itraconazole:

See benefits of oral itraconazole.

Oral terbinafine versus oral ketoconazole:

We found one systematic review (search date 2000), which found no RCTs.

Oral terbinafine versus oral fluconazole:

We found one systematic review (search date 2000), which found no RCTs.

Oral terbinafine versus topical treatments:

We found one RCT comparing three treatments: topical ciclopirox daily for 48 weeks plus pulsed terbinafine for the initial 12 weeks (250 mg daily for 4 weeks daily/4 weeks rest/4 weeks daily); topical ciclopirox plus continuous terbinafine for 12 weeks followed by topical ciclopirox alone for 36 weeks; and continuous terbinafine alone for 12 weeks. The RCT found no significant difference between the three treatments in mycological cure rates at 48 weeks (73 people; 14/21 [67%] with ciclopirox plus pulsed terbinafine v 19/27 [70%] with ciclopirox plus continuous terbinafine v 14/25 [56%] with continuous terbinafine alone; P value for overall comparison reported as not significant). We found also one longitudinal study comparing oral antifungals versus topical treatments (see comment on oral griseofulvin).

Harms

Adverse events unique to terbinafine include sensory loss such as taste, smell, or hearing disturbance (see harms of oral griseofulvin andharms of oral itraconazole).

Oral terbinafine versus topical treatments:

The RCT found that the incidence of adverse events (including gastrointestinal effects, and subcutaneous tissue and skin disorders) was similar between the three treatment groups (20.5% with ciclopirox plus pulsed terbinafine v 21.4% with ciclopirox plus continuous terbinafine v 22.0% with continuous terbinafine alone; significance not reported). No participants withdrew because of adverse events. One open-label RCT (249 people) compared amorolfine hydrochloride (5% nail lacquer for 12 months) plus oral terbinafine (250 mg/day for 3 months) versus terbinafine alone (250 mg/day for 3 months). The study reported adverse effects in 15/103 (12%) people with terbinafine alone versus 19/105 (16%) people with combination treatment (no significance assessment between groups performed). Only two adverse events were considered due to the amorolfine nail lacquer (ingrowing toenail and constipation).

Hepatotoxicity:

One case report described fulminant hepatic failure in a 48-year-old woman with onychomycosis. She had taken terbinafine 250 mg daily for 5 days and developed fulminant hepatic failure over a period of 4 weeks, which required liver transplantation. Histological examination reported tissue status compatible with a drug-related cause of disease. The woman additionally took dosulepin 75 mg daily and propranolol 40 mg twice daily. The RCTs involving terbinafine frequently measured levels of liver enzymes and found that increases were asymptomatic, and reversed once the drug was stopped.

High-risk populations:

Several prospective cohort studies have considered the safety of terbinafine to treat fungal nail infections in high-risk populations. One review paper reported the results of three studies involving people with diabetes mellitus, two studies in people with HIV infection, and two studies involving organ transplant recipients. The review found that no significant adverse effects were reported in the diabetes studies. No drug interactions were reported in people receiving terbinafine, and glucose levels were unchanged during the treatment period (207 people receiving 250 mg/day of terbinafine for 12 weeks). The review found that the HIV studies reported no serious adverse effects (10 people receiving 250 mg/day terbinafine for 12 weeks, 21 people receiving 250 mg/day terbinafine for 16 weeks). It found that blood ciclosporin levels significantly decreased in organ transplant patients taking terbinafine, but this did not cause significant clinical change in the people or lead to organ rejection. Renal function remained normal (11 people receiving 250 mg/day terbinafine for 12 weeks, 4 receiving 250 mg/day terbinafine for 4–24 weeks). One open-label prospective study examined the safety of terbinafine use in people aged over 60 years with onychomycosis of the feet confirmed by positive mycological culture. It found that a total of 18 adverse events occurred, all considered mild to moderate in severity, and transient in nature. No participants withdrew from the study because of adverse events (30 people receiving 250 mg/day for 12 weeks). The study also considered the 16 people taking drugs metabolised by the cytochrome P-450 isoenzyme, 2D6, because of specific in vitro data suggesting a potential interaction between terbinafine and drugs metabolised by this isoenzyme. No drug interactions between these cases and terbinafine were observed.

Comment

See comment on oral griseofulvin.

Oral terbinafine versus placebo:

Outcomes were measured at 12 weeks. It is more clinically relevant to measure outcomes after 9 months, because it takes at least 6 months for the toenail to regrow completely.

Oral terbinafine versus topical treatments:

The RCT comparing combinations of terbinafine plus ciclopirox versus terbinafine alone may have been underpowered to detect a significant difference between treatments.

Substantive changes

Oral terbinafine One RCT added to the benefits section comparing oral pulsed itraconazole versus oral terbinafine. The RCT found no significant difference in cure rates between groups at 48 weeks. One open-label RCT added to the harms section comparing oral itraconazole versus oral terbinfine. It found no significant difference in the rate of relapse between groups. One open-label RCT added to the harms section comparing amorolfine hydrochloride plus oral terbinafine versus terbinafine alone. It found similar rates of adverse effects in each group. Categorisation unchanged (Beneficial).

2008; 2008: 1715.
Published online 2008 December 15.

Fluconazole (oral)

Summary

CURE RATE Compared with placebo: Oral fluconazole may be more effective at curing fungal toenail infection after 16–52 weeks' treatment ( low-quality evidence ). Compared with topical treatments: Oral antifungal treatment may lead to greater patient satisfaction after 9 months ( very low-quality evidence ). NOTE We found no clinically important results about the effects of fluconazole compared with griseofulvin, terbinafine, itraconazole, or ketoconazole.

Benefits

Oral fluconazole versus placebo:

We found one systematic review (search date 2000, 2 RCTs). The first RCT identified by the review found that 16, 26, and 39 weeks of fluconazole 150 mg weekly significantly increased cure rates at the end of treatment compared with placebo (331 people with fungal toenail infection; AR after 16 weeks' treatment: 31% with fluconazole v 7% with placebo; ARI 24%, 95% CI 12% to 35%; AR after 26 weeks' treatment: 48% with fluconazole v 7% with placebo; ARI 40%, 95% CI 28% to 52%; AR after 39 weeks' treatment: 53% with fluconazole v 7% with placebo; ARI 46%, 95% CI 34% to 58%). The second RCT identified by the review found that fluconazole (150, 300, and 450 mg/week for a maximum of 12 months) significantly increased cure rates at the end of treatment compared with placebo (361 people with fungal toenail infection; AR: 43% with fluconazole 150 mg v 13% with placebo; ARI 30%, 95% CI 17% to 42%; AR: 47% with fluconazole 300 mg v 13% with placebo; ARI 35%, 95% CI 22% to 47%; AR: 51% with fluconazole 450 mg v 13% with placebo; ARI 38%, 95% CI 25% to 50%).

Oral fluconazole versus oral griseofulvin:

We found one systematic review (search date 2000), which found no RCTs.

Oral fluconazole versus oral itraconazole:

We found one systematic review (search date 2000), which found no RCTs.

Oral fluconazole versus oral terbinafine:

We found one systematic review (search date 2000), which found no RCTs.

Oral fluconazole versus oral ketoconazole:

We found one systematic review (search date 2000), which found no RCTs.

Oral fluconazole versus topical treatments:

We found no systematic review or RCTs. We found one longitudinal study comparing oral antifungals versus topical treatments (see comment on oral griseofulvin).

Harms

See harms of oral griseofulvin.

Comment

See comment on oral griseofulvin.

Substantive changes

No new evidence

2008; 2008: 1715.
Published online 2008 December 15.

Griseofulvin (oral)

Summary

CURE RATE Compared with oral itraconazole: Oral griseofulvin and oral itraconazole may be equally effective at curing fungal toenail infection after 24–72 weeks ( very low-quality evidence ). Compared with oral terbinafine: Oral griseofulvin for 24–52 weeks may be less effective at curing fungal toenail infection ( low-quality evidence ). Compared with oral ketoconazole: Oral griseofulvin and oral ketoconazole may be equally effective at curing fungal toenail infection after 24–49 weeks' treatment (very low-quality evidence). Compared with topical treatments: Oral antifungal treatment may lead to greater patient satisfaction after 9 months (very low-quality evidence). NOTE We found no direct information about whether oral griseofulvin is better than no active treatment. We found no clinically important results about the effects of griseofulvin compared with fluconazole.

Benefits

Oral griseofulvin versus placebo:

We found one systematic review (search date 2000), which found no RCTs.

Oral griseofulvin versus oral itraconazole:

We found one systematic review (search date 2000, 3 RCTs). None of the RCTs found a significant difference in cure rates between griseofulvin and itraconazole. The first RCT identified by the review found no significant difference in cure rates at the end of treatment between 24 weeks of griseofulvin 500 mg daily and 24 weeks of itraconazole 100 mg daily (19 people with fungal toenail infection; AR: 0% with griseofulvin v 0% with itraconazole; ARR 0%, –17% to +18%). The second RCT identified by the review found no significant difference in cure rates at 40 weeks between 24–36 weeks of griseofulvin 500 mg daily and 24–36 weeks of itraconazole 100 mg daily (61 people with fungal toenail infection; AR: 30% with griseofulvin v 37% with itraconazole; ARR +5%, 95% CI –18% to +28%). The third RCT identified by the review found no significant difference in cure rates at 77 weeks between 72 weeks of griseofulvin 660 mg daily, 72 weeks of griseofulvin 990 mg daily, and 72 weeks of itraconazole 100 mg daily (108 people with fungal toenail infection; AR: 6% with griseofulvin 660 mg/day v 8% with itraconazole 100 mg/day; ARR +2%, 95% CI –8% to +10%; AR: 6% with griseofulvin 990 mg/day v 8% with itraconazole 100 mg/day; ARR +2%, 95% CI –8% to +10%).

Oral griseofulvin versus oral terbinafine:

We found one systematic review (search date 2000, 3 RCTs). The first RCT identified by the review found that 52 weeks of griseofulvin 1000 mg daily produced significantly lower cure rates compared with 52 weeks of terbinafine 250 mg daily at the end of treatment (120 people with fungal toenail infection; AR: 63% with griseofulvin v 75% with terbinafine; ARR 12%, 95% CI 4% to 28%). The second RCT identified by the review found that 24 weeks of griseofulvin 1000 mg daily produced significantly lower cure rates compared with 24 weeks of terbinafine 250 mg daily at 72 weeks (171 people with fungal toenail infection; AR: 47% with griseofulvin v 62% with terbinafine; ARR 15%, 95% CI 0% to 30%). The third RCT identified by the review found that 52 weeks of griseofulvin 500 mg daily produced significantly lower cure rates compared with 16 weeks of terbinafine 250 mg daily at 52 weeks (84 people with fungal toenail infection; AR: 46% with griseofulvin v 84% with terbinafine; ARR 37%, 95% CI 17% to 55%).

Oral griseofulvin versus oral ketoconazole:

We found one systematic review (search date 2000, 2 RCTs). Neither RCT found a significant difference in cure rates between griseofulvin and ketoconazole. The first RCT identified by the review found no significant difference in cure rates at the end of treatment between an average of 49 weeks of griseofulvin compared with ketoconazole (16 people with fungal toenail infection; AR: 0% with griseofulvin v 11% with ketoconazole; ARI +11%, 95% CI –25% to +43%). The second RCT identified by the review found no significant difference in cure rates at the end of treatment between 24 weeks of griseofulvin 1000 mg daily and 24 weeks of ketoconazole 200 mg daily (26 people with fungal toenail infection; AR: 42% with griseofulvin v 36% with ketoconazole; ARR –6%, 95% CI –38% to +27%).

Oral griseofulvin versus oral fluconazole:

We found one systematic review (search date 2000), which found no RCTs.

Oral griseofulvin versus topical treatments:

We found no systematic review or RCTs. We found one longitudinal study comparing oral antifungals versus topical treatments (see comment below).

Harms

The review did not describe adverse effects of different oral antifungals separately. A total of 31 of the 32 included RCTs examining oral antifungals reported on adverse events. The most common adverse effects were gastrointestinal complaints (such as diarrhoea), rash, and respiratory complaints. It was rare for people to withdraw from an RCT because of adverse effects, although treatment was sometimes interrupted. The review found no significant difference in the frequency of adverse events between oral antifungals and placebo (reported as not significant; figures not reported).

Comment

The review included 32 RCTs, 22 of which were funded by the pharmaceutical industry. All 22 of these RCTs produced data that supported the sponsor's product. The reviewers highlighted the possibility that the conclusions of the review were compromised by a publication bias. The review found that the definitions of clinical cure in the included RCTs were so diverse and inconsistent that it was not possible to make meaningful comparisons between clinical cure rates reported in the RCTs.

Oral antifungals versus topical treatment:

We found one longitudinal study of 150 people with onychomycosis treated with mechanical (nail debridement), topical (clotrimazole, Fungi-Nail), and oral (terbinafine, itraconazole, fluconazole) treatments. People who had taken oral antifungal drugs reported significantly fewer onychomycosis-related problems, including embarrassment, self-consciousness, and being perceived as unclean by others, 9 months after treatment, compared with non-oral treatments. Satisfaction was significantly greater among people who had received oral drugs than non-oral treatment.

Substantive changes

No new evidence

2008; 2008: 1715.
Published online 2008 December 15.

Ketoconazole (oral)

Summary

CURE RATE Compared with oral griseofulvin: Oral ketoconazole and oral griseofulvin may be equally effective at curing fungal toenail infection after 24–49 weeks' treatment ( very low-quality evidence ). Compared with topical treatments: Oral antifungal treatment may lead to greater patient satisfaction after 9 months (very low-quality evidence). NOTE We found no direct information about whether oral ketoconazole is better than no active treatment. We found no clinically important results about the effects of oral ketoconazole compared with terbinafine, itraconazole, or fluconazole.

Benefits

Oral ketoconazole versus placebo:

We found one systematic review (search date 2000), which found no RCTs.

Oral ketoconazole versus oral griseofulvin:

See benefits of oral griseofulvin.

Oral ketoconazole versus oral itraconazole:

We found one systematic review (search date 2000), which found no RCTs.

Oral ketoconazole versus oral terbinafine:

We found one systematic review (search date 2000), which found no RCTs.

Oral ketoconazole versus oral fluconazole:

We found one systematic review (search date 2000), which found no RCTs.

Oral ketoconazole versus topical treatments:

We found no systematic review or RCTs. We found one longitudinal study comparing oral antifungals versus topical treatments (see comment on oral griseofulvin).

Harms

See harms of oral griseofulvin.

Hepatotoxicity:

We found one clinical case review of 3600 people by a pharmaceutical company in 1983. The pharmaceutical company identified 77 cases of symptomatic hepatotoxicity during ketoconazole treatment; men and women were equally affected: only the woman described below died. The review included one case report of fatal hepatitis in a previously healthy 67-year-old woman who received ketoconazole 200 mg daily for 2 months. We found a further case report of fatal hepatocyte necrosis in a 38-year-old woman receiving ketoconazole 200 mg daily for 103 days. After stopping treatment, she developed signs and symptoms of liver failure and died.

Comment

See comment on oral griseofulvin.

Substantive changes

No new evidence

2008; 2008: 1715.
Published online 2008 December 15.

Ciclopirox (topical)

Summary

CURE RATE Compared with placebo: Topical ciclopirox applied for 48 weeks is more effective at increasing cure rates ( high-quality evidence ). Topical ciclopirox plus oral terbinafine compared with oral terbinafine alone: Adding topical ciclopirox for 48 weeks to 12 weeks' treatment with oral terbinafine is no more effective than 12 weeks of oral terbinafine alone at increasing cure rates ( moderate-quality evidence ). Compared with oral treatments: Topical treatments may lead to less patient satisfaction after 9 months compared with oral antifungal treatments ( very low-quality evidence ). NOTE We found no clinically important results about the effects of topical ciclopirox compared with other topical treatments.

Benefits

Topical ciclopirox versus placebo:

We found one systematic review (search date 2005), which identified two RCTs found that ciclopirox significantly decreased cure failure rates compared versus placebo at 48 weeks (2 RCTs 22/229 [10%] with ciclopirox v 71/239 [30%] with placebo, RR 0.32, 95% CI 0.20 to 0.52).

Topical ciclopirox versus other topical antifungal treatments:

We found no RCTs comparing topical ciclopirox versus other topical antifungal treatments.

Topical ciclopirox versus oral treatments:

We found one RCT (see benefits of oral terbinafine). We also found one longitudinal study comparing topical treatments versus oral antifungals (see comment on oral griseofulvin).

Harms

Topical ciclopirox versus placebo:

The review gave no information on adverse effecs.However, one RCT included in the review found that ciclopirox nail laquer increased adverse events compared with placebo (AR: 11% with ciclopirox v 7% with placebo; significance not reported). Adverse events included tingling sensation, changes in nail shape or colour, and localised erythema.

Topical ciclopirox versus oral treatments:

See harms of oral terbinafine.

Comment

In one RCT included in the review, people were advised to coat the entire toenail with lacquer, including the entire nail plate and 5 mm of surrounding skin. Participants were advised to wait at least 8 hours before washing the nails, and not to remove the coat from the previous day but to apply new coats over the old. Every 7 days, isopropyl alcohol swabs were used to remove the build up of lacquer.

Substantive changes

Ciclopirox (topical) One systematic review comparing ciclopirox versus placebo updated. The review found that ciclopirox significantly decreased rates of treatment failure compared with placebo. Categorisation unchanged (Likely to be beneficial).

2008; 2008: 1715.
Published online 2008 December 15.

Mechanical debridement

Summary

We found no clinically important results about the effects of mechanical debridement in fungal toenail infection.

Benefits

We found no systematic review or RCTs. We found one longitudinal study comparing oral antifungals versus topical treatments (see comment on oral griseofulvin).

Harms

We found one open-label study (504 people aged over 65 years) comparing terbinafine 250 mg daily for 12 weeks alone versus terbinafine 250 mg daily plus mechanical debridement (see comment).The RCT reported that 43% (75) people reported adverse effects. This included ingrowing toenails (5%), sinusitis (5%), nausea (4%) and headache (1%). The study did not describe in which treatment arm these adverse effects occurred, or give absolute numbers, and no significance assessments were performed. Overall, 4% of the study group withdrew from the trial due to adverse effects. In the terbinafine group, one person withdrew due to nausea/headaches. In the terbinafine-plus-debridement group, two people withdrew due to nausea/headache and flank pain.

Comment

Mechanical (aggressive) debridement involved removal of the unattached distal portion of the nail plate and debridement of the infected nail plate using nail nippers or a nail drill or both. This was performed at intervals from baseline up to 48 weeks. No avulsion under anaesthetic was involved.

Substantive changes

Mechanical debridement One open-label study added. Harms data enhanced, categorisation unchanged (Unknown effectiveness).

2008; 2008: 1715.
Published online 2008 December 15.

Amorolfine (topical)

Summary

We found no clinically important results about the effects of topical amorolfine in fungal toenail infection.

Benefits

We found one systematic review (search date 2005), which found no RCTs. We found no subsequent RCTs comparing topical amorolfine versus placebo or other topical antifungal treatments.

Harms

We found one open-label RCT comparing combination treatment of amorolfine hydrochloride 5% nail lacquer plus oral terbinafine versus oral terbinafine alone (see harms of oral terbainafine versus topical treatments).

Comment

None.

Substantive changes

Amorolfine (topical) One systematic review updated, no new data added. One open-label RCT added to the harms section comparing amorolfine hydrochloride 5% nail lacquer plus oral terbinafine versus oral terbinafine alone. It found similar rates of adverse effects in each group. Categorisation unchanged (Unknown effectiveness).

2008; 2008: 1715.
Published online 2008 December 15.

Butenafine (topical)

Summary

We found no clinically important results about the effects of topical butenafine in fungal toenail infection.

Benefits

We found one systematic review (search date 2005), which found no RCTs. We found no subsequent RCTs comparing topical butenafine versus placebo or other topical antifungal treatments.

Harms

We found no RCTs or case studies investigating adverse effects of topical butenafine.

Comment

None.

Substantive changes

Butenafine (topical) One systemtaic review updated, no new data added. Categorisation unchanged (Unknown effectiveness).

2008; 2008: 1715.
Published online 2008 December 15.

Fluconazole (topical)

Summary

We found no clinically important results about the effects of topical fluconazole in fungal toenail infection.

Benefits

We found one systematic review (search date 2005), which found no RCTs. We found no subsequent RCTs comparing topical fluconazole versus placebo or other topical antifungal treatments.

Harms

We found no RCTs or case studies investigating adverse effects of topical fluconazole.

Comment

None.

Substantive changes

Fluconazole (topical) One systematic review updated, no new data added. Categorisation unchanged (Unknown effectiveness).

2008; 2008: 1715.
Published online 2008 December 15.

Ketoconazole (topical)

Summary

We found no clinically important results about the effects of topical ketoconazole in fungal toenail infection.

Benefits

We found one systematic review (search date 2005), which found no RCTs. We found no subsequent RCTs comparing topical ketoconazole versus placebo or other topical antifungal treatments.

Harms

We found no RCTs or case studies investigating adverse effects of topical ketoconazole.

Comment

None.

Substantive changes

Ketoconazole (topical) One systematic review updated, no new data added. Categorisation unchanged (Unknown effectiveness).

2008; 2008: 1715.
Published online 2008 December 15.

Terbinafine (topical)

Summary

We found no clinically important results about the effects of topical terbinafine in fungal toenail infection.

Benefits

We found one systematic review (search date 2005), which found no RCTs. We found no subsequent RCTs comparing topical terbinafine versus placebo or other topical antifungal treatments.

Harms

We found no RCTs or case studies investigating adverse effects of topical terbinafine.

Comment

None.

Substantive changes

Terbinafine (topical) One systematic review updated, no new data added. Categorisation unchanged (Unknown effectiveness).

2008; 2008: 1715.
Published online 2008 December 15.

Tioconazole (topical)

Summary

We found no clinically important results about the effects of topical tioconazole in fungal toenail infection.

Benefits

We found one systematic review (search date 2005), which found no RCTs. We found no RCTs comparing topical tioconazole versus placebo or other topical antifungal treatments.

Harms

We found no RCTs or case studies investigating adverse effects of topical tioconazole.

Comment

None.

Substantive changes

Tioconazole (topical) One systematic review updated, no new data added. Categorisation unchanged (Unknown effectiveness).


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