Fungal toenail infections

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% to 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 March 2011 (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 12 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% to 5% of people.

• Infection can cause discomfort in walking, pain, or limitation of activities.

People taking oral antifungal drugs reported greater satisfaction, and fewer onychomycosis-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; 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 compared with placebo.

• We found no evidence examining the effectiveness of other topical agents such as ketoconazole, fluconazole, amorolfine, terbinafine, tioconazole, or butenafine.

• We don't know whether mechanical debridement has any effect on fungal toenail infection, as we found no adequate studies.

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% to 5% of people. The prevalence varies among populations, which may be due to differences in screening techniques. In one 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 >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 >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 one 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 older 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 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

Cure rates; negative microscopy and culture; patient satisfaction with treatment; adverse effects of treatment, especially liver failure.

Methods

Clinical Evidence search and appraisal March 2011. The following databases were used to identify studies for this systematic review: Medline 1966 to March 2011, Embase 1980 to March 2011, and The Cochrane Database of Systematic Reviews, Issue 1, 2011. An additional search within The Cochrane Library was carried out for the Database of Abstracts of Reviews of Effects (DARE) and Health Technology Assessment (HTA). We also searched for retractions of studies included in the review. Abstracts of the studies retrieved from the initial search were assessed by an information specialist. Selected studies were then sent to the contributor for additional assessment, using predetermined criteria to identify relevant studies. Study design criteria for inclusion in this review were: published systematic reviews of RCTs and RCTs in any language, at least single blinded, and containing >20 individuals of whom >80% were followed up. There was no minimum length of follow-up required to include studies. We excluded all studies described as "open", "open label", or not blinded unless blinding was impossible. RCTs of treatment in fingernails and of infections related to candidal and yeast infections were also excluded. We included systematic reviews of RCTs and RCTs where harms of an included intervention were studied applying the same study design criteria for inclusion as we did for benefits. We also considered observational studies for 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 MHRA, which are added to the reviews as required. 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 relative risks (RRs) and odds ratios (ORs). We have performed a GRADE evaluation of the quality of evidence for interventions included in this review (see table). The categorisation of the quality of the evidence (high, moderate, low, or very low) reflects the quality of evidence available for our chosen outcomes in our defined populations of interest. These categorisations are not necessarily a reflection of the overall methodological quality of any individual study, because the Clinical Evidence population and outcome of choice may represent only a small subset of the total outcomes reported, and population included, in any individual trial. For further details of how we perform the GRADE evaluation and the scoring system we use, please see our website (www.clinicalevidence.com).

Table.

GRADE Evaluation of interventions for Fungal toenail infections.

Important outcomes	Cure rates, Patient satisfaction
Studies (Participants)	Outcome	Comparison	Type of evidence	Quality	Consistency	Directness	Effect size	GRADE	Comment
What are the effects of oral treatments for fungal toenail infections?
3 (433)	Cure rates	Oral itraconazole versus placebo	4	–3	0	0	0	Very low	Quality points deducted for short follow-up, possibility of publication bias, and inconsistent definitions of cure
5 (881)	Cure rates	Oral itraconazole versus oral terbinafine	4	–2	–1	0	0	Very low	Quality points deducted for possibility of publication bias and inconsistent definitions of cure. Consistency point deducted for conflicting results
3 (235)	Cure rates	Pulsed versus continuous itraconazole	4	–2	0	0	0	Low	Quality points deducted for possibility of publication bias and inconsistent definitions of cure
799 (5)	Cure rates	Oral terbinafine versus placebo	4	–3	0	0	0	Very low	Quality points deducted for possibility of publication bias, short follow-up, and inconsistent definitions of cure
1 (73)	Cure rates	Oral terbinafine versus topical treatment	4	–1	0	0	0	Moderate	Quality point deducted for sparse data
2 (692)	Cure rates	Oral fluconazole versus placebo	4	–2	0	0	0	Low	Quality points deducted for possibility of publication bias and inconsistent definitions of cure
3 (188)	Cure rates	Oral griseofulvin versus oral itraconazole	4	–3	0	0	0	Very low	Quality points deducted for sparse data, possibility of publication bias, and inconsistent definitions of cure
3 (375)	Cure rates	Oral griseofulvin versus oral terbinafine	4	–2	0	0	0	Low	Quality points deducted for possibility of publication bias and inconsistent definitions of cure
2 (42)	Cure rates	Oral griseofulvin versus oral ketoconazole	4	–3	0	0	0	Very low	Quality points deducted for sparse data, possibility of publication bias, and inconsistent definitions of cure
What are the effects of topical treatments for fungal toenail infections?
3 (935)	Cure rates	Topical ciclopirox versus placebo	4	0	0	0	0	High

We initially allocate 4 points to evidence from RCTs, and 2 points to evidence from observational studies. To attain the final GRADE score for a given comparison, points are deducted or added from this initial score based on preset criteria relating to the categories of quality, directness, consistency, and effect size. Quality: based on issues affecting methodological rigour (e.g., incomplete reporting of results, quasi-randomisation, sparse data [<200 people in the analysis]). Consistency: based on similarity of results across studies. Directness: based on generalisability of population or outcomes. Effect size: based on magnitude of effect as measured by statistics such as relative risk, odds ratio, or hazard ratio.

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.

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