Topical and device‐based treatments for fungal infections of the toenails
Onychomycosis refers to fungal infections of the nail apparatus that may cause pain, discomfort, and disfigurement. This is an update of a Cochrane Review published in 2007; a substantial amount of new research warrants a review exclusively on toenails.
To assess the clinical and mycological effects of topical drugs and device‐based therapies for toenail onychomycosis.
We searched the following databases up to May 2019: 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.
Randomised controlled trials of topical and device‐based therapies for onychomycosis in participants with toenail onychomycosis, confirmed by positive cultures, direct microscopy, or histological nail examination. Eligible comparators were placebo, vehicle, no treatment, or an active topical or device‐based treatment.
Data collection and analysis
We used standard methodological procedures expected by Cochrane. Primary outcomes were complete cure rate (normal‐looking nail plus fungus elimination, determined with laboratory methods) and number of participants reporting treatment‐related adverse events.
We included 56 studies (12,501 participants, average age: 27 to 68 years), with mainly mild‐to‐moderate onychomycosis without matrix involvement (where reported). Participants had more than one toenail affected. Most studies lasted 48 to 52 weeks; 23% reported disease duration (variable). Thirty‐five studies specifically examined dermatophyte‐caused onychomycosis. Forty‐three studies were carried out in outpatient settings. Most studies assessed topical treatments, 9% devices, and 11% both.
We rated three studies at low risk of bias across all domains. The most common high‐risk domain was performance bias. We present results for key comparisons, where treatment duration was 36 or 48 weeks, and clinical outcomes were measured at 40 to 52 weeks.
Based on two studies (460 participants), compared with vehicle, ciclopirox 8% lacquer may be more effective in achieving complete cure (risk ratio (RR) 9.29, 95% confidence interval (CI) 1.72 to 50.14; low‐quality evidence) and is probably more effective in achieving mycological cure (RR 3.15, 95% CI 1.93 to 5.12; moderate‐quality evidence). Ciclopirox lacquer may lead to increased adverse events, commonly application reactions, rashes, and nail alteration (e.g. colour, shape). However, the 95% CI indicates that ciclopirox lacquer may actually make little or no difference (RR 1.61, 95% CI 0.89 to 2.92; low‐quality evidence).
Efinaconazole 10% solution is more effective than vehicle in achieving complete cure (RR 3.54, 95% CI 2.24 to 5.60; 3 studies, 1716 participants) and clinical cure (RR 3.07, 95% CI 2.08 to 4.53; 2 studies, 1655 participants) (both high‐quality evidence) and is probably more effective in achieving mycological cure (RR 2.31, 95% CI 1.08 to 4.94; 3 studies, 1716 participants; moderate‐quality evidence). Risk of adverse events (such as dermatitis and vesicles) was slightly higher with efinaconazole (RR 1.10, 95% CI 1.01 to 1.20; 3 studies, 1701 participants; high‐quality evidence). No other key comparison measured clinical cure.
Based on two studies, compared with vehicle, tavaborole 5% solution is probably more effective in achieving complete cure (RR 7.40, 95% CI 2.71 to 20.24; 1198 participants), but probably has a higher risk of adverse events (application site reactions were most commonly reported) (RR 3.82, 95% CI 1.65 to 8.85; 1186 participants (both moderate‐quality evidence)). Tavaborole improves mycological cure (RR 3.40, 95% CI 2.34 to 4.93; 1198 participants; high‐quality evidence).
Moderate‐quality evidence from two studies (490 participants) indicates that P‐3051 (ciclopirox 8% hydrolacquer) is probably more effective than the comparators ciclopirox 8% lacquer or amorolfine 5% in achieving complete cure (RR 2.43, 95% CI 1.32 to 4.48), but there is probably little or no difference between the treatments in achieving mycological cure (RR 1.08, 95% CI 0.85 to 1.37). We found no difference in the risk of adverse events (RR 0.60, 95% CI 0.19 to 1.92; 2 studies, 487 participants; low‐quality evidence). The most common events were erythema, rash, and burning.
Three studies (112 participants) compared 1064‐nm Nd:YAG laser to no treatment or sham treatment. We are uncertain if there is a difference in adverse events (very low‐quality evidence) (two studies; 85 participants). There may be little or no difference in mycological cure at 52 weeks (RR 1.04, 95% CI 0.59 to 1.85; 2 studies, 85 participants; low‐quality evidence). Complete cure was not measured.
One study (293 participants) compared luliconazole 5% solution to vehicle. We are uncertain whether luliconazole leads to higher rates of complete cure (very low‐quality evidence). Low‐quality evidence indicates there may be little or no difference in adverse events (RR 1.02, 95% CI 0.90 to 1.16) and there may be increased mycological cure with luliconazole; however, the 95% CI indicates that luliconazole may make little or no difference to mycological cure (RR 1.39, 95% CI 0.98 to 1.97). Commonly‐reported adverse events were dry skin, paronychia, eczema, and hyperkeratosis, which improved or resolved post‐treatment.
Assessing complete cure, high‐quality evidence supports the effectiveness of efinaconazole, moderate‐quality evidence supports P‐3051 (ciclopirox 8% hydrolacquer) and tavaborole, and low‐quality evidence supports ciclopirox 8% lacquer. We are uncertain whether luliconazole 5% solution leads to complete cure (very low‐quality evidence); this outcome was not measured by the 1064‐nm Nd:YAG laser comparison. Although evidence supports topical treatments, complete cure rates with topical treatments are relatively low.
We are uncertain if 1064‐nm Nd:YAG laser increases adverse events compared with no treatment or sham treatment (very low‐quality evidence). Low‐quality evidence indicates that there is no difference in adverse events between P‐3051 (ciclopirox hydrolacquer), luliconazole 5% solution, and their comparators. Ciclopirox 8% lacquer may increase adverse events (low‐quality evidence). High‐ to moderate‐quality evidence suggests increased adverse events with efinaconazole 10% solution or tavaborole 5% solution.
We downgraded evidence for heterogeneity, lack of blinding, and small sample sizes. There is uncertainty about the effectiveness of device‐based treatments, which were under‐represented; 80% of studies assessed topical treatments, but we were unable to evaluate all of the currently relevant topical treatments.
Future studies of topical and device‐based therapies should be blinded, with patient‐centred outcomes and an adequate sample size. They should specify the causative organism and directly compare treatments.
Kelly Foley, Aditya K Gupta, Sarah Versteeg, Rachel Mays, Elmer Villanueva, Denny John
Plain language summary
Are topical and device‐based treatments effective in people with fungal infections of the toenails?
We reviewed evidence about the effect of topical and device‐based treatments for fungal infections of the toenails (toenail onychomycosis) when compared against each other, placebo (an identical but inactive treatment), vehicle (inactive ingredients that help deliver an active treatment), or no treatment. We assessed adults, whose infection was diagnosed based on studying nail samples.
Toenail onychomycosis causes pain, discomfort, and disfigurement. Topical and device‐based treatments can have less likelihood of drug interactions or side effects than oral drugs. Antifungal medications are either fungistatic (inhibiting fungal growth) or fungicidal (killing fungal pathogens). The shared goal of devices (e.g. laser, photodynamic therapy) is fungus destruction.
In searches up to May 2019, we found 56 studies including 12,501 men or women (average age: 27 to 68 years) who had mainly mild‐to‐moderate toenail onychomycosis. Onychomycosis duration was under‐reported, but varied from months to years. Approximately 63% of the studies assessed onychomycosis caused by dermatophytes (fungi). Most studies lasted 48 to 52 weeks and were conducted in an outpatient setting. The studies used either device‐based or topical treatments, including lacquers and creams, alone or in combination, compared to each other, to no treatment, to vehicle, or to placebo.
For the following key results, treatment lasted 36 or 48 weeks, and outcomes were measured at 40 to 52 weeks (side effects were measured throughout the study).
Compared to vehicle (no treatment), efinaconazole 10% topical solution is better at achieving complete cure (i.e. normal‐looking nail coupled with fungus elimination determined using laboratory methods) (high‐quality evidence). Tavaborole 5% solution (when compared to vehicle) and P‐3051 (ciclopirox 8% hydrolacquer) (when compared to two other treatments: ciclopirox 8% lacquer or amorolfine 5%) are probably better at achieving this outcome (both moderate‐quality evidence). Ciclopirox 8% lacquer may lead to higher complete cure rates than vehicle, but rates are low (not all patients can be expected to achieve complete cure) (low‐quality evidence).
Ciclopirox 8% lacquer and efinaconazole 10% are probably more effective at eliminating the fungus (mycological cure) than vehicle, but for P‐3051 (ciclopirox 8% hydrolacquer) there is probably little or no difference compared to the two comparator treatments (all moderate‐quality evidence). Tavaborole 5% improves mycological cure compared to vehicle (high‐quality evidence).
We found no evidence of a difference in side effects, including redness, rash, and burning, between P‐3051 (ciclopirox 8% hydrolacquer) and the two other treatments (low‐quality evidence), and ciclopirox 8% lacquer may increase side effects, including application‐site reactions, rashes, and changes in the nail compared with vehicle, although treatment effects vary, so it is possible that it may actually make little or no difference (low‐quality evidence). Compared to vehicle, participants were slightly more likely to experience side effects (commonly dermatitis and fluid‐filled sacs) with efinaconazole 10% (high‐quality evidence) and probably more likely to experience side effects with tavaborole 5% (commonly, application‐site reactions, such as dermatitis, redness, and pain) (moderate‐quality evidence).
We are uncertain of the effect of luliconazole 5% on complete cure when compared to vehicle (very low‐quality evidence); there may be little or no difference between these groups in side effects (dry skin, eczema, and thickening of the skin were commonly reported, but improved after stopping treatment), and luliconazole 5% solution might increase mycological cure; however, the effects of this treatment vary, so it is possible that it may actually make little or no difference to mycological cure (both low‐quality evidence).
Three studies compared laser to no treatment or sham treatment, and there may be little or no difference in mycological cure (low‐quality evidence). Complete cure was not measured, and we are uncertain if there is a difference in side effects between groups (very low‐quality evidence).
Efinaconazole 10% solution is more effective in achieving clinical cure than vehicle (high‐quality evidence); none of the other key comparisons measured this outcome.
Quality of the evidence
We base our conclusions on varied evidence quality. For complete cure, mycological cure, and side effects, quality ranged from low to high, with very low‐quality evidence found for three key results.
Many studies were small, had design issues, and did not directly compare therapies. No studies reported quality of life.
Kelly Foley, Aditya K Gupta, Sarah Versteeg, Rachel Mays, Elmer Villanueva, Denny John
Implications for practice
Some topical treatments for toenail onychomycosis are a viable alternative to traditional oral therapies in mild‐to‐moderate severity of onychomycosis, although it should be noted that we did not compare topical therapies to oral therapies in this review.
In comparison with vehicle, there is high‐quality evidence that efinaconazole 10% solution is more effective in achieving complete cure, low‐quality evidence that ciclopirox 8% lacquer may better lead to complete cure, and moderate‐quality evidence in support of tavaborole 5% solution and P‐3051 (ciclopirox 8% hydrolacquer) probably being more likely to achieve complete cure, although for P‐3051 the comparators are ciclopirox 8% lacquer or amorolfine 5%, rather than vehicle. However, not all patients can be expected to achieve complete cure, since reported cure rates in clinical studies, while better than vehicle, are still low.
Treatment‐related adverse events with efinaconazole (slightly increases adverse events compared with vehicle; high‐quality evidence) and tavaborole (probably increases adverse events compared with vehicle; moderate‐quality evidence) were limited to application‐site reactions, with erythema, rash, and burning reported for P‐3051 and its comparators ciclopirox 8% lacquer or amorolfine 5%, although for this comparison adverse events may not have been directly related to treatment, and we found no evidence of a difference in the risk of adverse events between the groups (low‐quality evidence). For ciclopirox 8% lacquer, application site reactions, rashes, and alterations in nail colour or shape were the most common events, and this intervention may lead to an increase in the number of participants reporting adverse events related to treatment compared with vehicle; however, the 95% confidence interval indicates that ciclopirox 8% lacquer may actually make little or no difference (low‐quality evidence).
In terms of mycological cure, when compared with vehicle, tavaborole 5% solution increases this outcome, and ciclopirox 8% lacquer and efinaconazole 10% probably increase the outcome. For mycological cure, there is probably little or no difference between P‐3051 (ciclopirox 8% hydrolacquer) and its comparators (ciclopirox 8% lacquer or amorolfine 5%).
Studies evaluating ciclopirox 8%, P‐3051, efinaconazole, or tavaborole topical treatments included infections caused by dermatophytes. Infections caused by non‐dermatophyte moulds, yeast, or mixed infections (a combination of dermatophytes and nondermatophyte moulds or yeast) may also benefit from these treatments and their use in everyday practice will be dictated by regulatory restrictions, clinicians' experience, and patient preferences. The study populations were representative of the general population afflicted with mild‐to‐moderate toenail onychomycosis caused by dermatophytes.
There is currently not enough evidence to recommend or discourage the use of luliconazole 5% solution, 1064‐nm Nd:YAG laser, or photodynamic therapy. We included a small number of device‐based studies and could not meet our objective in drawing conclusions on the clinical and mycological effectiveness of device‐based interventions. There were a number of topical interventions about which we could not draw conclusions. These include combinations of creams with urea, and treatments specific to geographic areas such as Finland (spruce resin lacquer) and Mexico (A. pichinchensis). We could not evaluate treatments that no published RCTs have assessed, such as amorolfine or urea‐based treatment alone.
Only one of our key comparisons measured clinical cure: efinaconazole 10% is more effective in achieving this outcome when compared with vehicle; high‐quality evidence. Most of the included trials did not measure the secondary outcomes of compliance, time to recurrence, or pharmaco‐economics, with no studies reporting quality of life.
The 22 studies in Studies awaiting classification may alter the conclusions of the review once assessed.
Implications for research
More randomised controlled studies of device‐based therapies (e.g. 1064‐nm Nd:YAG, photodynamic therapy, iontophoresis) are needed. Unlike drug treatments, there are no generally accepted outcomes that device‐based studies adopt. The US Food and Drug Administration (FDA) has published non‐binding guidance suggesting objective clinical measures that could be used for onychomycosis treatment, including mycological cure, defined as negative microscopy and negative culture (U.S. FDA 2015). Additional clinical outcomes that have been suggested for devices differ from those used for drug treatments; rather than focusing on complete cure, the non‐binding guidance suggests 0% nail involvement (clinical cure) if less than 12 mm of nail is infected prior to treatment (U.S. FDA 2015).
Patient‐centred outcomes are lacking in clinical studies. Further research could be conducted into patient satisfaction with treatment results, improvements in quality of life (e.g. social interactions, confidence), and compliance (e.g. ease and convenience of the intervention). Informal discussion has taken place as to what realistic and useful clinical outcomes may be for onychomycosis studies (Elewski 2016). Complete cure rates for topical treatments, while better than vehicle, are low, and there are no other consistently‐reported clinical outcomes. It may be worth considering attempts in line with Cochrane Skin Core Outcomes Set Initiative to guide studies worldwide (CS‐COUSIN). For both drug‐ and device‐based studies, clinical outcomes should be reported at a patient level, i.e. one target nail for analysis, usually the great (big) toenail.
Research to characterise therapy efficacy in patients with severe onychomycosis is warranted, as well as those with mild‐to‐moderate onychomycosis. Data are absent on the recurrence of onychomycosis following topical and device‐based treatment, and given documented recurrence with oral antifungal therapy, the same should be investigated with topical and device‐based interventions.
Of concern to both patients and physicians is the cost of treatments for onychomycosis. Clinical studies very rarely undertake cost‐effectiveness analysis.
There is also a paucity of studies that perform head‐to‐head comparisons of topical treatments. For example, there are no direct comparisons of amorolfine and ciclopirox with efinaconazole, luliconazole, or tavaborole. Device‐based treatments have not been compared to topical treatments in randomised controlled trials. Direct comparisons of treatments in clinical studies with the inclusion of cost‐effectiveness data will provide valuable information that can aid clinicians and patients in making treatment decisions. Network meta‐analysis may be considered in the future to overcome the lack of direct comparisons in clinical studies. Further research into, for example, region‐specific treatments, such as spruce resin lacquer or A. pichinchensis, or urea‐based treatments, would provide evidence for further onychomycosis treatment options.
Future investigations of topical and device‐based interventions would benefit from characterising outcomes of success according to causative organism. Current studies focus on dermatophyte infections and evidence for treatment success in nondermatophyte and mixed infections would be informative. All future studies, both topical and device‐based, should strive to maintain blinding of at least participants and outcome assessors. Adequate sample size will limit imprecision associated with small numbers of detected events. Heterogeneity among studies may be limited by characterising outcomes according to causative organism and, in the case of mycological cure, adopting the definition of negative KOH microscopy and negative culture.
Regardless of the modality, topical or device, future randomised controlled trials should adhere, and continue to adhere, to the reporting standards laid out in the Consolidated Standards of Reporting Trials (CONSORT) statement (Schulz 2010), to allow a fair and accurate assessment of the evidence for these interventions.