Background 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. Objectives To assess the clinical and mycological effects of topical drugs and device-based therapies for toenail onychomycosis. Search methods 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. Selection criteria 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. Main results 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. Authors' conclusions 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.

Topical and device-based treatments for fungal infections of the toenails

Background
Onychomycosis is a common fungal nail infection that responds poorly to antifungals.

Objective
To investigate the efficacy and safety of methyl aminolevulinate (MAL) photodynamic therapy (PDT) in the treatment of onychomycosis.

Methods
A multicentre (3), randomized, placebo-controlled clinical trial compared the effects of three sessions of urea (40%) plus conventional MAL-PDT with urea (40%) plus placebo (red light) photodynamic therapy (pPDT) in onychomycosis patients. Efficacy, both clinical (onychomycosis severity index, OSI) and microbiological, was blindly evaluated after 36 weeks of follow-up.

Results
Forty patients were analysed in the trial. Twenty-two received MAL-PDT and 18 pPDT. A complete response (OSI = 0) was observed for four patients (18.18%) in the MAL-PDT group and one (5.56%) in the pPDT group (NTT 7.92, 95% CI: 2.98–9.69, P = 0.23). A decrease in OSI score of over 75% (OSI75) was achieved by 40.91% of the patients in the MAL-PDT group and 16.67% in the pPDT group (P = 0.096). Microbiological cure was achieved by seven patients (31.82%) in the MAL-PDT group and two (11.11%) in the pPDT group (P = 0.178). MAL-PDT resulted in better rates of clinical response [OSI >75%: 53.85% vs. 18.75% (P =0.048)] and microbiological cure [41.56% vs. 7.14% (P = 0.037)] in non-dystrophic vs. dystrophic onychomycosis patients. No significant side-effects were reported. The limitations of the study were the reduced sample size and the unexpected efficacy of the control treatment, which was attributed to the 40% urea pre-treatment.

Conclusion
This study did not show significant differences between urea 40% + MAL-PDT and urea 40% + pPDT in the treatment of onychomycosis. However, some results suggest that this treatment may constitute an alternative for dermatophyte and non-dermatophyte mould onychomycosis in patients not eligible for systemic treatment, particularly in the absence of total nail dystrophy.

Methyl aminolevulinate photodynamic therapy for onychomycosis: a multicentre, randomized, controlled clinical trial

#### Summary points

Onychomycosis is the term used for fungal infections of nail. A recent review of population based studies of onychomycosis in Europe and the United States found a mean prevalence of 4.3%.1 Onychomycosis can be a source of pain and discomfort and can impact on patients’ quality of life, with psychosocial and physically detrimental effects.2 Disease of the fingernails can cause impaired or lost tactile function, whereas disease of the toenails can interfere with walking, exercise, and how shoes fit. Untreated patients can act as source of infection for family members and potentially contaminate communal areas. Infection may be chronic and resistant to treatment, with 16-25% of patients not achieving cure by current treatments.3 No spontaneous clearing is known to occur. This review provides an evidence based overview of the diagnosis and management of onychmoycosis.

#### Sources and selection criteria

We searched Medline, PubMed, the National Institute for Health and Care Excellence website, and the Cochrane Library for systematic reviews, meta-analyses, randomised and non-randomised controlled clinical trials, and case series and reports using the search words “fungal nail disease/infection”, “tinea unguium”, and “onychomycosis”. We also consulted recent guidelines submitted for publication by the British Association of Dermatologists.

Onychomycosis …

/pdf/fungal-nail-infection-diagnosis-and-management-24t5mw5cx8.pdf

Fungal nail infection: diagnosis and management.

https://www.cidjournal.com/article/S0738-081X(14)00309-5/pdf

Antifungal therapy for onychomycosis in children.

Onychomycosis remains difficult to cure by traditional methods. The aim of this study was to evaluate the efficacy of combination therapy with a fractional erbium yttrium aluminum garnet (Er:YAG) laser and 5 % amorolfine lacquer on onychomycosis. Nine patients with bilateral nails affected by distal and lateral subungual onychomycosis were included. The bilateral nails of each patient were divided into two groups. The 20 affected nails on one side of each patient as group 1 were treated with a fractional Er:YAG laser once a week and 5 % amorolfine lacquer twice weekly, while the 20 nails on the symmetrical side of each patient as group 2 were treated with amorolfine lacquer only. The laser treatment was conducted at weeks 1, 2, 3, 4, 8, and 12 in group 1. The clinical improvement, onychomycosis severity index (OSI), maximum linear clear nail growth (MLCNG), and mycological cure rate were evaluated. At week 24, 18 of 20 (90 %) nails in group 1 had achieved obvious clinical responses. The mean OSI score showed a significant decrease (5.24) and the average MLCNG was 3.1 mm in group 1. At week 24, 15 of 20 (75 %) nails achieved a negative mycological examination in group 1, compared with four of 20 (20 %) nails in group 2. The treatments were well-tolerated by most patients. This clinical study suggests that combination therapy of a fractional 2940-nm Er:YAG laser and 5 % amorolfine lacquer is an effective, safe, and convenient treatment method for onychomycosis.

Combination therapy for onychomycosis using a fractional 2940-nm Er:YAG laser and 5 % amorolfine lacquer

Background: The efficacy of topical antifungals is controversial. Objective: To compare the efficacy and safety of a sequential (SEQ) treatment with chemical nail avulsion and topical antifungals to amorolfine nail lacquer in dermatophytic onychomycosis. Methods: This was a randomized, parallel-group, controlled study comparing a 36-week SEQ treatment with chemical nail avulsion with RV4104A ointment (class I medical device containing 40% urea) followed by ciclopirox cream for 8 weeks and ciclopirox nail lacquer for 25 weeks (SEQ group) to amorolfine nail lacquer for 36 weeks (AMO group). Patients had to have a big toenail onychomycosis, sparing the matrix. The primary efficacy criterion was complete cure at week 48. A cost-effectiveness analysis was performed. Results: A total of 142 patients were randomized. The complete cure rate at week 48 was significantly higher in the SEQ group than in the AMO group (36.6 vs. 12.7%, p = 0.001). Clinical cure at week 48 was observed in 53.5% of patients in the SEQ group versus 17% in the AMO group (p Conclusion: A treatment of onychomycosis comprising chemical avulsion of the pathological nail, ciclopirox cream and nail lacquer is significantly more effective than amorolfine nail lacquer.

A multicenter, randomized, open-label, controlled study comparing the efficacy, safety and cost-effectiveness of a sequential therapy with RV4104A ointment, ciclopiroxolamine cream and ciclopirox film-forming solution with amorolfine nail lacquer alone in dermatophytic onychomycosis.

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A multicenter, randomized, open-label, controlled study comparing the efficacy, safety and cost-effectiveness of a sequential therapy with RV4104A ointment, ciclopiroxolamine cream and ciclopirox film-forming solution with amorolfine nail lacquer alone in dermatophytic onychomycosis.