Combination Therapy Should Be Reserved as Second-Line Treatment of Onychomycosis: A Systematic Review of Onychomycosis Clinical Trials.

Julianne M Falotico,Rebecca Lapides,Shari R Lipner

doi:10.3390/jof8030279

Abstract

Onychomycosis is the most common nail disease encountered in clinical practice. Its importance extends well beyond aesthetics, often causing pain, difficulty with ambulation and performing daily activities, and impairing quality of life. Many patients fail to achieve cure with antifungal monotherapy and recurrences are common. Combination therapy has therefore gained considerable interest, given the potential for drug synergy and prevention of antifungal resistance, but it has not been well studied. A systematic review of onychomycosis medication only, as well as medication and procedural (laser, debridement, photodynamic therapy), clinical or randomized controlled trials evaluating combination vs. monotherapies was performed. After exclusions, 30 studies were included in the final analysis. There were conflicting results for medication-only trials, with some showing significant benefit of combination therapy over monotherapy, however, trials were not robustly designed and lacked sufficient follow-up. Procedural studies also lacked long-term follow-up, and failed to demonstrate efficacy in some severe onychomycosis cases. Considering the high cure rates demonstrated in pivotal antifungal monotherapy trials, and conflicting results, costs, and safety concerns associated with combination therapy, we recommend that combination therapy be reserved as second-line treatment options in patients with poor prognostic factors or for those who failed monotherapy for onychomycosis.

Highlights

Publisher’s Note: MDPI stays neutralOnychomycosis is a fungal nail infection due to dermatophytes, nondermatophytes, and yeast [1], clinically presenting with nail plate onycholysis, thickening, and subungual hyperkeratosis [2], with significant physical, aesthetic, and psycho-social consequences.Currently, oral terbinafine, itraconazole, and griseofulvin, as well as topical ciclopirox, efinaconazole, and tavaborole, are United States (US) Food and Drug Administration (FDA) approved for onychomycosis treatment, and oral fluconazole is often used offlabel [3,4]
We examine clinical trials comparing combination vs. monotherapy for onychomycosis treatment, to guide clinical management
PubMed, Scopus, and Web of Science databases were searched for articles on onychomycosis combination therapy on 1 July 2021, for all peer-reviewed, English-language, human subject onychomycosis clinical and randomized controlled trials (RCT) with no date ranges, and using search terms “onychomycosis treatment”, “onychomycosis therapy”, and “onychomycosis combination therapy”

Summary

Introduction

Onychomycosis is a fungal nail infection due to dermatophytes, nondermatophytes, and yeast [1], clinically presenting with nail plate onycholysis, thickening, and subungual hyperkeratosis [2], with significant physical, aesthetic, and psycho-social consequences. Some disadvantages of onychomycosis monotherapy include potential antifungal resistance, and difficulty of achieving high concentrations of biologically effective drug in affected with regard to jurisdictional claims in published maps and institutional affiliations. In a five-year, blinded follow-up study of patients achieving mycological cure at 12 months following oral terbinafine or itraconazole monotherapy treatment, 23% and 53% of patients, respectively, experienced mycological relapse or reinfection [8]. Combinations of oral medications, topical medications, and devices, have been considered in cases where there are expected poor responses to monotherapy, greater than 50–60%. It is theorized that combination therapy allows for antimicrobial synergy, broader antifungal coverage with increased fungicidal activity, and decreased resistance [12], as well as improved clinical cures when using drugs with different mechanisms of action or administration routes [13]. We examine clinical trials comparing combination vs. monotherapy for onychomycosis treatment, to guide clinical management

Materials and Methods

Results

C: Excellent