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

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.