Oral Antifungal Therapies and Resistance in Onychomycosis

Conclusions

• Antifungal resistance in onychomycosis is increasing, driven in part by SQLE mutations that reduce terbinafine binding and may contribute to partial or complete treatment failure.
• SQLE mutations are now being detected in U.S. onychomycosis cases, but mutation presence and MIC shifts do not always perfectly predict clinical resistance.
• Because resistance and relapse are concerns, longer or higher-dose off-label regimens of terbinafine, itraconazole, and fluconazole may be needed in selected patients, with closer monitoring for toxicity and drug interactions.
• Combination therapy, especially an oral agent plus a topical antifungal, may be safer and more practical than using two systemic drugs together when response is poor.
• Newer or alternative agents such as voriconazole, posaconazole, oteseconazole, and fosravuconazole show promise for resistant onychomycosis, though most uses remain off-label in the U.S.
• Oteseconazole appears especially attractive because it has prolonged nail levels, few drug interactions, and potential activity against resistant species.
• Non-dermatophyte molds and mixed infections require tailored diagnosis and treatment rather than assuming standard dermatophyte therapy will work.
• Onychomycosis is difficult to eradicate long term, so prevention strategies such as prolonged topical prophylaxis, treatment of tinea pedis, and sanitizing shoes and socks are important to prevent recurrence.
• Minoxidil may become a useful adjunct by speeding nail outgrowth, potentially improving apparent cure and shortening the time needed for damaged nails to replace themselves.
• Successful management depends on confirming the diagnosis, considering resistance testing when treatment fails, and addressing relapse, reinfection, adherence, and comorbidities.