What are the treatment options for onychomycosis that is resistant to oral terbinafine (antifungal medication)?

Treatment for Terbinafine-Resistant Onychomycosis

Switch to itraconazole pulse therapy (400 mg daily for 1 week per month, repeated for 3-4 pulses for toenails or 2 pulses for fingernails) as the next-line treatment for dermatophyte onychomycosis that has failed terbinafine. 1

Understanding Treatment Failure

Before switching therapy, you must identify the reason for terbinafine failure, as this determines your next step:

• Confirm mycological diagnosis - Repeat culture to verify dermatophyte infection versus Candida or non-dermatophyte molds, as terbinafine has only fungistatic activity against Candida species 1, 2
• Assess for subungual dermatophytoma - This tightly packed fungal mass prevents adequate drug penetration and requires mechanical debridement or partial nail avulsion before retreatment 1
• Exclude poor compliance - Verify the patient completed the full 12-16 week course for toenails or 6 weeks for fingernails 1
• Rule out immunosuppression - HIV, diabetes, or iatrogenic immunosuppression increases failure rates and may require longer treatment duration 1
• Consider zero nail growth - If the nail is not growing, drug cannot be delivered to the infection site 1

Primary Alternative: Itraconazole

Itraconazole is the guideline-recommended second-line agent when terbinafine fails 1:

• Dosing regimen: 400 mg daily for 1 week per month (pulse therapy), repeated for 3 pulses for toenails or 2 pulses for fingernails 1
• Alternative continuous dosing: 200 mg daily for 12 weeks if pulse therapy is not suitable 1
• Expected outcomes: Mycological cure rates of 38-54% for toenails at 72 weeks, which is lower than terbinafine but still clinically meaningful 1, 3

Critical Caveats for Itraconazole

• Extensive drug interactions - Itraconazole interacts with warfarin, antihistamines, antipsychotics, anxiolytics, digoxin, cisapride, ciclosporin, simvastatin, and antiretrovirals 1, 2
• Contraindicated in heart failure - Negative inotropic effects make this particularly important in diabetic patients who have higher cardiac disease prevalence 1
• Requires baseline liver function tests - Active or chronic liver disease is a contraindication 1, 4

Secondary Alternative: Fluconazole

If both terbinafine and itraconazole are contraindicated or not tolerated 1:

• Dosing: 450 mg once weekly for at least 6 months for toenails, or 3 months for fingernails 1
• Efficacy: Mycological cure rates of 47-62% for toenails, but clinical cure rates are lower at 28-36% 1
• Major limitation: 20-58% discontinuation rate due to adverse effects (headache, rash, gastrointestinal complaints, insomnia), which is significantly higher than terbinafine's 10.5% adverse event rate 1, 2

Combination and Sequential Therapy

Sequential pulse therapy with itraconazole followed by terbinafine may achieve superior outcomes 5:

• Regimen: 2 pulses of itraconazole (200 mg twice daily for 1 week) followed by 1-2 pulses of terbinafine (250 mg twice daily for 1 week) 5
• Evidence: Complete cure rate of 52% versus 32% with terbinafine pulses alone at 72 weeks 5
• Rationale: This approach may overcome kinetic barriers and dermatophytoma formation that caused initial terbinafine failure 5

Surgical Intervention

Consider partial nail avulsion for isolated dermatophytoma or single-nail disease before retreating systemically 1:

• Cure rates approaching 100% can be achieved when all affected nail is removed under ring block prior to systemic therapy 1
• This is particularly indicated when you identify a subungual dermatophytoma on examination - the tightly packed fungal mass visible as a yellow-white thickened area 1
• Debridement alone without antifungal therapy is insufficient and not recommended 1

Newer Azoles (Off-Label)

While not FDA-approved for onychomycosis, emerging evidence supports consideration in refractory cases 6:

• Posaconazole: 200 mg daily for 24 weeks achieved 54% complete cure and 70% mycological cure in Phase IIB trials 6
• Fosravuconazole: 100 mg daily for 12 weeks achieved 59% complete cure and 82% mycological cure in Phase III trials 6
• Oteseconazole: 300 mg daily loading dose for 2 weeks, then 300 mg weekly for 10 weeks achieved 45% complete cure and 70% mycological cure 6

What NOT to Do

• Do not use photodynamic therapy - Cure rates of only 36-44% at 12-18 months with insufficient evidence to recommend 1
• Do not use laser therapy - Insufficient evidence for efficacy 1
• Do not retreat with terbinafine unless you have identified and corrected a specific cause of failure (poor compliance, immunosuppression, dermatophytoma requiring removal) 1
• Do not use griseofulvin - Inferior efficacy compared to all modern antifungals 1

Special Populations

• Diabetic patients: Terbinafine remains preferred even for retreatment due to low drug interaction risk, but itraconazole is contraindicated if heart failure is present 1
• Immunosuppressed patients: Terbinafine and fluconazole are preferred over itraconazole due to antiretroviral interactions 1
• Patients with liver disease: All systemic antifungals are relatively contraindicated; consider topical therapy alone with amorolfine 5% or ciclopirox 8% lacquer for superficial disease 4