What is the best next step for a patient with onychomycosis who has not responded to a course of terbinafine?

Treatment Approach for Terbinafine-Resistant Onychomycosis

Switch to itraconazole pulse therapy (400 mg daily for 1 week per month for 3 pulses for toenails or 2 pulses for fingernails) after confirming the diagnosis and ruling out correctable causes of treatment failure. 1

First: Confirm True Treatment Failure

Before switching agents, verify that the patient actually has treatment-resistant disease rather than a correctable problem:

• Re-culture the nail to confirm dermatophyte infection versus Candida or non-dermatophyte molds, as terbinafine has only fungistatic activity against Candida species and may fail in these cases 1
• Verify treatment adherence by confirming the patient completed the full 12-16 week course for toenails or 6 weeks for fingernails 1
• Assess for subungual dermatophytoma (fungal ball under the nail), which prevents adequate drug penetration and requires mechanical debridement or partial nail avulsion before any retreatment 1
• Evaluate for immunosuppression (HIV, diabetes, immunosuppressive medications) which increases failure rates and may require longer treatment duration 1
• Check for nail growth as the drug cannot reach the infection site if the nail is not growing 1

Primary Alternative: Itraconazole

Itraconazole is the guideline-recommended second-line agent when terbinafine fails 2, 1:

• Pulse therapy dosing: 400 mg daily for 1 week per month, repeated for 3 pulses for toenails or 2 pulses for fingernails 2, 1
• Alternative continuous dosing: 200 mg daily for 12 weeks if pulse therapy is not suitable 2, 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 Contraindications and Drug Interactions for Itraconazole

Do not use itraconazole in patients with heart failure due to negative inotropic effects, particularly important in diabetic patients who have higher cardiac disease prevalence 1:

• Extensive drug interactions include warfarin, antihistamines, antipsychotics, anxiolytics, digoxin, cisapride, ciclosporin, simvastatin, and antiretrovirals 1
• Contraindicated in active or chronic liver disease and requires baseline liver function tests 1

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 including headache, rash, gastrointestinal complaints, and insomnia 1

Surgical Intervention

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

• Cure rates approach 100% when all affected nail is removed under ring block prior to systemic therapy 1
• Debridement alone without antifungal therapy is insufficient and not recommended 1

What NOT to Do

• Do not retry terbinafine unless a specific cause of failure has been identified and corrected (poor compliance, immunosuppression, or dermatophytoma requiring removal) 1
• Do not use photodynamic therapy with cure rates of only 36-44% at 12-18 months and insufficient evidence 1
• Do not use laser therapy due to insufficient evidence for efficacy 1
• Do not use griseofulvin due to inferior efficacy compared to modern antifungals 2, 1

Special Population Considerations

• Diabetic patients: Prefer terbinafine for retreatment due to low drug interaction risk, but itraconazole is contraindicated if heart failure is present 1
• Immunocompromised patients: Prefer terbinafine and fluconazole over itraconazole due to antiretroviral interactions 1
• Patients with liver disease: Consider topical therapy alone with amorolfine 5% or ciclopirox 8% lacquer for superficial disease, as all systemic antifungals are relatively contraindicated 1