What is the best treatment approach for a patient with a nail fungal infection, considering their medical history and potential interactions with other medications?

Treatment of Nail Fungal Infection (Onychomycosis)

For most adult patients with dermatophyte onychomycosis, oral terbinafine 250 mg daily for 12-16 weeks (toenails) or 6 weeks (fingernails) is the first-line treatment, offering the highest cure rates and fungicidal activity. 1

Treatment Selection Algorithm

Step 1: Confirm Diagnosis

• Always obtain mycological confirmation (direct microscopy and culture) before initiating treatment 2
• Clinical diagnosis alone leads to frequent treatment failure 2
• Distinguish between dermatophytes, yeasts (Candida species), and non-dermatophyte molds, as this affects treatment choice 3

Step 2: Assess Disease Severity and Extent

Use topical therapy alone when: 1

• Superficial white onychomycosis (SWO) affecting only the dorsal nail plate
• Very early distal lateral subungual onychomycosis (DLSO) with <50% nail involvement
• Fewer than 3 nails affected
• Systemic therapy is contraindicated

Use systemic therapy when: 1

• More than 50% of nail plate is affected
• More than 3 nails are involved
• Matrix involvement is present
• Topical therapy has failed

Step 3: Select Appropriate Systemic Agent

First-Line: Terbinafine (Strength of Recommendation A) 1

• Dosing: 250 mg daily for 6 weeks (fingernails) or 12-16 weeks (toenails) 1
• Advantages: Fungicidal action, highest cure rates, superior to itraconazole for dermatophytes 1
• Monitoring: Baseline liver function tests and complete blood count in patients with history of hepatotoxicity or hematological abnormalities 1
• Key interactions: Plasma concentrations reduced by rifampicin, increased by cimetidine 1
• Important caveat: Can aggravate psoriasis and cause subacute lupus-like syndrome 1
• Reversible taste disturbance occurs in 1:400 patients 1

Alternative: Itraconazole (Strength of Recommendation A) 1

• Dosing: 200 mg daily for 12 weeks continuously, OR pulse therapy 400 mg daily for 1 week per month (2 pulses for fingernails, 3 pulses for toenails) 1
• Preferred when: Candida species are causative organisms 1
• Contraindication: Heart failure (negative inotropic effect) 1
• Monitoring: Hepatic function tests required for continuous therapy >1 month 1
• Critical drug interactions: Warfarin, terfenadine, astemizole, sertindole, midazolam, digoxin, cisapride, ciclosporin, simvastatin 1
• Take with food and acidic pH for optimal absorption 1

Second-Line: Fluconazole (Strength of Recommendation B) 1

• Dosing: 150-450 mg weekly for 3 months (fingernails) or at least 6 months (toenails) 1
• Use when: Patients cannot tolerate terbinafine or itraconazole 1
• Monitoring: Baseline liver function tests and full blood count; monitor LFTs in high-dose or prolonged therapy 1

Avoid: Griseofulvin (Strength of Recommendation C) 1

• Only 30-40% mycological cure rates for toenails 1
• Lengthy treatment: 12-18 months for toenails 1
• No longer treatment of choice unless other drugs unavailable or contraindicated 1
• Exception: Only antifungal licensed for children (10 mg/kg/day for age ≥1 month) 1

Step 4: Select Appropriate Topical Agent (When Indicated)

Amorolfine 5% Lacquer (Strength of Recommendation D) 1

• Dosing: Apply once or twice weekly for 6-12 months after filing diseased nail 1
• Efficacy: Approximately 50% cure rate for distal fingernail and toenail onychomycosis 1
• Side effects: Rare—local burning, pruritus, erythema 1
• Once-weekly application is as effective as twice-weekly 1

Ciclopirox 8% Lacquer (Strength of Recommendation C-D) 1

• Dosing: Apply once daily for up to 48 weeks (24 weeks for fingernails) 1
• Efficacy: 34% mycological cure vs. 10% placebo; 8% clinical cure vs. 1% placebo 1
• Lower cure rates than amorolfine 1
• Monthly professional removal of unattached infected nail required 4
• Important: Less than 12% of patients achieve completely clear or almost clear toenail 4

Efinaconazole 10% Solution (Strength of Recommendation D) 1, 2

• Dosing: Apply once daily for 48 weeks 1
• Efficacy: Mycological cure rates approaching 50%, complete cure in 15% 1
• Most common side effects: Application site dermatitis 2

Tioconazole 28% Solution 1

• Efficacy: Only 22% mycological and clinical cure 1
• Allergic contact dermatitis is not uncommon 1
• Contraindicated in pregnancy 1

Step 5: Consider Combination Therapy (Strength of Recommendation D) 1

• Recommended when response to topical monotherapy alone is likely to be poor 1
• Combining systemic and topical antifungals may improve cure rates 1

Special Populations

Diabetic Patients 1

• Terbinafine is preferred due to low risk of drug interactions and hypoglycemia 1
• Avoid itraconazole in patients with cardiac disease (increased prevalence in diabetics) 1
• Topical treatments appropriate for mild-to-moderate infections where drug interaction risk is high 1
• Onychomycosis is a significant predictor for foot ulcer development 1

Immunosuppressed Patients (HIV, Transplant) 1

• Terbinafine preferred due to increased risk of itraconazole/ketoconazole interactions with antiretrovirals 1
• Griseofulvin is least effective in HIV patients 1

Pediatric Patients (Age 1-12 years) 1

• First-line: Terbinafine 62.5 mg daily (<20 kg), 125 mg daily (20-40 kg), or 250 mg daily (>40 kg) for 6 weeks (fingernails) or 12 weeks (toenails) 1
• Alternative: Pulse itraconazole 5 mg/kg/day for 1 week per month (2 pulses for fingernails, 3 for toenails) 1
• Second-line: Fluconazole 3-6 mg/kg once weekly for 12-16 weeks (fingernails) or 18-26 weeks (toenails) 1
• Higher cure rates and faster response than adults 1

Critical Caveats and Pitfalls

Realistic Expectations 1, 2

• Mycological cure rates are typically 30% better than clinical cure rates 1, 2
• Clinical cure rates often below 50% even with effective treatment 1
• Patient satisfaction mirrors mycological cure rate, not clinical appearance 1
• Complete nail clearance may not be achieved—pre-existing dystrophy may persist 1

Treatment Duration 2, 4

• Complete cure takes time due to slow nail growth 2
• Six months may be required before initial improvement is noticed 4
• Full treatment with topical agents: up to 48 weeks 4

Adjunctive Measures 1, 4

• Remove as much diseased nail as possible by gentle filing before each topical application 1
• Professional removal of unattached infected nail monthly is needed with topical therapy 4
• Keep nails as short as possible 1
• Avoid sharing nail clippers 1

Drug Interactions Require Vigilance 1

• Itraconazole has extensive drug interactions including warfarin, antihistamines, antipsychotics, anxiolytics, digoxin, statins 1
• Griseofulvin interactions: Warfarin, ciclosporin, oral contraceptive pill 1
• May not be feasible to treat onychomycosis in patients with diabetes, heart disease, or depression due to DDI risk 5

Monitoring Requirements 1

• Terbinafine: Baseline LFTs and CBC in at-risk patients 1
• Itraconazole: Monitor LFTs if continuous therapy >1 month or with hepatotoxic drugs 1
• Fluconazole: Baseline LFTs and CBC; monitor in high-dose/prolonged therapy 1

When NOT to Treat 6

• Fungal nail infections are usually mild and asymptomatic 6
• Spontaneous regressions and complications both appear rare 6
• Better not to treat if risks outweigh expected benefits 6
• Severe adverse effects from oral agents (cutaneous, hepatic, hematological) occur in approximately 1 in 2000 patients and can be life-threatening 6