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 patients with nail fungal infection, oral terbinafine 250 mg daily for 12-16 weeks (toenails) or 6 weeks (fingernails) is the first-line treatment, offering the highest cure rates with an acceptable safety profile. 1

Treatment Selection Algorithm

Step 1: Confirm the Diagnosis

• Always obtain mycological confirmation (direct microscopy and culture) before initiating treatment 2
• Treatment failure is common when diagnosis is made on clinical grounds alone 2
• Clinical signs are non-specific and can mimic psoriasis or nail trauma 3

Step 2: Assess Disease Severity and Extent

Use topical therapy alone when:

• Superficial white onychomycosis (SWO) affecting only the nail surface 1
• Very early distal lateral subungual onychomycosis (DLSO) 1
• Less than 50% of nail plate affected AND fewer than 3 nails involved 4
• Systemic therapy is contraindicated 1

Use systemic therapy when:

• More than 50% of nail plate affected 4
• More than 3 nails involved 4
• Matrix involvement present 3
• Topical therapy has failed 1

First-Line Systemic Treatment

Terbinafine (Strength of Recommendation A)

• Dosing: 250 mg daily for 6 weeks (fingernails) or 12-16 weeks (toenails) 1
• Advantages: Fungicidal action, highest cure rates, good compliance, generally preferred over itraconazole for dermatophyte infections 1
• Monitoring: Baseline liver function tests and complete blood count recommended in patients with history of hepatotoxicity or hematological abnormalities 1
• Common adverse effects: Headache, taste disturbance (reversible in 1:400 patients), gastrointestinal upset 1
• Serious adverse effects: Idiosyncratic liver and skin reactions (severe in approximately 1 in 2000 patients), can aggravate psoriasis, may cause subacute lupus-like syndrome 1, 3
• Drug interactions: Plasma concentrations reduced by rifampicin, increased by cimetidine 1

Itraconazole (Strength of Recommendation A)

• Dosing options: 1
  • Continuous: 200 mg daily for 12 weeks
  • Pulse therapy: 400 mg daily for 1 week per month (2 pulses for fingernails, 3 pulses for toenails)
• Advantages: Active against Candida albicans, pulse treatment regimen available 1
• Disadvantages: Less effective than terbinafine for dermatophyte onychomycosis 1
• Monitoring: Hepatic function tests recommended in patients with pre-existing abnormalities, those receiving continuous therapy >1 month, and with concomitant hepatotoxic drugs 1
• Contraindications: Heart failure (negative inotropic effect), pregnancy 1, 5
• Critical drug interactions: Enhanced toxicity with warfarin, antihistamines (terfenadine, astemizole), antipsychotics (sertindole), anxiolytics (midazolam), digoxin, cisapride, ciclosporin, simvastatin 1, 5
• Important: Optimally absorbed with food and acidic pH 1

Second-Line Systemic Treatment

Fluconazole (Strength of Recommendation B)

• Dosing: 150-450 mg per week for 3 months (fingernails) or at least 6 months (toenails) 1
• Use when: Patients unable to tolerate terbinafine or itraconazole 1
• Monitoring: Baseline liver function tests and full blood count; monitor liver function in high-dose or prolonged therapy 1

Griseofulvin (Strength of Recommendation C)

• Dosing: 500-1000 mg daily for 6-9 months (fingernails) or 12-18 months (toenails) 1
• Major limitations: Lengthy treatment, poor cure rates (30-40% for toenails), high relapse rates 1
• Current role: No longer treatment of choice unless other drugs unavailable or contraindicated 1
• Only indication: The only antifungal licensed for children with onychomycosis (10 mg/kg/day for age ≥1 month) 1
• Drug interactions: Warfarin, ciclosporin, oral contraceptive pill 1

Topical Treatments

Amorolfine 5% Lacquer (Strength of Recommendation D)

• Application: Once or twice weekly for 6-12 months after filing diseased nail areas 1
• Efficacy: Effective in approximately 50% of distal fingernail and toenail onychomycosis 1
• Important caveat: Clinical improvement may not equal mycological cure, which is typically 30% lower 1
• Adverse effects: Rare—limited to local burning, pruritus, erythema 1

Ciclopirox 8% Lacquer (Strength of Recommendation C)

• Application: Once daily for up to 24 weeks (fingernails) or 48 weeks (toenails) 1
• Efficacy: 34% mycological cure vs. 10% placebo; 8% clinical cure vs. 1% placebo 1
• Note: Generally lower cure rates than amorolfine 1
• Adverse effects: Periungual and nail fold erythema 1
• FDA labeling: Less than 12% of patients achieve completely clear or almost clear toenail 6
• Special precaution: Risk of nail removal should be carefully considered in patients with insulin-dependent diabetes or diabetic neuropathy 6

Efinaconazole 10% (Strength of Recommendation D)

• Application: Once daily for 48 weeks 1
• Efficacy: Mycological cure rates approaching 50%, complete cure in 15% 1
• Monitoring: Watch for application site reactions including dermatitis 2

Tioconazole 28% Solution

• Efficacy: Variable results (20-70% cure rates) 1
• Adverse effects: Allergic contact dermatitis not uncommon, nausea and rashes in 8-15% 1
• Contraindication: Pregnancy; manufacturers caution against men fathering children for 6 months after therapy 1

Combination Therapy (Strength of Recommendation D)

• Recommended when: Response to topical monotherapy alone is likely to be poor 1
• Rationale: Provides antimicrobial synergy, wider antifungal spectrum, increased cure rates 1

Special Populations

Diabetic Patients

• Preferred agent: Terbinafine due to low risk of drug interactions and hypoglycemia 1
• Avoid: Itraconazole contraindicated in congestive heart failure (increased cardiac disease prevalence in diabetics) 1
• Consider: Topical treatments for mild-to-moderate infections when drug interaction risk is high 1

Immunosuppressed Patients (HIV, Iatrogenic)

• Preferred agent: Terbinafine due to increased risk of itraconazole/ketoconazole interactions with antiretrovirals 1
• Avoid: Griseofulvin (least effective in HIV patients) 1

Pediatric Patients

• First-line options: 1
  • Terbinafine: 62.5 mg daily (<20 kg), 125 mg daily (20-40 kg), 250 mg daily (>40 kg) for 6 weeks (fingernails) or 12 weeks (toenails)
  • Itraconazole pulse therapy: 5 mg/kg/day for 1 week per month (2 pulses for fingernails, 3 for toenails)
• Second-line: Fluconazole 3-6 mg/kg once weekly for 12-16 weeks (fingernails) or 18-26 weeks (toenails) 1
• Note: Higher cure rates and faster response in children compared to adults 1

Critical Pitfalls to Avoid

Systemic Therapy is Almost Always More Successful

• Topical treatment should only be used in superficial white onychomycosis, very early DLSO, or when systemic therapy is contraindicated 1

Mycological vs. Clinical Cure

• Mycological cure rates are typically 30% better than clinical cure rates 1
• Patient satisfaction mirrors mycological cure rate more closely than clinical appearance 1

Drug Interactions with Itraconazole

• Life-threatening cardiac dysrhythmias and sudden death can occur with cisapride, pimozide, methadone, quinidine 5
• Congestive heart failure risk increases, especially with calcium channel blockers 5
• Extensive list of contraindicated medications requires careful medication review 5

Treatment Duration and Expectations

• Complete cure takes time due to slow nail growth 2
• Six months may be required before initial improvement is noticed with topical therapy 6
• A completely clear nail may not be achieved even with treatment 6

Monitoring Requirements

• Professional removal of unattached, infected nail as frequently as monthly is needed with topical therapy 6
• Baseline and periodic liver function monitoring essential with systemic agents 1