What is the recommended approach to diagnose and treat onychomycosis in adults, including first‑line systemic therapy, alternative systemic options, and topical treatments?

Onychomycosis: Diagnosis and Treatment

Diagnosis

Always obtain mycological confirmation before initiating treatment—only about 50% of nail dystrophies are actually fungal. 1, 2

• Perform microscopy with potassium hydroxide (KOH) preparation plus fungal culture as the gold standard diagnostic approach 1, 3
• If culture is unavailable or cost-prohibitive, use periodic acid-Schiff (PAS) staining or PCR as alternatives 3, 4
• Dermatophytes (primarily Trichophyton rubrum) cause the vast majority of cases, while Candida and non-dermatophyte molds are often secondary colonizers in previously damaged nails 1, 2

First-Line Systemic Therapy

Terbinafine 250 mg once daily is the first-line treatment for dermatophyte onychomycosis, achieving cure rates of 70-80% for toenails and 80-90% for fingernails. 2, 5

Dosing regimen:

• Fingernails: 250 mg daily for 6 weeks 2, 5
• Toenails: 250 mg daily for 12 weeks (extend to 16 weeks for severe infections with extensive nail involvement) 2
• Pediatric dosing (ages 1-12 years):
  • <20 kg: 62.5 mg daily
  • 20-40 kg: 125 mg daily

  • 40 kg: 250 mg daily (adult dose)

  • Duration: 6 weeks for fingernails, 12 weeks for toenails 2, 5

Why terbinafine is superior:

• Demonstrates superior in-vitro and in-vivo activity against dermatophytes compared to all other antifungals 2, 5
• Persists in nails for 6 months after treatment completion due to long half-life 2
• Fewer drug interactions than azoles 2
• Preferred in diabetic patients (low risk of drug interactions and no hypoglycemia risk) 1, 5
• Preferred in immunocompromised patients (fewer interactions with antiretrovirals) 1, 5

Baseline monitoring for terbinafine:

• Obtain liver function tests (ALT, AST) and complete blood count before starting 2
• Ongoing monitoring is advised for patients with: prior hepatitis/liver disease, heavy alcohol consumption, concurrent hepatotoxic medications, or pre-existing abnormal liver enzymes 2

Common adverse effects:

• Gastrointestinal upset (nausea, diarrhea, abdominal pain), headache 2
• Reversible taste disturbance in approximately 1 in 400 patients 1, 2
• Rare but serious: Stevens-Johnson syndrome, toxic epidermal necrolysis, aggravation of psoriasis 2

Drug interactions:

• Rifampicin lowers terbinafine plasma levels 2
• Cimetidine increases terbinafine levels 2
• Potential interactions with CYP2D6-metabolized drugs (certain antidepressants, beta-blockers, antiarrhythmics) 2

Second-Line Systemic Therapy: Itraconazole

Use itraconazole when terbinafine is contraindicated, not tolerated, or when treating Candida onychomycosis (where it achieves 92% cure rate vs. 40% with terbinafine). 2, 5

Dosing options:

• Continuous regimen: 200 mg daily for 12 weeks 1, 2
• Pulse regimen: 400 mg daily (200 mg twice daily) for 1 week per month
  • Fingernails: 2 pulses (2 months total)
  • Toenails: 3 pulses (3 months total) 2
• Candida onychomycosis: 400 mg daily for 1 week per month, minimum 4 weeks for fingernails and 12 weeks for toenails 2

Critical administration requirements:

• Must be taken with food and acidic beverages for optimal absorption 1, 2

Monitoring:

• Baseline liver function tests required 2
• Monitor hepatic function tests when receiving continuous therapy >1 month or with concomitant hepatotoxic drugs 2

Contraindications:

• Heart failure (negative inotropic effects) 1, 2
• Pregnancy 2
• Active liver disease or hepatotoxicity 2

Critical drug interactions:

• Contraindicated with: terfenadine, astemizole, sertindole, midazolam, cisapride (enhanced toxicity) 2
• Increases levels of: warfarin, digoxin, ciclosporin, simvastatin (myopathy risk), statins generally 2
• Caution in elderly patients who commonly take statins and cardiac medications 2

Third-Line Systemic Therapy: Fluconazole

Fluconazole is reserved for cases where both terbinafine and itraconazole are unsuitable. 2

Dosing:

• 150-450 mg once weekly for minimum 6 months for toenail infections 2
• Treatment duration: 12-16 weeks for fingernails, 18-26 weeks for toenails 2

Monitoring:

• Baseline liver function tests and complete blood count 2
• Repeat testing during high-dose or prolonged courses 2

Advantages:

• Fewer drug interactions with statins compared to itraconazole 2

Topical Therapy

Topical treatments are inferior to systemic therapy and should only be used for superficial white onychomycosis (SWO), very early distal lateral subungual onychomycosis (DLSO) affecting <80% of nail plate without lunula involvement, or when systemic therapy is contraindicated. 1, 5

Amorolfine 5% lacquer:

• Apply once or twice weekly for 6-12 months 1, 2
• Achieves approximately 50% cure rate for distal infections 1, 2
• Remove as much diseased nail as possible by gentle filing before application 1
• Once-weekly application is as effective as twice-weekly 1

Ciclopirox 8% lacquer:

• Apply once daily for up to 48 weeks 1, 2
• Mycological cure: 34% vs. 10% with placebo 2
• Clinical cure: only 8% vs. 1% with placebo 2

Efinaconazole 10%:

• Mycological cure rates approaching 50%, complete cure in 15% after 48 weeks 2

Combination therapy:

• Adding topical antifungals to systemic therapy enhances cure rates through antimicrobial synergy, wider antifungal spectrum, and suppression of resistant mutants 2

Agents NOT Recommended as First-Line

Griseofulvin should not be used as first-line therapy due to low mycological cure rates (30-40%), prolonged treatment duration (12-18 months for toenails), and higher relapse rates. 2, 5

• Least effective oral antifungal in HIV-positive patients 1, 5

Treatment Failure Management

Even with optimal terbinafine therapy, expect a consistent failure rate of 20-30%. 2, 5

Common causes of failure:

• Poor patient adherence 2, 5
• Incorrect diagnosis (most common cause—treating non-fungal nail dystrophy) 5
• Poor drug absorption 2
• Immunosuppression 2
• Subungual dermatophytoma (compact mass of tightly packed hyphae visible as dense white lesion beneath nail that obstructs drug penetration) 1, 2
• Thick nails preventing adequate drug delivery 1

Management strategies:

• Reassess diagnosis with repeat mycological confirmation 2
• Evaluate adherence 2
• Consider partial nail avulsion or mechanical removal for dermatophytoma before restarting antifungal therapy 1, 2, 5
• Switch to alternative systemic agent (if terbinafine failed, try itraconazole or vice versa) 5
• Complete nail avulsion can achieve near-100% cure in selected cases 2

Follow-Up and Monitoring

Follow patients for at least 48 weeks (preferably 72 weeks) from treatment initiation to detect relapse. 2

• Reevaluate 3-6 months after initiating treatment 5
• End-of-therapy culture is recommended, especially in high-risk groups, to confirm mycological clearance 2
• Mycological cure rates are typically 30% higher than clinical cure rates—complete nail normalization may lag behind fungal eradication 1, 2
• Patients' satisfaction mirrors mycological cure rate more closely than clinical appearance scores 1

Prevention of Recurrence

Recurrence rates are high (25-50%) due to reinfection or incomplete cure. 3, 4

Footwear decontamination:

• Place naphthalene mothballs in shoes and seal in plastic bags for minimum 3 days to kill fungal arthroconidia 2
• Discard old contaminated footwear if possible 2
• Apply antifungal powders (miconazole, clotrimazole, tolnaftate) inside shoes regularly 2, 5
• Consider periodic spraying of terbinafine solution into shoes 2

Behavioral measures:

• Always wear protective footwear in communal bathing facilities, gyms, and hotel rooms 5
• Wear cotton absorbent socks 2
• Keep nails short and clean 2
• Avoid sharing nail clippers 2
• Avoid walking barefoot in public places 3

Prophylactic treatment:

• Amorolfine has been found effective as prophylactic treatment for recurrence 1

Special Population Considerations

Diabetic patients:

• Onychomycosis is a significant predictor for development of foot ulcers and cellulitis in diabetes 1, 5
• Terbinafine is the agent of choice due to low risk of drug interactions and no hypoglycemia risk 1, 5
• Itraconazole is contraindicated in congestive heart failure, which is more prevalent in diabetics 1

Immunocompromised patients (HIV, transplant):

• Prevalence of onychomycosis in HIV-positive patients is approximately 30% 1, 5
• Terbinafine and fluconazole are preferred due to lower risk of interactions with antiretrovirals and immunosuppressive medications 1, 5
• Griseofulvin should be avoided (least effective in this population) 1, 5

Critical Pitfalls to Avoid

• Never treat based on clinical appearance alone—incorrect diagnosis is the most common cause of treatment failure 5
• Do not expect complete clinical normalization even with mycological cure, as nails may have pre-existing dystrophy from trauma or non-fungal disease 1, 5
• Do not overlook dermatophytoma—it requires mechanical removal before antifungal therapy will succeed 1, 2
• Do not ignore drug interactions, especially itraconazole with statins, cardiac medications, and antiretrovirals 2