Overview

Toenail fungus, also known as onychomycosis, is a common fungal infection of nails. It affects both fingernails and toenails, but it is more common in toenails. The condition is caused by dermatophytes (Tinea unguium). Dermatophytes are the main cause of 90% of toenail fungal infections. When fungus infects the toenail, it becomes thick and yellow, with white spots or streaks. Toenail fungus is widespread among older adults, affecting 1 in 10 individuals. This number rises to 1 in 2 (50%) for individuals over 70.^1,2,3 The condition does not go away by itself and could get worse if left untreated, causing significant pain and discomfort while walking and potentially spreading to other nails.³ Several treatment options are available to improve the symptoms and prevent further spread.⁴ Oral antifungal medications are effective, especially for moderate to severe infections.⁵ 

Common oral antifungal medications

Terbinafine

Mechanism of action

Terbinafine inhibits the squalene epoxidase enzyme, the enzyme that converts the squalene to squalene epoxidase. This results in the accumulation of squalene within the fungal cells, ultimately causing cell death.⁶

Dosage and duration of treatment

• 250 mg tablet to be taken by mouth daily for up to 12 weeks.⁷ 

Effectiveness

A large systematic review of 48 studies involving 10,200 participants found terbinafine to be more effective than azoles in achieving both clinical cure and mycological cure. While the risk of adverse events and recurrence rate were similar between the two treatment groups.⁵  

Side effects

• Common: Headaches, gastrointestinal symptoms, and rash
• Uncommon: Visual disturbances and mild transaminitis
• Severe: Dysgeusia, fulminant liver failure, Stevens-Johnson syndrome, toxic epidermal necrolysis⁶

Itraconazole

Mechanism of action

Itraconazole inhibits lanosterol 14 alpha-demethylase, an enzyme essential in synthesising ergosterol, a component of fungal cell membranes. This disruption results in leaky and compromised fungal cell membranes, ultimately causing cell death.⁸

Dosage and duration of treatment

• 200 mg orally (capsules) each day for 12 weeks.⁷

Effectiveness

• A multicenter study of 635 patients receiving intermittent itraconazole therapy (400mg/day for 1 week a month for 3 months) achieved high rates of complete clinical and mycological cure⁹
• A meta-analysis review study found 1,741 patients receiving continuous itraconazole (200mg/day for 3 months), found a 52% clinical cure rate at 12 months, along with 86% showing clinical response and 74% achieving mycological cure¹⁰

Side effects

• Common: Gastrointestinal disturbances, such as nausea, mild diarrhoea, vomiting, abdominal pain, headache, rash, and injection site reactions
• Rare: Decreased heart contractility and left ventricular ejection fraction, hepatotoxicity, hypertension (rare)⁸

Fluconazole (less commonly used)

Mechanism of action

Fluconazole inhibits lanosterol 14 alpha-demethylase, an enzyme essential in synthesising ergosterol, a component of fungal cell membranes. Inhibiting this enzyme results in leaky and compromised fungal cell membranes, ultimately causing cell death.¹¹

Dosage and effectiveness

150 to 450 mg weekly for 6 months.¹¹

Effectiveness

• In a prospective study of 74 onychomycosis patients treated with 150mg of fluconazole per week for 3–12 months, a 95% clinical response was observed after three months and 96% after 11 months. About 52% of the patients achieved complete clinical cure, and 79% of the toenails achieved mycological cure¹²
• In another study of 16 onychomycosis patients treated with 100mg of oral fluconazole daily for six months, all showed clinical improvement based on visual assessment score¹³

Side effects

• Common: Nausea, headache, skin rash, vomiting, abdominal pain, diarrhea¹¹

Effectiveness and treatment duration

Expected results and time frame

Oral antifungal medications are typically taken daily for at least 6 to 12 weeks, but the results will be evident only after the infected nail grows completely. The medications need to be taken for four months or longer to eliminate an infection, but the success rates tend to be lower in adults over age 65.³

Factors influencing treatment success

Drug interactions

Azole antifungal medications inhibit the liver enzymes responsible for drug metabolism, affecting the effectiveness or safety of other medications.

Immunosuppression

Conditions such as HIV/AIDS or immunosuppressive medications can weaken the immune system, reducing the body's ability to fight fungal infections.

Pregnancy and breastfeeding

• Pregnant women should generally avoid taking oral antifungal medications, as they may affect fetal development
• Some antifungal drugs, such as ketoconazole, fluconazole, and terbinafine, can pass into breast milk, making breastfeeding inadvisable⁵

Precautions and contraindications

Who should avoid oral antifungal medications?

Healthcare providers may not recommend oral antifungal drugs for individuals with liver disease or congestive heart failure, or those taking certain medications.³

Alternative treatments for high-risk patients

For individuals who cannot take oral antifungal medications, several alternative treatment options are available:

Surgical and mechanical approaches

• Nail removal is usually suggested for severe infection or when other therapy fails
• Nail trimming and debridement are usually suggested along with oral or topical therapy. This procedure can improve the topical medication penetration or enhance the effectiveness of oral medications by reducing the thickness¹⁴

Light-based therapies

• Dual-wavelength infrared and fractional carbon dioxide laser therapies temporarily improve the cosmetic appearance of nails affected by toenail fungus. However, these treatments have limited ability to eradicate the underlying fungal infection. Hence, the therapy should be used along with oral or topical therapy to treat toenail fungus^15,16
• Photodynamic therapy, an off-label non-invasive treatment that combines light-based modalities with photosensitizers to treat toenail fungus. In a double-dummy RCT including 80 participants were compared biweekly photodynamic therapy with once-weekly fluconazole (300 mg) for 24 weeks. While photodynamic therapy showed a greater treatment response at 24 weeks (90% vs. 40%)¹⁷

Plasma therapy

• Plasma therapy uses pulses of a strong electric field to ionise air molecules, generating ozone, hydroxyl radicals, and nitric oxide, which possess antifungal properties. A pilot study involving 19 participants without a control group showed a 53.8% overall clinical cure rate¹⁸

Summary

Toenail fungus is a common fungal infection that can significantly impact quality of life. Oral antifungal medications such as terbinafine, itraconazole, and fluconazole are effective in treating moderate to severe infections. These medications disrupt the fungal cell membrane and lead to cell death. Antifungal medications can be taken orally or applied topically. 

Traditional topical medications have low success rates due to the nail's physical properties. Oral medications typically require several weeks to months, and complete cure may take longer. Although effective, oral antifungal medications may interfere with other medications. Hence, healthcare professionals should evaluate the treatment options to suggest the most suitable approach based on individual circumstances. 

FAQ’s

How do oral antifungal medications work?

Most antifungal medications work by inhibiting fungal membrane synthesis, leading to fungal cell death.

When are oral antifungal medicines recommended?

Oral antifungal medications are usually recommended for severe toenail fungal infections or when topical treatments are not effective. Oral medications work more effectively and improve the condition more quickly than topical treatment. While topical medications are less effective due to the nail's physical properties.

Which one is the most effective: oral antifungal medication or topical treatments?

Both oral and topical antifungal medications are effective in treating toenail fungus. The choice of medication depends on the type and severity of the infection, and the individual patient factors.
Oral antifungals, such as terbinafine and itraconazole, are more effective for moderate to severe infections. Topical Antifungals are effective for mild to moderate infections.

What happens if you have toenail fungus for too long?

Toenail fungus that is left untreated for too long may lead to permanent damage to nails, including loss of the nail. It can also lead to painful swelling of the skin around the nail.