Oral antifungals for onychomycosis
Onychomycosis is a chronic fungal infection of the nail that results in discoloration, onycholysis, and nail plate thickening. The infection most commonly occurs in the toenails and can involve any component of the nail unit, including the nail bed, nail matrix, and nail plate. Onychomycosis affects patients of all ages. However, several studies have established higher prevalence with older age. Other risk factors include diabetes, tinea pedis, poor circulation, immunosuppression, psoriasis, Down syndrome, occlusive footwear, and obesity.
I will be using materials by Bermudez et al. Onychomycosis: Old and New. J. Fungi 2023, 9(5), 559; https://doi.org/10.3390/jof9050559. There are also extracts from Axler et al. Antifungal Selection for the Treatment of Onychomycosis: Patient Considerations and Outcomes. Infection and Drug Resistance 2024:17 819–843.
The worldwide prevalence of onychomycosis is estimated at 10 per cent and accounts for up to 50 per cent of nail diseases. Dermatophytes are a common culprit of onychomycosis, with the species Trichophyton rubrum and Trichophyton mentagrophytes responsible for 60–70 per cent of infections. Yeasts are responsible for approximately 20 per cent of onychomycosis, and non-dermatophytes account for the remaining 10 per cent. Studies have demonstrated that mixed infections, non-dermatophytes, and yeasts are more prevalent than previously thought, especially in warmer climates.
Onychomycosis is challenging to treat and is associated with high recurrence rates and treatment failure. Given the limited cure rates with topical antifungals, oral antifungals are used in most cases. Oral treatments require lengthy duration of treatment, which poses a risk of adverse effects and drug interactions. Relapse rate can be as high as 25 per cent, and recurrence rates can vary from 6.5 per cent to 53 per cent.
Defining a cure
Onychomycosis studies often report the mycologic cure, clinical cure, and complete cure rates. A mycologic cure is achieved when both the culture and direct microscopy are negative after medical treatment. A clinical cure is defined as a normal appearance of the affected nail. A complete cure is defined as both negative mycology and absence of clinical signs in the nail. The goal of treatment is complete cure; however, patients often have nail abnormalities before the development of the fungal infections and will not achieve fully normal nails after treatment.
Griseofulvin
Griseofulvin, the first oral agent available for treating onychomycosis. Once the agent of choice, but its use has declined due to its longer treatment duration, lower efficacy, and higher recurrence rates compared to other oral antifungals.
Griseofulvin prevents the formation of intracellular microtubules, disrupts the mitotic spindle, and prevents fungal cell division. The drug reaches the infection site through uptake by newly produced nail, necessitating continuous treatment as the nail grows out. Griseofulvin requires extended durations in onychomycosis treatment, with recommended daily doses ranging from 500–1000mg for 6–9 months for fingernails and 12–18 months for toenails, aligned with average nail growth rates. As a result, there is low patient adherence.
Itraconazole
itraconazole inhibits 14a-demethylase in the ergosterol biosynthesis pathway, which disrupts the fungal membrane permeability and causes accumulation of lanosterol and other 14α-methyl sterols. It is indicated for dermatophyte onychomycosis treatment, with oral dosing of 200mg daily for 12 weeks for toenails and two treatment pulses of 200mg twice daily for 1 week separated by 3 weeks for fingernails.
Itraconazole demonstrates broad-spectrum activity against dermatophytes, non-dermatophyte moulds, and candida species. The oral formulation of itraconazole has 55% bioavailability, though maximal absorption occurs in acidic gastric environments. Therefore, efficacy may be decreased with histamine H2 blockers and proton pump inhibitors, with maximum absorption after a meal.
At 400mg/day for 1 week a month for 2 months for fingernails infection and 400mg/day for 1 week a month for 3 months for toenails achieve clinical and mycological cure rates of 91.4% and 85.3% for fingernails, respectively and 89.0% and 68.4% for toenails, respectively.
Liver enzyme monitoring is recommended before treatment initiation and every 4–6 weeks during treatment. Itraconazole may rarely lead to adverse cardiovascular events and should be avoided in patients with evidence of ventricular dysfunction, such as congestive heart failure (CHF) or a history of CHF.
Onychomycosis affects up to one-third of diabetic patients, particularly those over the age of 65 years. Itraconazole has less than 0.03% renal excretion and therefore preferred for diabetics with renal impairment. Of note, most diabetic drugs and insulin are not metabolized by the same cytochrome P-450 enzymes as itraconazole.
HMG-CoA reductase inhibitors such as atorvastatin, cerivastatin, lovastatin, and simvastatin are metabolized by CYP34A, and itraconazole may increase their plasma concentrations and potentiate rhabdomyolysis.
Terbinafine
First-line treatment of onychomycosis by the British Association of Dermatologists and the USA-FDA. Terbinafine, a synthetic allylamine, competitively inhibits squalene epoxidase, disrupting ergosterol synthesis and leading to intracellular squalene accumulation, which has fungicidal effects. In vitro, terbinafine has broad-spectrum antifungal activity against dermatophytes and some activity against yeasts and non-dermatophyte moulds.
Dosing is 250mg once daily for six weeks for fingernail onychomycosis and 12 weeks for toenail onychomycosis.
Terbinafine is reported to have mycological and complete cure rates of 70 per cent and 38 per cent, respectively.
Terbinafine undergoes hepatic first-pass metabolism followed by renal clearance, necessitating caution in patients with liver or kidney disease.
Liver enzyme abnormalities occurred in 3.3 per cent of patients, and taste and visual disturbances in 2.8 per cent and 1.1 per cent, respectively. In a retrospective study of adverse effects associated with terbinafine from January 1993 to June 2019 using the Federal Drug Administration Adverse Event Reporting System (FAERS) database (11,658 cases), “ageusia/dysgeusia” occurred in 12 per cent, ‘AST/ALT elevations’ in six per cent, and ‘pruritus’ in six per cent.
Diabetes mellitus is a risk factor for developing toenail onychomycosis. Since terbinafine is renally cleared, it is recommended that kidney function is checked in all patients before initiating treatment.
Immunosuppressed transplant patients are at increased risk for developing onychomycosis, necessitating caution due to drug-drug interactions with terbinafine. Terbinafine influences the metabolism of cyclosporine, and drug level monitoring is recommended for patients taking these medications concomitantly.
Terbinafine inhibits CPY-2D6. Caffeine clearance is decreased by 19 per cent and cyclosporine clearance is decreased by 15 per cent with terbinafine. Terbinafine may increase plasma concentrations of imipramine, desipramine, amitriptyline, nortriptyline, and paroxetine, and may induce thirst, nausea, and vertigo when taken together with these medications. Terbinafine also decreases clearance of beta-blockers.
Fluconazole
Fluconazole, an azole antifungal, inhibits lanosterol-14-α-demethylase, an enzyme important for the synthesis of ergosterol, a component of fungal cell walls. Fluconazole is approved for the treatment of onychomycosis in Europe. Although not USA-FDA-approved for the treatment of onychomycosis, it is commonly prescribed off-label in the USA, Australia, and Canada.
Fluconazole is active against dermatophytes and candida species and may be detected in the nail plate within two weeks of initiating treatment.
Fluconazole is not recommended for use in pregnancy. Exposure during the first trimester is associated with congenital malformations and spontaneous abortions. Fluconazole is excreted into human breast milk and should be avoided in lactation.
Fluconazole inhibits CYP-2C9 and CYP-3A4, therefore there are many potential drug-drug interactions. In a retrospective analysis of the FAERS database, the most common adverse event with fluconazole was drug-drug interactions. It may increase concentrations of sulfonylurea anti-diabetic agents, potentially leading to hypoglycaemia. Fluconazole may also elevate warfarin levels, increasing the risk of bleeding.
Fluconazole may cause QT interval prolongation, potentially causing torsade de pointes, therefore co-administration with any medication that may also prolong the QT interval is contraindicated.
Terbinafine vs Itraconazole vs Fluconazole
Terbinafine and itraconazole are the only approved oral therapies (USA-FDA), but fluconazole is commonly utilised off-label. However, complete cure rates (both mycologic clearance and visually clear nails) are limited, and they can range from 35–55 per cent for terbinafine, 14–43 per cent for itraconazole, and 21–48 per cent for fluconazole.
Due to the systemic nature of oral antifungal medications, side effects and drug–drug interactions should be considered in the selection of these medications.
Terbinafine has been associated with hepatic injury. Therefore, liver function tests are recommended prior to starting treatment.
Itraconazole therapy carries a high risk of drug interactions and should be used cautiously in patients with cardiac conditions due to its risk of heart failure and arrythmias.
Fluconazole is also associated with high risk of interactions (not much when used as pulse treatment), cardiovascular risk and has been reported to prolong the QT interval. Additional side effects with fluconazole include significant congenital defects, and avoidance of this medication during pregnancy is strongly advised.
DR. EDWARD O.
AMPORFUL
CHIEF PHARMACIST
COCOA CLINIC