Treating Onychomycosis | AAFP

PHILLIP RODGERS, M.D., AND MARY BASSLER, M.D.

Onychomycosis accounts for one third of fungal skin infections. Because only about one half of nail dystrophies are caused by fungus, the diagnosis should be confirmed by potassium hydroxide preparation, culture or histology before treatment is started. Newer, more effective antifungal agents have made treating onychomycosis easier. Terbinafine and itraconazole are the therapeutic agents of choice. Although the U.S. Food and Drug Administration has not labeled fluconazole for the treatment of onychomycosis, early efficacy data are promising. Continuous oral terbinafine therapy is most effective against dermatophytes, which are responsible for the majority of onychomycosis cases. Intermittent pulse dosing with itraconazole is as safe and effective as short-term continuous therapy but more economical and convenient. With careful monitoring, patients treated with the newer antifungal agents have a good chance of achieving relief from onychomycosis and its complications.

Onychomycosis (tinea unguium) is a fungal infection of the nail bed, matrix or plate. Toenails are affected more often than finger-nails.^1,2 Onychomycosis accounts for one third of integumentary fungal infections and one half of all nail disease.¹ Tinea unguium occurs primarily in adults, most commonly after 60 years of age. The incidence of this infection is probably much higher than the reported 2 to 14 percent.¹ Occlusive footwear, locker room exposure and the dissemination of different strains of fungus worldwide have contributed to the increased incidence of onychomycosis.³

Tinea unguium is more than a cosmetic problem, although persons with this infection are often embarrassed about their nail disfigurement. Because it can sometimes limit mobility, onychomycosis may indirectly decrease peripheral circulation, thereby worsening conditions such as venous stasis and diabetic foot ulcers.⁴ Fungal infections of the nails can also be spread to other areas of the body and, perhaps, to other persons.

Dermatophytes, yeasts and nondermatophytic molds can infect the nails.¹ The clinical significance of molds is uncertain, because they may be colonizing organisms that are not truly pathogenic.^3,5

Classification of Onychomycosis

DISTAL SUBUNGUAL ONYCHOMYCOSIS

The most common form of tinea unguium is distal subungual onychomycosis, which can also be distal and lateral (Figures 1 and 2). Distal subungual onychomycosis may develop in the toenails, fingernails or both. Some degree of tinea pedis is almost always present. The infection is usually caused byTrichophyton rubrum, which invades the nail bed and the underside of the nail plate, beginning at the hyponychium and then migrating proximally through the underlying nail matrix^2,3(Figure 3). Susceptibility to distal superficial onychomycosis may occur in an autosomal dominant pattern within families.¹

WHITE SUPERFICIAL ONYCHOMYCOSIS

White superficial onychomycosis accounts for only 10 percent of onychomycosis cases.³ The toenails are usually affected (Figure 4). White superficial onychomycosis is caused by certain fungi that directly invade the superficial layers of the nail plate and form well-delineated opaque “white islands” on the plate. As the disease progresses, these patches coalesce to involve the entire nail plate. The nail becomes rough, soft and crumbly. The most common causative agent isTrichophyton mentagrophytes.^1–3

PROXIMAL SUBUNGUAL ONYCHOMYCOSIS

Proximal subungual onychomycosis is the least common form of tinea unguium in healthy persons (Figure 5). It occurs when the infecting organism, usuallyT. rubrum, invades the nail unit through the proximal nail fold, penetrates the newly formed nail plate and then migrates distally. Fingernails and toenails are equally affected.¹ This form of onychomycosis usually occurs in immunocompromised persons and is considered a clinical marker of human immunodeficiency virus infection.¹ Proximal subungual onychomycosis can also arise secondary to local trauma.^1–3

CANDIDAL ONYCHOMYCOSIS

Patients with chronic mucocutaneous candidiasis may develop candidal infection of the nails. Candida species may invade nails previously damaged by infection or trauma.^1,3 Candidal paronychia more commonly affects the hands and usually occurs in persons who frequently immerse their hands in water.⁵

TOTAL DYSTROPHIC ONYCHOMYCOSIS

Total dystrophic onychomycosis may be the end result of any of the four main forms of onychomycosis. This condition is characterized by total destruction of the nail plate.³

Diagnosis

Because fungi are responsible for only about one half of nail dystrophies, the diagnosis of onychomycosis may need to be confirmed by potassium hydroxide (KOH) preparation, culture or histology. Psoriasis, lichen planus, contact dermatitis, trauma, nail bed tumor and yellow nail syndrome may be mistakenly diagnosed as onychomycosis.^1,2 A fungal etiology is unlikely if all fingernail or toenails are dystrophic.³

OBTAINING A SPECIMEN

The technique used to collect specimens depends on the site of the infection.^1,3

In distal subungual onychomycosis, the concentration of fungus is greatest in the nail bed. Therefore, the nail should be clipped short, and a small curette or number-15 scalpel blade should be used to obtain a specimen from the nail bed as close to the cuticle as possible. A specimen should also be taken from the underside of the nail plate.

In white superficial onychomycosis, a number-15 blade or curette can be used to scrape the nail surface or the white area, and remove infected debris.

In proximal superficial onychomycosis, the healthy nail plate should be gently pared away with a number-15 scalpel blade. A sharp curette can be used to remove material from the infected proximal nail bed as close to the lunula as possible.

In candidal onychomycosis, infected material should be collected from the proximal and lateral nail edges.

Treatment

Historically, the treatment of onychomycosis has been challenging. Orally administered griseofulvin (Grisactin, Gris-Peg) has been available for many years, but its use is limited by a narrow spectrum, the necessity for long courses of treatment and high relapse rates. The oral form of ketoconazole (Nizoral) is much more effective but carries a risk of hepatotoxicity.⁶

Onychomycosis has long been treated with topical antifungal preparations. However, these agents are inconvenient to use, and results are often disappointing. Treatment using nail avulsion in combination with topical therapy has been somewhat more successful, but this approach can be time-consuming, temporarily disabling and painful.

The U.S. Food and Drug Administration (FDA) has labeled ciclopirox (Penlac) nail lacquer for the treatment of mild to moderate onychomycosis caused byT. rubrum without involvement of the lunula. Although safe and relatively inexpensive, ciclopirox therapy is seldom effective.⁷

In recent years, treatment outcomes in patients with onychomycosis have improved substantially, primarily because of the introduction of more effective oral antifungal medications.⁸ Current evidence supports the use of these newer agents as part of individualized treatment plans that consider patient profiles, nail characteristics, infecting organism(s), potential drug toxicities and interactions, and adjuvant treatments.⁹

Triazole and allylamine antifungal drugs have largely replaced griseofulvin and ketoconazole as first-line medications in the treatment of onychomycosis. These agents offer shorter treatment courses, higher cure rates and fewer relapses.¹⁰ Of the newer drugs, terbinafine (Lamisil) and itraconazole (Sporanox) are the most widely used, with fluconazole (Diflucan) rapidly gaining acceptance. These medications share characteristics that enhance their effectiveness: prompt penetration of the nail and nail bed,^3,11 persistence in the nail for months after discontinuation of therapy^12,13 and generally good safety profiles. Published studies measuring “mycologic cure” (negative KOH preparation or negative cultures) and “clinical cure” (normal nail morphology) have demonstrated the effectiveness of all three medications.

TERBINAFINE

Terbinafine is an allylamine antifungal agent that is active against dermatophytes, which are responsible for the majority of onychomycosis cases. This agent is notably less effective against nondermatophytes, including Candida species and molds.

Adverse effects, including headache, rash and gastrointestinal upset, are reported more often with terbinafine than with placebo. Yet these side effects are uncommon and resolve with discontinuation of the drug.¹⁴ Because of its hepatic metabolism, terbinafine has several important drug interactions (Table 1). ^15–17

Drug or drug class	Terbinafine (Lamisil)	Itraconazole (Sporanox)	Fluconazole (Diflucan)
Benzodiazepines		Concomitant use of midazolam (Versed) and triazolam (Halcion) contraindicated; use of other benzodiazepines not recommended	Avoid concomitant use because of increased risk of sedation.
Cimetidine (Tagamet)	Increased terbinafine levels possible	Decreased itraconazole absorption	Decreased fluconazole levels possible
Gastric pH neutralizers (histamine H2 blockers, proton pump inhibitors, sucralfate [Carafate])		Monitor for treatment failure because of decreased itraconazole absorption with increased gastric pH.
HMG-CoA reductase inhibitors		Concomitant use contraindicated because of reported rhabdomyolysis
Hydrochlorothiazide (Esidrix) and hydrochlorothiazide combinations			Increased fluconazole levels possible
Oral hypoglycemics (all classes)		Increased hypoglycemia possible	Risk of significant hypoglycemia
Quinidines		Concomitant use contraindicated because of reported ventricular arrhythmias
Pimozide (Orap)		Concomitant use contraindicated because of reported ventricular arrhythmias
Rifampin (Rifadin)	Decreased terbinafine levels possible		Decreased fluconazole levels possible
Theophylline			Increased theophylline levels possible
Warfarin (Coumadin)	Bleeding events reported	Increased risk of bleeding	Increased risk of bleeding

Rare but serious complications, such as cholestatic hepatitis, blood dyscrasias and Stevens-Johnson syndrome, have been reported in patients treated with terbinafine. Consequently, liver enzyme levels and a complete blood count (including a platelet count) should be obtained before terbinafine is initiated and repeated every four to six weeks during treatment.¹⁸ Terbinafine should be discontinued if the aspartate aminotransferase or alanine aminotransferase level becomes elevated to two or more times normal.

The FDA-labeled dosage of terbinafine is 250 mg per day given continuously for 12 weeks to treat toenail infections and for six weeks to treat fingernail infections. Studies have shown that the regimen for toenails results in a mycologic cure rate of 71 to 82 percent and a clinical cure rate of 60 to 70 percent.^19,20 Shorter courses and pulse dosing of terbinafine have shown promise in small studies, but data are not yet sufficient to support the use of these regimens.²¹

ITRACONAZOLE

Itraconazole is a newer triazole medication with a broad antifungal spectrum that includes dermatophytes, many nondermatophytic molds and Candida species. Headache, rash and gastrointestinal upset occur in about 7 percent of treated patients, but hepatic toxicity is rare.²²

Because itraconazole is metabolized by the hepatic cytochrome P450 system, significant drug interactions can occur (Table 1).^15–17 Notably, concurrent use with quinidines and pimozide (Orap) is contraindicated because of the risk of ventricular arrhythmias. Itraconazole is also contraindicated for concomitant use with 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, such as atorvastatin (Lipitor), because of the increased risk of rhabdomyolysis. In addition, itraconazole should not be taken with some benzodiazepines, such as midazolam (Versed) and triazolam (Halcion), because of exaggerated sedation and potential airway compromise.¹⁵

Increased gastric pH decreases the absorption of itraconazole. Therefore, the effectiveness of this antifungal agent can be decreased by histamine H₂ blockers such as ranitidine (Zantac) and famotidine (Pepcid), and by proton pump inhibitors such as omeprazole (Prilosec) and lansoprazole (Prevacid). For this reason, itraconazole should be taken with food.

The FDA-labeled dosage of itraconazole is 200 mg once daily taken continuously for 12 weeks to treat toenail infections and for six weeks to treat fingernail infections. The FDA has labeled pulse therapy only for the treatment of fingernail infections. Pulse treatment consists of 200 mg taken twice daily for one week per month, with the treatment repeated for two to three months (i.e., two to three “pulses”).^7,8,22,23 This dosage, given in three to four pulses, has also been shown to be effective in the treatment of toenail infections.^7,8,22,23 Published studies have demonstrated similar success rates for continuous and pulse therapies, with mycologic cure rates ranging from 45 to 70 percent and clinical cure rates ranging from 35 to 80 percent.^22,24,25

Liver enzyme monitoring is recommended before continuous therapy is initiated and every four to six weeks during treatment. No monitoring recommendation is given for pulse therapy. ²⁶

FLUCONAZOLE

Like itraconazole, fluconazole is active against common dermatophytes, Candida species and some nondermatophytic molds. Adverse effects, including nausea, headache, pruritus and liver enzyme abnormalities, are reported in approximately 5 percent of treated patients.²⁶ These side effects remit after the discontinuation of fluconazole. The absorption of this drug is not pH sensitive and is not affected by acid suppression or food intake. However, fluconazole has important drug interactions¹⁵(Table 1).^15–17

Fluconazole is not currently labeled by the FDA for the treatment of onychomycosis, but early efficacy data are promising.^13,27,28 Attention has focused on once-weekly dosing (450 mg), taking advantage of the drug’s pharmacokinetics to reduce treatment costs, decrease rates of adverse effects and potentially improve compliance.

In one placebo-controlled study involving patients with fingernail onychomycosis,²⁹ fluconazole in a dosage of 450 mg taken once weekly for three months was associated with a 90 percent clinical cure rate and nearly total mycologic eradication. Lower dosages were slightly less effective. No differences in complication rates were observed between the treatment and placebo groups. Published outcomes data^27,28 on the use of fluconazole in toenail fungal infections demonstrated “clinical improvement” (i.e., less than 25 percent of the nail still affected) rates of 72 to 89 percent, compared with 3 percent for placebo.²⁷ Treatment duration in these studies varied from four to nine months, with a small but measurable advantage shown for longer courses.^27–29

Treatment guidelines for the newer antifungal medications are provided in Table 2.

Comparative Clinical Trials

Much of the published data on the treatment of onychomycosis are of limited clinical use. Many studies have been small and observational, and they have lacked randomization and control subjects. Recently, however, the results of a handful of larger randomized, controlled trials have been published. These studies provide more convincing guidance in choosing appropriate therapy.

In a 1998 study³⁰ of 378 patients with dermatophytic onychomycosis, continuous terbinafine therapy was shown to be more effective than continuous itraconazole therapy in patients with toenail onychomycosis. Intention-to-treat analysis showed nearly 85 percent negative cultures in the treatment group compared with 55 percent in the placebo group, and 65 percent clinical improvement in the terbinafine group compared with 37 percent in the itraconazole group.

Other studies comparing terbinafine and itraconazole had similar findings.^31,32 A recent prospective, double-blind, randomized, controlled trial³³ compared the use of continuous terbinafine therapy and pulsed itraconazole therapy in 496 patients with toenail fungal infection. This well-designed study showed that terbinafine provided superior clinical and mycologic outcomes up to 15 months after treatment. To date, fluconazole has not been included in published direct-comparison trials.

Most patients in the published studies were infected with dermatophytes, against which terbinafine is most effective. Outcomes data for the treatment of nondermatophytic and candidal onychomycosis are limited, but broader spectrum triazole medications may be more effective against these pathogens.

Onychomycosis is expensive to treat. Costs include medications, procedures, laboratory tests and health care providers’ time, as well as expenses associated with the management of adverse drug effects and treatment failures.

One pharmacoeconomic study³⁴ compared the cost-effectiveness of continuously dosed terbinafine and itraconazole in the treatment of toenail onychomycosis.³⁴ The investigators concluded that continuous terbinafine therapy is less expensive, at a little over one half the price of continuous itraconazole treatment. It should be noted, however, that itraconazole pulse therapy is less expensive than continuous treatment (lower overall drug cost and no need for blood monitoring). Furthermore, the pharmacoeconomic study used national reference pricing and wholesale drug costs. Local laboratory standards, retail pharmacy costs and increasingly common payor formulary considerations may significantly alter individual costs.

Adjuvant Treatments

In addition to oral medications, some patients benefit from other treatments. Surgical or chemical nail avulsion may be useful in patients with severe onycholysis, extensive nail thickening or longitudinal streaks or“spikes” in the nail. These nail changes can be caused by a granulated nidus of infection (dermatophytoma), which responds poorly to standard courses of medical therapy.^35,36

Longer courses of antifungal therapy may be useful in patients whose nails grow slowly, who have diminished blood supply to the nail bed as a result of conditions such as peripheral vascular occlusion or diabetes mellitus, or who have total or nearly total nail plate involvement. ⁹

Topical antifungal creams or powders may also be beneficial, especially in patients with concomitant tinea pedis.

To improve treatment outcomes and prevent recurrence, patients should be counseled about proper foot hygiene (Table 3). Patients should be encouraged to wear breathable footwear and 100 percent cotton soc ks when possible. They should be advised to keep their feet dry throughout the day. Similar infection patterns observed in households and patrons of communal bathing facilities suggest a role for foot protection in high-risk areas.²¹

Wearing 100 percent cotton socks and changing them often

Choosing breathable footwear

Protecting feet in shared bathing areas

Keeping feet dry throughout the day

Recognizing and treating tinea pedis

Maintaining and improving chronic health conditions (e. g., controlling diabetes, quitting smoking, etc.)

There may be a familial predisposition to someT. rubrum infections. In such instances, prophylactic treatment of family members can be considered.³⁷

Treatment Failure and Relapse

Rates of treatment failure can be extracted from published trials, but data on relapse are less readily available. Post-treatment follow-up is long, drop-out rates in many studies are significant or unreported, and most studies have not allowed crossover of treatment regimens. Furthermore, especially in outcomes of clinical improvement (as opposed to cure or fully normal nail appearance), evaluation criteria have not been standardized and often include subjective assessments that are difficult to quantify. Published studies have not specifically addressed the management of treatment failures or relapse.

Despite these difficulties, several measures may be helpful in managing unsuccessful treatment or relapse. The first step is to confirm mycology. If the initial diagnosis was based on a KOH preparation alone, culture of properly collected specimens is mandatory. Culture reports often identify multiple organisms, including possibly nonpathogenic molds, and treatment should be directed at the organism(s) most likely to be causative. A microbiology or infectious disease consultation may be valuable in interpreting the culture report.

Of note, there has been some concern about evolving drug resistance among fungal pathogens, particularly with the widespread use of systemic fluconazole therapy to treat oropharyngeal and recurrent vaginal candidiasis.⁵ However, the impact of antifungal resistance on the treatment of onychomycosis is not yet clear.

Careful clinical review may identify patient or nail characteristics that are impeding treatment. These factors can be addressed with appropriate medication changes or adjuvant measures. Because of superior efficacy, continuous antifungal therapy may be considered in patients who fail or relapse after pulse therapy.

Onychomycosis in Children

Onychomycosis in children is rare, with an estimated prevalence of 0.2 percent.³⁸ Most often, onychomycosis develops in children with immunosuppression (e.g., acquired immunodeficiency syndrome, chemotherapy, congenital immunodeficiency syndromes), a strong familial history of onychomycosis or extensive cutaneous mycosis (tinea capitis or pedis).

Although griseofulvin remains the mainstay of onychomycosis treatment in children, the efficacy of this drug is variable, and relapse is common. Newly available medications may improve the traditionally mediocre treatment outcomes in this age group.

The FDA has not yet labeled terbinafine for use in children. However, some studies have shown terbinafine to be safe and quite effective in the treatment of tinea capitis, and it is licensed for this purpose in several countries.³⁹ In more limited trials, itraconazole has also been shown to be safe and efficacious in the treatment of tinea capitis. ²¹ If the safety and effectiveness of terbinafine and itraconazole are established over the longer courses needed to treat nail infections, they may become potent first-line therapies for onychomycosis in children.

Terbinafine is probably first choice oral drug for fungal toenail infection

This is a plain English summary of an original research article

The oral antifungal drug terbinafine appears to be slightly better than alternative ‘azole’ drugs for treating fungal toenail infection. Fifty-eight percent of people had a normal nail appearance after a treatment course compared with 47% taking ‘azoles’. Both drug classes were more effective than placebo and had similar side effects.

Current guidelines recommend terbinafine or itraconazole as first-choice treatments, but consider terbinafine more effective. However, systematic reviews on the topic were outdated. This Cochrane review updates the evidence, pooling the findings from 43 trials comparing oral antifungals with each other or placebo.

The results support guidelines recommending terbinafine as the first choice for treatment unless contraindicated.

Antifungals are available in oral and topical forms (applied to the nail). Topical antifungals have long been thought less effective, but the review did not gather evidence to confirm this.

Why was this study needed?

Fungal nail infection is thought to affect somewhere between two and 14% of the adult population. It is most common in older people and those with diabetes.

Most cases of toenail infections (about 80%) are due to dermatophyte fungi such as Trichophyton; other fungi include Aspergillus, Scopulariopsis, Fusarium and Alternaria. Some are highly resistant to treatments.

Toenail infections have a low complication rate, but they may affect the function of the nail and quality of life. Topical treatments are commonly used, but they have a low success rate. The most common oral antifungal treatments are terbinafine and itraconazole (an azole drug). Drug treatment can be costly to the NHS as a standard course of oral treatment is three months, and it may take as long as six months to a year to treat infection successfully.

Though oral antifungal drugs are thought to be effective, systematic review evidence is outdated. The researchers wanted to perform an up-to-date review to find out which oral antifungal was most effective for toenail infections to help guide evidence-based treatment.

What did this study do?

This systematic review pooled 43 randomised controlled trials including 9,730 people and comparing oral antifungal treatment with another active treatment or placebo.

Seven trials compared terbinafine with placebo, nine compared itraconazole with placebo and 17 compared these two drugs with each other. Other studies assessed griseofulvin and other ‘azole’ drugs. Treatment duration ranged from four months to two years.

Lack of blinding of researchers and/or participants and potential for biased allocation to treatment group were common across studies. Over half the trials were published before the year 2000. Most were carried out in outpatient dermatology settings in Western countries, but only three were conducted in the UK. However, the evidence was assessed as high quality for most outcomes.

What did it find?

• Terbinafine was more effective than azoles. Forty-seven percent of people who took azoles were cured, based on normal nail appearance, compared with 58% who took terbinafine (relative risk [RR] 0.82, 95% confidence interval [CI] 0.72 to 0.95; 15 studies, 2,168 people). People taking azoles were similarly less likely to achieve a mycological cure as defined by negative results on microscopy or culture: 53% vs 68% with terbinafine (RR 0.77, 95% CI 0.68 to 0.88; 17 studies, 2,544 people). Adverse effects and recurrence rates were similar between the two drugs.
• In placebo comparisons, terbinafine was more effective. Forty-eight percent achieved a clinical cure compared with only 6% of the placebo group (RR 6. 00, 95% CI 3.96 to 9.08; 8 studies, 1,006 people). The mycological cure rate was 59% vs 17% with placebo (RR 4.53, 95% CI 2.47 to 8.33) though there was high variability between individual studies for this outcome. Gastrointestinal symptoms and respiratory infections were among side effects reported with terbinafine, but these were still not significantly more common than with placebo.
• Azoles were also more effective than placebo with 31% achieving a clinical cure vs 14% in the placebo group (RR 22.18, 95% CI 12.63 to 38.95; 9 studies, 3,440 people). They were also more likely to achieve mycological cure (35% vs 7%; RR 5.86, 95% CI 3.23 to 10.62), but as with terbinafine, there was high variability between studies for this outcome.
• There was low-quality evidence that griseofulvin was less effective than terbinafine regarding clinical cure (RR 0.32, 95% CI 0.14 to 0.72; four studies, 270 people) and mycological cure (RR 0.64, 95% CI 0.46 to 0.90; five studies, 465 people). There was no statistically significant difference in the likelihood of achieving clinical or mycological cure with griseofulvin compared with an azole.
• There was very low-quality evidence from a single study (176 people) that the combination of terbinafine plus an azole was more effective than terbinafine alone (clinical cure: RR 1.41, 95% CI 1.01 to 1.97; mycological cure: RR 1.41, 95% CI 1.08 to 1.83).

What does current guidance say on this issue?

The British Association of Dermatologists (2014) suggests either terbinafine or itraconazole as first options for the treatment of fungal nail infection in both adults and children. However, they say that unless there are contraindications terbinafine is preferred based on its higher efficacy and tolerability.

Griseofulvin has lower efficacy, higher relapse rates and more side effects than terbinafine or itraconazole but remains an option if these drugs are ineffective or not tolerated.

What are the implications?

These results support guideline recommendations that terbinafine is the most effective oral drug and should be considered the first-choice in fungal nail infection.

Topical treatments may still be in widespread use, particularly when purchased over-the-counter. This study was not able to assess or confirm their comparative lack of efficacy when compared with oral treatment.

Nail infection may recur after stopping treatment, so prevention is important. Healthcare professionals should advise people to wear protective shoes in public changing rooms (e.g. swimming pools or gyms), keep their nails short, avoid sharing nail clippers and wear shoes that fit properly.

Citation and Funding

Kreijkamp-Kaspers S, Hawke K, Guo L, et al. Oral antifungal medication for toenail onychomycosis. Cochrane Database Syst Rev. 2017;(7): CD010031.

Cochrane UK and the Cochrane Skin Group are supported by the National Institute for Health research via Cochrane Infrastructure funding.

Bibliography

Ameen M, Lear JT, Madan V, et al. British Association of Dermatologists’ guidelines for the management of onychomycosis 2014. Br J Dermatol. 2014;171(5):937-58.

NHS Choices. Fungal nail infections. London: Department of Health; 2015.

Produced by the University of Southampton and Bazian on behalf of NIHR through the NIHR Dissemination Centre

What helps, side effects, composition, indications

THERE ARE CONTRAINDICATIONS. POSSIBLE SIDE EFFECTS. A SPECIALIST’S CONSULTATION IS REQUIRED. Fungus Skin fungus

Author of the article

Podoinitsyna Alena Andreevna,

Diploma of pharmaceutical education: 105924 3510722 reg. number 31917

All authors

Contents of the article

• Terbinafine: composition
• Terbinafine cream: what helps
• Terbinafine ointment or cream: which is better
• Terbinafine: side effects
• Terbinafine vs. Itraconazole: which is better
• Lamisil vs. Terbinafine: what’s the difference
• Terbinafine vs. Clotrimazole: which is better
• Summary
• Ask an expert y on the topic of the article

Feet and interdigital space – an ideal place for the growth and development of fungal cells. An unpleasant smell, coarsening and discoloration of the skin, as well as thinning of the nails and the appearance of cracks are manifestations of mycosis or foot fungus. Especially “contagious” are warm rooms with high humidity: swimming pools and water parks. For this reason, the disease is commonly called “athlete’s foot”, since the fungus is more common in athletes attending public showers.

The pharmacist will tell you about the antifungal drug Terbinafine: introduce you to its composition, indications for use and side effects, and compare it with analogues.

Terbinafine: Composition

Terbinafine is an antifungal drug with the same active ingredient. It is produced by a large number of pharmaceutical companies under various trade names: Terbinafine Canon, Lamifungin, Exiter, Lamisil and others. The drug is available in several dosage forms:

• Terbinafine oral tablets
• Terbinafine topical cream and gel
• Terbinafine topical spray
• Terbinafine film-forming solution for surface application

The composition of the excipients depends on the form of release and the manufacturing company. The full list can be found in the instructions for the medicine or on the website of the state register of medicines.

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Terbinafine cream: what helps

Each dosage form of Terbinafine has specific application, so it is recommended to consult a doctor to make the right choice. So, tablets from the fungus Terbinafine are indicated for lesions of the feet, scalp and skin infections in severe moderate and severe cases. For example, it is sometimes advisable to prescribe Terbinafine tablets for thrush that is not amenable to other methods of treatment.

Perhaps the most popular type of Terbinafine for fungus is a cream. The external form of the drug is used to prevent and treat fungal infections of the skin, accompanied by itching, peeling, keratinization, cracks and other symptoms. In addition, the effectiveness of Terbinafine cream against lichen has been confirmed.

Terbinafine ointment or cream: which is better

A common request from patients: Terbinafine ointment, but this drug is not registered in Russia. However, there are other types of Terbinafine for external use, which have already been discussed above:

• The cream is light in texture, due to which it is quickly absorbed and applied up to 2 times a day for 1-2 weeks. It is prescribed for the treatment of fungus in children from the age of 12;
• The gel penetrates into the deeper layers of the skin, and therefore is applied once a day for a week. Contraindicated for use in children;
• The spray is easy to apply due to the functional bottle. Applies exclusively to adults;
• The film-forming solution is recommended to be used once for foot fungus. Appointed from the age of 15.

Terbinafine side effects

Each formulation of Terbinafine has its own side effects. The most severe are observed in tablets, in connection with which they are released only by prescription. Terbinafine cream may also cause adverse effects, which include:

• Skin rash
• Eye irritation
• Skin peeling and damage
• Pigmentation disorders
• Pain and irritation at the site of application

Terbinafine or Itraconazole: which is better

Itraconazole is an antifungal drug in the form of capsules and oral solution. Unlike Terbinafine, Intraconazole:

• Not available in topical form;
• Wider range of applications. For example, Itraconazole is used to treat tropical fungal infections and fungal infections of the oral mucosa;
• Itraconazole is incompatible with a significant number of drugs;
• Itraconazole can be considered a safer drug because it causes fewer adverse reactions.

For the treatment of external manifestations of the fungus, one option is Terbinafine. Dosage forms for oral administration are prescribed by the doctor based on the diagnosis and the individual characteristics of the patient.

Lamisil and Terbinafine: what is the difference

Lamisil is a medicine with Terbinafine as the active ingredient. The manufacturers of Lamisil (Terbinafine) include several countries: Russia, France, Germany and Switzerland.

Lamisil and Terbinafine are direct analogues available in identical forms and dosages. For this reason, it is impossible to say unequivocally which is better: Lamisil or Terbinafine. When choosing a drug for external use, it is recommended to be guided by doctor’s prescriptions, personal preferences or affordability.

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Terbinafine or Clotrimazole: which is better

Clotrimazole is another representative of antifungal drugs. Available in the form of a cream, ointment, solution and powder for external use, as well as vaginal tablets and cream. The drugs differ according to the following criteria:

• Clotrimazole is not manufactured in oral dosage forms, and therefore is not suitable for the treatment of severe fungal infections and systemic manifestations;
• Clotrimazole is used against more fungi and is also antimicrobial against some bacteria;
• Clotrimazole is indicated for more diseases. For example, the drug is prescribed for fungal infections of the outer ear;
• In the treatment of dermatomycosis of the trunk and feet, the course of treatment with Terbinafine is 7 days, with Clotrimazole for at least a month;
• Clotrimazole vaginal tablets are effective against genital infections and are also used to sanitize the birth canal before childbirth.

Based on the above, Terbinafine more effectively copes with foot and trunk fungi, and is also indicated when systemic action is required. Clotrimazole is effective in genital fungal diseases. Before use, it is recommended to consult a doctor.

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Summary

• Terbinafine is an antifungal drug with the same active ingredient.
• Each dosage form of Terbinafine has its own characteristics of use, so it is recommended to consult a doctor for the correct choice.
• A common request from patients: Terbinafine ointment, however, this medicinal product is not registered in Russia.
• Itraconazole is an antifungal drug in the form of capsules and oral solution.
• Lamisil is a drug with Terbinafine as an active ingredient.
• Clotrimazole vaginal tablets are indicated for genital fungal infections.

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Onychomycosis treatment program for adults | Potekaev N.S.

For fungal infections of the skin and its appendages, griseofulvin, fluconazole, itraconazole and terbinafine (Lamisil) are currently used mainly. Of these, terbinafine (Lamisil®) is the most effective in the treatment of onychomycosis. To confirm this point of view, it suffices to refer to an extensive review published last year by American authors [1]. The authors of the 26-page journal review summarized and analyzed 176 studies, including multicenter and multinational studies with long-term follow-up. In particular, in the L.I.ON. [2] (Lamisil vs Itraconazole in Onychomycosis) demonstrated that in patients with onychomycosis of the feet, after 72 weeks of long-term follow-up, mycological cure rates (76% vs. 38% of patients after 12 weeks of treatment; 81% vs. 49% of patients after 16 weeks of therapy) and complete cure rates were about twice as high after treatment with terbinafine (Lamisil®) than after treatment with itraconazole (3 or 4 cycles of 400 mg/day for 1 week every 4 weeks). In addition, an extended Icelandic study conducted as part of L.I.ON. (L.I.ON. Icelandic Extension study – L.I.ON. I.E.S.) [3] demonstrated that treatment with terbinafine (Lamisil®) was clinically more effective, with a statistically significant difference, than an intermittent course of itraconazole after 5 years of long-term follow-up. Terbinafine (Lamisil®) showed higher complete (35% vs. 14%), mycological (46% vs. 13%) and clinical (42% vs. 18%) cure rates compared to itraconazole. Mycological and clinical recurrence rates were 23% and 21% in the terbinafine (Lamisil®) group compared with 53% and 48% in the itraconazole group, respectively. The review authors came to the following conclusions:

• Terbinafine has a pronounced fungicidal effect against dermatophytes and an inconsistent effect against yeast and non-dermatophyte molds in vitro.
• After systemic use, terbinafine is rapidly absorbed into body tissues, including the poorly perfused nail bed.
• Accumulation of terbinafine in the nails occurs as early as 1 week after the start of therapy and persists for at least 30 weeks after the end of therapy.
• Systemic terbinafine (Lamisil) 250 mg daily for 12 or 16 weeks is more effective than itraconazole, fluconazole, and griseofulvin in the treatment of dermatophytic onychomycosis.
• Mycological cure is noted in 80% after the end of Lamisil and increases in the post-therapeutic period, reaching 94% after 6 months. A similar increase with itraconazole was not detected. The optimal clinical effect appears a few months after the completion of treatment with Lamisil and corresponds to the time required for a complete renewal of the nail.
Terbinafine is well tolerated. According to the generalized data, side effects and complications do not exceed 5%. They are reversible and are related mainly to the gastrointestinal tract: taste disturbance, anorexia, a feeling of fullness in the stomach, nausea, slight abdominal pain, dyspepsia, diarrhea, transient increase in liver enzymes. Rarely detected skin manifestations are usually reduced to urticaria, much less often – to squamous-erythematous, eczema-like and acneiform rashes. Terbinafine has a low potential for drug interactions.
In conclusion, the review authors state that terbinafine (Lamisil) is the drug of choice in the treatment of dermatophytic onychomycosis.
To this statement, it should be added that it is now generally accepted that Lamisil in dermatophyte onychomycosis is the “gold standard” of treatment.
High therapeutic activity of Lamisil in onychomycosis is noted by T. Fitzpatrick et al. [4] in the “Atlas-reference book”, translated into Russian in 1999. They achieved an 80% mycological cure with Lamisil 250 mg daily for 12 weeks. The well-known English mycologist Roberts [5] obtained the same results.
The high therapeutic efficacy of Lamisil in onychomycosis has been shown by Russian researchers. Their results are summarized in the monograph “Lamisil: 10 years in Russia” [6]. They are presented in the form of diagrams (Fig. 1).
Thus, the continuous use of Lamisil in dermatophytic onychomycosis is significantly more effective than treatment with griseofulvin, fluconazole and itraconazole, including pulse therapy with the latter. Failures and relapses in pulse therapy with itraconazole are especially frequent in total and proximal onychomycosis. They reach, as Andre J. Havu testifies, 36 and 32% [7].
It is well known that 1 week after discontinuation of itraconazole, its plasma concentration decreases to an undetectable level. Therefore, during pulse therapy the last two weeks of each month of treatment, itraconazole in plasma is not determined (Fig. 2).
At the same time, our research with pathomorphologist professor Yu.G. Parkhomenko [8] revealed that in total onychomycosis, pathogenic fungi from the nail plate penetrate into the epidermis of the nail bed (Fig. 3), and then into its connective tissue (Fig. 4). In one of our studies, pathogenic fungi were found even in the medullary canal of the first toe (Fig. 5).
Consequently, with total and proximal onychomycosis, pathogenic fungi in the second half of each cycle of pulse therapy remain without the effect of itraconazole. This circumstance is the reason for the failures and relapses identified by Andre J. Havu [7].
Dermatophyte onychomycosis, the drug of choice for which, as already noted, Lamisil, is the vast majority in the spectrum of onychomycosis – from 80 to 90 percent [9,10]. The proportion of candidiasis and mold onychomycosis is small. Lamisil and with them gives a positive result; its activity in vivo is higher than activity in vitro. Increasingly, mixed onychomycosis occurs, especially in old age, usually due to the addition of mold fungi. Nails become dark brown in color. At the same time, yeast-like and mold fungi do not play a causal role, but act as commensals.
The effectiveness of Lamisil in mixed onychomycosis is also very high. According to Australian researchers, it reaches 94% [11].
One of the reasons for the failure of the treatment of onychomycosis with Lamisil, according to Roberts, should be the formation of a mycotic formation (dermatophytoma) in the thickness of the nail plate, which is inaccessible to the action of an antimycotic agent [3]. This opinion was confirmed in our pathological studies of onychomycosis [6].
Summarizing the literature data and our ten years of experience, we propose the following program for the treatment of adult onychomycosis.
According to our observations, treatment with Lamisil can be carried out not only at a young and mature age, but also in the elderly, and even in a centenarian [12]. During pregnancy, treatment with Lamisil should be postponed until the end of pregnancy. During lactation, Lamisil should also be avoided, as the drug can be excreted in breast milk.
The diagnosis of onychomycosis must be reliable, because, as is quite clear, only with the mycotic nature of the lesion can Lamisil have a therapeutic effect. The drug should not be prescribed without laboratory confirmation of this nature. For this purpose, they resort to microscopy of pathological material and to the isolation of a culture of the fungus. Microscopically, it is possible to identify the mycelium of pathogenic fungi, and culturally – to determine their type. In everyday practice, it is quite enough for a doctor to recognize onychomycosis and control its treatment with microscopy with 20% KOH. This method is simple and more reliable than culture: according to Scher, when sowing nail material that is known to be infected with dermatophytes, negative results are possible up to 30%. One of the reasons for such failures is that easily accessible fungi in the distal areas of the affected nail are no longer viable.
Before you start taking Lamisil inside, you must carefully collect and analyze an allergic history regarding drug and alimentary tolerance. If, at the same time, drugs or foods that cause any manifestations of intolerance are identified, then, of course, it is necessary to exclude their intake.
It is recommended to perform a clinical (hemogram) and biochemical blood test (determine the level of transaminases). With an increased level of transaminases, the decision to prescribe Lamisil is made individually, taking into account other indicators – the state of the liver, alcohol consumption, the patient’s age and other characteristics. In the case of treatment with Lamisil against the background of an elevated level of transaminases, you should especially warn about the need to immediately inform the doctor about persistent nausea, pain in the right epigastric region, icteric staining of the skin or mucous membranes, dark urine, light stools. Repeat clinical and biochemical blood tests.
In order to prevent side effects of the gastrointestinal tract, foods that cause flatulence (black bread, legumes, milk, cabbage, fizzy drinks) should be excluded from the diet.
It is recommended to limit the use of other medicinal products during systemic treatment with Lamisil, as manifestations of possible intolerance to them may be attributed to Lamisil. Of course, this restriction does not apply to essential medicines.
It is advisable for elderly patients to prescribe pentoxifylline or another drug that improves peripheral circulation, which will facilitate the penetration of Lamisil into the affected nails.
Prescribe Lamisil 250 mg per day for onychomycosis of the feet – 12 weeks, hands – 6 weeks.
The patient is examined every 2 weeks. With itching, yellowness of the skin, oral mucosa and sclera, as well as with a progressive rash, Lamisil should be stopped and a biochemical blood test should be performed.
After the end of treatment – control microscopy; with a positive result, continue treatment with Lamisil for another 4 weeks, followed by microscopy.
In case of positive microscopy, we recommend not to treat, and after 6 months to do a second microscopic control. If it is positive, the affected nails should be removed (surgically or by filing) and the course of Lamisil should be repeated. The patient is advised to choose comfortable shoes.
By adhering to the proposed therapeutic program, it is possible to achieve 100% mycological and clinical cure of onychomycosis.

Literature
1. Darkes Malcolm J.M., Scott Leslei J. Joa Kazen L. Terbinafine: a review of its use in onichomycosisen adults. American Journal of Clinical Dermatology. 2003$ 4(1): 693–719.
2. Evans EG. Double blind, randomized study of continuous terbinafine compared with intermittent itraconazole in treatment of toenail onychomycosis. Br.Med.J. 1999; 318:1031–1035.
3. Sigurgeirsson B, Olafsson JH, Steinsson J, et al. Long-term effectiveness of treatment with terbinafine vs itraconazole in onychomycosis: a 5-year blinded prospective follow-up study. Arch Dermatol 2002; 138:353–7.
4. Fitzpatrick T, Johnson R, Wolf K et al. Dermatology. Atlas-reference book, p. 725.
5. Roberts D.T. The clinical efficacy of terbinafine in the treatment of fungal infection of the nails ‘Reviews in Contemporasy Pharmaco–therapy’1997; 8, LAS 787: 299–312.
6. N. S. Potekaev, N. N. Potekaev, and V. M. Rukavishnikova, Acoust. Lamisil: 10 years in Russia. 2003. 96 p.
7. Havu Andre J. V European experience with itraconazole puls therapy in the treatment of toenail onychomycosis. Proceedings of the II International Symposium on Onychomycosis, Florence, 1995: 22–25.