November 2014

Onychomycosis remains a major clinical challenge

11onychomycosis-fig1

Figure 1. This patient had onychomycosis for about 20 years, involving all the nails and the entirety of each nail, and extending to the back of each nail. (All images cour- tesy of Shari Lipner, MD, PhD.)

Despite the ongoing development of new treatments, onychomycosis is still an extremely recalcitrant disease with high rates of relapse and reinfection, and the associated physical and cosmetic implications can negatively affect patients’ quality of life and self esteem.

By Greg Gargiulo

Onychomycosis is a general term used to describe fungal infections of the nail unit, which includes the nail plate, nail bed, and periungual tissue.1,2 Usually caused by dermatophyte fungi, onychomycosis is the most common condition affecting the nails, accounting for 50% of all nail disorders and 33.3% of all mycotic infections of the skin.1-5

The prevalence of onychomycosis varies drastically throughout the world; occurrence rates have been reported as high as 23% in Europe and up to 14% in the US.1 It can occur in either fingernails or toenails—or sometimes both, often from spreading—but occurs more frequently in toenails due to their slower growth rate.6,7

Despite its prevalence, onychomycosis remains a major clinical challenge for dermatologists, podiatrists, and other healthcare professionals.3 This is primarily due to the overall ineffectiveness of available treatments—which include topical and oral medi­cations and laser therapy8-10—and the fact that onychomycosis is an extremely recalcitrant disease with high rates of relapse and reinfection.11,12

In addition, though onychomycosis is a relatively minor, nonthreatening condition, many patients experience negative social or emotional effects and a reduced quality of life (QoL) due to the aesthetic appearance of affected toenails.13,14

“It’s not a major public health issue, and I don’t think much attention is focused on it, but it’s still an important condition that’s very difficult to fix and therefore should not be taken lightly,” said Ella Toombs, MD, a dermatologist at Aesthetic Dermatology of Dupont Circle in Washington, DC.

Background

Up to 90% of onychomycosis cases in the US are caused by the dermatophytes Trichophyton rubrum or Trichophyton menta­grophytes, though yeasts and nondermatophyte molds can also be responsible.1 Often, patients with onychomycosis also have concurrent tinea pedis (athlete’s foot) since both are caused by T. rubrum.15,16

Advanced age is the greatest predisposing risk factor for the development of onychomycosis, as approximately 50% of the population older than 70 years has it.17,18 Reports have also shown that men are up to three times more likely to have onychomycosis than women, though it’s unclear why this discrepancy exists.17

According to Shari Lipner, MD, PhD, a dermatologist and assistant professor at Weill Cornell Medical Center in New York City, the gender difference may be related in part to the ability to cover it up.

“It’s probably fairly equal between men and women, but it’s a more common complaint in men because women have the advantage that they can camouflage the onychomychosis with manicures or nail polish, and it’s less obvious,” she said.

A number of other factors can increase the likelihood of incurring onychomycosis. Immunocompromised populations are at an especially elevated risk, as roughly 30% of patients with diabetes and 20% of HIV-positive patients have onychomycosis; other immunodeficiencies, poor peripheral circulation, nail trauma, obesity, and family history and genetics are all risk factors as well.3,19,20 Wearing occlusive footwear, perspiring heavily, and walking barefoot in public spaces are known environmental factors that can also increase the risk of infection.15

Onychomycosis usually affects one or two toenails and manifests with relatively minor symptoms like nail discoloration—often yellow-white, but it may also be orange or black—brittleness and thickening of the nail, and mild pain and discomfort.13 If the infection is left untreated, as it progresses, this pain and discomfort will increase and can lead to difficulty walking or performing daily activities. The risk of secondary infection also increases in neglected cases, especially in patients with impaired immunity, and it can spread to elsewhere in the body or to others.10,13

The physical and cosmetic implications of onychomycosis, however, don’t end there, as many patients also experience image and self-esteem issues, which can hinder QoL and lead to negative perceptions of those with the condition.8,13,21

“Onychomycosis is a disease that significantly impacts those with it, and a large percentage of patients have pain that affects their mobility—particularly elderly patients—which affects their quality of life,” said Mahmoud Ghannoum, PhD, director of the Center for Medical Mycology at University Hospitals in Cleveland, OH.

Patients with mild asymptomatic cases of onychomycosis generally don’t seek treatment until it has advanced to a more severe, sometimes debilitating, stage.22 When patients do present, an accurate diagnosis is critical, since other nail conditions like psoriasis and yellow nail syndrome can mimic onychomycosis.23

A fungal culture is regarded as the gold standard for diagnosing onychomycosis, but a positive microscopy test is also helpful to confirm the diagnosis.23,24 Clinicians should test for other fungal infections like tinea pedis, corporis, and cruris as well.23

Treatment options

Figure 2. This image shows a case of subungual hyperkeratosis, with debris under the nail. This nail is thicker than the one in Figure 1, so it may need to be debrided as well, as it’s difficult to deliver topical medication when the nail is this thick. Scales are also visible along the foot, meaning the patient also has tinea pedis around the toes. The two conditions will need to be treated together.

Figure 2. This image shows a case of subungual hyperkeratosis, with debris under the nail. This nail is thicker than the one in Figure 1, so it may need to be debrided as well, as it’s difficult to deliver topical medication when the nail is this thick. Scales are also visible along the foot, meaning the patient also has tinea pedis around the toes. The two conditions will need to be treated together.

Once onychomycosis has been diagnosed, most clinicians then offer patients treatment options focused on the overall goal of eliminating the fungus if possible and restoring the nail to its normal state when it grows out.15 The two main courses of action are usually topical or oral antifungal agents but, in some cases, laser therapy and other alternatives may be offered as well.8,22,25

“Given a diagnosis, I generally explain to patients that they have three options to treat the fungus: topicals, orals, and lasers, and I do a risk-benefit analysis of the pros and cons of each treatment,” said Carolyn McAloon, DPM, a podiatrist at Bay Area Foot Care in Dublin, CA. “I want to make sure they’re informed in their decision, and then following that conversation we’ll decide which way we want to go.”

It’s particularly important for patients to be aware that treatments are often long term, and that it may be 12 to 18 months before the nails appear normal again.9

Oral treatment is currently regarded as the gold standard and the first line of therapy for onychomycosis. If, after discussion with a clinician, a patient decides to try topical therapy first but doesn’t respond well after six months, the patient may be switched to oral medication.8 Oral medications, however, have the potential to interact with other drugs or cause side effects such as hepatotoxicity, particularly in the elderly population and those with comorbid conditions.10,13,25

Figure 3. In this less extreme case, the nail is somewhat thickened, and the infection doesn’t extend all the way back to the nail matrix.

Figure 3. In this less extreme case, the nail is somewhat thickened, and the infection doesn’t extend all the way back to the nail matrix.

Currently, terbinafine is the most frequently prescribed and efficacious oral antifungal used for onychomycosis in patients without contraindications.8,23,26 Terbinafine is usually taken as a 250-mg daily dose for 12 to 16 weeks and is generally well tolerated; however, those with hepatic dysfunction should avoid its use since it may cause further liver problems.8,23

One meta-analysis of oral monotherapies found the mean rate of mycological cure (clearance of the nail based on negative mycological test findings) among 18 studies was 76% at nine to 18 months with terbinafine.27 Another study reported a complete cure rate (when the nail is free from fungus and appears normal) of 38%.28

The only other oral medication approved by the US Food and Drug Administration (FDA) for onychomycosis is itraconazole, which is usually offered as a 200-mg pill and may be dosed daily or as a pulse regimen.9,23 Itraconazole has broader coverage than terbina­fine for Candida and nondermatophytes, but its effectiveness is lower, at 54% and 14% for mycological and complete cure rates, respectively. It also has been associated with multiple drug-drug interactions and is contraindicated for patients with ventricular dysfunction.23

“I only use terbinafine these days,” McAloon said. “I haven’t used itraconazole in years. Given their profiles of efficacy and safety, my experience is that terbinafine should definitely be the standard.”

Topical medications—which come in ointments, creams, and lacquers—present other challenges, since to be effective, they need to penetrate the nail plate and reach the nail bed in sufficient quantities.9,29 For this reason, they are generally less effective than oral treatment, but may be preferred in mild cases of onychomycosis or for patients at risk of side effects from oral medications.23

Figure 4. In this case, the nail is not extremely thick and the extent of the infection is not severe. However, it does extend to the matrix, includes nail dystrophy, and the nail is split down the middle, which will complicate topical treatment.

Figure 4. In this case, the nail is not extremely thick and the extent of the infection is not severe. However, it does extend to the matrix, includes nail dystrophy, and the nail is split down the middle, which will complicate topical treatment.

Until the summer of 2014, the only FDA-approved topical agent for onychomycosis was ciclopirox 8%.30 The nail lacquer, which is applied once daily for 48 weeks, has been associated with a mycological cure rate of 36% and complete cure rate of 8.5% with monthly nail debridement to increase penetration.31

The FDA approved efinaconazole 10% liquid solution for the treatment of onychomycosis in June.30 In recent clinical trials, efinaconazole showed a mycological cure rate of up to 53.4% and a complete cure rate as high as 17.8%.23 Efinaconazole also has a minimal side-effect profile and does not require debridement.22

One month later, the FDA approved tavaborole 5% liquid solution for treatment of onychomycosis based on clinical trials results that have not yet been published.32 In two trials of 1194 patients, complete cure rates were 6.5% in the first trial and 9.1% in the second; mycological cure rates were 31.1% and 35.9%, respectively. According to Del Rosso, only with further trials and the introduction of these two new drugs to the market will their overall effectiveness become more clearly understood.30

“Recent articles have shown efinaconazole to have a clinical success rate that’s much higher than the previous topicals,” McAloon said. “So I’m cautiously optimistic that those who choose this drug will have greater success and that the medications will be more effective than what we had previously.”

Figure 5. Both of these cases are much less severe than those in Figures 1-4. Each patient had onychomycosis for about one year. Both will likely respond to oral medications and possibly topicals.

Figure 5. Both of these cases are much less severe than those in Figures 1-4. Each patient had onychomycosis for about one year. Both will likely respond to oral medications and possibly topicals.

Luliconazole is another topical antifungal agent under development. It has a low binding affinity for keratin, allowing it to be released more readily from the nail plate matrix than other topicals before crossing into the nail bed. It has demonstrated potent and broad-spectrum activity against dermatophytes and has been reported to be safe and well tolerated, but is still being tested in clinical trials.33

Regardless of a whether a patient decides to go with an oral or topical approach, compliance is an important determinant of outcomes,3 particularly due to the long course of treatment with topicals and the high rate of recurrence for onychomycosis, which can be up to 25%.34 Over time, the repeated application of a medication and the discouraging effect of a relapse can negatively affect compliance.

The promise of lasers

Given the potential for side effects of oral therapy and the overall lack of effectiveness coupled with the compliance challenges of topicals, the search for a safe, noninvasive, and effective alternative has led to recent interest in lasers and other light-based treatments.10

Podiatrists have been using lasers in clinical practice since the 1980s, but they were first introduced for the treatment of onychomycosis in 2009. Unfortunately, since then, evidence has not yet met expectations.35

Five lasers are currently FDA-approved for treating onychomycosis, four of which use a 1064-nm neodymium-doped yttrium aluminum garnet wavelength and deliver energy in a short pulse duration.10,36 The exact mechanism of action for lasers is still not understood completely, but it has been proposed that they penetrate the nail plate and reach a temperature that kills the fungus.36

Some studies have reported preliminary success with lasers, but their overall effectiveness is still far from confirmed.23,36 A recent systematic review on laser treatment evaluated 12 studies, two of which were randomized controlled trials (RCTs), and concluded that most available research is reported at a low level of evidence with small numbers of patients, and that results are predominantly conflicting with no clear evidence of efficacy.35

Other types of lasers and similar systems—such as photodynamic therapy, carbon dioxide, near-infrared diode, and femtosecond infrared lasers—are also being studied, but are not yet FDA-approved, and their effectiveness is not well established.9,22

The cost of laser therapy is also a major consideration for patients, since, according to McAloon, “Treatments run approximately one thousand dollars, and there’s no insurance coverage for lasers, so that’s completely out of pocket.”

Ivan Bristow, PhD, the program lead in podiatry at the University of Southampton in the UK, and author of the aforementioned systematic review,35 called for more randomized controlled trials of laser systems.

“These need to demonstrate efficacy against current treatments like topical and oral therapies, as well as longer follow-ups, to truly assess the effectiveness of the systems,” Bristow said. “Fungal nails grow more slowly than normal nails, so a follow-up period of 52 weeks is probably needed to give lasers a fair trial.”

Several other therapeutic avenues have the potential to expand and improve treatment options for onychomycosis.

Combination therapy has been associated with more rapid recovery, higher cure rates, and reduced duration of oral drug exposure compared with individual modalities.37 One RCT found improved mycological cure rates (88.2%) when adding ciclopirox to a terbinafine monotherapy regimen (64.7%).38 Two other studies, by Sanmano et al and Nakano et al, combined oral terbinafine with topical terbinafine and also found impressive outcomes, with complete cure rates of 65.2% and 77.3%, respectively.39,40

Defining a cure

Some have proposed an alternative approach to the very definition of “cure” for onychomycosis, as this is not always straightforward and may be open to interpretation.10,25 As defined earlier, a mycological cure is clearance of the nail based on negative mycological test findings (eg, microscopy, culture, Periodic Acid-Schiff stain), but this can be complicated when the results of different tests for a single patient are conflicting. In addition, a negative culture does not always equate to an improvement in the nail appearance (a clinical cure).35

Based on this, Ghannoum has suggested that the definition of onychomycosis cure be reassessed, along with other changes such as longer treatment periods and follow-ups to better evaluate the effectiveness of available management protocols.25,35,41

“We plan to keep refining and discussing these concepts with our colleagues,” Ghannoum said. “Importantly, once this is done we need to enter into discussions with the FDA to make inroads in
incorporating these ideas into clinical trials for approval of novel antifungals.”

But, according to Richard Scher, MD, a professor of dermatology at Weill Cornell Medical College in New York City who specializes in nail disorders, this process is still ongoing.

“Primary endpoints really have not changed, and the FDA has remained firm on that,” he said. “However, many companies are trying to add more lenient secondary endpoints, which would not affect the FDA approval, necessarily, and, if the FDA goes along with that, then they can use that as a marketing tool. We’re going to have to wait to see what happens.”

Greg Gargiulo is a freelance medical writer based in the San Francisco Bay Area.

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  40. Nakano N, Hiruma M, Shiraki Y, et al. Combination of pulse therapy with terbinafine tablets and topical terbinafine cream for the treatment of dermatophyte onychomycosis: a pilot study. J Dermatol 2006;33(11):753-758.
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