Is Onychomycosis Still a Problem?
The great majority of superficial fungal infections are caused by dermatophytes, which
belong to one of three genera (Trichophyton, Epidermophyton, and Microsporum), with
T. rubrum being the most prominent cause of nail infection (Figure 1). Table 1 summarizes
the prevalence of various superficial fungal infections in different geographic areas
[1]. Among superficial fungal infections, by far the most difficult to cure is toenail
onychomycosis (Figure 2). The prevalence of onychomycosis has been reported to be
as high as 23% across Europe [2] and 20% in East Asia [3]. In North America, the incidence
of onychomycosis is up to 14% [4], with fungal infection responsible for 50% of all
nail disease [5]. With millions of dollars being spent annually on oral and topical
prescriptions, laser treatments, over-the-counter products, and home remedies, it
is obvious that people are still bothered by their fungal toenail infections and are
determined to get rid of them. Unfortunately, this is easier said than done. To successfully
cure toenail onychomycosis requires long treatment duration that may extend to a full
year. Even then, complete cure, defined as clinical cure (implying nail clearing)
plus mycological cure (both negative microscopy and dermatophyte culture), is often
unattainable.
10.1371/journal.ppat.1004105.g001
Figure 1
Trichophyton rubrum colony and microscopic appearance (40x).
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Figure 2
Distal subungual onychomycosis of the great toenail.
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Table 1
Most prevalent dermatophytosis in different regions worldwide.
Region
Dermatophytosis
Causative Organism
North/South America
Tinea pedis, onychomycosis
T. rubrum
Western Europe
Tinea pedis, onychomycosis
T. rubrum
Russia
Onychomycosis
T. rubrum
Mediterranean (Italy/Greece)
Tinea corporis, tinea capitis
M. canis
Turkey
Tinea pedis
T. rubrum
North Africa/tropical Africa
Tinea corporis
T. violaceum, M. audouinii
China/Japan
Tinea pedis, onychomycosis
T. rubrum
India
Tinea corporis
T. rubrum
Asia
Tinea pedis, onychomycosis
T. rubrum, T. mentagrophytes
Australia
Tinea pedis, onychomycosis
T. rubrum, T. mentagrophytes
*Data for this table was compiled from Havlickova et al. [1].
What Are the Risk Factors for Toenail Onychomycosis?
The most prevalent predisposing risk factor for developing onychomycosis is advanced
age, which is reported to be 18.2% in patients 60–79 years of age, compared to 0.7%
in patients younger than 19 years of age. Further, men are up to three times more
likely to have onychomycosis than women, though the reasons for this gender difference
are not clear [6]. Moreover, the low prevalence of infection in people whose spouses
have onychomycosis compared to the prevalence among their children suggests a genetic
risk factor [7]. Though extremely rare, one study reported four family members from
seven unrelated groups with a common genetic trait (autosomal recessive CARD9 deficiency)
who developed a dermatophyte infection of deep tissues that proved fatal [8].
Other risk factors include diabetes and conditions contributing to poor peripheral
circulation [9]. In fact, onychomycosis may represent an important predictor for the
development of diabetic foot syndrome and foot ulcers [10]. Patients who are immunosuppressed,
such as those with HIV infection and those undergoing cancer therapy, are also predisposed
to fungal nail infection [11]. There is at least one case report of a toenail infection
caused by Fusarium (a non-dermatophyte fungus) that developed into a fatal systemic
infection in a lymphoma patient following a bone marrow transplant [12].
Several nonclinical risk factors also affect a person's chance of developing fungal
nail infections. Toenail onychomycosis is not prevalent in tropical climates, presumably
because people in those areas are not in the habit of wearing occlusive footwear that
create a warm, moist environment for the proliferation of fungi. Further, the spread
of foot infections, including tinea pedis (athlete's foot), may occur in places such
as shower stalls, bathrooms, or locker rooms where floor surfaces often are wet and
people are barefoot [13]. Nail trauma will also increase the risk of fungal infection
of the affected nail, especially in the geriatric population [11].
A recent study by our group utilized regression analysis to show that history of tinea
pedis plus three clinical variables—onychomycosis, plantar scaling (a clinical sign
of tinea pedis), and nail discoloration (a clinical sign of onychomycosis and generally
indicative of severe nail infection) were statistically associated with spread of
infection in households with multiple infected members (P≤.044) [14].
How Is Onychomycosis Treated?
Treatment of onychomycosis includes chemical or surgical removal of the infected nail,
systemic or topical drugs, pulse therapy, or a combination thereof. Table 2 is a summary
of oral and topical therapy regimens; as can be seen, the course of treatment for
fingernail infections is shorter than for toenail infections. The treatment of onychomycosis
has improved considerably over the past several decades, following the introduction
of the oral antifungals terbinafine and itraconazole. However, these drugs may have
side effects such as liver damage or drug interactions, which are particularly relevant
in the elderly population [15]. Further, nail infections caused by non-dermatophyte
organisms, such as Fusarium, are especially difficult to treat [16].
10.1371/journal.ppat.1004105.t002
Table 2
Treatment of onychomycosis with antifungal agents.
Agent
Dose
Duration
Terbinafine
250 mg
Toenails: once per day for 12 weeks
Fingernails: once per day for 6 weeks
Itraconazole
200 mg
Toenails: once per day for 12 weeks
pulse therapy
Toenails: 200 mg twice per day for 1 week/no treatment for 3 weeks. Repeat for 3–4
months
Fingernails: 200 mg twice per day for 1 week/no treatment for 3 weeks. Repeat for
2 months
Fluconazole
300–450 mg
Toenails: once/week for 9–12 months
150–300 mg
Fingernails: once/week for 4–6 months
Ciclopirox nail lacquer
apply once per day
Remove lacquer once per week. Treat for up to 48 weeks
Amorolfine nail lacquer
apply once or twice a week
Remove lacquer before each new application. Toenails: 9–12 months. Fingernails: 6
months
Why Don't Topical Antifungals Work Better?
Unfortunately, currently available topical agents, such as amorolfine 5% and ciclopirox
8%, have low efficacy (approximately 5%–12%) [17], [18]. This low efficacy can mainly
be attributed to the inability of the drug to penetrate through the nail plate to
the nail bed where the infection resides [19]. Thickened nails, extensive involvement
of the entire nail, lateral disease, and yellow spikes contribute to a poor response
to topical treatment [11]. Figure 1 shows an example of distal subungual onychomycosis,
trimmed to demonstrate nail thickening.
Further complicating the scenario is the fact that certain antifungals will bind to
the nail plate and thus may not be available at the site of infection, which is the
nail bed. For example, terbinafine has been shown to accumulate rapidly in the nail,
reaching a maximum of 0.39 mg/g and persisting up to 2 months following the end of
treatment [20]. In this regard, Ryder et al. developed an in vitro nail model that
showed that the cidal action of terbinafine, when tested against an established dermatophyte
infection in the presence of human nail, was in fact less effective than in conventional
microdilution assays where no nail powder is present [21].
Many different approaches to solving the problem of nail penetration have been attempted
recently. For example, there have been attempts to develop penetration enhancers to
facilitate drug delivery through the nail plate, such as addition of dodecyl-2-N,N-dimethylaminopropionate
hydrochloride (DDAIP HCl, trade name NexACT-88; NexMed) to terbinafine nail lacquer
[19]. Another technique to enhance the penetration of nail lacquer was the incorporation
of terbinafine into transfersome lipid vesicles, which are highly deformable and thus
are able to pass through intercellular spaces [22]. Additionally, a novel small-molecule
oxaborole antifungal (AN2690) has recently been developed that is designed for greater
penetration through the nail plate [23]. However, to date, none of these topical products
has been commercialized.
In this regard, approval of topical onychomycosis drugs by regulatory agencies may
be negatively impacted by an overly stringent definition of complete cure, which includes
nail clearing plus mycological cure (negative microscopy and culture). Review of data
from several international clinical trials by Ghannoum et al. has suggested that reassessment
of the definition of onychomycosis cure is critical [24]. In these trials, a high
number of toenail samples collected from subjects at the end of clinical trials contained
visible fungal hyphae that subsequently failed to grow upon culture. However, current
technology does not differentiate between “live” and “dead” fungi, so even though
these samples had to be reported as microscopy-positive, the infection may in fact
have been cured. The authors propose that, for clinical trials of topical agents,
the length of treatment should be extended to 18 months, followed by a longer washout
period of 3–6 months before primary assessments to allow the removal of both residual
drug in the nail and nonviable fungal cells. Therefore, the absence of clinical signs
following an adequate wash out period, coupled with a negative culture, with or without
negative microscopy, should be considered the definition of onychomycosis cure. These
changes may enable more topical agents to be proven efficacious.
What's New in Onychomycosis Therapy?
Recent device-based therapies for onychomycosis include laser devices, photodynamic
therapy, iontophoresis, and ultrasound. Laser treatment has been approved for cosmetic
treatment only, but efficacy as a treatment to eradicate the fungal infection will
have to be determined by additional randomized controlled trials [25]. There have
been rare reports of onychomycosis cures following the use of phototherapy, which
involves the irradiation of accumulated protoporphyrin within the fungal hyphae, leading
to subsequent hyphal cell damage [26]. The ability of iontophoresis, or the use of
electric current (0.5 mA/cm2) to facilitate the passage of drug through the nail plate,
has been proven in studies with human cadaver nails, but relevant clinical studies
remain to be conducted [27]. Finally, though ultrasound therapy has preliminarily
demonstrated fungistatic activity against nail infections [28], the device itself
seems overly complicated, with ultrasound transducers and drug delivery compartments
needed above each toenail and the requirement for a computer software interface, making
it a physician-office–only treatment and likely very expensive [29].
Why Do Patients So Often Relapse?
There are multiple factors that may contribute to the high rate of fungal nail infection
recurrence. Patients with a genetic predisposition to onychomycosis, who are immunocompromised,
or who have diabetes, are likely to experience relapse and may never achieve a permanent
cure [11].
This may be due either to failure to eradicate the infecting fungus or to re-infection
with a new fungal strain following subsequent exposure. Arthroconidia, which are chains
of fungal conidia that are formed by breakage of the fungal hyphae, are considered
to be the primary means of nail invasion. These arthroconidia, which have thicker
cell walls than conidia formed in vitro, have been shown to be more resistant to antifungals
and, thus, may remain in the nail bed as a reservoir for recurrent disease [30]. However,
the incidence of innate resistance among dermatophytes is low. Our Center conducted
in vitro susceptibility testing of 140 sequential isolates from subjects who failed
treatment in an oral terbinafine clinical trial. In all cases, the minimum inhibitory
concentrations (MICs) of terbinafine against each patient set were identical or within
one tube dilution, implying no resistance development. The same results were obtained
within each set with fluconazole, itraconazole, and griseofulvin (with the exception
of one isolate having a 3-fold increase in the MIC). This further indicates that there
was no crossresistance between antifungal agents [31]. This study showed that failure
to cure the infected nails may be due to host/family factors.
Even in cases where the infecting fungus has been entirely eradicated by antifungal
therapy, patients remain at risk for re-infection. As mentioned above, people are
exposed to dermatophyte reservoirs in many of their day-to-day activities, including
trips to the gym and increased travel. Common sense measures, such as not walking
barefoot through public showers or hotel rooms, would help prevent unnecessary exposure.
That being said, one of the most common routes of infection is within households.
It has long been suspected that nail infections were spread by close contact with
family members. However, it wasn't until recently that our group was able to employ
molecular techniques to prove that persons within the same household were infected
by the same strain of T. rubrum
[14]. For those attempting to avoid re-infection, measures such as spraying their
shoes with a topical antifungal spray or treating them with a commercial ultraviolet
device [32] after each wearing would be prudent. Thus, a patient not only needs to
treat the infection but also break the cycle of re-infection.