Pearls
`
`Fungal Nail Infections (Onychomycosis): A Never-Ending
`Story?
`
`Mahmoud Ghannoum*, Nancy Isham
`
`Center for Medical Mycology, University Hospitals of Cleveland, Cleveland, Ohio, United States of America
`
`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.
`
`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 onychomy-
`cosis 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 immuno-
`suppressed,
`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—onycho-
`mycosis, 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-dermato-
`phyte organisms, such as Fusarium, are especially difficult to treat
`[16].
`
`Why Don’t Topical Antifungals Work Better?
`
`such as
`Unfortunately, currently available topical agents,
`amorolfine 5% and ciclopirox 8%, have low efficacy (approxi-
`mately 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
`
`Citation: Ghannoum M, Isham N (2014) Fungal Nail Infections (Onychomycosis):
`A Never-Ending Story? PLoS Pathog 10(6): e1004105. doi:10.1371/journal.ppat.
`1004105
`
`Editor: William E. Goldman, The University of North Carolina at Chapel Hill,
`United States of America
`
`Published June 5, 2014
`Copyright: ß 2014 Ghannoum, Isham. This is an open-access article distributed
`under the terms of the Creative Commons Attribution License, which permits
`unrestricted use, distribution, and reproduction in any medium, provided the
`original author and source are credited.
`
`Funding: The authors have received no specific funding for this work.
`
`Competing Interests: The authors have declared that no competing interests
`exist.
`
`* E-mail: mahmoud.ghannoum@case.edu
`
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`Figure 1. Trichophytonrubrumcolony and microscopic appearance (40x).
`doi:10.1371/journal.ppat.1004105.g001
`
`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 terbina-
`
`lacquer [19]. Another technique to enhance the
`fine nail
`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
`
`Table 1. Most prevalent dermatophytosis in different regions worldwide.
`
`Dermatophytosis
`
`Causative Organism
`
`T. rubrum
`
`T. rubrum
`
`T. rubrum
`
`M. canis
`
`T. rubrum
`
`T. violaceum, M. audouinii
`
`T. rubrum
`
`T. rubrum
`
`T. rubrum, T. mentagrophytes
`
`T. rubrum, T. mentagrophytes
`
`Region
`
`North/South America
`
`Western Europe
`
`Russia
`
`Tinea pedis, onychomycosis
`
`Tinea pedis, onychomycosis
`
`Onychomycosis
`
`Mediterranean (Italy/Greece)
`
`Tinea corporis, tinea capitis
`
`Turkey
`
`North Africa/tropical Africa
`
`China/Japan
`
`India
`
`Asia
`
`Australia
`
`Tinea pedis
`
`Tinea corporis
`
`Tinea pedis, onychomycosis
`
`Tinea corporis
`
`Tinea pedis, onychomycosis
`
`Tinea pedis, onychomycosis
`
`*Data for this table was compiled from Havlickova et al. [1].
`doi:10.1371/journal.ppat.1004105.t001
`
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`Figure 2. Distal subungual onychomycosis of the great toenail.
`doi:10.1371/journal.ppat.1004105.g002
`
`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 onychomy-
`cosis 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 photo-
`therapy, which involves
`the
`irradiation of accumulated
`protoporphyrin within the fungal hyphae,
`leading to subse-
`quent hyphal cell damage [26]. The ability of iontophoresis, or
`(0.5 mA/cm2)
`the use of electric current
`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].
`
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`Table 2. Treatment of onychomycosis with antifungal agents.
`
`Agent
`
`Terbinafine
`
`Itraconazole
`
`Fluconazole
`
`Dose
`
`250 mg
`
`200 mg
`
`pulse therapy
`
`300–450 mg
`
`150–300 mg
`
`Duration
`
`Toenails: once per day for 12 weeks
`
`Fingernails: once per day for 6 weeks
`
`Toenails: once per day for 12 weeks
`
`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
`
`Toenails: once/week for 9–12 months
`
`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
`
`doi:10.1371/journal.ppat.1004105.t002
`
`Why Do Patients So Often Relapse?
`
`There are multiple factors that may contribute to the high rate
`fungal nail
`infection recurrence. Patients with a genetic
`of
`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
`
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`Even in cases where the infecting fungus has been entirely
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`after each wearing would be prudent. Thus, a patient not only
`needs to treat the infection but also break the cycle of re-infection.
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