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      Fungal Nail Infections (Onychomycosis): A Never-Ending Story?

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      PLoS Pathogens

      Public Library of Science

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          Abstract

          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). 10.1371/journal.ppat.1004105.g002 Figure 2 Distal subungual onychomycosis of the great toenail. 10.1371/journal.ppat.1004105.t001 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.

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          Most cited references 37

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          A large-scale North American study of fungal isolates from nails: the frequency of onychomycosis, fungal distribution, and antifungal susceptibility patterns.

          Onychomycosis, a fungal infection of the nail bed, is responsible for up to 50% of nail disorders. Although several surveys have been conducted in different parts of the world, there have been no multicenter epidemiologic surveys of onychomycosis in North America. A 12-center study was undertaken to (1) determine the frequency of onychomycosis, (2) identify organisms recovered from the nails, and (3) determine the antifungal susceptibility of isolates. A total of 1832 subjects participated in this study and completed a comprehensive questionnaire, and nail clippings were collected for potassium hydroxide examination and culturing. The frequency of onychomycosis, as defined by the presence of septate hyphae on direct microscopy and/or the recovery of a dermatophyte, was found to be 13.8%. In general, the dermatophyte isolates were susceptible to the antifungals tested. Because of the limited number of large-scale studies, the baseline incidence is not firmly established. However, the higher frequency of onychomycosis in this study may confirm the suspected increase in incidence of disease in North America.
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            Prevalence and epidemiology of onychomycosis in patients visiting physicians' offices: a multicenter canadian survey of 15,000 patients.

            A prospective, multicenter study to determine the epidemiology of onychomycosis was performed in the offices of 3 dermatologists and 1 family physician in Ontario, Canada. In the sample of 15,000 patients, abnormal-appearing nails were observed in 2505 persons (16. 7%). There were 1199 patients (8%) with toenail or fingernail onychomycosis confirmed on mycologic examination, with 1137 patients (7.6%) who had only pedal onychomycosis, 40 patients with toenail and fingernail onychomycosis (0.27%), and 22 patients (0.15%) with only fingernail onychomycosis. The condition was more common in male patients (P or =75% nail involvement) in 27.6%, 39.9%, and 32.5% of patients, respectively. After adjusting for the age and sex distribution of the general population, the projected rate of onychomycosis in Canada is 6.5% (95% confidence interval [CI], 6. 1%-6.9%). The organisms causing toenail onychomycosis were 90.5% dermatophyte, 7.8% nondermatophyte molds, and 1.7% Candida spp. The corresponding organisms causing fingernail onychomycosis were 70.8%, 0%, and 29.2%, respectively. In a large sample of 15,000 patients, abnormal-appearing nails were present in 17% of the sample with mycologic evidence of toenail or fingernail onychomycosis in 8%. The projected prevalence of onychomycosis in Canada is 6.5% (95% CI, 6. 1%-6.9%).
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              Ecology and epidemiology of dermatophyte infections.

               Raza Aly (1994)
              Our knowledge of ecology and epidemiology of dermatophytes and the factors influencing their transmission has helped us understand better the natural history of dermatophytoses. It seems that the anthropophilic agents of scalp infection are being eradicated in developing nations. The exception is Trichophyton tonsurans-related tinea capitis in North America. Microsporum canis is a prevalent agent of tinea capitis in many regions of the world, and this could be related to close association of humans with their pets. Trichophyton violaceum is endemic in certain parts of Eastern Europe, Africa, Asia, and South America but not in North America. Trichophyton rubrum is the most common cause worldwide of tinea pedis, nail infection, tinea cruris, and tinea corporis. Although the incidence of tinea capitis is declining in developed nations, tinea pedis and onychomycosis are becoming more common. The increased use of athletic shoes both by men and women and communal bathing could be contributing factors. Five or six species account for most dermatophytoses globally.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS Pathog
                PLoS Pathog
                plos
                plospath
                PLoS Pathogens
                Public Library of Science (San Francisco, USA )
                1553-7366
                1553-7374
                June 2014
                5 June 2014
                : 10
                : 6
                Affiliations
                Center for Medical Mycology, University Hospitals of Cleveland, Cleveland, Ohio, United States of America
                The University of North Carolina at Chapel Hill, United States of America
                Author notes

                The authors have declared that no competing interests exist.

                Article
                PPATHOGENS-D-13-02833
                10.1371/journal.ppat.1004105
                4047123
                24901242

                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.

                Page count
                Pages: 5
                Funding
                The authors have received no specific funding for this work.
                Categories
                Pearls
                Medicine and Health Sciences
                Dermatology
                Hair and Nail Diseases

                Infectious disease & Microbiology

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