J. Fungi 2015, 1, 173-184; doi:10.3390/jof1020173
`
`OPEN ACCESS
`
`
`
`Journal of Fungi
`ISSN 2309-608X
`www.mdpi.com/journal/jof
`
`Review
`The Dermatologist’s Approach to Onychomycosis
`
`Jenna N. Queller 1 and Neal Bhatia 2,*
`
`1 Dermatology Chief Resident at Harbor-UCLA Medical Center, Torrance, CA 90502, USA;
`E-Mail: Jenna.Queller@gmail.com
`2 Director of Clinical Dermatology, Therapeutics Clinical Research, San Diego, CA 92123, USA
`
`* Author to whom correspondence should be addressed; E-Mail: bhatiaharbor@gmail.com;
`Tel.: +1-858-571-6800.
`
`Academic Editor: Theodore Rosen
`
`Received: 24 June 2015 / Accepted: 5 August 2015 / Published: 19 August 2015
`
`
`Abstract: Onychomycosis is a fungal infection of the toenails or fingernails that can involve
`any component of the nail unit, including the matrix, bed, and plate. It is a common disorder
`that may be a reservoir for infection resulting in significant medical problems. Moreover,
`onychomycosis can have a substantial influence on one’s quality of life. An understanding
`of the disorder and updated management is important for all health care professionals. Aside
`from reducing quality of life, sequelae of the disease may include pain and disfigurement,
`possibly leading to more serious physical and occupational limitations. Dermatologists,
`Podiatrists, and other clinicians who treat onychomycosis are now entering a new era when
`considering treatment options—topical modalities are proving more effective than those of
`the past. The once sought after concept of viable, effective, well-tolerated, and still
`easy-to-use monotherapy alternatives to oral therapy treatments for onychomycosis is now
`within reach given recent study data. In addition, these therapies may also find a role in
`combination and maintenance therapy; in order to treat the entire disease the practitioner
`needs to optimize these topical agents as sustained therapy after initial clearance to reduce
`recurrence or re-infection given the nature of the disease.
`
`Keywords: onychomycosis; onycholysis; subungual hyperkeratosis; recurrence; maintenance
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`1. Introduction
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`The diagnosis and treatment of onychomycosis has entered a new era, which in some ways is trivial
`due to the ease of “detection” by way of the internet and media, patients can deduce the diagnosis before
`it has been clinically proven. Yet in the same breadth clinicians are encouraged since topical therapies
`which were once thought to be ineffective now have been proven more effective and safe in multiple
`clinical trials. As the mechanisms of therapy have become more elucidated, so has the success rate which
`encourages both practitioners and patients to adhere to therapy despite the time needed to achieve that
`once elusive clearance of disease. Moreover, as the mechanisms of therapy are better understood and
`consolidated into potential treatment regiments there will be more study data and clinical experience
`necessary to dictate the utility of combinations between topical therapies and systemic treatments, in
`addition to topical keratolytics, concomitant use of nail polish, and the optimization in patients with
`diabetes mellitus, peripheral vascular diseases, and other comorbities.
`Unfortunately, as medicine continues during the era of patients making diagnoses from the internet
`and the photos driven by the media direct to consumer advertising, the perception of onychomycosis as
`a disease that requires objective proof of diagnosis and aggressive therapies continues to be an obstacle
`for successful treatment. The presence of any nail discoloration or change in the integrity leads to
`a presumptive diagnosis of onychomycosis to the untrained eye (Table 1).
`
`Table 1. Mimickers of Onychomycosis.
`Mimickers of Onychomycosis Reference
`Psoriasis
`Lichen Planus
`Bacterial Infections
`Onychogryphosis
`Traumatic onychodystrophies
`Yellow Nail Syndrome
`Toenail Cellulitis
`Contact Dermatitis
`Nail-bed Tumors
`Onycholysis, nonspecific
`Pachyonychia Congenita
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`[1]
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`2. Terminology
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`The appropriate diagnostic terminology is necessary when documenting the clinical findings of
`onychomycosis, not only to convey the objective assessment, but also as a marker of therapeutic milestones
`for improvement. Charting of the presentation is often difficult when there is a history of trauma to the
`nails, the chronicity of disease has obscured normal markers, and other nail disorders are present. The
`correct application of diagnostic terminology will convey an accurate presentation. Onychomycosis is a
`fungal infection of the nail unit [1]. Subungual thickening or hyperkeratosis can occur under the nail
`plate, resulting in onycholysis or lifting of the nail bed. Onycholysis, specifically is the loss of plate-bed
`adhesion. Onycholysis does not by itself signify onychomycosis. It can be seen in many other diseases
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`such as psoriasis and lichen planus [1]. There are numerous potential causes such as irritants or trauma,
`infections (Candidiasis, Syphilis), and drug-induced cases, which often affect multiple nails [1].
`Onychomycosis more commonly involves the toenails [1]. It is caused by a variety of fungi including
`dermatophytes, non-dermatophyte molds, and Candida [2,3]. More specifically, there are five subtypes
`related to the method of fungal invasion of the nail unit, the most common being distal lateral subungual
`onychomycosis (DLSO) (Table 2) [4,5]. In DLSO, the fungus enters the distal lateral part of the nail
`bed, the region of the hyponychium, often as an extension of tinea pedis. Hyperkeratosis occurs under
`the nail plate, resulting in onycholysis, with subungual thickening. White superficial onychomycosis is
`less common than DLSO, accounting for about 10% of onychomycosis cases [6]. The superficial nail
`plate is usually involved initially; most commonly caused by Trichophyton mentagrophytes and several
`non-dermatophyte molds (such as Fusarium, Aspergillus, and Acremonium spp.) [7]. To the patient the
`nail feels coarse but may become soft and crumbly where the fungus has initiated the infection [8], and
`it can be scraped off easily with a scalpel [7]. Proximal subungual onychomycosis (PSO), a relatively
`uncommon subtype, occurs when the fungus invades under the cuticle or nail plate, and advances from
`the proximal to distal part of the nail [5]. Endonyx onychomycosis differs from DLSO because of the
`absence of nail-bed hyperkeratosis and onycholysis, and is usually caused by Trichophyton soudanense [7]
`(not found in the United States). Candida onychomycosis only affects immunosuppressed patients and
`the presentation involves the entire nail plate, often with paronychia [7].
`
`Table 2. Subtypes of Onychomycosis.
`Subtypes of Onychomycosis
`Reference
`Distal lateral subungual onychomycosis (DLSO)
`White superficial onychomycosis (WSO)
`Proximal subungual onychomycosis (PSO)
`Endonyx onychomycosis (EO)
`Candidal onychomycosis
`
`[1]
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`3. Prevalence and Risk Factors
`
`The prevalence of onychomycosis is increasing; according to studies over the last 20 years, it
`has increased from 2% to 14% [7], especially with a rise in men and the elderly [9,10], but is
`relatively uncommon in children [11]. Psoriasis is also a risk factor, particularly in dermatophyte
`onychomycosis [12]. A 27% prevalence of onychomycosis was reported in psoriatic patients when the
`toenail was clinically abnormal, and 13% onychomycosis was found in psoriatic patients overall [13].
`
`4. Diagnosis
`
`A definitive diagnosis of onychomycosis is made by the presence or absence of fungal elements using
`potassium hydroxide (KOH) preparation or a periodic acid-Schiff (PAS) stain, and identification of the
`fungi with a culture. Most experts perform a KOH and do a fungal culture. Many dermatologists use a
`PAS stain because it is less subjective to errors than fungal cultures; however it may be more expensive.
`Only about 50% of dystrophic nails are attributed to fungi, the rest are a feature of something else such
`as trauma, psoriasis, or onychogryphosis [7]. There are varying techniques when sampling the different
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`subtypes of onychomycosis. In DLSO, the specimen should be obtained from the nail bed by curettage
`to maximize the yield for study. Removing the onycholytic nail plate will yield a more useful sample at
`a site most proximal to the cuticle, since that is where the highest concentration of hyphae are located.
`In PSO, clinicians should pare down the overlying nail plate before sampling the ventral plate to obtain
`the optimal exposure. In WSO, a 15 blade is often used to effectively remove a specimen from the
`nail surface. In Candidal onychomycosis, specimens should be sampled from the most proximal and
`lateral edges.
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`5. Determining Severity and Outcomes
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`In 2011, Carney et al. proposed a classification system for grading the severity of onychomycosis [14].
`The authors’ goals were to establish an objective method for defining mild, moderate and severe
`onychomycosis using a numerical scoring system. This scoring classification accounts for the area of
`involvement (range, 0–5), which is then multiplied by the score for the proximity of disease to the nail
`matrix (range,1–5), and 10 points are added if the presence of a longitudinal streak or patch is seen or
`if there is greater than 2 mm of subungual hyperkeratosis. Mild nail involvement with onychomycosis
`is classified as a score of 5 or less; moderate, 6 through 15; and severe, 16 through 35. A baseline or
`clinically cured nail is classified as a score of 0. This index provides a standardized method for evaluating
`onychomycosis that can be utilized throughout a patient’s treatment course. This is a promising tool,
`however, further research is necessary in order to properly correlate nail disease severity with
`prognostic outcomes.
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`6. To Treat or Not to Treat?
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`Onychomycosis is notoriously difficult to treat. The main goals of onychomycosis treatment include
`eradication of pathogens, restoration of healthy nails, and prevention of relapse or recurrence. It is an
`infectious disease that deserves prompt and appropriate care [4]. Successful management of onychomycosis
`can be challenging due to the limited availability of effective treatments, patient adherence, and recurrence
`or reinfection [15]. The disease is often associated with substantial distress, which can affect the patient’s
`quality of life. Aside from reducing quality of life, the disease sequelae can include pain and disfigurement,
`in addition to serious physical and occupational limitations resulting in disabilities [16,17]. There is also
`a high potential for dissemination to other nails and local skin. Complications do arise in immunocompromised
`patients, as well as those with Diabetes Mellitus. In general, most clinicians feel that onychomycosis is
`an important problem that should be properly diagnosed and treated, especially if it is symptomatic or
`bothersome. Patients often present to the dermatologist with a long history of onychomycosis; substantial
`nail involvement, and therefore usually require oral therapy. The addition of an effective topical
`antifungal to the physician’s therapeutic armamentarium would address an important unmet medical
`need. In the past, when encountering a patient with onychomycosis who was not a candidate for oral
`antifungals, most clinicians were left with no adequate treatment modalities. However, multiple clinical
`trials now have demonstrated that there are viable topical treatments. As of today, treatment options
`include systemic agents, topical agents, and laser procedures.
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`7. Systemic Therapies
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`Two systemic treatments, terbinafine and itraconazole, are approved by the US Food and Drug
`Administration (FDA) for onychomycosis, taken orally for three months, with lab monitoring every six
`weeks [18]. Pulsed itraconazole is only approved for the treatment of fingernail onychomycosis, and
`fluconazole is not FDA-approved at all for this indication [19].
`When deciding between systemic or topical therapies, several factors must be considered. One should
`take into account if there is lunular or matrix involvement, the overall severity (number of nail involvement),
`the patient’s risk factors, (hepatic, cardiac, etc.), concomitant medications and potential for CYP450
`drug interactions, lifestyle choices with alcohol intake, patient reliability for laboratory, follow-up and
`monitoring, and of course patient preference, concerns, and fears. Additionally, assessment of one’s risk
`of resistance to antifungal therapy should be considered, as Fusarium spp. and other non-dermatophyte
`filamentous fungi are especially difficult to eradicate using standard treatment with terbinafine and
`itraconazole [20] PCR fungal identification can aid in demonstrating the presence of molds in order to
`use an alternative treatment [20].
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`8. New Topical Therapies
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`The development of topical antifungals focusing on new formulations of existing antifungals and
`formulating new agents entirely has been ongoing in the recent years since there is an obvious need for
`an effective topical modality. The use of topical ciclopirox 8% lacquer was disappointing both in clinical
`trials and in practice given the low complete clearance percentages [21,22]. Poor nail penetration limited
`its effectiveness, and as a result topical ciclopirox has been reserved for mild cases of the disease [23].
`The reported mycological cure rates for ciclopirox topical lacquer are 29%–54.3% [21,24]; and complete
`cure rates by proof of a negative culture and negative KOH combined with investigator assessments are
`5.5%–8.5% [21].
`The new topical formulations seem to be very promising, thanks to new technology in the vehicles as
`well as optimal application of the active antifungal ingredients. The route of entry into the nail plate and
`the nail bed plays a vital role in determining the efficacy of a drug. Oral agents reach the nail bed by
`achieving antifungal levels in the blood stream that are in excess of the minimum inhibitory concentration.
`The primary route of drug delivery for topical lacquers is transungual, with the agent applied to the
`dorsal aspect of the nail plate and it then penetrates to the underlying nail bed. The new topical agents
`approved in the US for the treatment of onychomycosis are solutions with increased nail penetration
`characteristics and low surface tension; therefore, these agents penetrate via the transungual route, and
`through the space between the nail plate and the nail bed [25]. This low surface tension is believed to
`enhance penetration and achieve clinical success by providing a dual mode of delivery in accessing the
`nail bed [26]. This route is an essential means for its drug delivery by circumventing the thickness of the
`nail plate.
`Efinaconazole’s primary mechanism of action is blockage of ergosterol biosynthesis, through sterol
`14 α-demethylase inhibition [27,28]. Efinaconazole has a broad spectrum of activity against dermatophytes,
`non-dermatophytes, and yeasts. It works against the most common pathogens including, T. rubrum and
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`T. mentagrophytes and C. albicans, and was found to be more potent than previously available antifungal
`agents [27,29].
`Elewski et al. conducted a single-day study including 11 subjects with onychomycosis [30]. They
`evaluated the ability of efinaconazole 10% topical solution with fluorescein in its vehicle in order to
`demonstrate its spread into the subungual space between the nail plate and nail bed after application to
`the distal end of the toenail. The advantages of this study are the photographs they published that exhibit
`the location of the medication under UV light. Evaluations under both visible and UV light indicated
`that the vehicle had reached the subungual space, with deposition of fluorescein wherever vehicle had
`spread, including in the nail bed.
`Evaluation of concurrent use of nail polish in cadavers has been reported, most importantly revealing
`radiolabeled permeation of efinaconazole with minimal disruption to the integrity of the polish. Further
`phase IV studies with topical agents in combination with nail polish are necessary to determine long-term
`efficacy while giving patients options for cosmetic concealment of their dystrophic nails. Nevertheless,
`this study demonstrates that nail polish does not appear to effect efinaconazole 10% topical solution [31].
`In 2013, two pivotal multi-centered, randomized double-blind vehicle controlled trials were performed
`over 52 weeks and included 1655 participants with toenail distal lateral subungual onychomycosis [32].
`Patients were randomized (3:1) to efinaconazole or vehicle group and applied it once daily for 48 weeks,
`with a four-week post treatment follow-up visit. The primary endpoint of the study was a complete cure,
`with no clinical involvement of the target toenail, in addition to a negative potassium hydroxide examination
`and negative fungal culture at week 52. Mycological cure rate was 56%; significantly greater than
`vehicle. At the 52-week follow-up visit, nearly half of the subjects in both studies had treatment success
`with efinaconazole, shown by 90% toenail clearance in nearly 50% of subjects. Moreover, in contrast to
`previous studies with ciclopirox, efficacy was not dependent upon daily debridement.
`Tavaborole represents a new class of antifungals that consist of protein synthesis inhibitors that
`exhibit antifungal properties [33]. Tavaborole is a novel, boron-based topical agent approved for the
`treatment of onychomycosis caused by T. rubrum and T. mentagrophytes [34]. Tavaborole inhibits
`leucyl-tRNA-synthetase, resulting in inhibition of fungal protein synthesis and extinction of fungal cell
`growth [35]. In two phase-III trials in patients with mild-to-moderate DLSO affecting 20% to 60% of a
`target great toenail were randomized 2:1 to tavaborole or vehicle once daily for 48 weeks. They found
`rates of negative mycology (31.1%–35.9% vs. 7.2%–12.2%) and complete cure (6.5% and 9.1% vs. 0.5%
`and 1.5%), therefore rates were significantly better than vehicle after 48 weeks of treatment [36].
`Tavaborole was also found to penetrate through the nail plate approximately 250 times greater than
`ciclopirox [37]. The overall amount of Tavaborole that penetrated through the nail in the 14-day period
`amounted to 16% of the applied dose compared to 0.1% for ciclopirox.
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`9. Laser and Light Devices
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`9.1. Nd:YAG
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`The use of lasers has increased as a means of treating onychomycosis without the side effects of
`systemic therapy. A 1064 neodymium-doped yttrium aluminum garnet (Nd:YAG) laser called Pinpointe®
`Foot Laser (Cynosure, Westford, MA, USA), is marketed for the treatment of onychomycosis. It is
`understood that due to its longer wavelength, the 1064-nm Nd:YAG is able to deeply penetrate tissue
`and efficiently target fungal overgrowth in the nail bed [38].
`Unfortunately, in vitro effects of Nd:YAG laser systems on fungal growth have yielded differing
`results. One study showed that seven out of eight (87.5%) patients treated with a total of two to three
`treatments spaced three weeks apart (223 J/cm2, 0.65 ms, 2-mm spot size, two passes), obtained a
`negative culture after two to three sessions [39]. Another study yielded less striking results with only
`9.3% of the nails treated achieving a complete cure [40]. In comparison, Kimura and colleagues treated
`13 patients (37 total nails) with two to three sessions spaced four and eight weeks apart with 51% having
`microscopically negative complete clearance at the six-month follow-up [41].
`
`9.2. Carbon Dioxide Laser
`
`The carbon dioxide (CO2) laser was one of the first and oldest laser therapies employed to treat
`onychomycosis, relying on ablation to treat onychomycosis. While the studies were promising when
`they were first released, the advent of less invasive laser treatment options has made the CO2 laser a less
`favorable treatment option for onychomycosis. CO2 lasers are known to cause pain and penetrates deep
`into tissues, which can lead to scarring and disfigurement. Apfelberg et al. in 1984 reported nine cases
`of onychomycosis treated with CO2 laser therapy [42]. Years later, Borovoy et al. treated 200 patients
`with culture-confirmed onychomycosis with one CO2 laser session followed by 12–18 months of topical
`antifungal cream [43]. Nails were debulked prior to the laser treatment and then patients were instructed
`to file down their nails regularly with a single-use emery board. They reported 75% total clearance
`without recurrence with three years of follow-up.
`
`9.3. UV Light Therapy
`
`It is known that UV light is highly germicidal, therefore that led researchers to study the possible
`therapeutic applications of UV light in treating onychomycosis [44]. In 2008, Dai and colleagues studied
`in vitro susceptibility and resistance of T. rubrum with UVC (254 ± 2 nm) light [45]. After incubation of
`human nail fragments with T. rubrum for four weeks, dermatophyte clearance was seen in 50% of
`samples with 36 J/cm2 UVC, in 80% of samples with 72 J/cm2, and in 100% of samples with
`144 J/cm2 [42]. In addition, T. rubrum did not show any resistance to the UVC spectrum. These
`researchers suggested protecting adjacent tissues with UV blockers in order to address the mutagenic
`nature of UV light in normal tissue. In 2013, Chronin et al. found conflicting results [43]. The study
`demonstrated that treatment with UVC was not feasible, as UV light would not penetrate the nail until
`320nm and wavelengths of 320 nm or greater would not eradicate T. rubrum [46].
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`9.4. Photodynamic Therapy
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`Photodynamic therapy (PDT) has been a very widely investigated method for the treatment of
`onychomycosis, which is a combination of a photosensitizing agent followed by irradiation with specific
`wavelength of light, thus enabling maximal absorption of light by the desired target. T. rubrum metabolizes
`aminolevulinic acid to protoporphyrin IX which then can result in a 50% growth reduction. When using
`PDT for onychomycosis, the organism absorbs the photosensitizing agent, making it more susceptible
`to destruction than surrounding healthy tissue. While many photosensitizers have been evaluated for this
`purpose, 5-aminolevulinic acid (5-ALA) is the most frequently studied.
`A clinical trial evaluating PDT for treatment of onychomycosis did so after chemical avulsion of the
`toenail [47]. After chemical avulsion with urea, the nail bed was treated with 20% 5-ALA for 3 h,
`followed by red light. After three sessions, authors reported a 43.3% clinical and mycological cure rate
`at 12-month follow-up [47]. Similarly, Piraccini et al. reported a case of onychomycosis successfully
`treated after chemical avulsion and PDT with negative mycological and clinical assessment after two
`years of follow-up [48].
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`9.5. Dual Wavelength 870-/930-nm Laser
`
`Bornstein and colleagues found that 4074 J/cm2 of 870/930 nm resulted in 100% eradication of
`bacteria, fungi, and yeast [49]. The researchers treated patients with four sessions of the 870-/930-nm
`laser followed by the 930-nm laser alone. After 60 days, clear nail growth was observed in four out of
`seven patients, and all nail cultures were negative [44]. The investigators measured a decrease in
`trans-membrane potentials and an increase in reactive oxygen species (ROS) generated in MRSA and
`C. albicans. No observable damage to the nail matrix was observed, but photodamage to the pathogens
`was achieved at physiologic temperatures. The selective feature presents the possibility for future
`employment in human cutaneous antimicrobial therapy.
`Another trial confirmed the efficacy of the settings and found both negative cultures and at least
`3 mm of clear nail growth in four months in 39% of nails after the last treatment [50]. When evaluated
`at nine-month follow-up, 38% of patients maintained negative culture and microscopy [51].
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`10. Managing Expectations for Increased Patient Satisfaction
`
`Guidance strategies and a clear discussion of expectations can significantly impact long-term
`outcomes for onychomycosis patients being treated with a topical antifungal. A comprehensive overview
`of the benefits of oral therapies will be necessary to counter the inevitable search for side effects and
`potentially course-limiting bad information. First, it is important to emphasize that this will be a long-term
`solution, aiming to reverse a disease process that did not develop overnight and in many cases has been
`self-diagnosed, diagnosed but not cultured, and as a result progressively worse for several years [52].
`This is a condition where slow gains should be celebrated. This is a marathon and not a race, but this
`starts from the confirmation of the diagnosis. While it could take many months for the diseased nail to
`grow out completely, improvements are likely to be noticed as early as 12 weeks, especially in females
`and those with more recent disease. Optimizing concomitant management strategies is also critical to
`keeping the disease under control. This includes proper nail care, treatment of recurrent tinea pedis and
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`eradication of the nail reservoir of dermatophytes, use of nail polish and potential issues with therapies,
`and the potential for recurrence with non-adherence to the extent of the treatment course. Finally, the
`consequences of not treating this disease has to be part of routine counseling. The discussion of other
`nails potentially getting infected, dissemination to other body parts, and concomitant infections has to
`also be had with the patients. In other studies, it has been recognized that patients with long-standing
`disease had more non-target toenails affected [52,53].
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`11. Conclusions
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`The goals of treating onychomycosis are a mycological cure and a normal appearing nail. The recent
`development of topical antifungals has been successful at improving the nail permeation and efficacy.
`Incomplete treatment of onychomycosis provides an environment favorable to the development of
`“antifungal resistance”. New topical agents and device-based therapies expand the therapeutic options.
`In addition, combination therapy may also improve the overall efficacy of antifungal treatments.
`There is a clear need for further research, particularly randomized controlled trials, investigating the
`eradication and cure of onychomycosis. However, it is an exciting time with the advent of the new
`promising topical antifungals, and lasers and light systems that are relatively noninvasive treatment
`options; and thus, are on the forefront of fulfilling this critical need.
`
`Conflicts of Interest
`
`Dr. Queller has no conflicts of interest. Dr. Bhatia is an advisor, consultant, investigator, and speaker
`for Anacor, Merz, Sandoz, and Valeant.
`
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