the relevance of clinical data in dermatologic...

http://www.medscape.org/report/onychomycosis

The Relevance of Clinical Datain Dermatologic Fungus: Closing the Gaps CME/CE Supported by an independent educational grant from Valeant Pharmaceuticals North America LLC

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The Relevance of Clinical Data in Dermatologic Fungus: Closing the Gaps CME/CE

Target AudienceThis activity is intended for dermatologists, podiatrists, primary care physicians, nurses, and nurse practitioners who treat patients with onychomycosis.

GoalThe goal of this activity is to review new and emerging data relating to onychomycosis and its management.

Learning Objectives1. Summarize the latest clinical data of systemic, topical, and other treatment modalities for onychomycosis in the context of clinical decision making

2. Individualize treatments for onychomycosis based on clinical findings

3. Describe post-treatment management, including prevention of recurrent onychomycosis infection

Credits AvailablePhysicians - maximum of 1.00 AMA PRA Category 1 Credit(s)™

Nurses - 1.00 ANCC Contact Hour(s) (1 contact hours are in the area of pharmacology)

Podiatrists - 1.00 contact hour

Accreditation StatementsFor Physicians This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education through the joint providership of Medscape, LLC and New York College of Podiatric Medicine. Medscape, LLC is accredited by the ACCME to provide continuing medical education for physicians.

Medscape, LLC designates this enduring material for a maximum of 1.0 AMA PRA Category 1 Credit(s)™ . Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Medscape, LLC staff have disclosed that they have no relevant financial relationships.

For Nurses Medscape, LLC is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center’s Commission on Accreditation.

Awarded 1.0 contact hour(s) of continuing nursing education for RNs and APNs; 1.0 contact hours are in the area of pharmacology.

This article is a CME/CE certified activity.To earn credit for this activity visit:


CME/CE Released: 01/29/2016; Valid for credit through 01/29/2017


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For Podiatrists

This activity has been planned and implemented in accordance with the standards and requirements for approval of providers of continuing education in podiatric medicine through a joint provider agreement between New York College of Podiatric Medicine and Medscape, LLC. New York College of Podiatric Medicine is approved by the Council on Podiatric Medical Education as a provider of continuing education in podiatric medicine. New York College of Podiatric Medicine has approved this activity for a maximum of 1.0 continuing education contact hours.

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Authors and Disclosures

AuthorJeffrey M. Robbins, DPMProfessor, Podiatric Medicine, Kent State University College of Podiatric Medicine; Director, Podiatry Services VACO, Independence, Ohio

Disclosure: Jeffrey M. Robbins, DPM, has disclosed no relevant financial relationships.

Dr Robbins does intend to discuss off-label uses of drugs, mechanical devices, biologics, or diagnostics approved by the FDA for use in the United States.

Dr Robbins does intend to discuss investigational drugs, mechanical devices, biologics, or diagnostics not approved by the FDA for use in the United States.

Steering Committee ChairBoni E. Elewski, MDProfessor, University of Alabama, Birmingham

Disclosure: Boni E. Elewski, MD, has disclosed the following relevant financial relationships:

Served as an advisor or consultant for: Anacor Pharmaceuticals, Inc.; Novartis Pharmaceuticals Corporation; Pfizer Inc; Valeant Pharmaceuticals International

Received grants for clinical research from: AbbVie Inc; Amgen, Inc.; Lilly; Merck & Co., Inc.; Novartis Pharmaceuticals Corporation; Pfizer Inc; Valeant Pharmaceuticals International

MembersAditya K. Gupta, MD, PhD, FRCPC, FAAD, MBAProfessor, University of Toronto, Toronto, Ontario

Disclosure: Aditya K. Gupta, MD, PhD, FRCPC, FAAD, MBA, has disclosed the following relevant financial relationships:

Served as an advisor or consultant for: Anacor Pharmaceuticals, Inc.; Novartis Pharmaceuticals Corporation; Moberg Pharma; Valeant Pharmaceuticals International

Received grants for clinical research from: Valeant Pharmaceuticals International

Clinical trials investigator: Lilly; Merck & Co., Inc.; UCB Pharma, Inc.

Antonella Tosti, MDProfessor, Department of Dermatology & Cutaneous Surgery, University of Miami, Miami, Florida

Served as an advisor or consultant for: Anacor Pharmaceuticals, Inc.; PharmaDerm; Polichem; Valeant Pharmaceuticals International; Viamet Pharmaceuticals Holdings, LLC

Served as a speaker or a member of a speakers bureau for: PharmDerm; Sandoz


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Tracey C. Vlahovic, DPM, FFPM RCPS (Glasg)Associate Professor, Temple University School of Podiatric Medicine, Philadelphia, Pennsylvania

Disclosure: Tracey C. Vlahovic, DPM, FFPM RCPS (Glasg), has disclosed the following relevant financial relationships:

Served as a speaker or a member of a speakers bureau for: Pharmaderm; Valeant Pharmaceuticals International

Dyanne P. Westerberg, DOAssociate Professor, Cooper Medical School of Rowan University, Camden, New Jersey

Disclosure: Dyanne P. Westerberg, DO, has disclosed no relevant financial relationships.

Our Experts: This group of medical professionals have provided guidance on the creation of these programs and resources.

Editor(s)Shari J. Dermer, PhDScientific Director, Medscape, LLC

Disclosure: Shari J. Dermer, PhD, has disclosed no relevant financial relationships.

Eileen A. McCaffrey, MAFreelance Medical Writer, Whippany, New Jersey

Disclosure: Eileen A. McCaffrey, MA, has disclosed no relevant financial relationships.

CME Reviewer/Nurse PlannerAmy Bernard, MS, BSN, RN-BCLead Nurse Planner, Medscape, LLC

Disclosure: Amy Bernard, MS, BSN, RN-BC, has disclosed no relevant financial relationships.

Robert Eckles, DPM, MPHDean, Clinical and Graduate Medical Education Associate ProfessorDepartment of Orthopedic Sciences New York College of Podiatric Medicine

Disclosure: Robert Eckles, DPM, MPH, has disclosed no relevant financial relationships.

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OverviewOnychomycosis is among the most common nail disorders in adults.[1] It accounts for an average of more than 1 million physician office visits annually in the United States.[2] Prevalence estimates vary widely depending on geography and type of population. A recent literature review reported a mean prevalence in Europe and North America of 4.3% (95% confidence Interval [CI]: 1.9-6.8) in 11 population-based studies and 8.9% (95% CI: 4.3-13.6) in 21 hospital-based studies.[3] Prevalence in hospital-based studies in South America was reported as 18.8% and in Asia, as 12.1%.[3] A recent systematic literature review including publications mostly from the United States, Canada, and Europe, but also from Asia and Thailand, reported a general population prevalence rate of 3.22% for dermatophyte toenail onychomycosis.[4] Reported prevalence in North America based on data from physician office visits ranges from 6.5%[5] to 14%.[6]

The infection occurs much more often in toenails than in fingernails -- 10 to nearly 20 times more often, according to two estimates.[3,5] It is most commonly due to dermatophytes, with Candida and nondermatophyte molds accounting for the balance of cases.[1,5,7] The most frequently identified pathogen is Trichophyton rubrum.[1,3,6] The proportion of cases attributed to each type of infectious agent varies with geography and with patient demographic factors, although dermatophytes have been reported to account for 65% of cases globally[3] and 76.6% to 90% or more of cases in Europe, the United Kingdom, and Canada.[1,5,7]

Potential Consequences of OnychomycosisThe impact of onychomycosis extends beyond the cosmetic level. It is a progressive infection that can disrupt skin integrity,[1]

potentially facilitating bacterial infection and gangrene, especially in people with diabetes.[8-10] It can also permanently damage the nail bed and nail plate.[1,11,12]

When combined with neuropathy, the thickened toenails associated with onychomycosis create an environment that favors the formation of foot ulcers.[13] Indeed, onychomycosis predicts the development of foot ulcer in men with diabetes (hazard ratio [HR], 1.58, 1.16–2.16; P =.004; multivariate analysis).[14] Foot ulcers in patients with diabetes in turn often precipitate amputation.[13]

Gangrene also is associated with onychomycosis in patients with diabetes.[13] Thickened nails can tear the skin on the legs, facilitating the spread of infection.[11] Onychomycosis can lead to cellulitis and osteomyelitis, especially if left untreated, in patients with diabetes.[13] Even in a general population of patients, onychomycosis is a significant risk factor for acute bacterial cellulitis of the leg (odds ratio [OR]: 2.2; P <.001).[15]

Onychomycosis can exacerbate existing foot problems, potentially leading to difficulty walking and risk of falling.[16,17] Nail problems and disabling foot pain have been significantly associated with risk of falls in older adults.[18,19]

Onychomycosis can serve as a reservoir of infection in the body from which the fungus can spread.[12,20] Additional fungal skin infections, most commonly tinea pedis, were present in nearly 43% of more than 2700 patients with toenail onychomycosis.[21] Fungal infection is transmissible to other individuals as well as to other nails and body parts of the infected individual.[11,22] A molecular analysis of dermatophyte strains reported that households with multiple affected members were infected with the same pathogenic strains, supporting transmission. A history of concomitant tinea pedis, as well as plantar scaling and/or nail discoloration, was associated with infection spread.[22]

Foot pain, difficulty wearing shoes, and the appearance of onychomycosis also can cause embarrassment and stigmatization. Multiple studies have linked onychomycosis to reduced quality of life (QOL) and self-esteem.[23-26] The time required to treat the infection, the 12 to 18 months required for nail regrowth, and the high rate of recurrence lead some patients to opt for permanent nail removal.

Risk FactorsOlder age, male sex, impaired peripheral circulation, tinea pedis infection, altered nail structure, nail trauma, hallux valgus (bunions), diabetes, psoriasis, cancer, and other conditions associated with immunosuppression[4,7,27-31] have been linked to elevated rates of onychomycosis (Table 1). Factors associated with more than double the risk of onychomycosis compared with the general population were a history of cancer, psoriasis, tinea pedis, parents or children with onychomycosis, regular swimming (presumably due to walking barefoot in communal showers, pool decks, and other public surfaces), and older age (≥50 years).[31] Use of occlusive footwear and a personal history of onychomycosis also increase vulnerability to the condition.[7] Given the aging of the population and the growing rate of diabetes, the prevalence of onychomycosis is likely to increase.


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Family history of onychomycosis could stem from transmission, genetic susceptibility, or both.[32-34] High infection rates in certain families among children and parents but not spouses suggest genetic susceptibility rather than infection transmission.[32]

Certain human leukocyte antigen (HLA) genotypes are more common in individuals and families with a high prevalence of onychomycosis.[33] In patients with psoriasis, a small case-control study (n=45) found that certain HLAs are more common among individuals with onychomycosis.[34] Low levels of CD4+CD25+ regulatory T cells, observed in some individuals with onychomycosis, may impair full immune response and lead to chronic or recurrent infections.[33] Conversely, one HLA type appears to confer resistance to T rubrum onychomycosis in a Mexican Mestizo population.[35]

Table 1. Risk Factors for Onychomycosis: Comorbid Conditionsa

Risk Factor Onychomycosis Prevalence

Diabetes 8.75% to 22%[4,36]

Psoriasis 10.2%[4] to 13%[37]

HIV 10.4%[4], 20% and4%[38]

Dialysis 11.9%[4]

Renal transplant 5.2%[4]

HIV = human immunodeficiency virus.aAge ≥50 years vs general population of survey respondents.

Clinical Presentation and Severity ClassificationThe presentation of onychomycosis is classified based on the pattern of fungal invasion. Some individuals display multiple patterns of infection.[1] The following are the presentations of dermatophyte infection.

Distal lateral subungual onychomycosis (DLSO). This is the most common presentation of dermatophyte nail infection. The fungus invades the nail and nail bed starting at the distal or lateral margins. The nail plate is not affected initially, though onycholysis (separation of the nail plate from the nail bed) can develop. Subungual hyperkeratosis and dyspigmentation may occur. As with onychomycosis in general, toenails are affected more often than fingernails and T rubrum is the most common pathogen.[1,39]

Superficial white onychomycosis (SWO). This infection typically begins at the superficial layer of the nail plate and spreads from there until the entire nail plate is affected. T interdigitale is the most common pathogen. This manifestation most often develops in children.[1]

Proximal subungual onychomycosis (PSO). This starts at the proximal nail fold and penetrates the nail plate, or originates under the proximal nail plate.[1,39] It is often secondary to paronychia.[39] T rubrum is the most common pathogen and toenails are infected more often than fingernails. PSO is the least common presentation of onychomycosis in the general population but is observed in persons with human immunodeficiency virus (HIV) and others who are immunosuppressed. The nail plate may develop a white discoloration in these patients.[1,39]

Endonyx onychomycosis. This is caused by direct invasion of the nail plate keratin at its distal end. The nail plate becomes discolored and lamellar splitting may develop. T soudanense and T violaceum are the most common pathogens.[1,39]

Candidal onychomycosis presents somewhat differently from dermatophyte infections. Distal candidal nail infection typically affects individuals with vascular insufficiency (eg, Raynaud phenomenon) or those taking oral corticosteroids. Chronic paronychia of the fingernails with secondary nail dystrophy generally develops in children or in patients with occupations involving exposure of the fingers to wet environments. Chronic mucocutaneous candidosis is associated with immunosuppression. Mucous membranes are involved; gross nail thickening may occur in severe cases. Candidal onychomycosis can, and mold-related onychomycosis generally does, develop in patients with other nail diseases or injuries.[1]

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Any presentation of onychomycosis can progress to total dystrophic onychomycosis (TDO), in which the nail plate is crumbling and nearly destroyed. The nail bed is thickened and covered with debris. Primary TDO is rare, usually affects immunosuppressed patients, and is more commonly due to Candida than to dermatophyte infection.[1,39]

A severity classification score for DLSO, the most common presentation, has been developed (Table 2).[40] Rating disease severity may be helpful when choosing therapy. Factors considered in grading severity are those reflected in infection progression: percent of nail plate involved, proximity of infection to matrix, presence of dermatophytomas (ie, longitudinal streak or patch extending from free edge to proximal edge of the nail), and presence of severe subungual hyperkeratosis (>2-mm thickening of the stratum corneum).

The differential diagnoses of onychomycosis in adults should include nail psoriasis, nail trauma, chronic dermatitis, lichen planus, neoplasm, and bacterial infection.[1,41]

Table 2. Calculating Onychomycosis Severity: The Onychomycosis Severity Index

Points by Percent of Nail Plate Involved:

None = 0

1%–10% = 1

11%–25% = 2

26%–50% = 3

51%–75% = 4

76%–100% = 5

Points by Proximity to Matrix(amount of involvement from distal edge):

<1/4 = 1

1/4–1/2 = 2

>1/2–3/4 = 3

>3/4 = 4

Matrix involvement = 5

Adapted from Carney C, et al.[40]

Confirming the DiagnosisA clinical diagnosis of onychomycosis should be confirmed in the laboratory prior to starting therapy. Fungal culture and microscopy with potassium hydroxide (KOH) or tetraethylammoniumhydroxide (TEAH) staining are considered the gold standard confirmatory methods. Periodic-acid-Schiff (PAS) staining of nail plate clippings offers a higher degree of sensitivity for detection of fungal elements compared with fungal culture and microscopy -- 82%, 88%, 88% vs 53%, 30%, 50% and 48%, 56%, 53% sensitivity for PAS, fungal culture, and microscopy, respectively for series with 631, 93, and 64 patient samples.[42,43]

Direct microscopy is the simplest, quickest (≤30 minutes), and least expensive of the 3 methods (ie, KOH, TEAH, and PAS), but is subject to interpretation. It also cannot identify fungal species. Fungal culture is very specific but has a high false negative rate and requires 3 to 6 weeks to generate results. PAS staining is the most sensitive test and it yields results faster than culture (3 or 4 days). However, it is also the most expensive of the 3 methods and it cannot identify causal organisms. Like direct microscopy, PAS cannot distinguish viable from nonviable organisms. One algorithm suggests using a KOH smear for initial diagnosis and fungal culture to identify the organism in samples positive by microscopy. Because KOH microscopy has a low sensitivity, it can be repeated to increase accuracy. PAS staining can be used if repeated KOH microscopy is negative but onychomycosis is suspected.[42]

Nail clippings for analysis should be taken from the discolored, dystrophic, or brittle sections of nail and should include any crumbly material. The affected nail should be cut back as far as practical, through its full thickness. A curette may be used to obtain nail scrapings if superficial infection is present. Associated skin lesions also should be sampled for analysis.[1]


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Presence of tinea pedis should prompt histologic testing of nail clippings for onychomycosis, even in the absence of clinical signs of nail disease. Subclinical onychomycosis has been associated with tinea pedis.[20]

Choosing TherapyThe goals of therapy are to eradicate the pathogen and restore normal or at least acceptable nail appearance. The latter is incomplete without nail regrowth, which requires 6 months for fingernails and 12 to 18 months for toenails.[44] Both topical and systemic (oral) antifungal agents are available to treat onychomycosis. Terbinafine, in both oral and topical (nonprescription) formulations, was the therapy most commonly used to treat onychomycosis in the United States from 1993–2010.[2] Other systemic therapies are itraconazole and fluconazole, with the latter being used off-label. Prior to 2014, only 1 topical agent requiring a prescription was approved for onychomycosis therapy in the United States: ciclopirox 8% lacquer.[45] Options have since expanded with the introduction of 2 new topical agents in 2014: efinaconazole and tavaborole.

Considerations in treatment choice include effectiveness, safety, disease severity, pathogen(s), comorbid conditions, patient preference, and patient willingness to adhere to treatment and follow-up. Persistence is important to success; the new topical agents were studied over treatment periods of 48 weeks.[46,47] The potential for drug-drug interactions also should be evaluated. Many people with onychomycosis are older adults or individuals with comorbid medical conditions who are taking multiple medications.

A systematic review and meta-analysis of 19 trials published before March 2013 evaluated the likelihood of mycological, though not clinical or complete, cure with systemic and topical therapies.[48] Terbinafine 250 mg was significantly more likely to generate a mycological cure than all options except itraconazole 400 mg pulse therapy (1 week/month for 3 months [off-label use for toenails]; no significant difference between these therapies). Itraconazole 200 mg was significantly more likely to generate a mycological cure than fluconazole (off-label use) and all the topical therapies. Findings suggested that the efficacy of topical therapies was similar.[48] Studies of efinaconazole, but not of tavaborole, were included in this analysis.

Authorities recommend treating moderate-to-severe infections with systemic agents, alone or combined with topical therapy.[39,40]

Among systemic therapies, terbinafine is considered the first choice for onychomycosis due to dermatophytes.[1,39] Itraconazole is the first choice to treat candidal disease.[1,39] Nail infections due to nondermatophyte organisms (eg, Fusarium) can be challenging to treat.[49] An authoritative review recommends terbinafine as the first choice for these pathogens while the British Association of Dermatology lists itraconazole as first-line therapy in these cases.[1,39]

Systemic therapy. Both terbinafine and itraconazole are Food and Drug Administration (FDA)-approved to treat toenail or fingernail onychomycosis due to dermatophyte infection.[50,51] Itraconazole is indicated only for patients who are not immunocompromised.[51] Each agent is administered once daily (200 mg/day for itraconazole, 250 mg/day for terbinafine) for 12 weeks to treat toenail onychomycosis. Recommended regimens are shorter for fingernail onychomycosis. Terbinafine 250 mg is given once daily for 6 weeks. Itraconazole 400 mg/day is taken for 1 week out of every 4 weeks, with this cycle repeated once (8 weeks total).[51] There is no FDA-approved regimen for fluconazole in onychomycosis. A review of clinical trials recommended a dose of 150 mg/week for more than 6 months in dermatophyte infection.[52] Mycological cure rates for these systemic therapies reported in randomized controlled clinical trials are listed in Table 3.

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Table 3. Mycological Cure Rates With Systemic Therapies for Onychomycosisa

Study NTreatment

Period

Mycological Cure Rates at Follow-up

P-value for Difference

Terbinafine250 mg/d Itraconazole Fluconazoleb

DeBacker 1998[53] 372

12 wk; follow-up, 48 wk 73% 46%c N/A <.001

Sigurgeirsson 1999 (LION)[54]

49612 or 16 wk; follow-up,

18 mo

75.5% (12 wks), 80.8%

(16 wks)

38.3% (12 wks), 49.1%

(16 wks)dN/A <.001

Sigurgeirsson 2002 (LION)[55] 151

Follow-up, median 54 mo

46% 13%c N/A <.005

Scher 1998[56] 362

Treatment for a mean, 9.5 to 10.2 mo; maximum,

12 mo

N/A N/A

47%, 59%, 62% (150, 300, 450

mg once weekly, respectively)

.001 vs placebo

Havu 2000[57] 13712 wks (T), 12 or 24 wk (F);

f/u, 60 wk89% N/A 51% (12 wk)

49% (24 wk)<.001 T vs F

F = fluconazole; f/u = follow-up; N/A = not applicable, not included in the study; T =Terbinafine.aData are from randomized, double-blind, controlled trials.bNot FDA-approved for this use.c200 mg/day.d400 mg/day for 1 week every 4 weeks.

Safety of oral therapy. Among systemic therapies, terbinafine is regarded as safer than itraconazole due to its relatively lower potential for drug-drug interactions and hepatic toxicity.[58] Itraconazole inhibits CYP450 isoenzymes and is metabolized by CYP450-3A4, raising the potential for many drug-drug interactions (eg, oral hypoglycemic agents, HMG-CoA reductase inhibitors, calcium channel blockers, warfarin, cyclosporine, benzodiazepines, and some antiarrhythmic medications).[59]

Terbinafine inhibits CYP450-2D6,[50] which is associated with fewer clinically significant drug-drug interactions than CYP450-3A4.[58,59] A dose reduction of any drug metabolized by CYP450-2D6 should be considered if taken with terbinafine. Agents metabolized by CYP450-2D6 include tricyclic antidepressants, selective serotonin reuptake inhibitors, monoamine oxidase inhibitors type B, beta-blockers, and some anti-arrhythmic agents.[50] Rare instances of erythema multiforme, exfoliative dermatitis, Stevens-Johnson syndrome, and topical epidermal necrolysis have been reported with terbinafine.[60]

Terbinafine, itraconazole, and fluconazole each carry warnings about the potential for hepatotoxicity.[50,51,61] Analysis of a UK prescription database (n = 69,830) of patients with no liver disease who received ≥1 prescription for oral fluconazole, griseofulvin, itraconazole, ketoconazole, or terbinafine, revealed 5 cases of acute liver injury during use of antifungals. Incidence rates were 134.1/100,000 person-months for ketoconazole, 10.4 for itraconazole, and 2.5 for terbinafine.[62] Oral ketoconazole is no longer FDA indicated for cutaneous fungal infections due to risk of liver injury.[63 ] Risk of hepatotoxicity with terbinafine has been termed analogous to that of acetaminophen.[58]

Topical therapy. Topical monotherapy may be considered for mild-to-moderate infection (<50% to 60% of the nail affected, no matrix involvement, few digits involved) due to dermatophyte or dermatophyte/candidal infection, or when systemic therapy is contraindicated.[39,41,65] The British Association of Dermatology recommends restricting topical monotherapy to: (a) early DLSO without longitudinal streaks, less than 80% nail plate involvement and an unaffected lunula; (b) SWO without transverse or striate infections, and (c) cases in which systemic therapy is contraindicated.[1]


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Phase 3 clinical trials of newer topical therapies included only patients with toenail DLSO due to dermatophyte infection and 20% to 50% (efinaconazole) or 20% to 60% (tavaborole) nail involvement. Patients with certain characteristics predicting poor treatment response (eg, dermatophytoma, coinfection with nondermatophyte pathogens, psoriasis, immunodeficiency, significant peripheral vascular disease, or uncontrolled diabetes) were excluded from those studies.[46,47]

When topical agents are an option, then the patient’s ability to apply treatment to the feet as directed should be evaluated. Conditions such as neuropathy and retinopathy may leave some patients unable to see or feel any foot abnormalities. Patients with arthritis or other musculoskeletal conditions may lack the manual dexterity to care for their feet even if they can perceive abnormalities. Obesity also may complicate foot examination and application of medicine.

Three topical agents are FDA-approved for the treatment of onychomycosis. Table 4 lists cure rates in pivotal clinical trials. Ciclopirox 8% nail lacquer is approved for use in immunocompetent patients with mild-to-moderate toenail or fingernail onychomycosis due to T rubrum, without lunula involvement. Debridement and removal of residual lacquer should be performed by a healthcare professional as often as monthly as part of therapy. The active ingredient in ciclopirox is a synthetic antifungal agent. It may take up to 6 months of therapy before observable improvement occurs.[45] Patients should be instructed not to use nail polish on nails treated with ciclopirox.

The 2 new topical agents are characterized by better nail penetration than ciclopirox, likely due in part to their lower affinity for keratin.[66,67] Tavaborole 5% solution’s low molecular weight also facilitates nail penetration.[68] Debridement is not required with either agent,[46,47] potentially increasing ease of therapy and acceptability to patients. Cadaver studies have demonstrated that efinaconazole and tavaborole penetration is unaffected by 2 and 4 coats of nail polish, respectively.[69,70] This is noteworthy as patients may wish to use nail polish to mask the appearance of onychomycotic nails.

Both new agents are indicated for the treatment of toenail onychomycosis due to T rubrum and T mentagrophytes.[71,72] Efinaconazole 10% solution is an azole antifungal.[46] Tavaborole 5% solution represents a first-in-class, boron-based, oxaborole antifungal agent. It targets an enzyme essential for fungal protein synthesis.[47]

An analysis of efinaconazole pivotal trials reported higher rates of complete cure in patients treated with efinaconazole 10% compared with those who received vehicle in patients with mild (≤25% nail involvement) or moderate (>25% nail involvement) onychomycosis (25.8% vs 11.3%, P =.006 and 15.9% vs 2.7%, P <.001, respectively). Mycological cure rates were similar between these groups (58.2% and 55.6%, mild and moderate onychomycosis, respectively).[73] Cure rates were higher among those with earlier disease, underlining the importance of prompt treatment.[74] A post hoc analysis of the efinaconazole pivotal trials found no significant difference between mycological and complete cure rates among subjects with and without diabetes.[75] Clinical trials also examined the effect of clinical improvement on QOL. Among patients randomized to receive efinaconazole, improvement in mean QOL domain scores was significantly correlated with change in percent of nail affected.[76]

Table 4. Topical Therapies for Onychomycosis: Cure Ratesa

Agent NComplete

CureMycological

Cure

Ciclopirox[77] 223237

5.5%b

8.5%b29%36%

Efinaconazole[46] 870785

17.2%15.2%

55.2%52.4%

Tavaborole[47] 594604

6.5%9.1%

31.1%35.9%

aAll trials were randomized, double-blind, vehicle-controlled studies with treatment periods of 48 weeks. Data from 2 pivotal trials are listed for each agent.bTreatment cure, defined as negative KOH, negative culture, and global evaluation score = cleared.

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Safety of topical therapy. Adverse events reported in pivotal clinical trials of the topical medications are generally of mild to moderate severity.[46,47,77] Treatment-related events observed were most often local application-site reactions; discontinuation due to adverse events was rare.[46,47]

RecurrenceAs many as 25% to 50% of patients in clinical practice are classified as treatment failures.[78] Many patients have a long history of onychomycosis recurrence.[1] A long-term follow-up of 73 patients who were completely cured (clinically and mycologically) following oral therapy found a 16.3% recurrence rate over 7 years. The terms “recurrence,” “relapse,” and “reinfection” have different meanings. “Relapse” generally connotes infection following incomplete resolution of the original infection. “Reinfection” denotes a new infection following complete cure of a prior episode. “Recurrence” covers an episode attributed to either relapse or reinfection.[30] It can be challenging to distinguish relapse from reinfection.

Risk of recurrence (ie, relapse or reinfection) was higher following therapy with itraconazole compared with terbinafine (35.7% and 11.9%, respectively, P =.046). Recurrence occurred on average at 3 years after the end of therapy (range, 1 to 5 years), always with the same pathogen as the original infection.[79] Two other long-term studies reported higher mycological recurrence rates after therapy with itraconazole compared with terbinafine (22% and 9% at 18 months and 53% and 23% at 66 months, in 1 study[80] and 32%, 36%, 59%, and 57% for continuous terbinafine, intermittent terbinafine, pulsed itraconazole, and continuous overlapping therapy with terbinafine and itraconazole, respectively, with follow-up of 1.25 to 7 years).[81]

Factors predisposing to poor therapeutic response (ie, relapse) include poor nail penetration of antifungal therapy, partial/nonadherence, and premature discontinuation of therapy. Many of the same characteristics that raise the risk of infection also portend poor response to therapy: older age, male gender, poorly controlled diabetes, poor peripheral circulation, immunosuppression, and genetic predisposition.[30,40,64,82] Certain characteristics of the nail infection also are associated with poor treatment prognosis (Table 5, Figure). Trauma to or deformities of the feet, as well as gait irregularities, can also raise risk for recurrence.[30]

Immune system reconstitution may improve onychomycosis in HIV. A prospective study (n = 16) and a case series describe onychomycosis in HIV-infected individuals that improved following the institution of combined antiretroviral therapy, without the use of antifungal treatment.[83,84] Consistent with these findings, onychomycosis in HIV has been associated with a low CD4+ count (~370 cells/μL).[38]

Combination antifungal therapy (eg, oral terbinafine and itraconazole or topical and oral therapy) may be considered for patients with confirmed onychomycosis infection not cured by antifungal monotherapy.[41]

Table 5. Infection and Nail Characteristics Associated with Negative Treatment Prognosis

• Slow nail growth

• Lateral involvement

• Matrix involvement

• Dermatophytoma (streak or patch)

• Severe subungual hyperkeratosis (>2 mm)[40]

• Severe onycholysis[40]

• >50% nail involvement[40]

• Total dystropic onychomycosis[40]

• Positive culture at 24 weeks[82]

• Nondermatophyte infectious agent (mold, yeast, mixed bacterial/fungal infection)[40,49]

• Resistant organism[30]


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A. Dermatophytoma

Figure. Nail characteristics predictive of poor treatment outcomes.Photos courtesy of Antonella Tosti, MD, University of Miami

Treatment and Post-Treatment ManagementEstablishment of a patient-clinician partnership and open lines of communication is crucial during and after completion of therapy for onychomycosis, given the long duration of therapy, the amount of patient cooperation required for successful treatment, and the high risk of recurrence. Setting patient expectations at the outset regarding length of therapy and the persistence and vigilance required to achieve the best results is an important component of treatment. Given the association of transmission of and inherited susceptibility to onychomycosis, consider asking if others in the household have displayed signs of fungal infection. Any infected individuals should be treated at the same time to reduce the risk of in-house transmission.[1,41] Consider antifungal maintenance therapy for individuals at high risk for recurrence.[41]

After completion of therapy, monitor patients’ feet for signs of tinea pedis or onychomycosis and re-initiate treatment immediately upon detection of recurrence. In particular, patients with peripheral vascular disease, diabetes, or immunodeficiencies should regularly inspect their feet and visit dermatologists or podiatrists for follow-up.[12] Check footwear fit; patients with diabetic neuropathy in particular may be unaware that shoes are too tight, causing trauma to the nails.[13] Instructing patients about how to prevent recurrence may empower them to avert further infection (Table 6).

Table 6. Reducing Risk of Recurrence: Lifestyle Measures

• Avoid walking barefoot in public places, especially hotel rooms, gyms, public showers and changing rooms, and swimming pool decks[85]

• Keep feet cool and dry[86]

• Avoid tight, occlusive footwear that may cause trauma to the nail bed[13]

• Use absorbent and antifungal foot powder in shoes and on feet, or spray terbinafine solution into shoes periodically[1,85]

• Wear cotton, absorbent socks[86]; change socks that become wet[12]

• Keep nails trimmed short and neat, without cutting cuticles[12,86]

• Do not share toenail clippers

• Avoid frequent manicures and pedicures as these can predispose to multiple nail problems, including onychomycosis; suggest that patients patronizing salons bring their own instruments or assure that the salon practices sterile technique[1,12]

• Discard old or moldy footwear; if not possible, put naphthalene mothballs in the shoes and enclose them tightly in a plastic bad for at least 3 days[1]

B. Hyperkeratosis

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Investigational TherapiesTopical and oral agents approved for other conditions also have been evaluated in onychomycosis (eg, topical tazarotene, luliconazole, and oral posaconazole).[87-89] New agents also are in development (eg, oral albaconazole, topicals ME1111 and MOB015).[90-92]

At least 2 agents have been evaluated in phase 2 trials. A randomized, placebo-controlled, dose-ranging, phase 2b study compared 4 regimens of 12 or 24 weeks of oral posaconazole with 12 weeks of oral terbinafine and 24 weeks of placebo. At week 48, complete cure rates with each posaconazole regimen were significantly higher than those observed with placebo, and did not differ statistically from the rate associated with terbinafine. Posaconazole was well tolerated; 7 participants were removed from treatment for asymptomatic liver enzyme elevation.[89]

A phase 2 study of the novel triazole antifungal albaconazole 100 mg or 400 mg for 24 or 36 weeks reported mycological cure and clear/almost clear rates superior to those seen with placebo (21% to 54%) at 52 weeks.[91]

A small (n = 15), open, observational study of topical tazarotene 0.1% in subjects with toenail DLSO onychomycosis reported complete cure in all participants at 12 weeks of therapy.[87] The topical agents luliconazole and ME1111 have also demonstrated in vitro activity against dermatophytes.[90,93]

Conclusion Onychomycosis is a common condition that is challenging to manage in clinical practice. Early identification of patients with onychomycosis and prompt initiation of treatment is prudent to avoid complications from the infection. Topical therapies introduced since 2014 offer higher cure rates than the older topical agents, without requiring debridement. They offer new options for patients with mild-to-moderate disease, and may make more clinicians comfortable treating patients with less severe onychomycosis. Systemic therapy is the preferred choice for patients with moderate-to-severe disease, unless contraindicated. Regardless of treatment choice, patient education, persistence with therapy, regular monitoring, and hygiene and lifestyle measures are important aspects of care for and prevention of this fungal infection.


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