Managing Onychomycosis: New and Emerging Treatments and ... · Managing Onychomycosis: New and Emerging Treatments and Recurrence Prevention Strategies GUEST EDITORS David M. Pariser,

EDITORS Kenneth A. Arndt, MDPhilip E. LeBoit, MDBruce U. Wintroub, MD

SUPPLEMENT 3

VOL. 34, NO. 3S

JUNE 2015

Managing Onychomycosis: New and Emerging Treatments and

Recurrence Prevention Strategies

GUEST EDITORS

David M. Pariser, MD, Chair

Nathaniel J. Jellinek, MD

Phoebe Rich, MD

Melodie S. Young, MSN, RN, A/GNP-c

Introduction S45

Efficacy and Safety of Onychomycosis Treatments: S46 An Evidence-Based Overview

Understanding Onychomycosis Treatment: S51 Mechanisms of Action and Formulation

Management Strategies for Onychomycosis S54 in Special Patient Populations

Making Strides in Preventing S56 Onychomycosis Recurrence

Post-Test and Evaluation Form S60

A CME/CE CERTIFIED SUPPLEMENT TO

Managing Onychomycosis: New and Emerging Treatments and Recurrence Prevention Strategies

Original Release Date: June 2015 Most Recent Review Date: June 2015 Expiration Date: June 30, 2017 Estimated Time to Complete Activity: 2.5 hoursParticipants should read the activity information, review the activity in its entirety, and complete the online post-test and evaluation. Upon completing this activity as designed and achieving a passing score on the post-test you will be directed to a Web page that will allow you to receive your certificate of credit via email or you may print it out at that time.The online post-test and evaluation can be accessed at http://tinyurl.com/onycho15.Inquiries may be directed to Global Academy for Medical Education [email protected] or (973) 290-8225.

Accreditation StatementsPhysicians: This activity has been planned and implemented in accordance with the Essential Areas and Policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint providership of The University of Louisville and Global Academy for Medical Education, LLC. The University of Louisville is accredited by the ACCME to provide continuing medical education for physicians. The University of Louisville Office of Continuing Medical Education & Professional Development designates this enduring material for a maximum of 2.5 AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.Nurses: This program has been approved by the Kentucky Board of Nursing for 3.0 contact hours through the University of Louisville Hospital, provider number 4-0068-7-16-820. The Kentucky Board of Nursing approval of an individual nursing education provider does not constitute endorsement of program content. Participants must complete the entire activity, provide license, and complete the evaluation to receive contact hours.

Target AudienceThis educational activity is designed for dermatologists, family practitioners, internists, nurse practitioners, physician assistants, and other clinicians who treat patients with onychomycosis.

Educational NeedsWith the introduction of more effective treatments—particularly the recently approved topical agents—clinicians in dermatology as well as other specialties and general primary care have a renewed interest in diagnosing and treating onychomycosis, an infection that is now recognized as clinically important but was once considered largely a cosmetic problem with minimal or no medical implications.However, although efficacy with some treatments is good, the medications must be used consistently and correctly for several months before clinical evidence of improvement appears, and before patients perceive that treatment is working.Treatment options currently approved in the United States for onychomycosis include topical and oral agents, as well as laser therapy. Oral agents must be chosen for their activity against the involved pathogens (dermatophytes, nonder-matophytes, or yeast species, or combination infections). The currently approved systemic agents generally are safe for most patients, but concerns remain with respect to systemic side effects (for example, hepatotoxicity), particularly in pedi-atric patients, the elderly, and others with underlying medical conditions such as diabetes. The three agents currently approved for topical therapy are ciclopirox gel 0.77%, approved in 1999, and efinaconazole 10% topical solution and tavaborole topical solution, 5%, both approved in 2014. Other classes of topical antifungals are being evaluated both here and abroad. Clinicians must be able to effectively and safely use the currently approved agents, and must be prepared to evaluate the emerging data on medications now being investigated. Several laser devices are approved, and other types of lasers as well as other modalities (including photodynamic therapy) are being tested in clinical trials.This supplement focuses on the efficacy and safety of onychomycosis treat-ments, particularly those recently approved, and provides an overview of emerging therapies. Mechanisms of action of drugs and devices also are presented to help clinicians tailor therapy according to individual patient clinical profiles. Management strategies for challenging patient populations are offered, and practical approaches to preventing recurrence are addressed— in particular, strategies for enhancing patient adherence to medication use and avoidance of sources of reinfection.

Learning ObjectivesAs a result of participating in this activity, participants should be able to:• Explain the benefits of early diagnosis and treatment of onychomycosis and the

potential sequelae if this infection is untreated or is inadequately treated. • Establish or improve practice protocols for identifying patients with

onychomycosis, particularly in special populations (for example, the elderly, pediatric patients, immunocompromised patients, patients with psoriasis, and those with diabetes mellitus).

• Identify the mechanism of action for the currently available therapeutic options, including differences in formulation and associated efficacy, and use this knowledge to more effectively tailor treatment choices to individual patients.

• Incorporate or enhance monitoring for onychomycosis in patients in special, at-risk, or difficult-to-manage populations (for example, the elderly, pediatric patients, immunocompromised patients, patients with psoriasis, and those with diabetes mellitus).

• More effectively use currently available oral and topical medications to treat various patient populations.

• Discuss techniques, including obtaining good culture specimens, that permit more accurate diagnosis of the infecting organisms and the most appropriate choice of therapy.

• Review and, if necessary, improve patient education materials and teaching plans regarding the patient’s role in the treatment of onychomycosis and the prevention of recurrence to increase the chances of effective long-term management of this disease.

• Evaluate the results of clinical studies on new and emerging and available treatments for onychomycosis.

Disclosure DeclarationsAs a provider accredited by the ACCME, the Office of CME & PD, School of Medicine, University of Louisville must ensure balance, independence, objectivity, and scien-tific rigor in all its sponsored educational activities. All planners, faculty, reviewers, and other persons that affected the content of this CME activity were required to submit a financial disclosure form from which relevant conflicts of interest were determined. The persons below disclosed the following:

David M. Pariser, MD, Consultant: Anacor Pharmaceuticals, Inc., DUSA Pharmaceuticals, Inc., LEO Pharma Inc., and Valeant Pharmaceuticals North America LLC.Nathaniel J. Jellinek, MD, Advisory Board: Valeant Pharmaceuticals.Phoebe Rich, MD, Grant/Research: Anacor, Meiji Seika Pharma Co., Ltd., Topica Pharmaceuticals, Inc., and Valeant Pharmaceuticals.Melodie S. Young, MSN, RN, A/GNP-c, has no relevant financial relationships to disclose.CME Reviewer: Cindy England Owen, MD, Assistant Professor, Division of Dermatology, University of Louisville School of Medicine, has no relevant financial relationships to disclose.The CME & PD Staff and Advisory Board have nothing to disclose with the exception of Dr. Douglas Coldwell, Speaker: Sirtex, Inc. and Consultant: DFine, Inc.Global Academy for Medical Education Staff: Sylvia H. Reitman, MBA, DipEd; Shirley V. Jones, MBA; and Joanne Still, BA have no relevant financial relation-ships to disclose.

Off-Label/Investigational Use DisclosureThis CME/CE activity discusses the off-label use of fluconazole for the treatment of onychomycosis and unapproved dosing schedules for itraconazole and terbinafine. Also discussed is the use in pediatric patients of medications approved for the treatment of onychomycosis in adults; currently, no medication is approved for the treatment of onychomycosis in pediatric patients.

This continuing education supplement was developed from interviews with the faculty. The Guest Editors acknowledge the editorial assistance of Global Academy for Medical Education and Joanne Still, medical writer, in the development of this supplement. The manuscript was reviewed and approved by the Guest Editors as well as the Editors of Seminars in Cutaneous Medicine and Surgery. The ideas and opinions expressed in this supplement are those of the Guest Editors and do not necessarily reflect the views of the supporters, Global Academy for Medical Education, the University of Louisville, or the Publisher.

Supported by an educational grant from Valeant Pharmaceuticals North America LLC.

Jointly provided by

and

STATEMENT OF PURPOSESeminars in Cutaneous Medicine and Surgery presents well-rounded and authoritative discussions of important clinical areas, especially those undergoing rapid change in the specialty. Each issue, under the direction of the Editors and Guest Editors selected because of their expertise in the subject area, includes the most current information on the diagnosis and management of specific disorders of the skin, as well as the application of the latest scientific findings to patient care.

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Kenneth A. Arndt, MDClinical Professor of Dermatology, Emeritus Harvard Medical School Adjunct Professor of Surgery Dartmouth Medical School Hanover, New Hampshire Adjunct Professor of Dermatology Brown Medical School Providence, Rhode Island

EDITORS

Philip E. LeBoit, MDProfessor of Clinical Dermatology University of California, San Francisco San Francisco, California

Bruce U. Wintroub, MDAssociate Dean Professor and Chair of Dermatology School of Medicine University of California, San Francisco San Francisco, California

Melodie S. Young, MSN, RN, A/GNP-cModern Dermatology A Baylor Health Texas AffiliateDallas, Texas

GUEST EDITORS

June 2015, Vol. 34, No. 3S

Managing Onychomycosis: New and Emerging Treatments and Recurrence Prevention Strategies

TABLE OF CONTENTS

S45 Introduction

S46 Efficacy and Safety of Onychomycosis Treatments: An Evidence-Based Overview David M. Pariser, MD Nathaniel J. Jellinek, MD Phoebe Rich, MD

S51 Understanding Onychomycosis Treatment: Mechanisms of Action and FormulationNathaniel J. Jellinek, MD Phoebe Rich, MD David M. Pariser, MD

S54 Management Strategies for Onychomycosis in Special Patient Populations Phoebe Rich, MD Nathaniel J. Jellinek, MD David M. Pariser, MD

S56 Making Strides in Preventing Onychomycosis Recurrence Melodie S. Young, MSN, RN, A/GNP-c David M. Pariser, MD Phoebe Rich, MD Nathaniel J. Jellinek, MD

S60 Post-Test and Evaluation Form

David M. Pariser, MD, ChairProfessor of DermatologyEastern Virginia Medical School Department of DermatologyPariser DermatologyNorfolk, Virginia

Nathaniel J. Jellinek, MDAssistant Clinical Professor Department of Dermatology Warren Alpert Medical School Brown University Adjunct Assistant Clinical Professor Division of Dermatology University of Massachusetts Medical School Fellowship Director, Procedural Dermatology Dermatology Professionals, Inc. East Greenwich, Rhode Island

Phoebe Rich, MDClinical Adjunct Professor of DermatologyOregon Health Science UniversityPortland, Oregon

Vol. 34, No. 3S, June 2015, Seminars in Cutaneous Medicine and Surgery S45

Vol. 34, No. 3S, June 2015

INTRODUCTION

Until relatively recently, onychomycosis generally was not recognized as an infection that warranted serious clinical consideration. This was due, in part, to the fact that prior to the introduction of oral terbinafine, effective therapy was not available. With the approval by the US Food and Drug Administration (FDA) of terbinafine in 1996 and the subsequent approval of the topical agent

ciclopirox in 1999, interest in diagnosing and treating onychomycosis increased. However, although these new medications were effective in many cases, the achievement of a mycologic cure and cosmetic clearance of the infection were elusive goals for many other patients. Moreover, even after the introduction of these medications, patients typically sought attention for onychomycosis only when pain or other symptoms had progressed to the point at which the infection could no longer be ignored. Early cases of this fungal infection were not commonly identified by either patients or clinicians, and the importance of early treatment was not appreciated. Finally, recurrence was the rule rather than the exception.

Within the past decade, research regarding the pathogenesis of onychomycosis has led to a better understanding of the underlying infectious organisms, the introduction in 2014 of two new topical agents, and, as a result, a resurgence of interest in the diagnosis and treatment of both onychomycosis and a commonly related cutaneous infection, tinea pedis.

In this supplement, the faculty provides an overview of the state of the art in onychomycosis diagnosis and treatment, with a particular focus on the efficacy and safety data from clinical studies of the newer and emerging medications and devices. Also, a discussion of the mechanisms of action of these modalities is presented, to help clinicians tailor therapy according to individual patient profiles. In addition, management strategies for challenging patient populations are offered, as well as some practical approaches for improving treatment results and reducing the risk for recurrence of infection.

The goal of this educational activity is to provide clinicians with up-to-date information on the diagnosis and treatment of onychomycosis that will support their efforts to work with patients to manage or, when possible, eradicate this infection.

1085-5629/13/$-see front matter © 2015 Frontline Medical Communications doi:10.12788/j.sder.2015.0147

Publication of this CME/CE article was jointly provided by the University of Louisville School of Medicine Continuing Medical Education and Global Academy for Medical Education, LLC, and is supported by an educational grant from Valeant Pharmaceuticals North America LLC.

Dr Pariser has received an honorarium for his participation in this activity. He acknowledges the editorial assistance of Joanne Still, medical writer, and Global Academy for Medical Education in the development of this continuing medical education journal article.

David M. Pariser, Consultant: Anacor Pharmaceuticals, Inc., DUSA Pharmaceuticals, Inc., LEO Pharma Inc., and Valeant Pharmaceuticals.

Address reprint requests to: David M. Pariser, MD, Professor of Dermatology, Eastern Virginia Medical School, Department of Dermatology, Pariser Dermatology, 601 Medical Tower, Norfolk, VA 23507; [email protected]

David M. Pariser, MDProfessor of Dermatology

Eastern Virginia Medical SchoolDepartment of Dermatology

Pariser DermatologyNorfolk, Virginia

Journal Supplement Chair

Since the introduction of oral terbinafine in 1996, interest in onychomycosis diagnosis and treatment has increased; the availability of newer medications and devices both reflects

and is a result of that increasing interest. This article provides an evidence-based overview of drug therapy (including systemic and topical antifungal agents and over-the-counter herbal and homeo-pathic topical remedies), laser treatments, and mechanical modalities.

Drug Therapy: Oral Antifungal AgentsFor most cases of onychomycosis seen in the United States, the causative organism is a dermatophyte, most commonly, Trichophyton rubrum. Three oral agents typically are used: fluconazole (not approved by the US Food and Drug Administration [FDA] for this indication), itraconazole, and terbinafine (both of

which are FDA-approved for the treatment of onychomycosis). The Table summarizes the cure rates reported for the agents discussed below.

FluconazoleFluconazole, a triazole, was introduced in 1990 for the treatment and prophylaxis of both localized and systemic Candida albicans infections. For several decades, it also has been studied and used throughout the world for treating onychomycosis. Although fluconazole is approved in other countries for onychomycosis, it is not FDA-approved for this indication.

This agent has not been rigorously examined in large, random-ized, double-blind, placebo-controlled trials for onychomycosis, but several studies of fluconazole suggest that this agent is effective for many patients with onychomycosis. In a multicenter, double-blind study of 362 patients, Scher and colleagues1 tested three dosages of fluconazole in patients with onychomycosis: 150, 300, and 450 mg/week for up to 9 months or until the nail was determined to be clear. The investigators reported clinical cures in 37% of patients who received 150 mg/week, in 46% of patients who received 300 mg/week, and in 48% of patients who received 450 mg/week.

More recently, a group from Poland published the results of a study of fluconazole pulse therapy in 50 patients with laboratory-confirmed dermatophyte infections (in most cases, the infecting organism was T. rubrum).2 Patients were given one 400-mg dose of fluconazole once weekly, for a maximum of 12 months.

Thirty-three patients (66%) completed the trial, which included a 2-month follow-up period. Of the 17 patients who did not complete the trial, 11 (22%) withdrew (4 cited lack of therapeutic effect; 7 gave no reason) and 6 (12%) were excluded because of drug-related adverse effects (including gastrointestinal symp-toms, a transient increase in liver enzyme levels, and skin lesions). Among the 33 patients who completed the treatment and follow-up protocol, 22 (66.7%) had a complete clinical and mycologic cure; 7 (21.2%) had mycologic eradication but not a clinical cure; and 4 (12.1%) had neither clinical nor mycologic cure. The median duration of treatment was 9 months in the group of patients who had complete clinical and mycologic cures. The investigators also noted that the patients with more extensive disease (a greater number of nails and more nail surface involved) and/or longer duration of infection required a longer course of treatment.2

In this study, the relapse rate was low—the investigators reported that only one patient (4.6%) experienced a relapse during the 2-month follow-up period after ending treatment (ie, within 2 months after the achievement of clinical and mycologic cure).2

Among the oral antifungals, fluconazole’s main advantages are once-weekly dosing, few drug-drug interactions, and a relatively low incidence of adverse effects.

ItraconazoleThe FDA-approved regimen for itraconazole treatment of toenail onychomycosis is 200 mg/day continuously for 3 months; according to the prescribing information for this drug, the cure rate with this regimen in the pivotal clinical trials was 14%.3 However, a pulsed-dose regimen—400 mg/day for 7 days for 1 week/month for 4 months—has been shown to be more effec-tive (pulsed dosing is FDA-approved for treating fingernail but not toenail onychomycosis). In a study comparing continuous terbinafine with intermittent (pulsed-dose) itraconazole in almost 500 patients with toenail fungus, Evans and colleagues4

■ AbstractThree systemic agents commonly are used for the treatment of onychomycosis. Until the introduction of ciclopirox in 1999, these were the only FDA-approved therapeutic options for managing these infections. With the recent approval of two new topical antifungal agents—efinaconazole in the azole class, and tavaborole, a unique boron-containing medication— clinicians and patients have an improved roster of medica-tions for managing onychomycosis.Semin Cutan Med Surg 34(supp3):S46-S50 © 2015 published by Frontline Medical Communications

■ Keywords Ciclopirox; dermatophyte infections; efinaconazole; fluconazole; itraconazole; laser therapy; onychomycosis; tavaborole; terbinafine

Efficacy and Safety of Onychomycosis Treatments: An Evidence-Based Overview David M. Pariser, MD,* Nathaniel J. Jellinek, MD,† and Phoebe Rich, MD‡

* Professor of Dermatology, Eastern Virginia Medical School, Department of Dermatology, Pariser Dermatology, Norfolk, Virginia

† Assistant Clinical Professor, Department of Dermatology, Warren Alpert Medical School at Brown University, Adjunct Assistant Clinical Professor, Division of Dermatology, University of Massachusetts Medical School, Fellowship Director, Procedural Dermatology, Dermatology Professionals, Inc., East Greenwich, Rhode Island

‡ Clinical Adjunct Professor of Dermatology, Oregon Health Science University, Portland, Oregon


Dr Pariser, Dr Jellinek, and Dr Rich have received an honorarium for their participation in this activity. They acknowledge the editorial assistance of Joanne Still, medical writer, and Global Academy for Medical Education in the development of this continuing medical education journal article.

David M. Pariser, MD, Consultant: Anacor Pharmaceuticals, Inc., DUSA Pharmaceuticals, Inc., LEO Pharma Inc., and Valeant Pharmaceuticals.

Nathaniel J. Jellinek, MD, Advisory Board: Valeant Pharmaceuticals.

Phoebe Rich, MD, Grant/Research: Anacor, Meiji Seika Pharma Co., Ltd., Topica Pharmaceuticals, Inc., and Valeant Pharmaceuticals.

Address reprint requests to: David M. Pariser, MD, Professor of Dermatology, Eastern Virginia Medical School, Department of Dermatology, Pariser Dermatology, 601 Medical Tower, Norfolk, VA 23507; [email protected]

S46 Seminars in Cutaneous Medicine and Surgery, Vol. 34, No. 3S, June 2015© 2015 Frontline Medical Communications 1085-5629/13/$-see front matter

doi:10.12788/j.sder.2015.0148

reported complete cure (both clinical and mycologic cure) in 25 of 107 patients (23%) after three cycles of intermittent itraconazole and in 28 of 108 patients (26%) after four cycles.

Similar to fluconazole, itraconazole is generally well tolerated; Scher reported adverse effects in approximately 3% of patients.5 The more commonly reported adverse effects were headache, gastrointestinal effects (including diarrhea, dyspepsia, nausea, and abdominal pain), and cutaneous symptoms including rash, pruritus, and urticaria. Acute generalized exanthematous pustulosis has been reported as a rare adverse event that resolves almost completely within a few weeks of cessation of the drug and use of corticosteroids.6 Gupta and Shear reported liver enzyme elevations in 0.3% to 0.5% of patients treated with itraconazole.7

The use of itraconazole for onychomycosis is contraindicated in patients with congestive heart failure (CHF) or a history of CHF or evidence of other types of ventricular dysfunction. Also, because itraconazole is a potent inhibitor of cytochrome p450 3A4, it can elevate plasma concentrations of some medica-tions, resulting in serious cardiovascular events. Simultaneous use of itraconazole with these medications (such as cisapride, quini-dine, and simvastatin) is contraindicated.3 In addition, Ahmad and colleagues8 reported that itraconazole has a negative inotropic effect on the heart in healthy individuals.

Because of itraconazole’s greater risk for adverse effects compared to terbinafine, itraconazole is considered a second-line agent. It is an option in patients who have failed treatment with

or cannot tolerate terbinafine, or when culture and sensitivity testing indicates that the infecting organisms are more susceptible to itraconazole.

TerbinafineTerbinafine’s FDA-approved toenail onychomycosis regimen is 250 mg/day for 12 weeks.9 Drake and colleagues10

reported

a complete cure rate of 38% with terbinafine 250 mg/day for 3 months and no significant difference in response between 12-week and 24-week treatment courses. In the Lamisil® vs Itraconazole in ONychomycosis (LION) study of 496 patients,4 a complete cure was seen in 49% of patients with a 12-week course of terbinafine; 54% of patients had a complete cure with a 16-week regimen.

Tosti and colleagues11 examined the relapse rates of patients who had mycologic cures with terbinafine compared to those who had mycologic cures with itraconazole in an open, randomized study. The investigators followed 47 patients with T. rubrum infections who had been treated with intermittent itraconazole or contin-uous or intermittent terbinafine. From the point at which they ended treatment, patients were examined every 3 months for up to 3 years; evaluations included direct microscopy and cultures. Of the 36 patients who completed the study, 8 (22.2%) experienced a relapse by the end of the 36-month follow-up period: two patients who had received 250 mg/day of terbinafine continuously for 12 weeks, two patients who had been treated with 500 mg/day of terbinafine for 1 week of each month for 3 months, and four patients treated with itraconazole, 400 mg/day for 1 week of each month for 3 months. The investigators reported that pulse-dosed itraconazole was more commonly associated with relapse (4 out of 11 patients) than continuous (2 out of 12 patients) or pulse-dosed terbinafine (2 out of 13 patients), although the differences in relapse among the three groups was not statistically significant. (Pulsed-dose therapy with terbinafine is not FDA-approved at this time.)

Drug Therapy: Topical Antifungal AgentsThree medications are FDA-approved for the topical treatment of onychomycosis. Ciclopirox, FDA-approved in 1999, was the first of these to be introduced. Efinaconazole and tavaborole were both FDA-approved in 2014.

CiclopiroxCiclopirox 8% solution is a lacquer formulation indicated for use in immunocompetent patients with mild to moderate onychomy-cosis without involvement of the lunula and due to T. rubrum. Its use requires regular debridement consisting of removal by a health care professional (as frequently as once a month) of unattached, infected nails, along with trimming and filing affected nails. In addition, the treatment protocol requires patients to remove the lacquer with alcohol every 7 days, to keep nails trimmed, and to use an emery board to file away loose nail material.

Ciclopirox is associated with complete cure rates ranging from 5.5% to 8.5%, as part of the management protocol (with frequent nail debridement) described above.12 In controlled clinical trials, the reported mycologic cure rate is 29% to 36%, and the clinical cure rate (clear or almost clear nails) ranges from 6% to 9%.13

Ciclopirox has also been investigated as an adjunct to improve the efficacy of systemic therapy. In one such study, Avner and colleagues14 compared oral terbinafine monotherapy with oral terbinafine plus ciclopirox and found that the combination yielded a complete cure rate of 68% and a mycologic cure rate of 88%, whereas the oral agent alone was associated with a complete cure rate of 50% and a mycologic cure rate of 65%.

The adverse effects associated with the use of ciclopirox gener-ally are mild, including burning, itching, and stinging at the application site.15

EfinaconazoleEfinaconazole solution, which does not require removal each week, is a topical triazole antifungal FDA-approved for once-daily


■ TABLE Efficacy of Antifungals in Onychomycosis: Complete Cure Rates Reported in Selected Clinical Trials*

Oral Antifungal Agents

Medication and Regimen Complete Cure Rates

Fluconazole1

150 mg/week 37%

300 mg/week 46%

450 mg/week 48%

Itraconazole

200 mg/day x 12 weeks3 14%

400 mg/day for 1 week/month4

Repeated for 3 pulses 23%Repeated for 4 pulses 26%

Terbinafine

250 mg/day x 12 weeks10 38%

250 mg/day for 1 week/month4

Repeated for 3 pulses 49%Repeated for 4 pulses 54%

Topical Antifungal Agents

Ciclopirox 8%12 5.5% to 8.5%

Efinaconazole16 15% and 18% (in two phase III trials, respectively)

Tavaborole17 6.5% and 9.1% (in two phase III trials, respectively)

*The dosage regimens shown are not necessarily FDA-approved. Itraconazole is not FDA-approved for intermittent dosing for the treatment of toenail onychomycosis.

David M. Pariser, MD, Nathaniel J. Jellinek, MD, and Phoebe Rich, MD

application for 48 weeks. Application instructions specify that the medication must completely cover the toenail folds and bed, the hyponychium, and the undersurface of the nail plate.

In two identical multicenter, randomized, double-blind, vehicle-controlled studies, Elewski and colleagues16 evaluated the efficacy and safety of efinaconazole 10% solution versus placebo in a total pool of 1,655 subjects. To be included in the studies, subjects were required to be between 18 and 70 years of age and have a clinical diagnosis of distal lateral subungual (DLS) onychomycosis of at least one great toenail, with 20% to 50% clinical involvement. Women with childbearing potential were required to use birth control during the study. Other eligibility requirements included 3 mm or more of uninfected nail on the target toenail from the proximal nail fold, evidence of toenail growth, a positive result on potassium hydroxide (KOH) microscopy, and a culture demonstrating the presence of dermatophyte or mixed dermatophyte and Candida organisms 42 days or less before beginning the study.

Excluded from participation were individuals with a history of immunosuppression and/or clinical signs that indicated possible immunosuppression, HIV infection, uncontrolled diabetes mellitus, the presence of toenail infection with organisms other than dermatophytes, the presence of severe moccasin-type tinea pedis at screening or baseline, previous surgery involving the target toenail, or any disease or condition that might have resulted in toenail abnormalities or interfered with clinical evaluation.

In study 1, 870 patients were randomized to receive either efina-conazole (n=656) or vehicle (n=214); in study 2, 785 patients were randomized to receive either the study medication (n=583) or vehicle (n=202). Subjects applied the medication or vehicle to the target toenail once daily for 48 weeks.

The primary end point for efficacy was the proportion of patients who achieved a complete cure, as evaluated at week 52—ie, 4 weeks after the final application. Cure was defined as complete clinical clearance of the target toenail and mycologic cure demonstrated by a negative result on potassium hydroxide examination and negative culture.

A total of 1,436 patients completed the 48-week treatment period, and 1,420 (85.5%) completed through the 4-week follow-up at week 52. Early discontinuations—235 patients—were due to patient request (98 patients; 41.7%), lost to follow-up (78 patients; 33.2%); adverse events (33 patients; 14.0%); protocol violation (7 patients; 3.0%); worsening condition (1 patient; 0.5%), and pregnancy (1 patient; 0.5%). The other discontinuations (17 patients; 7.2%) were for other reasons.

At the follow-up evaluation at week 52, 17.8% of patients in study 1 and 15.2% of patients in study 2 had a complete cure with efinaconazole compared to 3.3% and 5.5% of patients in the vehicle groups in study 1 and study 2, respectively. The differences in both studies were significant (P<0.001 for both comparisons).

In study 1, mycologic cures were seen in 55.2% of patients on efinaconazole compared with 16.8% of patients in the vehicle group (P<0.001). In study 2, mycologic cures were seen in 53.4% of patients on efinaconazole compared with 16.9% of those in the vehicle group (P<0.001). Treatment success—that is, improvement to less than 10% clinical involvement of the target nail—was seen in 35.7% of patients on efinaconazole in study 1 and 31.0% of patients on the active medication in study 2, compared with 11.7% (study 1) and 11.9% (study 2) of patients in the vehicle groups (P<0.001).

The investigators noted that both of these studies were 52 weeks in duration, whereas complete toenail regrowth requires up to 78 weeks. Thus, they say, the cure rates for efinaconazole actually may be higher than reported in these studies.

The adverse events in efinaconazole-treated patients were similar to those seen in the vehicle-only group in both studies. In study 1, the adverse event rates were 66% in the active-treatment group versus 61% in the control group; in study 2, the adverse

event rates were 64.5% versus 58.5% for efinaconazole and vehicle groups, respectively. Almost all of the reported adverse events were unrelated to the study drug. In study 1, 91.8% and 98.6% of the adverse events in the efinaconazole and vehicle-only groups, respectively, were unrelated to treatment. In study 2, the corresponding rates were 92.7% versus 96.9%. The most common adverse events that led to study discontinuation—dermatitis and vesicles—were treatment-related and occurred at the application sites. Application site dermatitis was seen in 23 patients (3.5%) on efinaconazole in study 1; no patients in the vehicle group in study 1 or in either the active-treatment or vehicle group in study 2 had application site dermatitis. Application site vesicles were seen in 13 patients (2.0%) in the efinaconazole group in study 1 and 7 patients (1.2%) in the active-treatment group in study 2; no vesicles were seen in the vehicle groups in either study.

TavaboroleTavaborole solution 5% is a novel, boron-based topical agent that inhibits the synthesis of fungal proteins and halts fungal cell growth. Tavaborole solution is applied with a dropper to the entire nail surface and under the nail tips; as with efinaconazole, removal of the medication is not required. The FDA-approved dosing is once-daily application for 48 weeks.

The results of two phase III clinical trials led to the FDA approval of tavaborole in 2014.17 These multicenter, double-blind, vehicle-controlled, parallel-group, randomized studies involved a total of 1,198 participants (n=594 in study 1; n=604 in study 2) with distal subungual onychomycosis involving between 20% and 60% of at least one great toenail. Infection was established by a positive KOH wet mount and a positive culture for dermato-phytes. Eligibility also required at least 3 mm of clear nail between the proximal nail fold and the most proximal visible border of infection on the target great toenail (TGT); a thickness of 3 mm or less on the distal TGT also was required.

Excluded from the study were patients with proximal subungual or superficial white onychomycosis, severe disease, dermatophy-toma, exclusively lateral infection, yellow/brown spikes in the nail plate, coinfection with nondermatophyte fungal organisms, active tinea pedis infections requiring treatment or a history of moccasin-pattern tinea pedis (ie, involving the sides or back of the foot), a history of other significant fungal disease, or one of several comorbid diseases (psoriasis, lichen planus, immunode-ficiency, peripheral vascular disease, structural heart disease, or uncontrolled diabetes mellitus).

Patients who met the eligibility criteria were randomly assigned in a 2:1 ratio to receive either tavaborole or vehicle, which was applied by the patient to the TGT daily for 48 weeks. Patients were instructed to apply an even, thin layer of the study treatment on, under, and around the TGT as well as any infected nontarget toenails. Nail debridement was not permitted in this study.

Assessments for disease involvement were done at screening, on day 1 (the baseline assessment), at weeks 2 and 6, and then every 6 weeks through week 48. At 4 weeks post-treatment (ie, week 52), follow-up assessments were done.

Complete cure of the TGT—completely clear nail and nega-tive mycology (that is, negative KOH wet mount plus negative fungal culture) at week 52—was the primary endpoint for efficacy. A completely clear nail was defined as absence of clinical evidence of fungal infection compared to a normal toenail plate, no onycholysis, and no subungual keratosis. At each visit, patients were monitored for adverse events (AEs), treatment-emergent AEs, and serious AEs; each patient’s vital signs, laboratory param-eters, and EKG also were monitored throughout the study.

Complete cure was seen in study 1 in 6.5% of patients on tava-borole versus 0.5% of patients treated with vehicle alone in study 1 (P=0.001); in study 2, the primary end point was reached in 9.1% of patients on tavaborole versus 1.5% of patients in the vehicle-only group (P<0.001).

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The secondary endpoints included completely or almost clear nail (10% or less affected) of the TGT, negative mycology, and completely clear or almost clear nail plus negative mycology. Achievement of all of these secondary endpoints was significantly greater in the tavaborole-treated patients in both studies compared to the vehicle groups (P<0.001 for all comparisons). Specifically, the combined rates of completely clear or almost clear nail at week 52 in the tavaborole-treated patients were 26.1% in study 1 and 27.5% in study 2, compared to 9.3% and 14.6% in the vehicle-only patients in study 1 and 2, respectively (P<0.001 for both compari-sons). A negative fungal culture was reported at week 52 in 31.1% and 35.9% of patients on tavaborole in study 1 and 2, respectively, compared to 7.2% and 12.2% (P<0.001 for both comparisons).

The most commonly seen treatment-emergent AEs were mild or moderate in severity and included tinea pedis, nasopharyngitis, upper respiratory infection, back pain, and ingrowing nail; most of the treatment-emergent AEs were considered either unrelated or not likely to be related to the use of tavaborole. The most commonly reported application site treatment-related AEs were exfoliation (2.7%), erythema (1.6%), and dermatitis (1.3%) for both studies combined. The incidence of treatment-emergent AEs that were related to treatment was higher in the tavaborole group than in the vehicle group in both studies—8.8% vs. 0.5%, respec-tively, in study 1; 3.3% vs. 2.6%, respectively, in study 2. The rates of discontinuation as a result of treatment-emergent AEs was low in both studies and similar in treatment and vehicle groups: one patient in the tavaborole group in study 1 and two patients in the active-treatment group in study 2 discontinued treatment; in the vehicle groups two patients in study 1 and one patient in study 2 discontinued because of treatment-emergent AEs.

Self-Medication With Other Topical Antifungal AgentsMany so-called natural, folk, or home remedies or other agents have been used and are touted in lay literature sources as effective treatments—even complete cures—for onychomy-cosis. Clinicians frequently hear reports from patients that they “read about” and tried one or more of these regimens, either as monotherapy or as adjuncts that they believe will enhance the efficacy of their prescription medications. Testimonials abound on Internet sites focused on toenail fungus, which also carry advertisements for numerous remedies, some of which promise to cure onychomycosis within a short time with no side effects. Such proprietary over-the-counter agents, household products, and methods include daily applications of tea tree oil, a popular camphor-containing ointment, chlorine bleach, hydrogen peroxide, and oregano oil, as well as acidic (typically vinegar) or antifungal foot baths (such as chlorine bleach solutions or antiseptic mouthwash).

Although rigorous, evidence-based studies are lacking, the claims of efficacy by patients for many of these products do have some theoretical scientific basis. For example, the active ingredients in one popular brand of antiseptic mouthwash are essential oils (menthol, thymol, methyl salicylate, and eucalyptol) that may have antifungal activity.

Experience with the use of several products in patients with onychomycosis has been discussed in the literature. Derby and colleagues18 published the results of a pilot study of a brand of camphor-containing ointment in 18 patients with laboratory-confirmed onychomycosis. The patients were seen at baseline and at 4, 8, 12, 24, 36, and 48 weeks. The primary outcome measures were mycologic and clinical cure; the latter was assessed by both appearance of the nail and the degree of change in the treated nail according to an analysis of digital photographs before and after treatment. According to these investigators, 5 patients (27.8%) achieved the primary end point of both mycologic and clinical cure at 48 weeks. In addition, 10 patients (55.6%) had partial clear-ance of the treated nail. Although three patients (16.7%) had no

change, all 18 patients said they were either satisfied (9 patients) or very satisfied (9 patients) with the appearance of the treated nail.

Two studies examined the possible efficacy of tea tree oil (essen-tial oil of Melaleuca alternifolia) for onychomycosis. Flores and colleagues19 reported that nanocapsules and nanoemulsions containing tea tree oil demonstrated antifungal activity in vitro on samples of nail powder and nail fragments infected with T. rubrum. Buck and coworkers20 compared tea tree oil and clotrimazole in a double-blind, multicenter, randomized, controlled trial involving 117 patients with culture-proven distal subungual onychomycosis. In that study, patients applied either clotrimazole solution, 1%, or a 100% tea tree oil to the affected nail twice daily for 6 months. Debridement was performed at baseline and at follow-up visits at 1, 3, and 6 months. Cultures were obtained at baseline and at month 6. These investigators reported that after 6 months of treat-ment, mycologic cure (based on culture) was seen in 13 (11.1%) of the patients who used clotrimazole and 21 (17.9%) of those who used tea tree oil. Partial or full clinical clearance was seen in 71 (61%) of the patients who used clotrimazole and in 70 (60%) of those who used tea tree oil. Continued improvement or resolution was reported in 64 patients (55%) in the clotrimazole group and 65 patients (56%) treated with tea tree oil.

Many of these products are not harmful and are inexpensive, although when patients use these instead of FDA-approved prescription medication, control of the infection is delayed. In such cases, the clinician’s role is to discuss what is known about products such as essential oils and to suggest a time frame. Nevertheless, patients who are resistant to prescription medica-tions and prefer to try these alternatives instead of prescription medications should be advised to return in a specified period of time if the infection does not clear or worsens.

Efficacy and Safety of Pharmaceutical Onychomycosis Treatments: Meta-AnalysesNo head-to-head studies have been done comparing systemic and topical agents for onychomycosis, but several meta-analyses have been published that can help guide clinicians regarding therapeutic choices. Gupta and colleagues21 systematically reviewed the literature on onychomycosis treatments published prior to March 2013. According to their network meta-analysis, terbinafine 250 mg was significantly superior to all treatments and regimens considered, except for intermittent treatment with itraconazole 400 mg, administered for 1 week/month for 3 months (ie, a pulse-dosed therapy regimen). The authors also noted that the results from studies of topical treatments suggested these agents had equivalent efficacy.

A meta-analysis of studies of systemic antifungals by de Sá et al22 demonstrated that terbinafine was superior to itraconazole and fluconazole for dermatophyte infections, and that itraconazole was superior to both of the other agents for onychomycosis caused by Candida spp and nondermatophyte molds.

Lasers and Photodynamic TherapyThe potential benefits of both laser treatment and photodynamic therapy for onychomycosis are that these are clinician-applied treatments, requiring no compliance on the part of the patient, and are associated with no systemic effects. However, the data regarding efficacy of these types of modalities are limited, and the cure rates similar to what are required for drug approval by the FDA generally are unsatisfactory or unreported.

A number of laser systems are FDA-approved for the treatment of onychomycosis. However, the FDA approval of these devices specifies that they are indicated for the “temporary increase of clear nail in onychomycosis,” and no claims are made regarding the rates of mycologic or clinical cures. Moreover, the clinical studies on lasers in onychomycosis are limited, and it is not possible to compare the efficacy of these devices to the efficacy of oral and topical medications.


David M. Pariser, MD, Nathaniel J. Jellinek, MD, and Phoebe Rich, MD

Recently, Bristow23 published a systematic review of 12 studies on the use of lasers for treating onychomycosis. The studies consid-ered were two randomized, controlled trials, four comparative studies with no placebo or control groups, and six case series. In all 12 studies, the primary outcome measures were mycologic cure and clearance of the target nail (clinical cure). From the review, the investigator concluded that the evidence on laser treatment of onychomycosis was “limited and of poor methodological quality.” The level of evidence generally was considered to be low because of the small sample sizes in the studies and the lack of control groups. In addition, the author noted that the study results were conflicting and the follow-up periods were short.

In a rigorous evaluation of the submillisecond neodymium: yttrium-aluminum-garnet (Nd:YAG) 1064-nm laser, Carney and colleagues24 evaluated the in vitro effects of this device on common fungal nail pathogens as well as its clinical efficacy and safety in patients with onychomycosis of the toenails. The in vitro portions of the study involved thermal exposure and irradia-tion of pathogens. The thermal tests included the dermatophytes T. rubrum, Epidermophyton floccosum, and Scytalidium dimidiatum, and a nondermatophyte mold organism, Scytalidium hyalinum, prepared in liquid suspensions subjected to various heat and time exposures. The laser tests involved direct exposure of T. rubrum colonies or irradiation of organisms in suspensions.

The in vivo portion of the study involved 10 patients with clinically diagnosed DLS onychomycosis of at least one great toenail and at least 2 mm of healthy nail measured from the proximal nail fold; 18 great toenails were eligible as treatment targets. Dermatophyte infection was demonstrated by culture. In this 24-week pilot study, the entire nail plates in the target toenails were treated with the submillisecond Nd:YAG laser, 1064-nm wavelength. Patients were seen monthly for 6 months, and at each of those visits, investigators measured healthy nail growth from the proximal nail fold and the percent of disease involvement; the Onychomycosis Severity Index (OSI) score also was calculated. The OSI, developed by Carney and colleagues,25 is a score derived from an evaluation of four factors: the percentage of nail plate involvement, the proximity of infection to the matrix, the degree of subungual hyperkeratosis, and the presence of dermatophytoma. At weeks 2, 7, 15, and 24, potassium hydroxide and mycologic studies were performed.

The primary outcome measure was clinical improvement in the target toenail within the 24-week study period, based on healthy nail growth from the proximal nail fold, percentage of disease involvement, and OSI score. Mycologic cure at week 24 was the secondary outcome measure.

The in vitro testing showed some fungicidal effects with thermal exposures, but no inhibition of growth was seen in the laser-treated organisms. The patients in the in vivo study had no improvement in OSI.

Although studies of photodynamic therapy (PDT) have demon-strated that this modality eradicates dermatophytes involved in onychomycosis,26-28 no PDT system is FDA-approved for treating onychomycosis. This modality may be an option for chronic infec-tions that have not responded to other therapies, and/or when the causative organism is a nondermatophyte mold.29

Iontophoresis has been used to create perforations in the nail plate to enhance penetration of topical agents; however, this modality is still in the investigational stages of development.30

Surgical InterventionUnder certain selected circumstances, mechanical modalities—nail avulsion or matrixectomy—may be appropriate to manage onychomycosis. These techniques may be considered when only one nail is infected and other treatments for dermatophyte organisms have not been successful or when a nondermatophyte mold is the culprit.

ConclusionThe introduction in recent months of two FDA-approved topical agents for treatment of onychomycosis—efinaconazole and tavaborole—has renewed interest of patients and practitioners in this common condition. Patients and practitioners reluctant to use systemic medications now have two treatment alternatives with higher efficacy than previously available topical therapies.

References1. Scher RK, Breneman D, Rich P, et al. Once-weekly fluconazole (150, 300, or 450 mg)

in the treatment of distal subungual onychomycosis of the toenail. J Am Acad Dermatol. 1998;38 (6, pt 2):S77-S86.

2. Hryncewicz-Gwózdz A, Plomer-Niezgoda E, Kalinowska K, Czarnecka A, Maj J, Jagielski T. Efficacy of fluconazole at a 400 mg weekly dose for the treatment of onychomycosis. Acta Derm Venereol. 2015;95:251-252.

3. Sporanox® (itraconazole) [package insert]. Raritan, NJ: PriCara, Division of Ortho-McNeil-Janssen Pharmaceuticals, Inc; 2011.

4. Evans EGV, Sigurgeirsson B, for the LION Study Group. Double blind, randomised study of continuous terbinafine compared with intermittent itraconazole in treatment of toenail onychomycosis. BMJ. 1999;318:1031-1035.

5. Scher RK. Onychomycosis: Therapeutic update. J Am Acad Dermatol. 1999;40:S21-S26.

6. Hall AP, Tate B. Acute generalized exanthematous pustulosis associated with oral terbinafine. Australasian J Dermatol. 2000;41:42-45.

7. Gupta AK, Shear NH. A risk-benefit assessment of the newer oral antifungal agents used to treat onychomycosis. Drug Safety. 2000;22:1-52.

8. Ahmad SR, Singer SJ, Leissa BG. Congestive heart failure associated with itracon-azole. Lancet. 2001;357:1766-1767.

9. Lamisil® (terbinafine) [package insert]. East Hanover, NJ: Novartis Pharmaceuticals; 2012.

10. Drake LA, Shear NH, Arlette JP, et al. Oral terbinafine in the treatment of toenail onychomycosis: North American multicenter trial. J Am Acad Dermatol. 1997;37(5, pt1):740-745.

11. Tosti A, Piraccini BM, Stinchi C, Colombo MD. Relapses of onychomycosis after successful treatment with systemic antifungals: A three-year follow-up. Dermatology. 1998;197:162-166.

12. Penlac® (ciclopirox 8%) [package insert]. Bridgewater, NJ: Dermik Laboratories; 2006.

13. Gupta AK, Fleckman P, Baran R. Ciclopirox nail lacquer topical solution 8% in the treatment of toenail onychomycosis. J Am Acad Dermatol. 2000;43 (4 suppl):S70-S80.

14. Avner S, Nir N, Henri T. Combination of oral terbinafine and topical ciclopirox compared to oral terbinafine for the treatment of onychomycosis. J Dermatolog Treat. 2005;16(5-6):327-330.

15. Rotta I, Sanchez A, Gonçalves PR, Otuki MF, Correr CJ. Efficacy and safety of topical antifungals in the treatment of dermatomycosis: A systematic review. Br J Dermatol. 2012;166:927-933.

16. Elewski BE, Rich P, Pollak R, et al. Efinaconazole 10% solution in the treatment of toenail onychomycosis: Two phase III multicenter, randomized, double-blind studies. J Am Acad Dermatol. 2013;68:600-608.

17. Eleweski BE, Aly R, Baldwin SL, et al. Efficacy and safety of tavaborole topical solution, 5%, a novel boron-based anti fungal agent, for the treatment of toenail onychomycosis: Results from 2 randomized phase III studies. J Am Acad Dermatol. 2015;73:62-69.

18. Derby R, Rohal P, Jackson C, Beutler A, Olsen C. Novel treatment of onychomy-cosis using over-the-counter mentholated ointment: A clinical case series. J Am Board Fam Med. 2011;24:69-74.

19. Flores FC, de Lima JA, Ribeiro RF, et al. Antifungal activity of nanocapsule suspensions containing tea tree oil on the growth of Trichophyton rubrum. Mycopathologia. 2013;175:281-286.

20. Buck DS, Nidorf DM, Addino JG. Comparison of two topical preparations for the treatment of onychomycosis: Melaleuca alternifolia (tea tree) oil and clotrimazole. J Fam Pract. 1994;38:601-605.

21. Gupta AK, Daigle D, Paquet M. Therapies for onychomycosis: A systematic review and network meta-analysis of mycological cure [published online ahead of print July 17, 2014]. J Am Podiatr Med Assoc. 2014. doi: http://dx.doi.org/ 10.7547/13-110.1.

22. de Sá DC, Lamas AP, Tosti A. Oral therapy for onychomycosis: An evidence-based review. Am J Clin Dermatol. 2014;15:17-36.

23. Bristow IR. The effectiveness of lasers in the treatment of onychomycosis: A systematic review. J Foot Ankle Res. 2014;7:34.

24. Carney C, Cantrell W, Warner J, Elewski B. Treatment of onychomycosis using a submillisecond 1064-nm neodymium:yttrium-aluminum-garnet laser. J Am Acad Dermatol. 2013;69:578-582.

25. Carney C, Tosti A, Daniel R, et al. A new classification system of grading the severity of onychomycosis: Onychomycosis severity index. Arch Dermatol. 2011;147:1277-1282.

26. Piraccini BM, Rech G, Tosti A. Photodynamic therapy of onychomycosis caused by Trichophyton rubrum. J Am Acad Dermatol. 2008;59(5 suppl):S75-S76.

27. Watanabe D, Kawamura C, Masuda Y, Akita Y, Tamada Y, Matsumoto Y. Successful treatment of toenail onychomycosis with photodynamic therapy. Arch Dermatol. 2008;144:19-21.

28. Donnelly RF, McCarron PA, Lightowler JM, Woolfson AD. Bioadhesive patch- based delivery of 5-aminolevulinic acid to the nail for photodynamic therapy of onychomycosis. J Control Release. 2005;103:381-392.

29. Gilaberte Y, Aspiroz C, Martes MP, Alcalde V, Espinel-Ingroff A, Rezusta A. Treatment of refractory fingernail onychomycosis caused by nondermatophyte molds with methylaminolevulinate photodynamic therapy. J Am Acad Dermatol. 2011;65:669-671.

30. Gupta A, Brintnell W. Onychomycosis therapy: Past, present, and future. J Am Acad Dermatol. 2012;66(4 suppl 1):AB120.

■ ❚ ❙ Efficacy and Safety of Onychomycosis Treatments: An Evidence-Based Overview


1085-5629/13/$-see front matter © 2015 Frontline Medical Communications doi:10.12788/j.sder.2015.0149

The majority of onychomycosis cases in the United States are caused by a dermatophyte, most commonly, Trichophyton rubrum, also the most common cause of tinea pedis

(commonly referred to as athlete’s foot).1 Less common causative organisms include other dermatophytes, nondermatophyte molds, and occasionally yeasts (Table on page 52). The medications used to treat these infections demonstrate different sensitivities, depending on the causative organism(s).

The purpose of this article is to review the agents and devices used to treat onychomycosis, describing their mechanisms of action.

Systemic AgentsTwo classes of systemic agents commonly are used for the treat-ment of onychomycosis: azole antifungal agents—specifically, the triazoles fluconazole and itraconazole—and an agent from the allylamine class, terbinafine. Only itraconazole and terbinafine have received approval by the US Food and Drug Administration (FDA) for this indication. The most common adverse effects associated with the use of the systemic agents are headache and gastrointestinal symptoms (nausea, vomiting, and diarrhea). Transient mild to moderate elevations in serum aminotransferase have been seen with these medications,2 and hepatotoxicity also has been reported, with rare hematologic effects. Before beginning treatment and after 1 month of therapy, laboratory studies are advisable—at least serum transaminases, but some clinicians also obtain a full liver profile and blood count.

Triazole Antifungal Agents—Fluconazole and ItraconazoleTriazole antifungal agents inhibit the fungal p450 enzyme 14 alpha-demethylase, which, in turn, blocks conversion of lanosterol to ergosterol and ultimately inhibits the essential production of ergosterol in fungal cell membranes. Ergosterol depletion causes growth-inhibiting disruption of these cell membranes. Triazole antifungal agents are considered fungistatic rather than fungicidal.

Fluconazole is FDA-approved for the treatment of superficial and systemic Candida albicans infections as well as cryptococcal meningitis; although it is not specifically indicated for onycho-mycosis, it has been widely studied and is commonly used to treat this infection.

Itraconazole has demonstrated effective minimum inhibitory concentration (MIC) in vitro activity against Trichophyton species, other less commonly associated causative organisms in onycho-mycosis (Aspergillus flavus and Aspergillus fumigatus), and several other fungal species that do not cause onychomycosis. Itraconazole is not effective against Fusarium spp, one of the most common nondermatophyte mold causes of onychomycosis, nor against the mold Scopulariopsis spp. Prolonged treatment with itraconazole may result in resistance of some fungal organisms, and cross- resistance with other azole antifungal agents has been reported.

TerbinafineTerbinafine inhibits ergosterol biosynthesis through inhibition of the enzyme squalene oxidase (rather than p450 and lanosterol-converting enzymes). Fungal cell death results primarily through cell membrane changes mediated by squalene instead of by ergosterol deficiency.3 Terbinafine is considered fungicidal rather than fungistatic. In vivo and in vitro testing have demonstrated that terbinafine is highly effective against dermatophyte organisms, and may be effective against some azole-resistant strains of Candida albicans, as well as Candida parapsilosis.

Topical Antifungal AgentsTopical antifungal agents lack the systemic adverse effects or drug-drug interactions associated with fluconazole, itraconazole, and terbinafine, as described above, and generally feature a low

■ AbstractHistorically, the eradication of onychomycosis has been a frustrating and often unsuccessful endeavor. However, new understanding about the mechanisms of action of anti-fungal agents, the introduction of two new topical agents, and the drugs and devices now being investigated offer greatly improved options for current and future management of these infections. The mechanisms of action of systemic and topical antifungal agents and devices effective against the most common dermatophyte and nondermatophyte causes of onychomycosis are discussed. Semin Cutan Med Surg 34(supp3):S51-S53 © 2015 published by Frontline Medical Communications

■ Keywords Ciclopirox; efinaconazole; fluconazole; itraconazole; laser therapy; onychomycosis; photodynamic therapy; tavaborole; terbinafine

Understanding Onychomycosis Treatment:Mechanisms of Action and FormulationNathaniel J. Jellinek, MD,* Phoebe Rich, MD,† and David M. Pariser, MD‡

* Assistant Clinical Professor, Department of Dermatology, Warren Alpert Medical School at Brown University, Adjunct Assistant Clinical Professor, Division of Dermatology, University of Massachusetts Medical School, Fellowship Director, Procedural Dermatology, Dermatology Professionals, Inc., East Greenwich, Rhode Island

† Clinical Adjunct Professor of Dermatology, Oregon Health Science University, Portland, Oregon

‡ Professor of Dermatology, Eastern Virginia Medical School, Department of Dermatology, Pariser Dermatology, Norfolk, Virginia


Dr Jellinek, Dr Rich, and Dr Pariser have received an honorarium for their participation in this activity. They acknowledge the editorial assistance of Joanne Still, medical writer, and Global Academy for Medical Education in the development of this continuing medical education journal article.


Phoebe Rich, MD, Grant/Research: Anacor Pharmaceuticals, Inc., Meiji Seika Pharma Co., Ltd., Topica Pharmaceuticals, Inc., and Valeant Pharmaceuticals.

David M. Pariser, MD, Consultant: Anacor, DUSA Pharmaceuticals, Inc., LEO Pharma Inc., and Valeant Pharmaceuticals.

Address reprint requests to: Nathaniel J. Jellinek, MD, Fellowship Director, Procedural Dermatology, Dermatology Professionals, Inc., 1672 South County Trail, Suite 101, East Greenwich, RI 02818; [email protected]


incidence of serious local adverse effects. Historically, the main disadvantages of topical therapy were poor bioavailability—and, in turn, less efficacy compared to systemic agents—and the need for frequent debridement of the affected nails by a clinician and weekly removal of the lacquer by patients. Two newer topical agents, efinaconazole and tavaborole, have demonstrated improved efficacy compared with other topical agents and are not formulated as lacquers (thus, removal is not necessary).

Ciclopirox 8% SolutionCiclopirox, a synthetic antifungal agent, has been available in the United States since 1996. It was the first topical medication approved by the FDA for the treatment of onychomycosis. Its mechanism of action is poorly understood. Leem and colleagues4 investigated the activity of this agent against the yeast Saccharomyces cerevisiae and found that ciclopirox seemed to target proteins in the yeast that affected the replication and repair of DNA as well as cellular trans-port. These researchers proposed that ciclopirox inhibits cell growth and metabolism, possibly through several targets in the organism.

EfinaconazoleEfinaconazole is an azole antifungal agent, with a mechanism of action identical to that of the systemic triazole agents discussed above—ie, inhibition of 14-alpha demethylase, with resulting downstream disruption of fungal cell membranes. However, the systemic adverse effects that are problematic with itraconazole and fluconazole are not seen with this topical agent.

Efinaconazole shows in vitro activity against T. rubrum and Trichophyton mentagrophytes. No clinically significant evidence of drug resistance to efinaconazole has been observed.

In addition, efinaconazole has been shown to have low keratin affinity; Sugiura and colleagues5 suggested that this prop-erty enhances efinaconazole’s nail penetration and contributes to its fungicidal activity. These investigators tested free-drug concentrations—in suspensions prepared from keratin samples— of efinaconazole, ciclopirox, and amorolfine (similar to ciclopirox, amorolfine is an agent in a lacquer formulation; amorolfine is not FDA-approved). The free-drug concentration of efinaconazole was 14.3%, compared to 0.7% for ciclopirox and 1.9% for amorol-fine, respectively (P<0.001). They also tested the penetrations of these three agents through full-thickness, T. rubrum–infected

human nails. Efinaconazole’s fungicidal activity was comparable to that observed with amorolfine and superior to the fungicidal activity of ciclopirox. In another experiment in a guinea pig model with T. mentagrophytes onychomycosis, efinaconazole decreased the fungal burden significantly more than ciclopirox and amorol-fine lacquers (P<0.01).5

TavaboroleTavaborole represents a new class of boron-containing drugs; it is a low-molecular weight, water-soluble agent, formulated in a topical nail solution that retains antifungal properties in the presence of keratin. Its mechanism of action is thought to be through inhibition of the enzyme aminoacyl-transfer ribonucleic acid synthetase, which downstream inhibits fungal protein synthesis. Tavaborole is active against most strains of T. rubrum and T. mentagrophytes, the two species most commonly found in onychomycosis. No resistance to tavaborole has been observed in studies involving repeated exposure of these organisms to the drug.

LasersCurrently, a number of laser devices are FDA-approved for the treatment of onychomycosis. The first laser devices to be approved were the short-pulse neodymium:yttrium-aluminum-garnet (Nd:YAG) 1064 devices. The exact mechanism(s) of action of laser systems in the treatment of onychomycosis is still poorly understood.6 Although thermal damage was considered a possible explanation for the fungistatic or fungicidal activity of lasers, it is clear from in vitro studies that the level of laser-generated heat that would be lethal to T. rubrum is much higher than would be tolerable to patients.7 It is possible—and more likely—that exposure to lasers elicits an immunologic effect in the host, or that these devices induce denaturization of enzymes, which is important to sustain the function and growth of fungi; moreover, experiments involving direct laser exposure did not demonstrate inhibition of fungal activity or growth.8

Thus, at this point in time, the FDA-approved labeling on lasers notes only the indication of “temporary increase of clear nail in onychomycosis,” and these devices are not considered to be sufficiently effective to warrant their use as first-line mono-therapy for these infections. Future discoveries may alter this paradigm dramatically.


■ ❚ ❙ Understanding Onychomycosis Treatment: Mechanisms of Action and Formulation

■ TABLE Onychomycosis Causative Organisms in the United States

Dermatophytes Yeasts Nondermatophyte Molds

Most Common Trichophyton rubrum Candida parapsilosis Acremonium spp

Fusarium spp

Less Common Trichophyton mentagrophytes Candida albicans Scopulariopsis spp

Least Common Trichophyton tonsurans

Microsporum canis

Epidermophyton floccosum

Candida guilliermondii

Candida tropicalis

Candida lusitaniae

Scytalidium spp

Aspergillus versicolor

Aspergillus flavus

Aspergillus fumigatus

Aspergillus terreus

Source: Ghannoum MD, Hajjeh RA, Scher R. A large-scale North American study of fungal isolates from nails: The frequency of onychomycosis, fungal distribution, and antifungal susceptibility patterns. J Am Acad Dermatol. 2000;43:641-648.

Nathaniel J. Jellinek, MD, Phoebe Rich, MD, and David M. Pariser, MD


Photodynamic TherapyResearch by a number of investigators has demonstrated that photodynamic therapy (PDT) has promise in the treatment of onychomycosis.9-11 The mechanism of action involves fungal absorption of a chemical, which is metabolized into a photosen-sitizer, followed by exposure to a specific wavelength light that results in subsequent reactive oxygen species and fungal death.12-14

PDT is not currently a practical option for widespread use in treating onychomycosis, and to date no PDT system has been FDA-approved for this indication. However, PDT may be considered when onychomycosis is chronic and is refractory to other therapies, especially when the infection involves fewer nails and less common and more resistant organisms, such as nondermatophyte molds.15

Penetration-Enhancing MethodsThe cure rates—mycologic, clinical, and complete—achieved under the best conditions with currently available medications are still suboptimal. The main obstacle to better efficacy appears to be the mechanics of the nail plate itself, not drug resistance. The plate presents a formidable barrier to topical antifungal agents, limiting topical bioavailability.

A number of methods have been proposed and tested to improve penetration through the nail plate, and several appear promising. Low-level electrical current (iontophoresis) may increase the transport of topical antifungal agents through the nail plate to the nail bed and matrix.16,17 Several devices are currently being studied in clinical trials.

Other researchers have investigated lasers—which are not particularly effective as primary monotherapy—to enhance the pharmacologic bioavailability of topical agents.18 Borovoy and Tracy19 proposed that fenestration—ie, creating “windows” through the nail plate—using a carbon dioxide laser may be useful to enhance topical antifungal penetration. More recently, Lim and colleagues20 tested this hypothesis using a fractional carbon dioxide laser and antifungal cream in a pilot study of 24 patients. The investigators found a 92% clinical response and a 50% complete response (including complete mycologic cure). No recurrences of infection were seen in the responders 3 months after the last treatment. Indeed, this strategy is promising.

ConclusionClinicians can now offer several treatment options when discussing therapies for onychomycosis with the availability of two new FDA-approved topical agents—including a new antifungal class—and generic formulations of the most effective systemic drugs. In addition, promising and novel approaches are being tested that involve direct laser targeting of the onychomycotic nail and fungal organisms themselves, laser-enhancing penetration systems, and PDT. All of these treatment options have different mechanisms of action, and through a better understanding of the different therapeutic approaches, the clinician will be able to target cases of onychomycosis with increasing specificity—and perhaps combine therapies as future information unfolds.

References1. Ghannoum MD, Hajjeh RA, Scher R. A large-scale North American study of

fungal isolates from nails: The frequency of onychomycosis, fungal distribution, and antifungal susceptibility patterns. J Am Acad Dermatol. 2000;43:641-648.

2. Chang CH, Young-Xu Y, Kurth T, Orav JE, Chan AK. The safety of oral antifungal treatments for superficial dermatophytosis and onychomycosis: A meta-analysis. Am J Med. 2007;120:791-798.

3. Ghannoum MA, Rice LB. Antifungal agents: Mode of action, mechanisms of resistance and correlation of these mechanisms with bacterial resistance. Clin Microbiol Rev. 1999; 12:501-517.

4. Leem SH, Park JE, Kim IS, Chae JY, Sugino A, Sunwoo Y. The possible mechanism of action of ciclopirox olamine in the yeast Saccharomyces cerevisiae. Mol Cells. 2003; 15(1):55-61.

5. Sugiura K, Sugimoto N, Hosaka S, et al. The low keratin affinity of efinaconazole contributes to its nail penetration and fungicidal activity in topical onychomycosis treatment. Antimicrob Agents Chemother. 2014;58:3837-3842.

6. Carney C, Cantrell W, Warner J, Elewski B. Treatment of onychomycosis using a sub millisecond 1064-nm neodymium:yttrium-aluminum-garnet laser. J Am Acad Dermatol. 2013;69:578-582.

7. Vural E, Winfield HL, Shingleton AW, Horn TD, Shafirstein G. The effects of laser irradiation on Trichophyton rubrum growth. Laser Med Sci. 2008;23(4):349-353.

8. Carney C, Tosti A, Daniel R, et al. A new classification system of grading the severity of onychomycosis: Onychomycosis severity index. Arch Dermatol. 2011;147:1277-1282.

9. Piraccini BM, Rech G, Tosti A. Photodynamic therapy of onychomycosis caused by Trichophyton rubrum. J Am Acad Dermatol. 2008;59(5 suppl):S75-S76.

10. Watanabe D, Kawamura C, Masuda Y, Akita Y, Tamada Y, Matsumoto Y. Successful treatment of toenail onychomycosis with photodynamic therapy. Arch Dermatol. 2008;144:19-21.

11. Donnelly RF, McCarron PA, Lightowler JM, Woolfson AD. Bioadhesive patch-based delivery of 5-aminolevulinic acid to the nail for photodynamic therapy of onychomycosis. J Control Release. 2005;103:381-392.

12. Harris F, Pierpoint L. Photodynamic therapy based on 5-aminolevulinic acid and its use as an antimicrobial agent. Med Res Rev. 2011;32(6):1292-1327. doi:10.1002/med.20251.

13. Smijs TG, van der Haas RN, Lugtenburg J, et al. Photodynamic treatment of the dermatophyte Trichophyton rubrum and its microconidia with porphyrin photosen-sitizers. Photochem Photobiol. 2004;80:197-202.

14. Dai T, Fuchs BB, Coleman JJ, et al. Concepts and principles of photody-namic therapy as an alternative antifungal discovery platform. Front Microbiol. 2012;3:120. doi:10.3389/fmicb.2012.00120.

15. Gilaberte Y, Aspiroz C, Martes MP, Alcalde V, Espinel-Ingroff A, Rezusta A. Treatment of refractory fingernail onychomycosis caused by nondermatophyte molds with methylaminolevulinate photodynamic therapy. J Am Acad Dermatol. 2011;65:669-671.

16. Barsness M, Davis SP, Etheredge R, et al. Studies in drug transport vs. current in iontophoretic onychomycosis treatment. Conf Proc IEEE Eng Med Biol Soc. 2009;2009:289-294.

17. Amichai B, Nitzan B, Mosckovitz R, et al. Iontophoretic delivery of terbinafine in onychomycosis: A preliminary study. Br J Dermatol. 2010;162:46-50.

18. Murdan S. Enhancing the nail permeability of topically applied drugs. Expert Opin Drug Deliv. 2008;5:1267-1282.

19. Borovoy M, Tracy M. Noninvasive CO2 laser fenestration improves treatment of onychomycosis. Clin Laser Mon. 1992;10:123-124.

20. Lim EH, Kim HR, Park YO, et al. Toenail onychomycosis treated with a fractional carbon-dioxide laser and topical antifungal cream. J Am Acad Dermatol. 2014; 70:918-923.

© 2015 Frontline Medical Communications 1085-5629/13/$-see front matter doi:10.12788/j.sder.2015.0150

Several populations of patients who acquire onychomycosis warrant special attention with respect to potential clinical sequelae and treatment. These populations include pediatric

and geriatric patients, individuals with medical comorbidities (including those with psoriasis, diabetes, and compromised vascular status), and patients who are medically or pharmaco-logically immunocompromised.

Age-Related IssuesPediatric PatientsAccording to the most recent epidemiologic evidence available from a large-scale study, onychomycosis is uncommon in children prior to adolescence, and is rare in children less than 6 years

of age.1 However, such findings should not be interpreted to mean that young children never present with onychomycosis. In fact, this condition has been reported in pediatric patients of all ages, including neonates, and always must be considered in the differential in any patient who presents with nail dystrophy.2

In general, children who present with onychomycosis have a family history of onychomycosis and/or tinea pedis. The under-lying cause may be a genetic predisposition, but the most likely source of early exposure to causative organisms is family members with onychomycosis or tinea pedis. Whenever a child presents with signs and symptoms of onychomycosis and/or tinea pedis, clinicians should ask about others in the household (adolescents as well as adults) who share these signs and symptoms or who have been diagnosed with either of these infections.

It is important to identify and treat children with onychomy-cosis as early as possible. Because it is likely that these patients have a genetic susceptibility, it is also probable that they will be at increased risk for recurrent and/or refractory infections in the future. To date, no medication—systemic or topical—has received approval from the US Food and Drug Administration (FDA) for use in children with onychomycosis. Some systemic antifungal agents are FDA-approved for other indications—for example, the treatment of tinea capitis—and commonly are used off-label to treat onychomycosis in children.

With this caveat stated, Feldstein and colleagues3 recently reviewed the topic of treatment for pediatric onychomycosis and concluded that the evidence on terbinafine, itraconazole, and fluconazole shows good efficacy and a low incidence of adverse effects in the pediatric population. These findings echo the experience of many clinicians that monotherapy with a topical agent may be more effective in children with onychomycosis than in adults because children’s nails are thinner and grow faster than those of adults. Whereas complete nail turnover is typically 12 to 18 months in adults, complete turnover in children may take as little as 4 months.

The characteristics of thinner, faster-growing nails also allow clini-cians to more quickly assess efficacy of treatment in an individual patient. Patients and their parents also are able to recognize the bene-fits of an effective therapy, which helps promote continued adherence.

In addition to treating nails directly, the long-term attention to and management of tinea pedis are as important in pediatric patients as they are in adults with onychomycosis.Geriatric PatientsAn estimated 40% of elderly patients have onychomycosis, making this one of the most common infections seen in this population.4

It is also an important and challenging clinical condition among older individuals, for several reasons.

Comorbidities are increasingly common with advancing age, and many older people have circulatory compromise in their lower extremities, as a primary disease or secondary to diabetes mellitus. This complicates systemic treatment choices for onychomycosis for two main reasons. First, systemic medications are problematic. Older patients tend to require multiple medications to manage various medical issues and the chances for drug-drug interac-tions increase with each addition to an individual’s prescription regimen. Second, compromised circulation and slower drug metabolism related to age can interfere with effective drug concen-trations in target tissues in the lower extremities.

■ AbstractClinicians must be aware of characteristics unique to certain populations when diagnosing and treating onychomycosis. For example, although onychomycosis is uncommon in children, it should be considered in the differential diag-nosis when young patients have nail changes, particularly if a family history of onychomycosis is present. In elderly patients, comorbid medical conditions may complicate systemic treatment, and physical impairments may interfere with topical therapy. Nondermatophyte molds and yeasts should be considered as possible pathogens in patients with diabetes and psoriasis. Patients who are immunosuppressed for any reason are at increased risk for nail infections. Semin Cutan Med Surg 34(supp3):S54-S55 © 2015 published by Frontline Medical Communications

■ Keywords Compromised vascular circulation; diabetes; geriatric patients; onychomycosis; pediatric patients; psoriasis

Management Strategies for Onychomycosis in Special Patient Populations Phoebe Rich, MD,* Nathaniel J. Jellinek, MD,† and David M. Pariser, MD‡

* Clinical Adjunct Professor of Dermatology, Oregon Health Science University, Portland, Oregon

† Assistant Clinical Professor, Department of Dermatology, Warren Alpert Medical School at Brown University, Adjunct Assistant Clinical Professor, Division of Dermatology, University of Massachusetts Medical School, Fellowship Director, Procedural Dermatology, Dermatology Professionals, Inc., East Greenwich, Rhode Island

‡ Professor of Dermatology, Eastern Virginia Medical School, Department of Dermatology, Pariser Dermatology, Norfolk, Virginia

Publication of this CME/CE article was jointly provided by the University of Louisville School of Medicine Continuing Medical Education and Global Academy for Medical Education, LLC, and is supported by an educational grant from Valeant Pharmaceuticals North America LLC.Dr Rich, Dr Jellinek, and Dr Pariser have received an honorarium for their participation in this activity. They acknowledge the editorial assistance of Joanne Still, medical writer, and Global Academy for Medical Education in the development of this continuing medical education journal article.

Phoebe Rich, MD, Grant/Research: Anacor Pharmaceuticals, Inc., Meiji Seika Pharma Co., Ltd., Topica Pharmaceuticals, Inc., and Valeant Pharmaceuticals.Nathaniel J. Jellinek, MD, Advisory Board: Valeant Pharmaceuticals.David M. Pariser, MD, Consultant: Anacor, DUSA Pharmaceuticals, Inc., LEO Pharma Inc., and Valeant Pharmaceuticals.

Address reprint requests to: Phoebe Rich, MD, 2565 NW Lovejoy Street, Suite 200, Portland, OR 97210; [email protected]


For these reasons, collaboration with the patient’s primary care clinician (or a selected specialist, depending on an individual’s specific medical issues) is advisable if a systemic antifungal medi-cation is being considered.

When a topical medication is preferred, it is important to establish how the medication will be applied correctly and consistently— that is, whether the patient is able to do the applications or if daily assistance is available, if needed. Because of diminished flexibility from arthritis and other age-related conditions, many elderly patients find it difficult to self-administer topical therapy.

The assessment of treatment efficacy also is complicated in elderly patients. The age-related changes that are common— thickened, yellowed, brittle nails, and deformation resulting in ingrown nails or severe curvature of the nail plate (“pincer nails”)5—do not permit the achievement of a therapeutic goal of clear or almost clear nails, or even, in some cases, an appreciable improvement in appearance. However, mycologic cure or substan-tial reduction in mycologic burden is a reasonable goal, even in the absence of improvement in appearance.

Medical ComorbiditiesDiabetesEpidemiologic studies worldwide suggest that the prevalence of onychomycosis in patients with diabetes is high, with some reports estimating a range of about 20% to 30%.6,7 Several studies have demonstrated the presence of onychomycosis predicts the devel-opment of a constellation of complications referred to as diabetic foot syndrome (including bacterial infections that increase the risk for ulceration and, ultimately, amputation).6,8-10 Boyko and colleagues8 reported that the risk for foot ulceration was 1.6 times greater among patients with diabetes who had onychomycosis.

Adding to the risk for bacterial infections in patients with diabetes is the high prevalence of peripheral neuropathy. Patients with onychomycosis-related nail changes may experience—but not feel or be aware of—injuries sustained to the periungual tissue that can lead to cellulitis and limb-threatening secondary infections.

Onychomycosis involving atypical organisms, especially yeasts, are more common in patients with diabetes than in people without diabetes.11

For patients with diabetes in whom topical therapy is being considered, the two newer agents—efinaconazole and tavaborole— have demonstrated efficacy in this population. Patients with diabetes were not excluded from the pivotal trials of efinacon-azole and tavaborole, but the disease was a cause for exclusion in the pivotal clinical studies of ciclopirox. In addition, the use of ciclopirox requires that patients keep their nails trimmed and that they follow up with their clinicians for regular removal of unat-tached, infected nails and debris; these activities potentially increase the risk for trauma and secondary infection, particularly in patients with diabetic neuropathy. No “relevant clinical experience” has been reported with the use of ciclopirox in insulin-dependent patients with diabetes or patients with diabetic neuropathy.12

Vlahovic and Joseph13 published the results of a post-hoc anal-ysis of data on 112 patients with diabetes in the efinaconazole trials. These investigators reported that, in the two multicenter, double-blind, vehicle-controlled, 48-week pivotal studies of efina-conazole, the patients with diabetes who were randomized to receive the study medication had significantly greater mycologic cure rates compared to those in the vehicle-only control group (P=0.016). Complete cure—the primary end point—was also greater for the efinaconazole-treated group versus vehicle-only group (13.0% vs 3.7%, respectively), although the difference did not achieve statistical significance.PsoriasisOnychomycosis can be difficult to distinguish from nail psoriasis, and in many cases the two conditions coexist. Psoriasis should be considered in the differential diagnosis of any patient with signs and symptoms that suggest onychomycosis. Psoriasis as a

comorbid cause for nail symptoms should be considered when mycologic cure is achieved but appearance does not improve completely; the portion of a nail affected by psoriasis will not change with antifungal treatment.

Patients with psoriasis also tend to have mixed dermatophyte and Candida infections. Efinaconazole and tavaborole both have good activity against Trichophyton rubrum as well as Candida organisms and nondermatophyte molds. In addition, any patient with psoriasis who is being treated with certain biologic agents—particularly those that target the interleukin-17 pathway, such as secukinumab—should be monitored for nail infections caused by yeasts.ImmunosuppressionPatients who are immunosuppressed for any reason are at increased risk for nail infections; this is particularly true for patients who have a history of onychomycosis or tinea pedis.

Systemic antifungal agents have been the treatments of choice prior to the introduction of efinaconazole and tavaborole. As in patients with psoriasis, antifungal medication must reach the nail bed to be effective, and the two newer topical agents have good penetration through the nail plate. In addition, efinaconazole and tavaborole have excellent minimum inhibitory concentra-tions against Candida albicans, Candida parapsilosis, and many nondermatophyte molds; these organisms are not uncommon pathogens in onychomycosis in this population. Patients on long-term immunosuppressant therapy—such as those who have undergone renal transplantation and patients with a history of recurrent onychomycosis—may benefit from the preventive use of a topical antifungal medication; however, no antifungal agents are FDA-approved for the prevention of onychomycosis.

ConclusionOnychomycosis presents special clinical challenges in some patient populations. These include children, the elderly, and patients who are immunosuppressed or who have comorbid conditions, particu-larly diabetes and psoriasis. To manage onychomycosis effectively in these special patient populations, clinicians must consider the species of organisms most commonly present, the potential adverse events associated with antifungal medications that may complicate treatment, and the patient characteristics that may affect the choice of therapy.

References1. Ghannoum MD, Hajjeh RA, Scher R. A large-scale North American study of

fungal isolates from nails: The frequency of onychomycosis, fungal distribution, and antifungal susceptibility patterns. J Am Acad Dermatol. 2000;43:641-648.

2. Piraccini BM, Starace M. Nail disorders in infants and children. Curr Opin Pediatr. 2014;26:440-445.

3. Feldstein S, Totri C, Friedlander SF. Antifungal therapy for onychomycosis in children. Clin Dermatol. 2015;33:333-339.

4. Elewski B, Charif MA. Prevalence of onychomycosis in patients attending a dermatology clinic in northeastern Ohio for other conditions. Arch Dermatol. 1997;133:1172-1173.

5. Abdullah L, Abbas O. Common nail changes and disorders in older people: Diagnosis and management. Can Fam Physician. 2011;57:173-181.

6. Chang SJ, Hsu SC, Tien KJ, et al. Metabolic syndrome associated with toenail onycho-mycosis in Taiwanese with diabetes mellitus. Int J Dermatol. 2008;47:467-472.

7. Saunte DM, Holgersen JB, Haedersdal M, et al. Prevalence of toe nail onychomycosis in diabetic patients. J Eur Acad Dermatol Venereol. 2006;22:279-282.

8. Boyko EJ, Ahroni JH, Cohen V, et al. Prediction of diabetic foot ulcer occurrence using commonly available clinical information: The Seattle Diabetic Foot Study. Diabetes Care. 2006;29:1202-1207.

9. Gupta S, Koirala J, Khardori R, Khardori N. Infections in diabetes mellitus and hyper-glycemia. Infect Dis Clin North Am. 2007;21:617-638.

10. Tan JS, Joseph WS. Common fungal infections of the feet in patients with diabetes mellitus. Drugs Aging. 2004;21:101-112.

11. Winston JA, Miller JL. Treatment of onychomycosis in diabetic patients. Clin Diabetes. 2006;24:160-166.

12. Penlac® (ciclopirox 8%) [package insert]. Bridgewater, NJ: Dermik Laboratories; 2006.13. Vlahovic TC, Joseph WS. Efinaconazole topical, 10% for the treatment of toenail

onychomycosis in patients with diabetes. J Drugs Dermatol. 2014;13:1186-1190.


Phoebe Rich, MD, Nathaniel J. Jellinek, MD, and David M. Pariser, MD

© 2015 Frontline Medical Communications 1085-5629/13/$-see front matter doi:110.12788/j.sder.2015.0151

Onychomycosis is an important medical condition that warrants clinical intervention.1 Untreated or undertreated, onychomycosis often is progressive and is associated with

a number of possible clinical sequelae. In addition, this contagious infectious disease can be transmitted to others via direct contact or on surfaces such as shoes, patios surrounding pools or spas, or showers and bathtubs. Fungal infection in the toenails also may spread from the feet to other areas of the body.

In individuals with comorbidities, onychomycosis can lead to complications. In select circumstances (such as for patients with immunosuppression or diabetes), thick onychomycotic nails may traumatize adjacent skin, leading to secondary bacterial infections

that may develop and can result in cellulitis and ulcerations.1,2

Permanent damage may occur to the nail plate and its attachments, possibly leading to interference with normal gait. This, in turn, may increase the associated risk for falls in older patients. Finally, onychomycosis may adversely affect overall quality of life, including embarrassment, self-consciousness, and interference with relation-ships when patients fear transmitting the infection to others.3,4

Patients who seek medical attention for onychomycosis do so because of a variety of signs or symptoms that they find bother-some, which include pain and discomfort in the affected toenail, a history of nail shedding, concern that the infection will spread to other nails or other parts of the body, the presence of a secondary infection of the skin surrounding the nail plate, unsightly appear-ance, or interference with a patient’s ability to walk normally.

In contrast, patients with mild onychomycosis in one or two toes may be less bothered either by symptoms or the appearance of the nails and less likely to request evaluation and manage-ment of nail changes during a visit with the clinician. Even those with long-standing infections and moderate to severe signs of onychomycosis (such as yellowing, brittleness, and lifting of the nail plate) may not mention such changes. Thus, the presence of onychomycosis may come to the attention of the clinician only as an incidental finding during a clinical encounter for some other purpose, such as an annual full-body dermatologic skin examina-tion and careful inspection of unpainted nails.

When a clinician notes the likely presence of fungal infection as an incidental finding, some patients express no interest in pursuing further diagnostic measures (to confirm the diagnosis and identify the causative organism) or treatment. This is especially true when the disease is mild and not symptomatically or cosmetically both-ersome, but sometimes patients with more severe disease decline a clinician’s offer to “do something about your toenail fungus.” It is important for clinicians to understand and communicate the rationale for definitive medical treatment of onychomycosis and the availability of recently improved options for therapy.

Treatment Goals Ideally, treatment should result in both mycologic and clinical cure—or complete cure. Mycologic cure is defined as a negative result on potassium hydroxide (KOH) preparation and the absence of organisms on fungal culture and/or periodic acid-Schiff (PAS) staining on pathologic analysis. Clinical cure is the completely normal appearance of the nail. In clinical trials, complete cure is used as the primary end point to determine efficacy.

In the clinical setting, the rigorous standard of complete cure is not always achieved and cannot always be expected. In many cases, particularly when patients have not been treated previously for onychomycosis, a negative result on KOH examination may be acceptable evidence of mycologic cure, without the need for the additional step of obtaining a fungal culture, if the affected nails show complete clinical clearance—that is, the previously infected nail plate has grown out and been replaced with a normal-appearing nail. Although resolution of the infection in patients who are treated early and effectively may result in a completely

■ AbstractOnychomycosis is a clinically important infection that is frequently progressive and may be associated with clin-ical sequelae. Accurate diagnosis, appropriate choice of antifungal agent—with consideration given to partic-ular patient characteristics, including the presence of concomitant diseases and ability to comply with a given regimen—careful follow-up, and consideration of long-term management and reinfection prevention strategies are crucial to successful treatment.Semin Cutan Med Surg 34(supp3):S56-S58 © 2015 published by Frontline Medical Communications

■ Keywords Onychomycosis

Making Strides in Preventing Onychomycosis Recurrence Melodie S. Young, MSN, RN, A/GNP-c,* David M. Pariser, MD,† Phoebe Rich, MD,‡ and Nathaniel J. Jellinek, MD§


* Modern Dermatology, a Baylor Health Texas Affiliate, Dallas, Texas† Professor of Dermatology, Eastern Virginia Medical School, Department of

Dermatology, Pariser Dermatology, Norfolk, Virginia‡ Clinical Adjunct Professor of Dermatology, Oregon Health Science

University, Portland, Oregon§ Assistant Clinical Professor, Department of Dermatology, Warren

Alpert Medical School at Brown University, Adjunct Assistant Clinical Professor, Division of Dermatology, University of Massachusetts Medical School, Fellowship Director, Procedural Dermatology, Dermatology Professionals, Inc., East Greenwich, Rhode Island


Melodie S. Young, Dr Pariser, Dr Rich, and Dr Jellinek have received an honorarium for their participation in this activity. They acknowledge the editorial assistance of Joanne Still, medical writer, and Global Academy for Medical Education in the development of this continuing medical education journal article.

Melodie S. Young, MSN, RN, A/GNP-c, has no relevant financial relationships to disclose.

David M. Pariser, MD, Consultant: Anacor Pharmaceuticals, Inc., DUSA Pharmaceuticals, Inc., LEO Pharma Inc., and Valeant Pharmaceuticals.

Phoebe Rich, MD, Grant/Research: Anacor, Meiji Seika Pharma Co., Ltd., Topica Pharmaceuticals, Inc., and Valeant Pharmaceuticals.


Address reprint requests to: Melodie S. Young, MSN, RN, A/GNP-c, Modern Dermatology – Aesthetics Center Dallas, 9101 N. Central Expressway, Suite 160, Dallas, TX 75231; [email protected]

normal-appearing nail, individuals with long-standing infec-tions or recurrent onychomycosis may have sustained permanent damage to the nail matrix or subungual tissue. In the latter group, mycologic cure may be achieved but the nails may still appear discolored or dystrophic and onycholysis (lifting of the nail plate) may persist. Furthermore, some patients have thickened, discolored, or dystrophic nails for reasons unrelated to nail infec-tion—for example, changes related to chronic microtrauma, aging, or concomitant psoriatic nail disease. For those patients, achieving complete cure is much more difficult or, in some cases, impossible.

These concepts of cure must be considered and applied to indi-vidual patients, and expectations for treatment outcomes should be carefully explained to patients before therapy is initiated.

Onychomycosis Persistence and Recurrence Onychomycosis has a high relapse rate after successful therapy, so successful eradication of signs and symptoms represents only the first step in management. Clinicians and patients must under-stand that adherence to initial treatment and follow-up—as well as attention to measures that reduce the risk for recurrence, and, when necessary, retreatment—all optimize the chances for long-term control of onychomycosis.

Onychomycosis is a chronic problem for as many as 25% of patients seen in clinical practice5 and may persist or recur for any of several reasons. In many cases, the risk for recurrence is modifiable. Perhaps the most common—and most readily avoid-able—reason for lack of treatment efficacy is inaccurate diagnosis. Although onychomycosis is the most common nail disease, several nonfungal causes of nail symptoms that may mimic onychomy-cosis must be considered in the differential diagnosis in adults (Table 1).6-8 These causes are multiple and include psoriasis, lichen planus and other immune-mediated inflammatory diseases, chronic microtrauma or macrotrauma, and local tumors. Thus, clinical inspection is not sufficient for a diagnosis of onychomy-cosis; some objective test is required for a definitive diagnosis. A KOH preparation can be done to detect the presence of fungal organisms; if no fungi are detected, nonfungal or noninfectious causes for symptoms should be considered. A nail specimen can be obtained for culture to determine whether nonfungal organisms are present or infections are mixed, including both dermatophyte organisms and nondermatophyte molds or yeast. Identification of the infecting organisms can substantially affect treatment

choices and prognosis. Sampling of the nail plate and bed debris for pathologic analysis (and PAS staining) is considered by many to be the most sensitive and specific test, although it lacks speci-ficity in identifying organism species. Often clinicians will perform several of these tests to achieve the most accurate diagnosis.

Another important modifiable cause for treatment failure or infection recurrence is poor adherence to treatment. Patients must understand that even if the onychomycosis treatment they are using is maximally effective, the results will not be apparent until the nail grows out in the absence of fungal organisms and associ-ated trauma and/or inflammation. Because toenails grow at the rate of approximately 1 mm per month—and more slowly in older individuals—an effectively treated nail may not appear completely normal for 12 to 18 months.

Recurrence also is associated with tinea pedis; the latter infec-tion often is caused by the dermatophyte T. rubrum, the most common causative organism in onychomycosis. Thus, one impor-tant strategy for preventing recurrence of onychomycosis is preventing, monitoring for, and effectively treating tinea pedis.

Melodie S. Young, MSN, RN, A/GNP-c, David M. Pariser, MD, Phoebe Rich, MD, and Nathaniel J. Jellinek, MD

■ TABLE 1 Differential Diagnosis of Onychomycosis in Adults

• Bacterial infection

• Chronic paronychia

• Contact irritants/dermatitis

• Lichen planus

• Nail trauma (eg, from ill-fitting footwear, injury during pedicure)

• Neoplasms (squamous cell carcinoma, fibroma, melanoma)

• Psoriasis

• Vascular conditions

• Verrucae of nail folds or subungual tissue

Sources: Allevato6; Cockerell and Odom7; Daniel8


Onychomycosis Diagnostic Techniques and the Office-Based Clinician

Because of Clinical Laboratory Improvement Amendments certification requirements, many dermatologists no longer perform certain laboratory tests in office-based practices. However, no special training is required to perform a micro-scopic inspection of a specimen prepared with 10% to 15% potassium hydroxide. This method allows on-site and rapid confirmation of the presence of a fungal infection.

In patients with distal subungual onychomycosis, the nail should be debrided as far back as possible and a specimen of subungual debris should be scraped from an area as close to the cuticle as possible; scale from the nail plate also can be used. A sample from deeper under the nail plate and the nail bed is needed for proximal subungual onychomycosis. In patients with suspected superficial white onychomycosis, nail plate scrapings are preferred. Adding dimethyl sulfoxide on the slide will help dissolve debris and facilitate visualization of the fungus; the use of chlorazol black E or Parker blue-black ink will enhance visualization, if necessary.

A more sensitive method of diagnosis is histologic examination of periodic-acid Schiff stained preparations of nail plate and subungual tissue specimens, performed by a dermatopathology laboratory. The disadvantages of this test are the lack of immediacy (results usually are available in a few days), the possibility that results may not be conclusive (the presence of septate hyphae is diagnostic, but the presence of yeast forms alone is not definitive), and the inability to identify specific organisms and species.

Fungal culture is the only widely available method for establishing both the presence of infection and the causative organism. Although many laboratories perform mycology studies, only a few in the United States specialize in such cultures and can, on request, also test for drug sensitivity.

■ ❚ ❙ Making Strides in Preventing Onychomycosis Recurrence


Topical medication for hyperkeratotic (moccasin-type) infection should be applied to the bottoms and sides of the feet. Patients with interdigital infection should be instructed to apply topical medication to these areas as well as to the soles of the feet. Recurrence of tinea pedis often is due to a patient’s discontinuance of medication after symptoms resolve; thus, patient education about the importance of controlling the fungal carriage on the feet is crucial to adherence to a treatment regimen.

Guiding Patient Expectations Clinicians are in an ideal position to discuss treatment options, noting that systemic and topical agents are available, and to clearly explain the reason for recommending either type of approach and specific agent(s) in the particular patient’s case. Patients should be advised about any potential adverse effects associated with the recommended therapy and about the expected cure rates. If systemic therapy is considered, the patient should be informed about any baseline and/or monitoring tests (such as liver function tests) that will be required.

As noted previously, many patients will not experience completely normal nail growth, despite the improved appearance of the nail. At the very least, most patients can expect mycologic improvement, if not complete cure. Several factors have been identified as indicators of a poor prognosis for a complete cure in adults5,9 (Table 2), including a greater than 50% area of nail involvement, significant lateral disease, subungual hyperkeratosis (greater than 2 mm), the appearance of white/yellow or orange/brown streaks in the nail, the presence of dermatophytoma, total dystrophic onychomycosis with matrix involvement, or infection with nondermatophyte molds. In addition, complete cures may be less likely in patients who are immunocompromised or who have compromised peripheral circulation.

Promoting Treatment Adherence Because adherence is such an important modifiable factor in the recurrence of onychomycosis, special attention should be paid to strategies for improving the proper and consistent use of medica-tions. Clinicians typically encounter two major underlying causes for lack of adherence in patients with onychomycosis: patient

perception that the medication is not working fast enough (ie, the growth of normal nail is not recognized) and patient perception that the medication is not working well enough (ie, the changes in the nail are seen by the patient as an improvement, but the patient does not judge the new growth to appear “normal”). Both issues should be addressed at the time of diagnosis and prior to the initiation of therapy as well as during follow-up visits.

Patients must be told that toenails grow slowly, at the rate of approximately 1 mm per month. A visual reference may be helpful, such as showing the patient the side of a US nickel and noting that it is 1.95 mm thick. Even if the medication eliminated all active fungal organisms on the first day of treatment, the amount of normal nail that could be seen after 1 month would be about one half to a full thickness of a nickel. Therefore, it is difficult to judge the effectiveness of a treatment that is used correctly and consistently until after at least 3 to 4 months of treatment, and a completely “new” nail should not be expected for 12 to 18 months (longer in older individuals whose nails grow more slowly than in younger individuals).

Although dermatologists routinely document skin and nail conditions photographically at diagnosis and during follow-up visits, these photos are maintained in patient files. As most patients have cell phones with cameras, one way to overcome the hurdle of delayed treatment gratification and provide encouragement for persistence with onychomycosis therapy is for patients to use their cell phones to take a clinical photograph prior to the start of treatment and then take a new photograph each month so that the clinician and the patient can review the pictures together at the next follow-up visit.

Finally, incorporating antifungal treatment—whether systemic or topical—into the daily grooming routine can be one way to promote adherence, including storing the medication in a place where it is most likely to be accessible for dosing or application. For example, systemic antifungal agents might be kept on a kitchen shelf with other medications or supplements that already are part of a patient’s daily routine. Topical medications might be stored in the bathroom, readily at hand for application right after a daily shower, or on the bedside table near the chair the patient sits in to put on socks and shoes.

Patient-Focused Strategies for Preventing Recurrence Patients must appreciate that fungi are ubiquitous and that nearly everyone comes into contact with these organisms. However, some individuals seem to have a natural immunity for fungal infections despite regular contact with dermatophytes, and others acquire a fungal infection once or twice in a lifetime. Other individuals are so prone to infections and reinfections that they develop a pattern of repeated involvement over a period of time or even a lifetime. Clinicians must be clear with patients that onychomycosis tends to recur and, for some patients, episodic treatment will be neces-sary to manage recurrent infections. Strategies exist that may help reduce an individual’s risk for infection recurrence. The more thoroughly patients understand the nature of onychomycosis, the more likely they will be to implement these recurrence-reducing measures and to seek treatment when they experience recurrences.

Patients must recognize that onychomycosis is an infectious disease that is caused, in most cases, by dermatophyte fungal species. It is acquired from some source, and often is reacquired from the same or similar sources. Onychomycosis infection is unrelated specifically to hygiene; it is related to individual susceptibility. However, even susceptible individuals can take measures to limit their exposure to sources of fungal infections and to enhance their ability to resist recurrence of onychomycosis (Table 3).

■ TABLE 2 Indicators of a Poor Prognosis for

Complete Cure of Onychomycosis

Nail-specific factors

• >50% area of nail involvement

• Significant lateral disease

• Subungual hyperkeratosis (>2 mm)

• White/yellow or orange/brown streaks in the nail

• Presence of dermatophytoma

• Total dystrophic onychomycosis with matrix involvement

• Infection with nondermatophyte molds

Patient-specific factors

• Immunocompromised host

• Compromised peripheral circulation

Sources: Scher and Baran5; Scher et al9


Patients may ask about the possibility of “sanitizing” footwear to prevent reinfection. Several methods of decontamination have been investigated, but it is not clear whether elimination of fungal reserves from footwear is possible.

Conclusion Research over the past two decades has led to advances in understanding the natural history and clinical importance of mycologic infections of the toenails. Onychomycosis frequently is a progressive infection and is associated with a number of clinical sequelae. This relatively recent recognition of the clinical importance of onychomycosis—as well as the availability of more effective antifungal medications, including newer topical agents—have contributed to the appreciation of this infectious disease as a treatable condition that warrants intervention. Successful treatment depends on an accurate diagnosis (see “Onychomycosis Diagnostic Techniques and the Office-Based Clinician” on page 57) and patient adherence to long-term therapy, as well as the recognition that recurrence is common and requires follow-up treatment. It is possible that a maintenance regimen of topical therapy may either prevent or reduce the number of recurrences of onychomycosis and its associated infection, tinea pedis. However, to date, no study has been conducted to determine the efficacy, safety, and feasibility of such a maintenance topical therapy strategy.

References1. Scher RK. Onychomycosis: A significant medical disorder. J Am Acad Dermatol.

1996;35:S2-S5.

2. Elewski BE. Bacterial infection in a patient with onychomycosis. J Am Acad Dermatol. 1997;37:493-494.

3. Drake LA, Scher RK, Smith EB, et al. Effect of onychomycosis on quality of life. J Am Acad Dermatol. 1998;38:702-704.

4. Elewski BE. The effect of toenail onychomycosis on patient quality of life. Int J Dermatol. 1997;36:754-756.

5. Scher RK, Baran R. Onychomycosis in clinical practice: Factors contributing to recurrence. Br J Dermatol. 2003;149(suppl 65):5-9.

6. Allevato MA. Diseases mimicking onychomycosis. Clin Dermatol. 2010;28:164-177.

7. Cockerell C, Odom R. The differential diagnosis of nail disease. AIDS Patient Care. 1995;9(suppl 1):S5-S10.

8. Daniel CR III. The diagnosis of nail fungal infection. Arch Dermatol. 1991;127: 1566-1567.

9. Scher RK, Elewski B, Rich P, Pariser D. The epidemiology, etiology, and patho-physiology of onychomycosis. Semin Cutan Med Surg. 2013;33:7-9.

Melodie S. Young, MSN, RN, A/GNP-c, David M. Pariser, MD, Phoebe Rich, MD, and Nathaniel J. Jellinek, MD

■ TABLE 3 Common Sources of Reinfection With Organisms That Cause Onychomycosis

• Infected footwear

• Improperly fitting footwear

• Tinea pedis infection

• Exposure to other household members with tinea pedis

• Sharing nail clippers and files with an individual with onychomycosis

• Improper nail grooming

• Exposure to fungal organisms at nail salons (manicure/pedicure tools and soaking containers/tubs)

• Public facilities such as pools, spas, locker rooms, and gyms

1. Most cases of onychomycosis in the United States are caused by:A. CandidaB. DermatophytesC. Nondermatophyte moldsD. Yeasts

2. The first-line systemic agent approved by the FDA for onychomycosis therapy is:A. FluconazoleB. ItraconazoleC. TavaboroleD. Terbinafine

3. In the clinical studies of topical antifungal agents in patients with onychomycosis, the definition of “complete cure” is:A. Complete clinical clearance of the nailB. Complete clinical clearance of the nail plus complete mycologic

clearance demonstrated on potassium hydroxide examination and culture

C. Mycologic cureD. Negative result on potassium hydroxide examination and

significant improvement in nail appearance4. Which of the following is an allylamine anti-fungal agent?

A. CiclopiroxB. EfinaconazoleC. TavaboroleD. Terbinafine

5. Inhibition of 14-alpha demethylase, with resulting downstream disruption of fungal cell membranes, describes the mechanism of action of:A. Allylamine antifungal agentsB. Azole antifungal agentsC. Boron-containing agentsD. Photodynamic therapy

6. The main obstacle to optimal onychomycosis cure rates with topical antifungal agents is:A. Drug resistanceB. Formulation issuesC. Nail plate mechanicsD. Side effects, leading to patient noncompliance

7. Which one of the following is a true statement with respect to pediatric onychomycosis? A. All of the FDA-approved onychomycosis antifungals are indicated

for children as young as 3 years of ageB. No medication has been approved by the US Food and Drug

Administration for the treatment of onychomycosis in childrenC. Only the topical antifungal agents have been approved for use in

pediatric onychomycosisD. Onychomycosis is not seen in preadolescent children

8. When mycologic cure is achieved but the appearance of the nail does not improve completely, __________ should be suspected.A. Compliance issues—improper or nonuse of medication B. Concomitant psoriatic nail diseaseC. Resistant dermatophyte speciesD. Treatment failure

9. Which one of the following methods can be used to establish both the presence of fungal infection and the causative organism in patients with onychomycosis?A. Fungal culture of a specimenB. Genetic analysis of a specimenC. Microscopic examination of a specimen of subungual debris

prepared with 10% to 15% potassium hydroxideD. Periodic-acid Schiff-stained preparations of nail plate and

subungual tissue specimens

10. Onychomycosis is a chronic problem for as many as _______ of patients seen in clinical practice.A. 15%B. 25%C. 35%D. 45%

Managing Onychomycosis: New and Emerging Treatments and Recurrence Prevention Strategies Post-Test and Evaluation FormOriginal Release Date: June 2015 • Most Recent Review Date: June 2015 • Expiration Date: June 30, 2017 • Estimated Time to Complete Activity: 2.5 hoursTo get instant CME/CE credits online, go to http://tinyurl.com/onycho15. Upon successful completion of the online test and evaluation form, you will be directed to a Web page that will allow you to receive your certificate of credit via e-mail. Please add [email protected] to your e-mail “safe” list. If you have any questions or difficulties, please contact the University of Louisville School of Medicine Continuing Medical Education (CME & PD) office at [email protected].

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Explain the benefits of early diagnosis and treatment of onychomycosis and the potential sequelae if this infection is untreated or is inadequately treated.

5 4 3 2 1

Establish or improve practice protocols for identifying patients with onychomycosis, particularly in special populations (for example, the elderly, pediatric patients, immunocompromised patients, patients with psoriasis, and those with diabetes mellitus).

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Identify the mechanism of action for the currently available therapeutic options, including differences in formulation and associated efficacy, and use this knowledge to more effectively tailor treatment choices to individual patients.

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Incorporate or enhance monitoring for onychomycosis in patients in special, at-risk, or difficult-to-manage populations (for example, the elderly, pediatric patients, immunocompromised patients, patients with psoriasis, and those with diabetes mellitus).

5 4 3 2 1

More effectively use currently available oral and topical medications to treat various patient populations. 5 4 3 2 1

Discuss techniques, including obtaining good culture specimens, that permit more accurate diagnosis of the infecting organisms and the most appropriate choice of therapy.

5 4 3 2 1

Review and, if necessary, improve patient education materials and teaching plans regarding the patient’s role in the treatment of onychomycosis and the prevention of recurrence to increase the chances of effective long-term management of this disease.

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Evaluate the results of clinical studies on new and emerging and available treatments for onychomycosis. 5 4 3 2 1

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OVERALL EVALUATION Strongly Agree Agree Somewhat Agree Disagree Strongly Disagree

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