A CME/CE CERTIFIED SUPPLEMENT TO
`
`SUPPLEMENT 3
`VOL. 35, NO. 3S
`MARCH 2016
`
`EDITORS
`Kenneth A. Arndt, MD
`Philip E. LeBoit, MD
`Bruce U. Wintroub, MD
`
`Onychomycosis:
`Diagnosis, Treatment, and
`Prevention Strategies
`
`GUEST EDITORS
`Linda F. Stein Gold, MD
`Theodore Rosen, MD
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Introduction S47
`
`Understanding Onychomycosis:
`Resolving Diagnostic Dilemmas S48
`
`Antifungal Drugs for Onychomycosis:
`Efficacy, Safety, and Mechanisms of Action S51
`
`Concepts in Onychomycosis Treatment
`and Recurrence Prevention: An Update S56
`
`Using Topical Antifungal Medications:
`Instructions for Patients S60
`
`Post-Test and Evaluation Form S61
`
`Page 1 of 20
`
`ACRUX DDS PTY LTD. et al.
`
`EXHIBIT 1522(a)
`
`IPR Petition for
`
`U.S. Patent No. 7,214,506
`
`

`

`A CME/CE CERTIFIED SUPPLEMENT TO
`
`SUPPLEMENT 3
`VOL. 35, NO. 3S
`MARCH 2016
`
`EDITORS
`Kenneth A. Arndt, MD
`Philip E. LeBoit, MD
`Bruce U. Wintroub, MD
`
`Onychomycosis:
`Diagnosis, Treatment, and
`Prevention Strategies
`
`GUEST EDITORS
`Linda F. Stein Gold, MD
`Theodore Rosen, MD
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Introduction S47
`
`Understanding Onychomycosis:
`Resolving Diagnostic Dilemmas S48
`
`Antifungal Drugs for Onychomycosis:
`Efficacy, Safety, and Mechanisms of Action S51
`
`Concepts in Onychomycosis Treatment
`and Recurrence Prevention: An Update S56
`
`Using Topical Antifungal Medications:
`Instructions for Patients S60
`
`Post-Test and Evaluation Form S61
`
`Page 1 of 20
`
`

`

`Onychomycosis:
`Diagnosis, Treatment, and Prevention Strategies
`
`Original Release Date: March 2016
`Most Recent Review Date: March 2016
`Expiration Date: February 28, 2018
`Estimated Time to Complete Activity: 2.5 hours
`Participants 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 e-mail or you may print it out at that time. The online post-test and
`evaluation can be accessed at http://tinyurl.com/onychosuppl16.
`Inquiries about CME accreditation may be directed to the University of Louisville
`CME & PD at cmepd@louisville.edu or (502)852-5329.
`Accreditation Statements
`Physicians: 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 accred-
`ited 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 Credits™. 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 4-0068-7-16-895. The Kentucky Board of Nursing approval of an indi-
`vidual nursing education provider does not constitute endorsement of program
`content. Participants must complete the entire session, provide their license
`number, and complete the evaluation to receive contact hours.
`Target Audience
`This journal supplement is intended for dermatologists, family practitioners,
`internists, nurse practitioners, physician assistants, and other clinicians who
`treat patients with onychomycosis.
`Educational Needs
`For many years, the treatment of onychomycosis was frustrating for clinicians
`and patients alike, and the perceived futility of addressing fungal nail infec-
`tions meant that many patients failed to seek treatment, and many others with
`suspected infections were neither definitively diagnosed nor treated. With the
`introduction of oral terbinafine in 1996 and the approval of the first topical agent
`in 1999, more effective control—if not cure—became possible, and clinicians
`showed increased interest in diagnosing and treating the condition. The intro-
`duction of two new topical agents in 2014 broadened the therapeutic options.
`The optimum results with these agents requires the correct diagnosis, which
`cannot be made reliably on visual inspection alone. To use antifungals most
`effectively, clinicians must test to confirm the presence of infecting organ-
`isms and, in appropriate cases, identify the species involved so that the most
`appropriate antifungal can be prescribed. Patient selection also is important:
`for example, the potential for drug-drug interactions with systemic antifungals
`must be considered, the presence of certain comorbid conditions may affect
`the choice of antifungal employed, and the patient’s ability to adhere to the
`long treatment regimens required must be addressed.
`Clinicians must remain up-to-date on these issues, and must be able to effec-
`tively and safely use the available antifungal, evaluate the emerging data on
`medications and devices now being investigated, and educate patients to
`improve adherence.
`Learning Objectives
`After reading and studying this journal supplement, participants will be better
`able to:
`• Establish or improve practice protocols for identifying patients with
`onychomycosis, particularly in special populations (eg, the elderly, pediatric
`patients, immunocompromised patients, patients with psoriasis, and those
`with diabetes mellitus).
`• Discuss techniques, including obtaining good culture specimens, that
`
`permit more accurate diagnosis of the infecting organisms and the most
`appropriate choice of therapy.
`• Explain the drug classes and mechanisms of action for the currently
`available therapeutic options, including differences in formulation and
`associated efficacy.
`• More effectively use currently available oral and topical medications to
`treat various patient populations.
`• Review and, if necessary, improve patient education materials designed
`to enhance patient adherence with the treatment regimen and to change
`habits that increase the chances of good long-term management of
`onychomycosis.
`• Determine and help each patient recognize the realistic expectations for
`improvement in his or her individual case.
`• Evaluate the results of clinical studies on new and emerging and available
`treatments for onychomycosis based on an understanding of possible
`differences in testing protocols (eg, inclusion or exclusion of patients with
`psoriasis or diabetes mellitus).
`Disclosure Declarations
`As a provider accredited by the ACCME, the Office of CME & PD, School of
`Medicine, University of Louisville must ensure balance, independence, objec-
`tivity, and scientific 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 rele-
`vant conflicts of interest were determined. The persons below disclosed the
`following:
`Linda F. Stein Gold, MD, Consultant: Anacor Pharmaceuticals Inc., Eli Lilly
`and Company, Galderma Laboratories, L.P., LEO Pharma
`Inc., Novartis
`Pharmaceuticals Corporation, Pfizer
`Inc., Sandoz, Taro Pharmaceutical
`Industries Ltd., and Valeant Pharmaceuticals North America LLC. Speaker:
`Galderma, LEO, Novartis, and Valeant. Grant Research/Support: Anacor,
`Galderma, GlaxoSmithKline, LEO, Novartis, Pfizer Inc., Sandoz, Taro, and Valeant.
`Theodore Rosen, MD, Consultant: Anacor Pharmaceuticals and Valeant
`Pharmaceuticals North America LLC.
`CME Reviewer: Cindy England Owen, MD, Assistant Professor, Division of
`Dermatology, University of Louisville School of Medicine, has no relevant finan-
`cial relationships to disclose.
`The CME & PD Staff and Advisory Board have nothing to disclose with the
`exception of Douglas Coldwell, MD, Speaker: Sirtex, Inc.; Consultant: DFine, Inc.
`Global Academy for Medical Education Staff: Sylvia H. Reitman, MBA, DipEd;
`Shirley V. Jones, MBA; Jenny Campano; and Joanne Still have no relevant
`financial relationships to disclose.
`Off-Label/Investigational Use Disclosure
`This CME/CE activity discusses the off-label use of fluconazole for the treatment
`of onychomycosis. Also discussed are off-label, alternative dosing sched-
`ules for itraconazole, as well as the use in pediatric patients of medications
`approved for the treatment of onychomycosis in adults; currently, no medica-
`tion is approved for the treatment of onychomycosis in pediatric patients.
`
`This continuing education supplement was developed from a satellite
`symposium held at Skin Disease Education Foundation (SDEF)‘s 16th Annual
`Las Vegas Dermatology Seminar, which took place Friday, November 6, 2015,
`in Las Vegas, Nevada. 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.
`
`Jointly provided by
`
`and
`
`Supported by an educational grant from
`PharmaDerm, a Fougera Pharmaceuticals company
`
`Page 2 of 20
`
`

`

`STATEMENT OF PURPOSE
`Seminars 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.
`
`Seminars in Cutaneous Medicine and Surgery (ISSN 1085-5629) is
`published quarterly by Frontline Medical Communications Inc., 7 Century
`Drive, Suite 302, Parsippany, NJ 07054-4609. Months of issue are March,
`June, September, and December. Periodicals postage paid at Parsippany, NJ,
`and additional mailing offices.
`
`POSTMASTER: Send address changes to Seminars in Cutaneous Medicine
`and Surgery, Subscription Services, 151 Fairchild Ave., Suite 2, Plainview,
`NY 11803-1709.
`
`RECIPIENT: To change your address, contact Subscription Services at
`1-800-480-4851.
`
`Editorial correspondence should be addressed to Kenneth A. Arndt, MD,
`SkinCare Physicians of Chestnut Hill, 1244 Boylston St, Suite 302, Chestnut
`Hill, MA 02467. Correspondence regarding subscriptions or change of
`address should be directed to the Publisher, Subscription Services, 151
`Fairchild Ave., Suite 2, Plainview, NY 11803-1709, 1-800-480-4851.
`
`Yearly subscription rate: $121.00 per year.
`
`Prices are subject to change without notice. Current prices are in effect for
`back volumes and back issues. Single issues, both current and back, exist in
`limited quantities and are offered for sale subject to availability. Back issues
`sold in conjunction with a subscription are on a prorated basis.
`
`Copyright © 2016 by Frontline Medical Communications Inc. No part of
`this publication may be reproduced or transmitted in any form or by any
`means, electronic or mechanical, including photocopy, recording, or any
`information storage and retrieval system, without written permission from
`the Publisher. Printed in the United States of America.
`
`Advertising representative: Sally Cioci, 7 Century Drive, Suite 302,
`Parsippany, NJ 07054-4609. Phone: 973-206-3434; Fax: 973-206-9378;
`email: scioci@frontlinemedcom.com
`
`Publication of an advertisement in Seminars in Cutaneous Medicine and
`Surgery does not imply endorsement of its claims by the Editor(s) or
`Publisher of the journal.
`
`The ideas and opinions expressed in Seminars in Cutaneous Medicine
`and Surgery do not necessarily reflect those of the Editors or Publisher.
`Publication of an advertisement or other product mention in Seminars in
`Cutaneous Medicine and Surgery should not be construed as an endorsement
`of the product or the manufacturer’s claims. Readers are encouraged to
`contact the manufacturer with any questions about the features or limitations
`of the products mentioned. The Publisher does not assume any responsibility
`for any injury and/or damage to persons or property arising out of or related
`to any use of the material contained in this periodical. The reader is advised
`to check the appropriate medical literature and the product information
`currently provided by the manufacturer of each drug to be administered
`to verify the dosage, the method and duration of administration, or
`contraindications. It is the responsibility of the treating physician or other
`health care professional, relying on independent experience and knowledge
`of the patient, to determine drug dosages and the best treatment for
`the patient.
`
`Seminars in Cutaneous Medicine and Surgery is indexed in Index
`Medicus/MEDLINE
`
` EDITORS
`
`Kenneth A. Arndt, MD
`Clinical 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
`
`Philip E. LeBoit, MD
`Professor of
` Clinical Dermatology
`University of California,
` San Francisco
`San Francisco, California
`
`Bruce U. Wintroub, MD
`Associate Dean
`Professor and Chair
` of Dermatology
`School of Medicine
`University of California,
` San Francisco
`San Francisco, California
`
`Page 3 of 20
`
`

`

`March 2016, Vol. 35, No. 3S
` TABLE OF CONTENTS
`
`Onychomycosis: Diagnosis, Treatment,
`and Prevention Strategies
`
`S47 Introduction
`Linda F. Stein Gold, MD
`
`S56 Concepts in Onychomycosis
`Treatment and Recurrence
`Prevention: An Update
`Theodore Rosen, MD
`
`S48 Understanding Onychomycosis:
`Resolving Diagnostic Dilemmas
`Linda F. Stein Gold, MD
`
`S51 Antifungal Drugs for Onychomycosis:
`Efficacy, Safety, and Mechanisms
`of Action
`Theodore Rosen, MD, and
`Linda F. Stein Gold, MD
`
`S60 Using Topical Antifungal
`Medications: Instructions for Patients
`Theodore Rosen, MD
`
`S61 Post-Test and Evaluation Form
`
` GUEST EDITORS
`
`Linda F. Stein Gold, MD
`Director of Dermatology Research
`Henry Ford Health System
`Detroit, Michigan
`
`Theodore Rosen, MD,
`Professor of Dermatology
`Baylor College of Medicine
`Houston, TX
`
`iv Seminars in Cutaneous Medicine and Surgery, Vol. 35, No. 3S, March 2016
`
`Page 4 of 20
`
`

`

`Vol. 35, No. 3S, March 2016
`
` INTRODUCTION
`
`Onychomycosis recently has become more widely rec-
`
`ognized as a medical condition having importance well
`beyond the cosmetic appearance of nails. Failure to di-
`agnose this infection accurately and treat it effectively may lead
`to medical sequelae such as permanent damage to the nail plate
`and its attachments, and the potential for secondary bacterial
`infections, as well as spread of the fungus locally and to other
`parts of the body and transmission of the infection to others. In
`addition, quality-of-life and psychosocial consequences cannot
`be overlooked. However, until the introduction of newer, more
`effective medications over the past 2 decades, most patients with
`onychomycosis remained undiagnosed and untreated or ineffec-
`tively managed.
`The introduction of terbinafine in 1996 marked the beginning of
`a new era in the diagnosis and treatment of onychomycosis. The
`approval of the first topical antifungal for the treatment of this in-
`
`fection followed soon afterward; in 1999, the topical antifungal
`agent, ciclopirox, was approved by the US Food and Drug Admin-
`istration (FDA).
`Research focusing on a clearer understanding of the underlying
`infectious organisms subsequently led to the introduction of two
`new topical agents, efinaconazole and tavaborole, both approved
`by the FDA in 2014.
`This educational supplement features highlights of a CME/CE
`independent satellite symposium, which was held on November
`6, 2015, at Skin Disease Education Foundation’s 16th Annual Las
`Vegas Dermatology Seminar. It reviews the efficacy and safety of
`onychomycosis treatments, provides an overview of the mecha-
`nisms of action of the available antifungal agents, addresses ony-
`chomycosis in special patient populations, and discusses strategies
`for improving patient adherence to recommended therapy and re-
`ducing the risk for recurrence of infection.
`
`Linda F. Stein Gold, MD
`Director of Dermatology Research
`Henry Ford Health System
`Detroit, Michigan
`
`Theodore Rosen, MD
`Professor of Dermatology
`Baylor College of Medicine
`Houston, TX
`
`Publication of this CME/CE article was jointly provided by University of
`Louisville, and Global Academy for Medical Education, LLC with Skin
`Disease Education Foundation (SDEF) and is supported by an educational
`grant from PharmaDerm, a Fougera Pharmaceuticals company.
`Dr Rosen and Dr Stein Gold 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 supplement.
`Linda F. Stein Gold, MD, Consultant: Anacor Pharmaceuticals Inc., Eli Lilly
`and Company, Galderma Laboratories, L.P., LEO Pharma Inc., Novartis
`Pharmaceuticals Corporation, Pfizer Inc., Sandoz, Taro Pharmaceutical
`Industries Ltd., and Valeant Pharmaceuticals North America LLC. Speaker:
`Galderma, LEO, Novartis, and Valeant. Grant Research/Support: Anacor,
`Galderma, GlaxoSmithKline, LEO, Novartis, Pfizer Inc., Sandoz, Taro, and
`Valeant.
`Theodore Rosen, MD, Consultant: Anacor Pharmaceuticals and Valeant
`Pharmaceuticals North America LLC.
`Address reprint requests to: Linda F. Stein Gold, MD, 2360 Heronwood Drive,
`Bloomfield Hills, MI 48302; lstein1@hfhs.org.
`
`1085-5629/13/$-see front matter © 2016 Frontline Medical Communications
`DOI:10.12788/j.sder.2016.007
`
`Vol. 35, No. 3S, March 2016, Seminars in Cutaneous Medicine and Surgery S47
`
`Page 5 of 20
`
`

`

`Understanding Onychomycosis:
`Resolving Diagnostic Dilemmas
`
`Linda F. Stein Gold, MD*
`
`n Abstract
`No scientifically rigorous, large, prospective studies have
`been done to document the true prevalence of onycho-
`mycosis; the reported rates vary mainly by climate and
`by population, but the overall prevalence in the United
`States is estimated to be at least 10%. Advanced age and
`diabetes are the most commonly reported risk factors for
`onychomycosis. The differential diagnosis of onychomyco-
`sis is lengthy, and visual inspection alone is not sufficient
`for a definitive diagnosis—direct microscopic examination
`of a wet-mount preparation with 10% to 20% potassium
`hydroxide is the first-line diagnostic test.
`Key Words
`Dermatophyte; onychomycosis; Trichophyton rubrum
`Semin Cutan Med Surg 35(supp3):S50-S52
`© 2016 Frontline Medical Communications
`
`n TABLE 1. Risk Factors for Onychomycosis
`
`• Tinea pedis4,5
`• Nail trauma5
`• Diabetes6-8
`• Psoriasis9
` – 18% in a systematic review of the literature10
` – 28% in a prospective study of hospitalized psoriasis
`patients11
`• Advanced age12-15
`• Peripheral vascular disease5
`• Compromised immune function16
`• Personal/family history of onychomycosis17
`
`Onychomycosis prevalence estimates vary widely; based
`
`on the available studies, the overall prevalence of ony-
`chomycosis is probably at least 10% to 12%, possibly
`higher.1-3 The vast majority of cases of onychomycosis involve
`dermatophyte molds, particularly Trichophyton rubrum, which ac-
`counts for 90% of infections, and T. mentagrophytes. Candida spe-
`cies cause between 10% and 20% of onychomycosis, and a small
`number of cases can be attributed to nondermatophyte molds, such
`as Acremonium, Fusarium, and Scopulariopsis spp.1-3
`
`Risk Factors for Onychomycosis
`Despite the lack of more exact epidemiologic data, climate, popu-
`lation, and other risk factors can be helpful in narrowing the di-
`
`* Director of Dermatology Research, Henry Ford Health System, Detroit,
`Michigan.
`Publication of this CME/CE article was jointly provided by the University
`of Louisville, and Global Academy for Medical Education, LLC with Skin
`Disease Education Foundation (SDEF) and is supported by an educational
`grant from PharmaDerm, a Fougera Pharmaceuticals company.
`Dr Stein Gold has received an honorarium for her participation in this activity.
`She acknowledges the editorial assistance of Joanne Still, medical writer, and
`Global Academy for Medical Education in the development of this continuing
`medical education journal supplement.
`Linda F. Stein Gold, MD, Consultant: Anacor Pharmaceuticals Inc., Eli Lilly
`and Company, Galderma Laboratories, L.P., LEO Pharma Inc., Novartis
`Pharmaceuticals Corporation, Pfizer Inc., Sandoz, Taro Pharmaceutical
`Industries Ltd., and Valeant Pharmaceuticals North America LLC. Speaker:
`Galderma, LEO, Novartis, and Valeant. Grant Research/Support: Anacor,
`Galderma, GlaxoSmithKline, LEO, Novartis, Pfizer Inc., Sandoz, Taro, and
`Valeant.
`Address reprint requests to: Linda F. Stein Gold, MD, 2360 Heronwood Drive,
`Bloomfield Hills, MI 48302; lstein1@hfhs.org.
`
`agnosis in patients with nail symptoms. Onychomycosis is more
`common in hot, humid regions and is less commonly seen in tem-
`perate or cold, dry climates. Other environmental risk factors in-
`clude public areas where individuals may walk barefoot—pools,
`spas, gym locker rooms, and hot tubs. In addition, increasing age
`is a risk factor: it is clear that onychomycosis is uncommon in pe-
`diatric patients, whereas its prevalence in geriatric populations is
`estimated to be as high as 60%.3
`A number of medical conditions also are associated with an
`increased risk for onychomycosis (Table 1), including several
`comorbid conditions: diabetes, psoriasis, peripheral vascular
`disease, tinea pedis, and diseases that adversely affect immune
`function.4-17 Among these, diabetes is the most common—up to
`one-third of patients with diabetes also have onychomycosis.6-8
`Patients with psoriasis also are at increased risk for onychomy-
`cosis. In one review of the literature, Klaassen et al10 reported that
`about 18% of patients with psoriasis have onychomycosis, and
`Méndez-Tovar and colleagues11 found onychomycosis in 28% of
`hospitalized patients.
`Tinea pedis increases the risk for nail infection (Figure 1). Al-
`though such coinfections are not among the most common, when
`onychomycosis is suspected, examination should be done for
`signs of tinea pedis between the toes (interdigital distribution)
`and on the soles of the feet (moccasin distribution). Individuals
`who share a residence with a patient who has onychomycosis
`also should be asked about and, if possible, examined for fungal
`infections of both nail and skin. This is particularly important
`in cases of pediatric onychomycosis or recurrent nail infections.
`Onychomycosis is uncommon in young children in general but
`is more common among children whose parents or older siblings
`have onychomycosis or tinea pedis. In patients with recurrent in-
`
`S48 Seminars in Cutaneous Medicine and Surgery, Vol. 35, No. 3S, March 2016
`
`1085-5629/13$-see front matter © 2016 Frontline Medical Communications
`DOI: 10.12788/j.sder.2016.008
`
`Page 6 of 20
`
`

`

`n TABLE 2. Differential Diagnosis
`of Onychomycosis18-21
`
`• Nail trauma
`• Psoriasis
`• Lichen planus
`• Paronychia
`• Bacterial infection
`• Pachyonychia congenita
`• Nail bed tumors (squamous cell carcinoma) and verrucae
`• Yellow nail syndrome
`• Alopecia areata
`• Contact/atopic dermatitis
`• Idiopathic onycholysis
`• Twenty-nail dystrophy (trachyonychia)
`• Nail changes associated with systemic disease or nail
`cosmetics
`
`terial contamination of the sample. In obtaining a sample, a cu-
`rette may be more helpful than a blade to minimize bleeding and
`patient discomfort.
`
`Mycologic Culture
`A mycologic culture can be considered if onychomycosis is sus-
`pected but KOH findings are negative, or to identify the specific
`organism when hyphae, spores, or other fungal structures are seen
`on direct microscopy. The results usually are available in 4 to 6
`weeks; meanwhile, therapy can be initiated, if indicated.
`
`Histologic Evaluation
`Histologic evaluation of a sample of nail clippings using PAS stain
`also can be ordered to identify the infecting organism. In contrast
`to culture, the results of PAS studies are available in 1 to 2 days.
`Moreover, PAS results are more specific than fungal culture find-
`ings. This superior sensitivity was demonstrated in a study of 100
`consecutive cases of suspected onychomycosis in which direct
`
`n FIGURE 2. White Superficial Onychomycosis. Several clinical
`signs, including erythema and swelling of the nail folds, make
`visual inspection alone an unreliable diagnostic method. This
`patient has white superficial onychomycosis, confirmed by diag-
`nostic testing. Photo courtesy of Theodore Rosen, MD.
`
`Vol. 35, No. 3S, March 2016, Seminars in Cutaneous Medicine and Surgery S49
`
`n FIGURE 1. Onychomycosis and Tinea Pedis. When onychomy-
`cosis is suspected, the skin should be inspected for signs of tinea
`pedis. The reverse is also true—if a patient complains of symptoms
`of athlete’s foot, the toenails should be examined for evidence of
`onychomycosis. Photo courtesy of Theodore Rosen, MD.
`
`fections, other individuals in the household who have untreated
`tinea pedis may be a source of chronic reinfection.
`In addition, any type of nail trauma can increase the risk for
`onychomycosis, as damage to the nail plate—and, consequently,
`disruption of the plate from the nail bed—allows introduction of
`potentially pathogenic organisms.
`
`Differential Diagnosis
`Although onychomycosis is a common nail disease, it is impor-
`tant to note that 50% of cases of nail disease can be attributed to
`causes other than fungus or yeast infections.18 As shown in Table 2,
`a number of other conditions can mimic onychomycosis, including
`other infections or diseases and trauma.18-21 Because discoloration,
`brittleness, and other signs of nail dystrophy are common to many
`clinical entities, visual inspection alone is not sufficient to estab-
`lish a diagnosis of onychomycosis (Figure 2); objective diagnostic
`techniques should be used.
`
`Diagnostic Techniques
`The first-line diagnostic technique for onychomycosis is direct
`microscopy of a carefully prepared specimen of affected sub-
`ungual tissue in 10% to 20% potassium hydroxide (KOH). For
`more a more definitive diagnosis—ie, identification of the infect-
`ing organism(s)—a culture or histopathologic techniques (peri-
`odic acid–Schiff [PAS] stain or polymerase chain reaction [PCR]
`testing) may be considered. An overview of these recommended
`diagnostic techniques is provided below. [For a more detailed
`discussion of onychomycosis presentations, mycology, and diag-
`nostic testing, the reader is referred to the comprehensive article
`published by Elewski.5]
`
`Potassium Hydroxide Preparation:
`Examination and Culture
`Microscopic examination of a specimen prepared with 10% to
`20% KOH is a readily accessible technique for determining wheth-
`er fungal organisms are present in a sample; however, proper sam-
`pling is essential to its value as a first-line diagnostic tool.
`To obtain a good subungual sample, it is necessary to trim back
`the nail to access the moist debris that lies behind the dry, flaky
`material at the end of the distal nail. After trimming, the nail and
`surrounding tissue should be cleaned thoroughly to prevent bac-
`
`Linda F. Stein Gold, MD
`
`Page 7 of 20
`
`

`

`9.
`
`7.
`
`mellitus. Drugs Aging. 2004;21:101-112.
`Gupta S, Koirala J, Khardori R, Khardori N. Infections in diabetes mellitus and
`hyperglycemia. Infect Dis Clin North Am. 2007;21:617-638.
`8. Winston JA, Miller JL. Treatment of onychomycosis in diabetic patients. Clin Dia-
`betes. 2006;24:160-166.
`Rich P, Griffiths CE, Reich K, et al. Baseline nail disease in patients with moderate
`to severe psoriasis and response to treatment with infliximab during 1 year. J Am
`Acad Dermatol. 2008;58:224-231.
`10. Klaassen KM, Dulak MG, van de Kerkhof PC, Paasch MC. The prevalence of ony-
`chomycosis in psoriatic patients: A systematic review. J Eur Acad Dermatol Vene-
`reol. 2014;28:533-541.
`11. Méndez-Tovar LJ, Arévalo-López A, Domínguez-Aguilar S, et al. Onychomycosis
`frequency in psoriatic patients in a tertiary care hospital [in Spanish]. Rev Med Inst
`Mex Seguro Soc. 2015;53:374-379.
`12. Smith ES, Fleischer AB Jr, Feldman SR. Demographics of aging and skin disease.
`Clin Geriatr Med. 2001;17:631-641.
`13. 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.
`14. Htew TH, Mushtaq A, Robinson SB, Rosher RB, Khardori N. Infection in the el-
`derly. Infect Dis Clin North Am. 2007;21:711-743.
`15. Abdullah L, Abbas O. Common nail changes and disorders in older people: Diagno-
`sis and management. Can Fam Physician. 2011;57:173-181.
`16. Gupta AK, Taborda P, Taborda V, et al. Epidemiology and prevalence of onychomy-
`cosis in HIV-positive individuals. Int J Dermatol. 2000;39:746-753.
`17. Piraccini BM, Sisti A, Tosti A. Long-term follow-up of toenail onychomycosis
`caused by dermatophytes after successful treatment with systemic antifungal agents.
`J Am Acad Dermatol. 2010;62:411-414.
`18. Faergemann J, Baran R. Epidemiology, clinical presentation and diagnosis of ony-
`chomycosis. Br J Dermatol. 2003;149(suppl 65):1-4.
`19. Allevato MA. Diseases mimicking onychomycosis. Clin Dermatol. 2010;28:164-
`177.
`20. Cockerell C, Odom R. The differential diagnosis of nail disease. AIDS Patient Care.
`1995;9(suppl 1):S5-S10.
`21. Daniel CR III. The diagnosis of nail fungal infection. Arch Dermatol. 1991;127:1566-
`1567.
`22. Mayer E, Izhak OB, Bergman R. Histopathological periodic acid-Schiff stains of
`nail clippings as a second-line diagnostic tool in onychomycosis. Am J Dermatopa-
`thol. 2012;34:270-273.
`23. Luk NM, Hui M, Cheng TS, Tang LS, Ho KM. Evaluation of PCR for the diagnosis
`of dermatophytes in nail specimens from patients with suspected onychomycosis.
`Clin Exp Dermatol. 2012;37:230-234.
`
`microscopy and fungal culture results were negative. Mayer and
`colleagues22 showed that 38 patients (38%) had positive fungal ele-
`ments when the nail clippings were processed with hematoxylin,
`eosin, and PAS.
`PCR testing also has been shown to be more sensitive than
`PAS in detecting the presence of mycologic organisms compared
`with direct microscopy with KOH or culture. In one study that
`compared the positivity rates with KOH/microscopy, culture, and
`PCR, the investigators reported rates of 10%, 29%, and 40%, re-
`spectively.23 The results of PCR testing usually are available in
`about 3 days.
`
`Conclusion
`The accurate diagnosis and early treatment of onychomycosis is
`important to the preservation and function of the nail plate in pa-
`tients with early disease and to the prevention of progressive de-
`struction and deformity in patients with long-standing disease. In
`addition, onychomycosis represents a reservoir of fungus that can
`seed the skin of other areas of the body, and can be transmitted to
`others with whom the patient comes in contact. Effective therapy
`is available.
`
`References
`1.
`Ghannoum MD, Hajjeh RA, Scher R, et al. 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.
`Heikkilä H, Stubb S. The prevalence of onychomycosis in Finland. Br J Dermatol.
`1995;133:699-703.
`Scher RK, Rich P, Pariser D, Elewski B. The epidemiology, etiology, and patho-
`physiology of onychomycosis. Semin Cutan Med Surg. 2013;32(2 suppl 1):S2-S4.
`Pleacher MD, Dexter WW. Cutaneous fungal and viral infections in athletes. Clin
`Sports Med. 2007;26:397-411.
`Elewski B. Onychomycosis: Pathogenesis, diagnosis, and management. Clin Micro-
`biol Rev. 1998;11:415-429.
`Tan JS, Joseph WS. Common fungal infections of the feet in patients with diabetes
`
`2.
`
`3.
`
`4.
`
`5.
`
`6.
`
`S50 Seminars in Cutaneous Medicine and Surgery, Vol. 35, No. 3S, March 2016
`
`n n n Understanding Onychomycosis: Resolving Diagnostic Dilemmas
`
`Page 8 of 20
`
`

`

`Antifungal Drugs for Onychomycosis: Efficacy,
`Safety, and Mechanisms of Action
`
`Theodore Rosen, MD*, and Linda F. Stein Gold, MD†
`
`n Abstract
`In 1996, oral terbinafine j