Seminars in Cutaneous Medicine and Surgery

Supplement 1 Vol. 32, No. 2S June 2013

A CME-certified Supplement to Seminars in Cutaneous Medicine and Surgery

Editors Kenneth A. Arndt, MD Philip E. LeBoit, MD Bruce U. Wintroub, MD

Update on Onychomycosis: Effective Strategies for Diagnosis and Treatment

Guest Editors David Pariser, MD Boni Elewski, MD Phoebe Rich, MD Richard K. Scher, MD Update on Onychomycosis: Effective Strategies for Diagnosis and Treatment

Original Release Date: June 2013 Target Audience Most Recent Review Date: June 2013 This continuing medical education activity has been devel- Expiration Date: June 30, 2015 oped for dermatologists, family practice and internal medicine Estimated Time to Complete Activity: 2.5 hours physicians, and other health care providers who treat diseases Medium or Combination of Media Used: Written Supplement of the skin. Method of Physician Participation: Journal Supplement Disclosure Hardware/Software Requirements: As a sponsor accredited by the ACCME, the University of High Speed Internet Connection Louisville School of Medicine must ensure balance, inde- To get instant CME credits online, go to http://uofl.me/onycho13. pendence, objectivity, and scientific rigor in all its sponsored Upon successful completion of the online test and evaluation educational activities. All faculty participating in this CME form, you will be directed to a webpage that will allow you activity were asked to disclose the following: to receive your certificate of credit via e-mail. Please add 1. Names of proprietary entities producing health care goods [email protected] to your e-mail “safe” list. If you have or services—with the exemption of nonprofit or government any questions or difficulties, please contact the University of organizations and non–health-related companies—with Louisville School of Medicine Continuing Medical Education which they or their spouse/partner have, or have had, a (CME & PD) office at [email protected]. relevant financial relationship within the past 12 months. For this purpose, we consider the relevant financial Joint Sponsorship relationships of a spouse/partner of which they are aware This activity has been planned and implemented in accor- to be their financial relationships. dance with the Essential Areas and Policies of the Accreditation 2. Describe what they or their spouse/partner received Council for Continuing Medical Education (ACCME) through (eg, salary, honorarium). the joint sponsorship of the University of Louisville School of Medicine and Global Academy for Medical Education, LLC. 3. Describe their role. The University of Louisville School of Medicine is accredited by 4. No relevant financial relationships. the ACCME to provide continuing education for physicians. CME & PD Advisory Board Members: have no relevant finan- Designation Statement cial relationships with any commercial interests: Lisa J. Pfitzer, The University of Louisville Continuing Medical Education MD; Soon Bahrami, MD; Douglas Coldwell, MD, PhD; W. Daniel designates this enduring material for a maximum of 2.5 AMA Cogan, Ed.D., FAODME; Justin L. Costa, MD; James Creg; Daniel PRA Category 1 Credit(s)™. Physicians should claim only the Da Justa, MD; Adair Heyl, PhD; Christopher Jones, MD;Lucy Juett, credit commensurate with the extent of their participation in MS; Gerald Larson, MD; Rana Latif, MD; Kimberly Moore; Karen the activity. Napolilli; Scott Plantz, MD;Kerri Remmel, MD, PhD; Michael D. Stillman, MD; Uldis Streips, PhD; Kathy M. Vincent, MD; Lori Wagner, Educational Needs MD; Angela Wetherton, MD; and Stephen Wheeler, MD have no Onychomycosis has become recognized as an infection relevant financial relationships with any commercial interests. of clinical importance well beyond its cosmetic effects. This CME Reviewer: Timothy Brown, MD, Professor, Division of is especially true for elderly individuals, patients who are Dermatology, University of Louisville, School of Medicine has no immunocompromised (eg, because of post-transplant immu- relevant financial relationships with any commercial interests. nosuppressive drug therapy or HIV infection), and those with Boni Elewski, MD, has been an investigator for Anacor and diabetes. The number of patients who present with onychomy- Valeant Pharmaceuticals. cosis has grown substantially as these high-risk populations increase, with increased longevity, greater survival among David Pariser, MD, has been a consultant and/or investigator people with HIV infections, and the growing prevalence of and/or advisory board member with Abbott Laboratories, diabetes mellitus. Clinicians must be prepared to make a Amgen, Astellas Pharma US, Inc, Basilea, Celgene Corporation, clinical diagnosis of onychomycosis based on physical exami- Dow Pharmaceutical Sciences, Inc., DUSA Pharmaceuticals, Inc., nation and personal and family history. The current standard Eli Lily and Company, Galderma Laboratories, L.P., Genentech, Inc., Graceway Pharmaceuticals, LLC, Intendis, Inc., Janssen- of care is definitive diagnosis using recognized laboratory Ortho Inc, Johnson & Johnson Consumer Products Company, methods for identifying the presence of causative organisms. LEO Pharma, US, Medicis Pharmaceutical Corporation, This supplement provides up-to-date information on epide- MelaSciences, Novartis Pharmaceutical Corporation, Novo miology, pathophysiology, and diagnosis of onychomycosis, Nordisk A/S, Ortho Dermatologics, Peplin Inc., Pfizer, Photocure and reviews and provides expert recommendations on the ASA, Proctor & Gamble Company, Stiefel a GSK company, and currently available systemic and topical medications and Valeant Pharmaceuticals International. devices for treating this infection. Phoebe Rich, MD, has been a principal investigator and/or Learning Objectives consultant for Valeant, Dow Pharmaceuticals, Topica, and Tolmar. After participating in this continuing medical educational Richard K. Scher, MD, is an advisor/consultant to Valeant. activity, clinicians should be able to: Joanne Still, BA has no relevant financial relationships with • List and describe the differential diagnosis of onychomycosis any commercial interests. and the expert-recommended methods for establishing the diagnosis of this infection. Sylvia H. Reitman, MBA and Shirley V. Jones, MBA, Global Academy for Medical Education, have no relevant financial Explain the benefits of early diagnosis and treatment of • relationships with any commercial interests. onychomycosis and the potential sequelae if this infection is untreated or is inadequately treated. Acknowledgments • Apply practice protocols for identifying patients with onycho- The authors would like to thank Global Academy for Medical mycosis, particularly the elderly, patients with diabetes mellitus, Education and Joanne Still for assistance with the preparation and other high-risk populations. of this supplement. • Integrate effective, office-based diagnostic tests into the This activity is supported by an educational grant from Medicis, workup of patients with symptoms of onychomycosis. a division of Valeant Pharmaceuticals. • Use currently available oral and topical medications to University of Louisville CME & PD Privacy Policy treat various patient populations. All information provided by course participants is confidential • Evaluate the results of clinical studies on new and emerging and will not be shared with any other parties for any reason treatments for onychomycosis. without permission. Seminars in Cutaneous Medicine and Surgery

Editors

Kenneth A. Arndt, MD Clinical Professor of Dermatology, Emeritus Harvard Medical School Boston, Massachusetts 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

Seminars in Cutaneous Medicine and Surgery presents well-rounded and authoritative discussions of Statement 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 of Purpose 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. Guest Editors

David Pariser, MD, Chair Professor of Dermatology Eastern Virginia Medical School Department of Dermatology Pariser Dermatology Norfolk, Virginia

Boni Elewski, MD Vice-Chair for Clinical Affairs Professor of Dermatology University of Alabama School of Medicine Birmingham, Alabama

Phoebe Rich, MD Clinical Adjunct Professor of Dermatology Oregon Health Science University Portland, Oregon

Richard K. Scher, MD Clinical Professor of Dermatology Weill Cornell Medical College New York, New York

The Guest Editors acknowledge the editorial assistance of Global Academy for Medical Education, LLC, and Joanne Still, medical writer, in the development of this supplement.

This continuing medical education (CME) supplement was developed from a clinical roundtable. 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 supporter or of the Publisher.

This educational supplement is supported by

Jointly sponsored by and

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The ideas and opinions expressed in Seminars in Cutaneous Medicine and Surgery do not necessarily reflect those Editors 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 Kenneth A. Arndt, MD 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 Philip E. LeBoit, MD arising out of or related to any use of the material contained in this periodical. The reader is advised to check the Bruce U. Wintroub, MD 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.

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Volume 32 Number 2S

Update on Onychomycosis: Effective Strategies for Diagnosis and Treatment

S1 The Rationale for Renewed Attention to Onychomycosis David Pariser

S2 The Epidemiology, Etiology, and Pathophysiology of Onychomycosis Richard K. Scher, Phoebe Rich, David Pariser and Boni Elewski

S5 Diagnosis, Clinical Implications, and Complications of Onychomycosis Phoebe Rich, Boni Elewski, Richard K. Scher and David Pariser

S9 Current and Emerging Options in the Treatment of Onychomycosis Boni Elewski, David Pariser, Phoebe Rich and Richard K. Scher

S13 Promoting and Maintaining or Restoring Healthy Nails: Practical Recommendations for Clinicians and Patients David Pariser, Richard K. Scher, Boni Elewski and Phoebe Rich

a publication by IMNG Medical Media, a division of Frontline Medical Communications Inc. Volume 32, Number 2S June 2013 The Rationale for Renewed Attention to Onychomycosis David Pariser, MD

nychomycosis is a common problem that the average The consequences of failure to treat include permanent Odermatologic practitioner encounters every day. Our damage to the nail plate and its attachments, the develop- experiences with this infection are as varied as the patients ment of secondary infections with bacteria and other who present with onychomycosis. organisms, local spread of the infection (paronychia) or All clinicians certainly have encountered patients with very spread to other parts of the body, and transmission of the mild, asymptomatic cases of onychomycosis of the toenails, infection to others.2 For example, Trichophyton rubrum—the about which the patient expresses little or no interest in treat- most common causative organism of both onychomycosis ment. Even those whose infection has progressed to yellowing, and tinea pedis—can be transmitted to the groin area as brittleness, and lifting of the nail plate in several toes may individuals step into and pull clothing up the legs. In addi- mention the condition inside their shoes only as an after- tion, minor wounds on the legs may be colonized by fungal thought in a medical encounter for a different complaint. organisms in this manner, and secondary bacterial infec- Patients who do seek medical attention for onychomycosis as tions and cellulitis may result. their primary complaint usually do so because of one or more In addition, in elderly patients—in whom onychomycosis of the following: pain and discomfort, a secondary infection is highly prevalent—the infection may complicate any exist- 2 of the skin around the nail plate, unsightly appearance, or ing foot problems and may lead to decreased mobility. Any alterations in normal gait represent an increased risk for interference with normal function. Other patients come to falls, and as the population continues to age—and as older the attention of clinicians because their nail disease is associ- persons live longer—both the individual and public health ated with other systemic diseases. consequences are evident. Few in our specialty today would consider the infection too The adverse effects of onychomycosis on quality of life trivial to treat, even in cases in which the clinical manifesta- also must be considered. In addition to embarrassment and tions are, to all appearances, mainly cosmetic. Onychomycosis self-consciousness, untreated or ineffectively treated ony- often is a progressive condition that warrants intervention. chomycosis often interferes with social interactions (particularly intimate relationships) because of fear of con- Clinical Sequelae tagion. Furthermore, adverse effects on job function or on new or continued employment is possible when onychomy- The understanding of nail disease as an important medical cosis of the toenails affects mobility and when infections of condition is a relatively recent development. As Richard K. the fingernails interfere with a job that involves direct Scher, MD, noted in an editorial, “Nail disorders—One of contact with the public (such as restaurant wait staff, health dermatology’s last frontiers,” few articles appeared in the care workers, and retail sales). literature on this topic until the 1980s.1 This lack of attention Clearly, onychomycosis is an infectious disease of signifi- can be attributed in part to underappreciation of the impor- cant importance. tance of infections of the nail and in part to the dearth of available effective modalities to treat these conditions. Conclusion Publication of this CME article was jointly sponsored by the University of Louisville School of Medicine Continuing Medical Education and Clinicians need to know about how onychomycosis presents Global Academy for Medical Education, LLC and is supported by an educational grant from Medicis, a division of Valeant Pharmaceuticals. clinically, how to make a definitive diagnosis (which involves Dr Pariser has been a consultant and/or investigator and/or advisory board identifying the causative organism in each patient prior to member with Abbott Laboratories, Amgen, Astellas Pharma US, Inc, initiating therapy), which treatments currently are available Basilea, Celgene Corporation, Dow Pharmaceutical Sciences, Inc., DUSA Pharmaceuticals, Inc., Eli Lily and Company, Galderma Laboratories, L.P., and how best to use them, and which new agents are now in Genentech, Inc., Graceway Pharmaceuticals, LLC, Intendis, Inc., Janssen- clinical trials and may soon be options for therapy. Ortho Inc, Johnson & Johnson Consumer Products Company, LEO The purpose of the articles in this supplement is to offer Pharma, US, Medicis Pharmaceutical Corporation, MelaSciences, Novartis Pharmaceutical Corporation, Novo Nordisk A/S, Ortho Dermatologics, a convenient compendium of current information in all of Peplin Inc., Pfizer, Photocure ASA, Proctor & Gamble Company, Stiefel these areas for both clinician and patient. a GSK company, and Valeant Pharmaceuticals International. David Pariser, MD, has received an honorarium from Global Academy for Medical Education for his participation in this activity. He acknowledges References the editorial assistance of Joanne Still, medical writer, and Global 1. Scher RK. Nail disorders—One of dermatology’s last frontiers. Dermatol Ther. Academy for Medical Education in the development of this continuing 2007;20:1-2. medical education journal article. Joanne Still has no relevant financial 2. Scher RK. Onychomycosis: A significant medical disorder. J Am Acad Dermatol. relationships with any commercial interests. 1996;35:S2-S5.

1058/5629/13/$-see front matter © Frontline Medical Communications S1 http://dx.doi.org/10.12788/j.sder.0013 The Epidemiology, Etiology, and Pathophysiology of Onychomycosis Richard K. Scher, MD,* Phoebe Rich, MD,† David Pariser, MD,‡ Boni Elewski, MD§

ABSTRACT The prevalence of onychomycosis in the United States is estimated to be at least 12%; prevalence increases with increasing age and is highest in individuals more than 65 years of age. Trichophyton rubrum, which also causes tinea pedis, is responsible for approximately 90% of cases of toenail onychomycosis. Risk factors include a family history of onychomycosis and previous injury to the nails, as well as advanced age and compromised peripheral circulation. Patients with compromised immune function may have an increased risk for onychomycosis and are susceptible to infection with less common dermatophytes and nondermatophyte organisms. Semin Cutan Med Surg 32(suppl):S2-S4 © 2013 published by Frontline Medical Communications

KEYWORDS fungal infections; nail infections; onychomycosis; Trichophyton rubrum

he reported prevalence of onychomycosis in the United higher.1,2 However, it also should be noted that onychomy- TStates varies considerably, as no scientifically rigorous, cosis is rare in children (less than 1%)2 and increases in large epidemiologic studies have been done to date. The prevalence with increasing age (the prevalence in the geriatric prevalence varies according to patient population (including population has been estimated at 60%).1 age, family history, comorbid conditions) and also depends on variables such as geography and climate. The authors concur that the median figure probably is 10% to 12% or Etiology and Pathophysiology The causative organisms in most cases of onychomyco- * Clinical Professor of Dermatology, Weill Cornell Medical College sis are dermatophytes. (The term “tinea unguium” often New York, NY † Clinical Adjunct Professor of Dermatology, Oregon Health Science is used interchangeably with onychomycosis; however, University, Portland, OR tinea unguium applies only to cases of onychomycosis ‡ Professor of Dermatology, Eastern Virginia Medical School caused by dermatophyte fungi.) Dermatophyte organisms Department of Dermatology, Pariser Dermatology, Norfolk, VA § Vice-Chair for Clinical Affairs, Professor of Dermatology are ubiquitous and are found in soil (geophilic), animals University of Alabama School of Medicine, Birmingham, AL (zoophilic), and humans (anthropophilic). Species of three Publication of this CME article was jointly sponsored by the University genera are anthropophilic: Trichophyton, Microsporum, and of Louisville School of Medicine Continuing Medical Education and Global Academy for Medical Education, LLC and is supported by an Epidermophyton. These are keratinophilic organisms, and, as educational grant from Medicis, a division of Valeant Pharmaceuticals. such, they invade keratinized tissues, including the stratum The faculty have received an honorarium from Global Academy for corneum, the hair, and the nails. Medical Education for their participation in this activity. They acknowledge the editorial assistance of Joanne Still, medical writer, The most common organisms found in onychomycosis and Global Academy for Medical Education in the development of this (Table on page S3) are Trichophyton rubrum, which is respon- continuing medical education journal article. Joanne Still has no sible for an estimated 90% of infections, and relevant financial relationships with any commercial interests. Trichophyton mentagrophytes, which is implicated most commonly in the Boni Elewski, MD, has been an investigator for Anacor and Valeant. balance of cases.1 Not surprisingly, onychomycosis of the David Pariser, MD, has been a consultant and/or investigator and/or toenails typically occurs in individuals who have concurrent advisory board member with Abbott Laboratories, Amgen, Astellas Pharma US, Inc, Basilea, Celgene Corporation, Dow Pharmaceutical tinea pedis infections (“athlete’s foot”), also caused by Sciences, Inc., DUSA Pharmaceuticals, Inc., Eli Lily and Company, T. rubrum. Microsporum spp and Epidermophyton floccosum Galderma Laboratories, L.P., Genentech, Inc., Graceway Pharmaceuticals, LLC, Intendis, Inc., Janssen-Ortho Inc, Johnson & Johnson Consumer (the only Epidermophyton species found in humans) are Products Company, LEO Pharma, US, Medicis Pharmaceutical unusual causes of onychomycosis in the United States. Corporation, MelaSciences, Novartis Pharmaceutical Corporation, Novo A number of other organisms also may be involved in nail Nordisk A/S, Ortho Dermatologics, Peplin Inc., Pfizer, Photocure ASA, Proctor & Gamble Company, Stiefel a GSK company, and Valeant infections, including some yeasts—especially Candida spp, Pharmaceuticals International. which most commonly occur in fingernails and most often Phoebe Rich, MD, has been a principal investigator and/or consultant are seen in tropical regions—and some nondermatophyte for Valeant, Dow Pharmaceuticals, Topica, and Tolmar. molds (such as Fusarium and Aspergillus spp).1 Although Richard K. Scher, MD, is an advisor/consultant to Valeant. these occur much less frequently than do the dermatophyte Address reprint requests to: Richard K. Scher, MD, Weill Cornell Center for Dermatology. 1305 York Avenue and 70th Street, 9th Floor, New York, NY infections, it is important to be aware that yeasts and non- 10021, Telephone: (646) 962-3376, E-mail: [email protected] dermatophyte molds may be present, particularly in certain

S2 1058/5629/13/$-see front matter © Frontline Medical Communications http://dx.doi.org/10.12788/j.sder.0014 The Epidemiology, Etiology, and Pathophysiology of Onychomycosis S3

Table. Nail Infections in the United States: Causative Organisms1

Types of Organisms Most Common Less Common Least Common Dermatophytes Trichophyton rubrum Trichophyton mentagrophytes Trichophyton tonsurans Microsporum canis Epidermophyton floccosum Nondermatophytes Acremonium spp Scopulariopsis spp Scytalidium spp Fusarium spp Aspergillus versicolor Aspergillus flavus Aspergillus fumigatus Aspergillus terreus Yeasts Candida parapsilosis Candida albicans Candida guilliermondii Candida tropicalis Candida lusitaniae groups of patients (see the section, “Special Patient with poor peripheral circulation may need higher dosages of Populations,” below). Candida spp and nondermatophyte systemic medications and/or may require a longer course of molds tend to be more difficult to treat effectively, and therapy than do individuals with good circulation. earlier identification of these organisms and prompt initia- tion of therapy may improve outcomes. Advanced Age Certain factors are known to increase the risk for develop- Onychomycosis is among the most common infections that ing onychomycosis. Individuals who perspire heavily or affect older individuals.5 Elewski and Charif6 report that whose occupations or recreational activities expose them to approximately 40% of elderly patients have onychomycosis. humid, moist environments are at increased risk. In such The presence of arthritis and other conditions that affect persons, footwear that crowds the toes or prevents adequate physical flexibility contributes to the increased prevalence of air circulation—and, therefore, evaporation of excess mois- onychomycosis in this population. Gait changes and circula- ture—compounds the problem. tory problems contribute to the development of corns, Individuals with a previous history of nail injury or previ- calluses, and bunions, and minor repeated trauma to the toes ous infection are particularly susceptible under these is common. It is difficult for many older individuals to exer- conditions. Also, the risk for onychomycosis is increased cise careful hygiene of the feet and nails, increasing with participation in occupations, sports, or exercise in susceptibility to colonization by infectious organisms.7 which chronic minor trauma to the toes is sustained. Many older patients have one or more conditions—such In addition, practices such as walking barefoot in public as diabetes and peripheral vascular compromise—that places where moisture is an integral part of the environment contribute to an increased risk for onychomycosis and can (eg, swimming pools, spas, gyms, locker rooms) are represent potential impediments to a good therapeutic common sources of transmission of causative organisms.3 response. As in patients with poor circulation, slower nail Another frequent source of onychomycosis is nail salons; growth increases the risk for onychomycosis in older indi- disinfection regimens for clippers, scissors, and other instru- viduals. The reduction in nail growth rate ranges from about ments are not always effective (even if rigorously followed), 40% to 60% in persons more than 65 years of age; nail and emery boards retain dust from person to person and may growth can slow even more as age increases.8 be a source of organism transmission. Finally, slower drug metabolism, which occurs with Onychomycosis also is a topic of concern among several aging, may interfere with effective systemic therapy for special patient populations: individuals with compromised onychomycosis. In addition, many older patients take mul- peripheral circulation, the elderly, those with diabetes, tiple medications, so the possibility of interactions with persons with a family history of onychomycosis, those with systemic antifungal agents must be considered. compromised immune function, and possibly also patients with psoriasis and pediatric patients. Diabetes Some controversy exists as to whether individuals with dia- Special Patient Populations betes are more susceptible to onychomycosis than are those without diabetes and whether the treatment of those with Compromised Peripheral Circulation diabetes is more difficult than the treatment of those Impaired circulation from any cause—for example, diabetes, without diabetes. Less debatable is the observation that vascular disease, or advanced age—is associated with an onychomycosis is more prevalent in patients with diabetes increased risk for onychomycosis as well as with a dimin- than in patients without the condition. There is no question, ished response to therapy. Poor circulation is associated with however, that onychomycosis makes patients with diabetes a decrease in nail growth rate, which increases the risk for more susceptible to secondary infection9,10 and that nail colonization by dermatophytes and other organisms.4 Patients infections contribute to the development of cellulitis and S4 phlebitis. In addition, patients with diabetes tend to have adolescent and adult family members is warranted whenever onychomycosis from atypical organisms,11 particularly a child presents with signs or symptoms of onychomycosis. yeasts, than do those without diabetes, and infections with Systemic therapy for onychomycosis in children is not these organisms often are more difficult to treat than are approved by the US Food and Drug Administration, those caused by dermatophytes. although terbinafine, fluconazole, and itraconazole are used commonly for treating fungal infections in pediatric Family History patients. Recently, Gupta and Paquet proposed dosing regimens, based on the patient’s weight, for children with either Good evidence demonstrates that a family history of onycho- fingernail or toenail onychomycosis.15 mycosis predisposes individuals to nail infection.12 It is likely that a genetic predisposition exists, but it is also probable that transmission of the causative organism(s) is increased among Conclusion family members living in the same household. For the same reasons, a family history of onychomycosis is associated with Onychomycosis is a common infection that requires appro- recurrence of nail infections after treatment and almost priate diagnosis and treatment. In most patients, the always is associated with pediatric onychomycosis. causative organism is a dermatophyte—usually T. rubrum— that is readily and easily treatable. Patients in some special populations are at higher risk for infections with nonder- Compromised Immune Function matophyte fungi and yeasts. Nail infections with these Immunocompromised patients can be problematic both in organisms may have a protracted course and may be diffi- terms of susceptibility and because they are susceptible to cult to eradicate. Treatment in such patients may be invasion by less common organisms—that is, unusual complicated by the presence of systemic illnesses that dermatophytes and nondermatophyte microbes. require the use of multiple potent systemic medications. Candida albicans, which is implicated predominantly in fingernail infections, may be acquired by direct contact with References a lesion caused by the same organism. Interestingly, Candida 1. Ghannoum MD, Hajjeh RA, Scher R. A large-scale North American study of species do not produce the enzymes necessary to effectively fungal isolates from nails: The frequency of onychomycosis, fungal distribu- invade keratin in healthy individuals. It is seen primarily in tion, and antifungal susceptibility patterns. J Am Acad Dermatol. 2000;43: 641-648. immunocompromised hosts who already have onycholysis, 2. Heikkilä H, Stubb S. The prevalence of onychomycosis in Finland. Br J Dermatol. which creates a warm, moist, dark environment underneath 1995;133:699-703. the nail plates. It can also sometimes cause paronychia. 3. Pleacher MD, Dexter WW. Cutaneous fungal and viral infections in athletes. Clin Sports Med. 2007;26:397-411. Individuals with HIV/AIDS also have a higher susceptibil- 4. Elewski BE. Onychomycosis: Pathogenesis, diagnosis, and management. Clin ity and may have the proximal white subungual type of Microbiol Rev. 1998;11:415-429. onychomycosis.13 In addition, the number of medications 5. Smith ES, Fleischer AB Jr, Feldman SR. Demographics of aging and skin disease. Clin Geriatr Med. 2001;17:631-641. these patients must take on a daily basis makes the prescrip- 6. Elewski B, Charif MA. Prevalence of onychomycosis in patients attending a tion of yet another systemic medication an issue to be dermatology clinic in northeastern Ohio for other conditions. Arch Dermatol. carefully considered. 1997;133:1172-1173. 7. Htwe TH, Mushtaq A, Robinson SB, Rosher RB, Khardori N. Infection in the elderly. Infect Dis Clin North Am. 2007;21:711-743. 8. Abdullah L, Abbas O. Common nail changes and disorders in older people: Psoriasis Diagnosis and management. Can Fam Physician. 2011;57:173-181. Nail psoriasis very closely resembles onychomycosis, par- 9. Tan JS, Joseph WS. Common fungal infections of the feet in patients with ticularly in toenails.14 Several studies have shown that in diabetes mellitus. Drugs Aging. 2004;21:101-112. 10. Gupta S, Koirala J, Khardori R, Khardori N. Infections in diabetes mellitus and almost 30% of individuals with psoriasis who have abnor- hyperglycemia. Infect Dis Clin North Am. 2007;21:617-638. mal toenails, a dermatophyte organism can be cultured 11. Winston JA, Miller JL. Treatment of onychomycosis in diabetic patients. Clin from the nail. Treatment for onychomycosis in these cases Diabetes. 2006;24:160-166. 12. Piraccini BM, Sisti A, Tosti A. Long-term follow-up of toenail onychomycosis will clear the dermatophyte infection, but the portion of caused by dermatophytes after successful treatment with systemic antifungal the nail affected by psoriasis will not improve. About 5% agents. J Am Acad Dermatol. 2010;62:411-414. of patients have nail involvement as their initial presenta- 13. Gupta AK, Taborda P, Taborda V, et al. Epidemiology and prevalence of onychomycosis in HIV-positive individuals. Int J Dermatol. 2000;39:746-753. 14 tion of psoriasis. Therefore, psoriasis should be 14. Rich P, Griffiths CEM, Reich K, et al. Baseline nail disease in patients with considered as a possible diagnosis—or concomitant diag- moderate to severe psoriasis and response to treatment with infliximab during nosis—in patients with onychomycosis. 1 year. J Am Acad Dermatol. 2008;58:224-231. 15. Gupta A, Paquet M. Onychomycosis in children. J Am Acad Dermatol. 2012; 66(4 suppl 1):AB120. Pediatric Patients A prevailing myth from years past was that children do not get onychomycosis. More recent observation and evidence demonstrates that children do indeed acquire the infection; the prevalence is very low, now estimated at less than 1%,1 although it may be increasing. In general, pediatric patients who develop onychomycosis have a family history of the infection. Therefore, an examination of the nails of Diagnosis, Clinical Implications, and Complications of Onychomycosis Phoebe Rich, MD,* Boni Elewski, MD,† Richard K. Scher, MD,‡ David Pariser, MD§

ABSTRACT The diagnosis of onychomycosis is suggested by the clinical presentation as well as the family history and patient age. The definitive diagnosis of onychomycosis is based on (1) establishing the presence or absence of fungal elements using laboratory methods and/or (2) identifying the fungus using fungal culture or, in the future, by polymerase chain reaction as new developments emerge in this technology, making more widespread application of this technique possible. Semin Cutan Med Surg 32(suppl):S5-S8 © 2013 published by Frontline Medical Communications

KEYWORDS fungal infections; nail infections; onychomycosis; potassium hydroxide preparations

nychomycosis is defined as a fungal infection of the nail populations, such as patients with diabetes, the elderly, and Ounit (Figure 1): the nail plate, nail bed, and periungual immunocompromised individuals. (For further discussion tissue. The most common culprits in immunocompetent in this supplement, see Scher et al.2) Onychomycosis caused patients are Trichophyton rubrum (90% of cases) and by dermatophytes is significantly more common in toenails Trichophyton mentagrophytes (most of the remaining 10% of than in fingernails; the opposite is true of Candida infec- cases).1 Less commonly, yeasts and nondermatophyte molds tions, which are significantly more common in fingernails may be causative organisms, particularly in certain patient than in toenails.3

* Clinical Adjunct Professor of Dermatology, Oregon Health Science University, Portland, OR Proximal Nail Fold † Vice-Chair for Clinical Affairs, Professor of Dermatology Eponychium True Cuticle University of Alabama School of Medicine, Birmingham, AL Nail Plate Lunuta ‡ Clinical Professor of Dermatology, Weill Cornell Medical College Distal Edge New York, NY Side View Nail Bed § Professor of Dermatology, Eastern Virginia Medical School Department of Dermatology, Pariser Dermatology, Norfolk, VA Publication of this CME article was jointly sponsored by the University of Louisville School of Medicine Continuing Medical Education and Global Academy for Medical Education, LLC and is supported by an Hyponychium Onychocomeal/ educational grant from Medicis, a division of Valeant Pharmaceuticals. Onychodermal Band The faculty have received an honorarium from Global Academy for Medical Education for their participation in this activity. They Nail Plate Lateral acknowledge the editorial assistance of Joanne Still, medical writer, Nail Fold and Global Academy for Medical Education in the development of this Surface View Eponychium/ continuing medical education journal article. Joanne Still has no Lunuta relevant financial relationships with any commercial interests. Cuticle Proximal Nail Fold Boni Elewski, MD, has been an investigator for Anacor and Valeant. David Pariser, MD, has been a consultant and/or investigator and/or advisory board member with Abbott Laboratories, Amgen, Astellas Pharma US, Inc, Basilea, Celgene Corporation, Dow Pharmaceutical Sciences, Inc., DUSA Pharmaceuticals, Inc., Eli Lily and Company, Figure 1. Nail Anatomy The nail plate (consisting of keratin) forms in the matrix Galderma Laboratories, L.P., Genentech, Inc., Graceway Pharmaceuticals, and is attached to the nail bed as it grows. Although the distal portion of the matrix is typically visible (as the lunula) in the thumb and forefinger, it is concealed under LLC, Intendis, Inc., Janssen-Ortho Inc, Johnson & Johnson Consumer the proximal nail fold in the rest of the fingers and the toes. The proximal nail fold Products Company, LEO Pharma, US, Medicis Pharmaceutical covers and adheres to the base of the nail; the distal portion of the proximal fold Corporation, MelaSciences, Novartis Pharmaceutical Corporation, Novo is the cuticle. Lateral nail folds form soft tissue boundaries at the sides of the nails. Nordisk A/S, Ortho Dermatologics, Peplin Inc., Pfizer, Photocure ASA, Proctor & Gamble Company, Stiefel a GSK company, and Valeant Pharmaceuticals International. Phoebe Rich, MD, has been a principal investigator and/or consultant Physical Examination for Valeant, Dow Pharmaceuticals, Topica, and Tolmar. The physical examination should include careful inspection Richard K. Scher, MD, is an advisor/consultant to Valeant. of all fingernails and toenails. The extent of involvement Address reprint requests to: Phoebe Rich, MD, 2565 NW Lovejoy Street, Suite 200, Portland, OR 97210, Telephone: (503) 226-3376, E-mail: (the number of nails and the percentage of involvement of [email protected] each nail unit) should be noted.

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Figure 2. Distal-lateral-subungual onychomycosis. Note the onycholysis, along with Figure 4. Superficial white onychomycosis. Leuconychia and crumbling, as seen in thickening, crumbling, and discoloration of the nail plate and subungual debris. this patient, is a result of direct invasion of the nail plate surface. Photo courtesy of Photo courtesy of Phoebe Rich, MD. Phoebe Rich, MD.

Figure 3. Proximal subungual onychomycosis. Proximal subungual onychomycosis. Figure 5. Candidal onychomycosis.Onycholysis and chronic paronychia may result This presentation is marked by invasion of the proximal nail bed via the cuticle. It is from invasion of Candida. In immunocompetent patients, this is secondary to other unusual in immunocompetent patients. Photo courtesy of Antonella Tosti, MD, Professor causes such as trauma or chronic exposure to water. Photo courtesy of Phoebe Rich, MD. of Dermatology, Department of Dermatology and Cutaneous Surgery, University of Miami, Leonard M Miller School of Medicine. The clinical features of onychomycosis (Table 1) include Clinical Presentations: nail bed hyperkeratosis with subsequent separation of the nail plate from the nail bed (onycholysis), the presence of Patterns of Nail Plate Invasion subungual debris, and nail plate dyschromia. Individuals Several patterns of nail plate invasion have been described.4 with onychomycosis also may experience associated The most common of these is invasion of the nail plate from inflammation and tenderness of the nail bed or periun- the hyponychium (distal-lateral-subungual onychomycosis) gual tissue. Concomitant tinea pedis infection (also (Figure 2). In the presentation known as proximal subungual caused by T. rubrum) is extremely common in patients onychomycosis (Figure 3), the organisms invade the proximal with toenail onychomycosis. nail bed via the cuticle. This is an unusual presentation in immunocompetent individuals; the presence of proximal Table 1. Clinical Signs of Onychomycosis subungual onychomycosis should raise the index of suspi- (Toenails or Fingernails) cion for an underlying cause of immunosuppression. Superficial white onychomycosis is characterized by direct • Onycholysis invasion of the nail plate surface, causing leuconychia and • Debris under the nail plate crumbling of the plate (Figure 4). • Subungual hyperkeratosis Chronic mucocutaneous candidiasis is a presentation that is • Discoloration (usually nontransparent white or yellow caused by Candida albicans, which affects the entire nail discoloration; less frequently, brown pigmentation) unit. Normally, Candida cannot invade the nail plate in immunocompetent patients. Candida may be a secondary • Destruction of all or part of the nail plate invader in onycholysis and chronic paronychia (Figure 5). Diagnosis, Clinical Implications, and Complications of Onychomycosis S7

Differential Diagnosis Onychomycosis can mimic many other clinical conditions that affect the nail, such as trauma, other infections, and inflammatory processes including psoriasis and, occasionally, neoplastic conditions. When a solitary nail is involved, the possibility of a subungual tumor such as onychomat- ricoma or exostosis may be considered. The differential diagnosis of onychomycosis in adults is listed in Table 2.5,6 Exogenous substances can cause nail dyschromia that can mimic onychomycosis. Nail polish can stain the nail yellow, and other products, such as self-tanning cream, can stain the nail plate brown. Exposure to a number of substances can cause changes in nails that resemble infec- Figure 7. Sampling scrapings for KOH preparation or culture. A scraping of the surface of the nail (A) usually does not provide sufficient material for study. The tious processes. In addition, physiologic changes occur most viable hyphae are under the nail plate; clipping followed by paring (B) yields with aging that resemble fungal dyschromia and dystrophy the most useful sample. Photo courtesy of Phoebe Rich, MD. (Figure 6). Finally, certain systemic medications are known to Laboratory Confirmation induce nail changes. For example, antineoplastic drugs of Clinical Diagnosis may cause onycholysis, and sun exposure during tetracy- cline therapy may cause photo-onycholysis. Retinoids may The diagnosis of onychomycosis should be confirmed prior cause nail brittleness. to institution of treatment. A diagnosis of onychomycosis In children, the differential diagnosis includes several often has been made based on clinical impressions alone, uncommon clinical conditions (Table 3).7 However, a history particularly in cases of mild infections limited to partial of onychomycosis and/or tinea pedis in the family or other involvement of one or only a few nails and especially when household members suggests a dermatophyte infection. topical therapy—rather than systemic therapy—is prescribed. However, this is no longer considered the ideal practice, given what is now known about the potential clinical sequelae of onychomycosis, the importance of selecting the most appropriate treatment, and the possibility of misdiagnosis of nail disease from other causes (such as immune dysfunction8 or psoriasis9). A definitive diagnosis of the presence of a fungal infection may be readily made in the office by use of a potassium hydroxide (KOH) preparation. In patients with the distal subungual pattern, the nail should be debrided as far back as possible and a specimen of subungual debris obtained from the area as close to the cuticle as possible (Figure 7). Alternatively, scale from the involved portion of the nail plate can be used. Scrapings from the surface of the involved nail plate is preferred in patients with suspected superficial white onychomycosis. In those with a proximal subungual presentation, it is necessary to sample the deeper nail plate and bed. To dissolve the subungual debris and make it easier to visualize the fungus, dimethyl sulfoxide can be added to the 10% to 15% KOH solution on the glass slide. Fungal Figure 6. Dyschromia. Yellowing and discoloration may result from both onychomycosis and aging. Even after the infection has been successfully treated, stains (chlorazol black E or Parker blue-black ink) may be age-related dyschromia can be expected to persist. Photo courtesy of Phoebe Rich, MD. used to enhance microscopic visualization.

Table 2. Differential Diagnosis of Onychomycosis in Adults5,6 Table 3. Differential Diagnosis of Onychomycosis in Children7 • Psoriasis • Nail psoriasis • Nail trauma • Congenital malalignment of large toenail • Contact irritants • Subungual exostosis • Lichen planus • Subungual warts • Neoplasms • Subungual hematoma • Bacterial infection • Paronychia secondary to finger sucking (Pseudomonas aeruginosa, Proteus mirabilis) • Parakeratosis pustolosa S8

The main advantage of office-based testing is rapid con- Conclusion firmation that a fungus is present. The main disadvantage In most patients, it is likely that a clinical suspicion of der- is that the fungus itself is not specifically identified nor is matophytic onychomycosis can be derived based on the the presence of nondermatophyte organisms. Another dis- patient’s personal and family history and on careful inspec- advantage of direct microscopy is that an inexperienced tion of both fingernails and toenails. However, the diagnosis observer may misinterpret the results. should be confirmed—using, at minimum, an office-based KOH of subungual debris and periodic-acid Schiff (PAS) KOH preparation—prior to initiating therapy. In addition, staining of nail plate samples provide confirmation of under the circumstances described in this article, a culture organisms but do not identify or ascertain the viability of should be performed to obtain a definitive diagnosis and organisms present. Culture is slower and less sensitive but identification of the causative organism. currently is the standard method for identifying the causative organism. Polymerase chain reaction may become a References useful method. 1. Ghannoum MD, Hajjeh RA, Scher R, et al. A large-scale North American study PAS showing septate hyphae is diagnostic, but PAS showing of fungal isolates from nails: The frequency of onychomycosis, fungal distribution, only yeast forms is not conclusive evidence of infection. and antifungal susceptibility patterns. J Am Acad Dermatol. 2000;43:641-648. 2. Scher RK, Elewski B, Rich P, Pariser D. The epidemiology, etiology, and patho- Laboratory results of PAS staining of nail clippings are usually physiology of onychomycosis. Semin Cutan Med Surg 2013;33:7-9. available within a few days. Nail clippings also may be 3. Foster KW, Ghannoum MA, Elewski BE. Epidemiologic surveillance of cutane- obtained for histologic analysis. ous fungal infection in the United States from 1999 to 2002. J Am Acad Dermatol. 2004;50:748-752. The gold standard of diagnosis for onychomycosis is a 4. Baran R, Hay RJ, Tosti A, Haneke E. A new classification of onychomycosis. fungal culture. Culturing is the only method that is widely Br J Dermatol. 1998;139:567-571. available at this time that provides definitive identification 5. Cockerell C, Odom R. The differential diagnosis of nail disease. AIDS Patient of a specific organism, which is particularly important when Care. 1995;9(suppl 1):S5-S10. 6. Daniel CR III. The diagnosis of nail fungal infection. Arch Dermatol. 1991; yeasts or other nondermatophyte organisms are a suspected 127:1566-1567. cause of onychomycosis. Such identification allows choice 7. Tosti A, Piraccini BM, Iorizzo M. Management of onychomycosis in children. of a systemic agent that is most likely to be effective. Dermatol Clin. 2003;21:507-509. 8. Sherber N, Wigley FM, Scher RK. Autoimmune disorders: Nail signs and When other tests fail to provide definitive results, a nail therapeutic approaches. Dermatol Ther. 2007;20:17-30. biopsy should be considered.10 9. Rich P, Griffiths CEM, 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. Rich P. Nail biopsy: Indications and methods. Dermatol Surg. 2001;27:229-234. Current and Emerging Options in the Treatment of Onychomycosis Boni Elewski, MD,* David Pariser, MD,† Phoebe Rich, MD,‡ Richard K. Scher, MD§

ABSTRACT Currently approved options for the treatment of onychomycosis include systemic therapy (the antifungal agents fluconazole, itraconazole, and terbinafine), topical agents (ciclopirox, which has been available since 1996, efinaconazole, currently pending approval), and laser systems. Phase III studies on another topical, tavaborole, have been completed and this medication also shows promise. Mechanical modalities are sometimes used but are seldom necessary. Recurrence of infection is common; the risk for recurrence may be reduced by adherence to preventive measures, especially avoiding (if possible) or promptly treating tinea pedis infections. Semin Cutan Med Surg 32(suppl):S9-S12 © 2013 published by Frontline Medical Communications

KEYWORDS ciclopirox; efinaconazole; fluconazole; fungal infections; itraconazole; nail infections; onychomycosis; tavaborole; terbinafines

he goal of onychomycosis treatment is to eradicate the initiated and, for toenails, 12 to 18 months. Toenails grow Tcausative organism. Elimination of the fungus generally at the rate of about 1 to 2 mm per month and fingernails restores the appearance of the nail in most cases. However, grow faster, at the rate of 2 to 3 mm per month; however, patients should not expect to see normal-appearing nails nail growth rate peaks during the teenage years and until after the fungi are eliminated and until the damaged decreases with advancing age.1 nail has grown out—a process that, for fingernails, may Some onychomycosis infections, especially those involv- take 6 months or more from the time effective treatment is ing the nail matrix, may produce permanent scarring of the matrix, and, thus, the nail may never appear normal even * Vice-Chair for Clinical Affairs, Professor of Dermatology after the infection is completely eradicated (Figure 1). University of Alabama School of Medicine, Birmingham, AL The definition of “complete cure,” as defined by the US † Professor of Dermatology, Eastern Virginia Medical School Department of Dermatology, Pariser Dermatology, Norfolk, VA Food and Drug Administration (FDA) for the evaluation of ‡ Clinical Adjunct Professor of Dermatology, Oregon Health Science clinical trial results, is negative results on potassium University, Portland, OR hydroxide (KOH) preparation and on fungal culture, as well § Clinical Professor of Dermatology, Weill Cornell Medical College as a completely normal appearance of the nail. In clinical New York, NY Publication of this CME article was jointly sponsored by the University practice—and for practical purposes—most cures will be of Louisville School of Medicine Continuing Medical Education and defined by the absence of fungus on KOH preparation and Global Academy for Medical Education, LLC and is supported by an possibly, but not always, by a completely normal nail educational grant from Medicis, a division of Valeant Pharmaceuticals. The faculty have received an honorarium from Global Academy for (Figure 2). Realistically, patients who have had long-stand- Medical Education for their participation in this activity. They ing infections or chronic onychomycosis are likely to have acknowledge the editorial assistance of Joanne Still, medical writer, sustained damage to the nail matrix or subungual area so and Global Academy for Medical Education in the development of this continuing medical education journal article. Joanne Still has no that, despite the clearance of infectious organisms, new nail relevant financial relationships with any commercial interests. growth may be permanently discolored and/or dystrophic, and some onycholysis (lifting of the nail plate) may persist. Boni Elewski, MD, has been an investigator for Anacor and Valeant. David Pariser, MD, has been a consultant and/or investigator and/or Furthermore, nails may be thickened, discolored, and dys- advisory board member with Abbott Laboratories, Amgen, Astellas trophic for reasons other than mycotic infection—as is Pharma US, Inc, Basilea, Celgene Corporation, Dow Pharmaceutical Sciences, Inc., DUSA Pharmaceuticals, Inc., Eli Lily and Company, Galderma Laboratories, L.P., Genentech, Inc., Graceway Pharmaceuticals, LLC, Intendis, Inc., Janssen-Ortho Inc, Johnson & Johnson Consumer Products Company, LEO Pharma, US, Medicis Pharmaceutical Corporation, MelaSciences, Novartis Pharmaceutical Corporation, Novo Nordisk A/S, Ortho Dermatologics, Peplin Inc., Pfizer, Photocure ASA, Proctor & Gamble Company, Stiefel a GSK company, and Valeant Pharmaceuticals International. Phoebe Rich, MD, has been a principal investigator and/or consultant for Valeant, Dow Pharmaceuticals, Topica, and Tolmar. Richard K. Scher, MD, is an advisor/consultant to Valeant. Address reprint requests to: Boni Elewski, MD, UAB Department of Figure 1. Persistence of dystrophia after mycologic cure. In some cases, permanent Dermatology, 1720 2nd Avenue South, EFH – Suite 414, Birmingham, AL scarring of the nail matrix may occur, so a normal appearance may not be restored 35294-0009, Telephone: (205) 975-4917, E-mail: [email protected] even after the infection is eradicated. Photo courtesy of Phoebe Rich, MD.

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Table 1. Summary of Treatment Options for Onychomycosis

A. Topical Therapy Fingernails and Toenails Ciclopirox 8% Apply daily, up to 48 weeks10 Efinaconazole Phase III clinical trials studied daily application for 48 weeks11 Tavaborole Phase III clinical trial (data available on first of two recently completed) studied daily application for 52 weeks12 B. Systemic Therapy Fingernails Fluconazole3* 3 to 8 mg/kg pulsed-dose weekly for 6 weeks OR 200 mg/week for 8 to 16 weeks Itraconazole4 400 mg/day for 1 week/month, repeated for 2 or 3 months† Terbinafine7 250 mg/day for 6 weeks Toenails Fluconazole3 200 mg/week for 12 to 24 weeks Itraconazole5 400 mg/day for 1 week/month, repeated for 3 or 4 months‡ Terbinafine7 250 mg/day for 12 weeks * Although it is commonly used for onychomycosis, this is not an FDA-approved indication for fluconazole. † Note that the dosage recommended in the prescribing information for fingernails is 400 mg/day (two 200-mg capsules twice daily) for 1 week, followed by a 3-week period of no treatment, then a second treatment pulse of 400 mg/day/1week. ‡ Note that the dosage recommended in the prescribing information for toenails, with or without fingernail involvement, is 200 mg (2 capsules) once daily for 12 consecutive weeks. common, for example, in elderly patients who have age- dosing schedules, for a duration of 2 to 3 months for fin- related changes in the nails or onychogryphosis, or even in gernail infections and 3 to 4 months for toenail infections.4 patients with inflammatory disorders such as psoriasis. Regimen 1 is 400 mg/day for 7 days for 1 week out of each month for 4 months. Regimen 2 is 200 mg/day continuously Systemic Therapy for 3 months. Regimen 1 (pulsed dosage) is not approved for treating toenail onychomycosis. The cure rate for Systemic antifungal therapy options currently include Regimen 2 (continuous dosage) per the package insert is itraconazole, terbinafine, and fluconazole. A summary of 14%.4 Evans and colleagues5 reported higher cure rates for systemic antifungal agents and cure rates can be found in pulsed (intermittent) dosing in the Lamisil vs Itraconazole Tables 1 and 2. A meta-analysis of studies involving these in Onychomycosis (LION) study: 25% complete cure in medications demonstrated low risk for side effects in three cycles; 28% complete cure in four cycles. immunocompetent patients.2 Itraconazole is a potent inhibitor of CYP3A4 and may result Fluconazole is not approved by the FDA for this indication, in serious cardiovascular events if used simultaneously with although it is approved for fingernail and toenail onychomy- cisapride, pimozine, quinidine, or levomethadyl. It must be cosis in other countries. It was originally tested in dosages of used with caution when treating onychomycosis in patients 150 mg/week, 300 mg/week, and 450 mg/week for up to 9 with congestive heart failure or other ventricular dysfunction. months or until clearance of the nail.3 In an FDA study, clini- Ahmad and colleagues6 reported that itraconazole has a nega- cal cures were seen in 48% of patients who received 450 mg/ tive inotropic effect on the heart in healthy individuals. week, 46% of those who received 300 mg/week, and 37% of Terbinafine is used at a dosage of 250 mg/day for 6 weeks those who received 150 mg/week.3 However, probably a for fingernails and for 12 weeks for toenails.7 Drake and dosage of 200 mg or 400 mg once weekly is effective, and colleagues8 reported a complete cure rate of 38% with once-weekly dosing is convenient for patients on multiple 250 mg/day for 3 months and no significant difference in medications and the elderly. Fluconazole can be taken with response between 12-week and 24-week treatment courses. or without food; the drug must be avoided in pregnant In the LION study, Evans and colleagues5 found that terbi- women. Drug interactions are via CYP2C9. nafine produced a 49% complete cure with a 12-week Itraconazole can be used to treat fingernail or toenail course and a 54% complete cure with a 16-week course. onychomycosis. It may be given according to either of two Pulsed-dose therapy with terbinafine is not FDA approved. Tosti and colleagues9 noted that most studies show that continuous therapy of daily 250-mg dosing was more efficacious than 500 mg daily for 1 week followed by 3 weeks of no treatment.

Topical Therapy Assuming reasonable efficacy could be assured, topical therapy would be the preferred methodology for onychomy- Figure 2. Before and after successful systemic therapy. This patient presented with cosis to avoid systemic side effects and the need for laboratory distal subungual oncyhomycosis. Note the distortion of the nail before treatment monitoring. In addition, if adverse reactions occur from (left) and the resolution of onycholysis and discoloration after 4 months of systemic therapy (right). Photo courtesy of Phoebe Rich, MD. topical agents, the effect is site-specific and, as such, Current and Emerging Options in the Treatment of Onychomycosis S11

Table 2. Complete Cure Rates in Onychomycosis Reported in Clinical Studies*

A. Topical Therapy

Medication and Regimen (Once-daily Application) Complete Cure Rates Ciclopirox 8%10 5.5% to 8.5% Efinaconazole11 15% and 18%† Tavaborole12 6.5%‡ B. Systemic Therapy

Medication (Regimen) Complete Cure Rates

Fluconazole3 150 mg/week 37% 300 mg/week 46% 450 mg/week 48% Itraconazole 200 mg/day for 12 weeks4 14% 400 mg/day for 1 week/month5 Repeated for 3 pulses 25% Repeated for 4 pulses 28% Terbinafine 38% 250 mg/day for 12 weeks8 38% 250 mg/day for 1 week/month5 Repeated for 3 pulses 49% Repeated for 4 pulses 54%

* The dosages shown above are not necessarily those approved by the US Food and Drug Administration. † Data from two phase III, double-blind studies. ‡ Data from the first of two phase III clinical trials recently completed. generally is more acceptable to patients. However, no topical second phase III study. Cure classified as “almost complete” treatment has been approved as monotherapy to date. A exceeded 20%.11 summary of topical antifungal agents and cure rates can be Currently in the research pipeline is topical tavaborole found in Tables 1 and 2. 5% solution. In the first of two phase III clinical trials The development of topical therapy for onychomycosis recently completed, the primary end point of complete cure presents unique challenges. First, to be effective, the drug (both mycologic cure and a completely clear nail) was seen must penetrate through the nail plate and reach the nail bed in 6.5% of patients versus 0.5% of patients treated with in sufficient quantities. This requires overcoming the vehicle alone (P=0.001). In addition, a negative fungal unique properties of the nail plate—its thickness and rela- culture was reported after 52 weeks of treatment in 87% of tively compact structure. The factors involved probably patients on tavaborole versus 47.9% of those in the vehicle include the proper molecular weight, lipophilicity, and group (P<0.001); at the same time point, a negative nail keratin-binding properties. culture and “completely clear” or “almost clear” nail was Ciclopirox 8% lacquer, which was approved by the FDA seen in 24.6% of patients in the tavaborole group versus in 1999, is associated with a complete cure rate ranging 5.7% in the vehicle group (P<0.001).12 from 5.5% to 8.5% but requires frequent nail debridement. In clinical studies, fewer than 12% of patients were able to Over-the-Counter (OTC) Treatments achieve a clear or almost-clear nail.10 A mention of nonspecific topical OTC and “folk” remedies is appropriate here. Many such remedies have been used— New and Investigational Topical Agents usually self-prescribed by patients—as monotherapy or in A new topical agent, efinaconazole, currently pending approval the belief that these agents will enhance the efficacy of by the FDA, will be the first topical triazole to become avail- prescription medications. Currently popular are tea tree oil able for dermatologic use and the first new antifungal for and a camphor-containing ointment marketed as a chest onychomycosis to be introduced in more than a decade. rub. Many other substances have been used, including foot Unlike ciclopirox, no debridement of nails is required. soaks with hydrogen peroxide or household chlorine bleach Efinaconazole is a solution, not a lacquer, so, unlike and applications of salicylic acid, as well as OTC solutions, ciclopirox, efinaconazole does not need to be removed each creams, and ointments. week. The solution is applied on, under, and around the Evidence-based studies have not been done demonstrat- nail. In the pivotal clinical trials, efinaconazole yielded a ing that these agents are helpful, but there is some theoretical mycologic cure in the range of 50%. Complete cure was seen scientific basis for anecdotal claims of efficacy by patients— in 15% of patients in one study and 18% of patients in the and by some clinicians—when these remedies have been S12 used diligently. Although they cannot be recommended on However, it is important to emphasize that the risk for the basis of evidence of efficacy, most of these methods are reinfection can be reduced by avoiding practices that expose neither harmful nor costly. Patients who choose to forgo pre- the nails to infectious organisms and that create a milieu scription therapy for whatever reason should not be discouraged that encourages fungal colonization. (See the patient from trying these remedies for a time and told to reconsider handout in the article in this supplement by Pariser et al.23) definitive treatment if the infection does not clear or worsens. Conclusion Mechanical Modalities Onychomycosis is a common problem that increases in Nail avulsion and matrixectomy are seldom needed. These prevalence with increasing age. Simple techniques are readily techniques may be appropriate if only one nail is affected available for making an accurate diagnosis in all patients. The and the infection does not respond to other treatments, as only prescription topical agent available has been ciclopirox well as in cases of infections with nondermatophyte mold 8% lacquer. A new topical agent, efinaconazole, currently organisms. However, most patients have involvement of pending approval by the FDA, provides better efficacy. more than one nail. Occasionally, patients develop thick- Another topical agent, tavaborole, has shown good results in ened dystrophic nails that are painful or interfere with phase III studies to date. Systemic agents are highly effective proper ambulation. Such circumstances also may constitute for many patients but are contraindicated or otherwise inad- an indication for surgical intervention. visable for some because of the potential for drug interactions Lasers, photodynamic therapy (PDT), and other methods or the presence of certain comorbidities. have been used with varying degrees of success in treating onychomycosis. The laser devices approved by the U.S. FDA References to date are the short-pulse neodymium-doped yttrium alu- 1. Abdullah L, Abbas O. Common nail changes and disorders in older people: minum garnet (Nd:Yag) type, although other types currently Diagnosis and management. Can Fam Physician. 2011;57:173-181. 2. Chang CH, Young-Xu Y, Kurth T, Orav JE, Chan AK. The safety of oral anti- are being studied; these include carbon dioxide, near infra- fungal treatments for superficial dermatophytosis and onychomycosis: red diode, and femtosecond infrared laser systems. A meta-analysis. Am J Med. 2007;120:791-798. 3. Scher RK, Breneman D, Rich P, et al. Once-weekly fluconazole (150, 300, or The exact mechanism of action of laser systems in ony- 450 mg) in the treatment of distal subungual onychomycosis of the toenail. chomycosis has not been established. One early proposed J Am Acad Dermatol. 1998;38 (6, pt 2):S77-S86. 4. Sporanox (itraconazole) [package insert]. Raritan, NJ: PriCara, Division of mechanism was the direct action of heat on the infecting Ortho-McNeil-Janssen Pharmaceuticals, Inc; 2011. organisms,13 but recent in vitro studies show that laser- 5. Evans EGV, Sigurgeirsson B for the LION Study Group. Double blind, ran- generated heat to a level required to kill Trichophyton rubrum domised study of continuous terbinafine compared with intermittent itraconazole in treatment of toenail onychomycosis. BMJ. 1999;318:1031-1035. is much higher than what would be tolerable; experiments 6. Ahmad SR, Singer SJ, Leissa BG. Congestive heart failure associated with with direct lasering of fungi have not affected the growth itraconazole. Lancet. 2001;357:1766-1767. 7. Lamisil (terbinafine) [package insert]. East Hanover, NJ: Novartis Pharmaceuticals; of fungal organisms. Others have suggested that the use of 2012. lasers may enhance the efficacy of other modalities.14,15 8. Drake LA, Shear NH, Arlette JP, et al. Oral terbinafine in the treatment of toenail onychomycosis: North American multicenter trial. J Am Acad Dermatol. More likely mechanisms of action are the triggering of an 1997;37(5, pt1):740-745. immunologic effect or laser-induced denaturization of 9. Tosti A, Piraccini BM, Stinchi C, Colombo MD. Relapses of onychomycosis enzymes essential to fungal activity. after successful treatment with systemic antifungals: A three-year follow-up. Dermatology. 1998;197:162-166. As the results of ongoing research provide additional 10. Penlac (ciclopirox 8%) [package insert]. Bridgewater, NJ: Dermik Laboratories; 2006. insights regarding treatment regimens and patient selection 11. Elewski BE, Rich P, Pollak R, et al. Efinaconazole 10% solution in the treatment of toenail onychomycosis: Two phase III multicenter, randomized, double-blind along with longer-term evidence of efficacy, laser systems may studies. J Am Acad Dermatol. 2013;68:600-608. become more widely used for treating onychomycosis. 12. Tavaborole (AN2690). Available at: http://www.anacor.com/an2690.php. Accessed March 24, 2013. The mechanism of action of PDT in dermatophytic ony- 13. Vural E, Winfield HL, Shingleton AW, Horn TD, Shafirstein G. The effects of laser chomycosis has been established and involves eradication irradiation on Trichophyton rubrum growth. Lasers Med Sci. 2008;23:349-353. 16-18 14. Murdan S. Enhancing the nail permeability of topically applied drugs. Expert of the organism. No PDT system has been approved by Opin Drug Deliv. 2008;5:1267-1282. the FDA for the treatment of onychomycosis, and it is not 15. Borovoy M, Tracy M. Noninvasive CO2 laser fenestration improves treatment a practical therapeutic option. However, PDT may be useful of onychomycosis. Clin Laser Mon. 1992;10:123-124. 16. Piraccini BM, Rech G, Tosti A. Photodynamic therapy of onychomycosis caused in chronic cases that are refractory to other modalities, by Trichophyton rubrum. J Am Acad Dermatol. 2008;59(5 suppl):S75-S76. particularly when the causative organism is uncommon, 17. Watanabe D, Kawamura C, Masuda Y, Akita Y, Tamada Y, Matsumoto Y. 19 Successful treatment of toenail onychomycosis with photodynamic therapy. such as a nondermatophyte mold. Arch Dermatol. 2008;144:19-21. Other devices and modalities continue to be developed and 18. Donnelly RF, McCarron PA, Lightowler JM, Woolfson AD. Bioadhesive patch- based delivery of 5-aminolevulinic acid to the nail for photodynamic therapy investigated, including the use of iontophoresis to enhance of onychomycosis. J Control Release. 2005;103:381-392. penetration of a topical medication through the nail plate.20 19. 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. Preventing Recurrence 20. Gupta A, Brintnell W. Onychomycosis therapy: Past, present, and future. J Am Acad Dermatol. 2012;66(4 suppl 1):AB120. Reinfection with dermatophytic onychomycosis is 21. Piraccini BM, Sisti A, Tosti A. Long-term follow-up of toenail onychomycosis common.21,22 It is difficult to know whether subsequent caused by dermatophytes after successful treatment with systemic antifungal infection is a new infection or whether the original infection agents. J Am Acad Dermatol. 2010;62:411-414. 22. Gupta A, Cooper E. Examination of cure and relapse of dermatophyte toenail was not cleared completely and recurred after weeks, onychomycosis during long-term follow-up after oral therapy. J Am Acad months, or years of dormancy. In either case, patients must Dermatol. 2012;66(4 suppl 1):AB119. 23. Pariser D, Elewski B, Scher RK, Rich P. Promoting and maintaining or restoring understand that it is unlikely that one course of treatment healthy nails: Practical recommendations for clinicians and patients. Semin will be all that is required over the long term. Cutan Med Surg. 2013;33:19-20. Promoting and Maintaining or Restoring Healthy Nails: Practical Recommendations for Clinicians and Patients David Pariser, MD,* Richard K. Scher, MD,† Boni Elewski, MD,‡ Phoebe Rich, MD§

ABSTRACT The American Academy of Dermatology guidelines for managing patients with onychomycosis, published almost 2 decades ago, provide sound, basic recommendations for clinicians. This article provides a quick reference for clinicians and includes a handout for patients to support the health care provider’s educational efforts. Semin Cutan Med Surg 32(suppl):S13-S14 © 2013 published by Frontline Medical Communications

KEYWORDS fungal infections; nail infections; onychomycosis

uidelines for managing patients with onychomycosis management of onychomycosis is straightforward and can Gwere last published in 1996.1 In the absence of the be summarized as follows: availability of new medications since that time or of new • Inspect clinically and take a thorough personal and data on existing agents that suggested the need for a change family history. in the guidelines, an update has not been necessary. The • Consider the differential diagnosis. Onychomycosis accounts * Professor of Dermatology, Eastern Virginia Medical School for at least half of all cases of nail infection, particularly Department of Dermatology, Pariser Dermatology, Norfolk, VA toenail infections. In patients who are not immunocom- † Clinical Professor of Dermatology, Weill Cornell Medical College New York, NY promised, psoriasis and lichen planus should be the first ‡ Vice-Chair for Clinical Affairs, Professor of Dermatology two considerations in the differential diagnosis. University of Alabama School of Medicine, Birmingham, AL § Clinical Adjunct Professor of Dermatology, Oregon Health Science • Confirm the diagnosis with a laboratory study: potassium University, Portland, OR hydroxide, periodic-acid Schiff stain, or fungal culture. Publication of this CME article was jointly sponsored by the University of (In the future, analysis by polymerase chain reaction may Louisville School of Medicine Continuing Medical Education and Global Academy for Medical Education, LLC and is supported by an educational become widely available.) grant from Medicis, a division of Valeant Pharmaceuticals. The faculty have received an honorarium from Global Academy for • Consider the treatment options. If onychomycosis is con- Medical Education for their participation in this activity. They firmed, consider the available treatments. Factors to acknowledge the editorial assistance of Joanne Still, medical writer, and Global Academy for Medical Education in the development of this include are the site of disease (toenails or fingernails), the continuing medical education journal article. Joanne Still has no extent of disease, and the patient’s age, immune status, relevant financial relationships with any commercial interests. and concomitant conditions that may limit systemic Boni Elewski, MD, has been an investigator for Anacor and Valeant. choices or are likely to affect treatment efficacy, including David Pariser, MD, has been a consultant and/or investigator and/or severely thickened nails, compromised peripheral circula- advisory board member with Abbott Laboratories, Amgen, Astellas tion, and the presence of diabetes mellitus. In addition, Pharma US, Inc, Basilea, Celgene Corporation, Dow Pharmaceutical Sciences, Inc., DUSA Pharmaceuticals, Inc., Eli Lily and Company, consider the patient’s health insurance coverage in the Galderma Laboratories, L.P., Genentech, Inc., Graceway Pharmaceuticals, equation; some carriers will cover topical therapy only LLC, Intendis, Inc., Janssen-Ortho Inc, Johnson & Johnson Consumer after a systemic treatment has been tried first. Products Company, LEO Pharma, US, Medicis Pharmaceutical Corporation, MelaSciences, Novartis Pharmaceutical Corporation, Novo Nordisk A/S, Ortho Dermatologics, Peplin Inc., Pfizer, Photocure ASA, • Discuss your recommendations with the patient. If the infec- Proctor & Gamble Company, Stiefel a GSK company, and Valeant tion is limited to 50% or less of the nail plate of only one Pharmaceuticals International. or a few toes, topical therapy is an option. Be clear about Phoebe Rich, MD, has been a principal investigator and/or consultant for Valeant, Dow Pharmaceuticals, Topica, and Tolmar. the cure rates associated with the proposed therapies. If Richard K. Scher, MD, is an advisor/consultant to Valeant. systemic therapy is considered, discuss the potential side Address reprint requests to: David Pariser, MD, Professor of Dermatology, effects of the available systemic agents and inform the Eastern Virginia Medical School, Department of Dermatology, Pariser patient about any baseline and follow-up blood testing Dermatology, 601 Medical Tower, Norfolk, VA 23507, E-mail: dpariser@ pariserderm.com that will be required.

• Discuss realistic expectations for immediate and long-term Reference treatment results. Patients must understand that one course 1. Drake LA, Dinehart SM, Farmer ER, et al. Guidelines of care for superficial mycotic infections of the skin: Onychomycosis. J Am Acad Dermatol. 1996; of treatment may not produce the optimum result and 34:116-121. that recurrence of onychomycosis is very common. It is also important to advise patients about the point in time that visible results can be expected (ie, the rate of nail growth), and that clearance of an infection will be evident only as nails grow. • Emphasize the role of preventive measures to avoid reinfection. For example, one of the most common ways that patients acquire infection with organisms such as T. rubrum is walking barefoot in pools, spas, gymnasiums, and locker rooms-areas where moisture is present and where fungi can thrive. Another common source of infection is the nail salon. Individuals should bring their own nail clippers, files, and emery boards to the salon, and ensure that the tech- nician washes the nail-soaking dish or pedicure tub with bleach between clients. Prompt treatment at the first signs of athlete’s foot infection can also reduce the recurrence of onychomycosis.

Onychomycosis Patient Handout

toenails but Onychomycosis Information for Patients fungus ld w Proximal Nail Fo Side Vie (ON-ick-co-my-CO-sis), usually affects the Eponychium An educational handout accompanies this article on the of onychomycosis are caused/ by the sameTrue Cuticle a View Onychocomeal e Lunut What is onychomycosis? Surface Onychodermal Band Nail Plat Hyponychium eral Distal Edge . Lat ld Nail fungus infection, called onychomycosis e Nail Fo Nail Bed Nail Plat nails. / also may occur on the fingernails. Most cases Eponychium Cuticle following two pages. The handout may be freely copied by that is responsible for athlete’s foot the nail bed Lunuta ld Sometimes Proximal Nail Fo Nail infections most commonly affect the toe infection. Is treatment always effective? The fungus organisms usually invade for the from the outside (distal) edge of the nail. There is no “quick fix,” and not ev clinicians and distributed to patients. Other uses, such as the nail plate itself is the original site of ple than in others.experience a clearance of t omycosis, it completely, your health care prov onychomycosis. However, this is an averagechomycosis. ery medication will work for e follow these recommendations.he fungus with the first treatment. Who gets onychomycosis? is more common in some groups of peo dividuals more inclusion in published materials or presentations, require en in children. When children get onych Remember, though, that nails grow slowlider may recommend a differentveryone. medi About 50% of patients About 10% to 12% of people, overall, have lt in the household has athlete’s foot and ony grows in. For this reason, it may If your infection does not clear population. Actually, onychomycosis of the toenails. in older people; a large percentage of in grow faster than toenails, and nails For example, onychomycosis is seldom se chomycosis. y, and improvement can be seen ocation. It is important to . younger people. take several months to see clearing of is usually because a teenager or adu proper attribution for the authors and permission from the tions also have a higher risk for onychomycosisetes, psoriasis or in older individuals tend to grow Also, onychomycosis is most common It is also important to remember nds. nly when the “new” nail than 70 years of age have the infection also can increase the chances of getting ony This does not mean that medical treat onychomycosis. Fingernails stubborn and requires attention ov more slowly than do those in People who tend to get athlete’s foot infec ople with certain medical conditions: diab that even if the fungus is cleared, it is publisher. A Spanish-language version of this handout is Injuries to the toes—even minor injuries— infection, and poor circulation in the feet and ha ment is useless; it means that onych er the long term. Onychomycosis is also more common in pe How can new infections be prevented? common for it to return. other autoimmune disease, HIV/AIDS The following tips can help prevent omycosis tends to be chomycosis are:• Change in nail shape available online at at www.globalacademycme.com/sdef in • Debris trapped underAt the home: nail new infections: What are the signs and symptoms of onychomycosis? • Loss of luster and shine he nails • Throw away old shoes, particularly sne The most common signs and symptoms of ony • White or yellow streaksbased on onthe a nail firm outside edges that you have used for exercise or sp • Brittleness of the nail(s) er’s office the CME Library under the title, “Onychomycosis Information • Crumbling of the outside edges of t • Useetermine antifungal whether spray or powder in y akers, running shoes, or other types of at • Loosening or lifting up of the nails at the ion, but the proper treatment is chosen orts. nosis can be made in the health care• provid • Thickening of the nail Apply antifungal creams to your f (whichcessary, can and then he invade or the nails). our shoes every day. hletic shoes ining the sample under a microscope to d by culture These suggest the presence of an infect are immediate. eet periodically to slow the grow for Patients.” diagnosis by a medical professional. The diag • Treat all signs and symptoms of at by taking scrapings of the nail and exam • Do not share tools used for manicure ider will decideoratory that identification more involved of thetesting infecting is ne organism th of athlete’s foot fungus a fungus is present. The results of this test ine the best method in your case. hlete’s foot immediately. • Do not use the same nail clippers and fi Sometimes the health care prov fungus infection.clear ony- s and pedicures. she will send the sample for a culture. Lab • If you seealth signs care of providera nail infe les on normal nails that are used on nail can take several weeks. Your clinician will determ o your needs. pical (applied to the nail) offer •the Wash best and chance dry yourto hands thoroug il and hydrogen ction, treat it immediately; do not wait un How is onychomycosis treated?drug therapies such as laser treatment.• Your he s with a e a treatment recommendation thatTake is propertailored care tprofessionals— of your nails. Keep toe Prescription medications, either oral or to hly after contact with any fungal i straight across help (not prevent rounded the or in a V shap til it has progressed. chomycosis. Also available are non- s and “folk” remedies (such as tea tree o • will discuss these with you and will mak r, many people—includingWear many properly health fitting shoes with a wide nails trimmed and clean. Nailsnfection. shoul of the prescription medicationshit up againstand may the front of the shoe e). Nonprescription over-the-counter product toes and can damage the natural skin se enough toe box so that your toes are d be cut or filed peroxide) generally do not work. Howeve Richard K. Scher, MD may be freely duplicated and distributed, without charge, uire proper attributionallowing for the fungus authors and to permission invade from under the publisher. the. (High heels and narrow-toed shoe think they might help support the activity • recurrence of onychomycosis later on. Make sure that household members w al between the nail itself and th not cramped or proper precautions to avoid spread nail.) s cause trauma to the This two-sided handout developed by Boni Elewski,Supported MD, by David an educational Pariser, MD, grant Phoebe from Rich, Medicis, MD, and a division of Valeant Pharmaceuticals. e skin underneath, to patients and parents. Other uses, such as inclusion in published materials or presentations, req ith athlete’s foot infections receive Outside the home: ing the fungus to others. • Do not walk barefoot in public facilit treatment and take gyms. Wear water shoes or rub • Bring your own instruments (espe ies, such as around pools and in ber sandals. • Make sure your manicurist/pedicurist spas, locker rooms, and between clients. cially clippers and emery boards) to the washes the nail-soaking dish or pe nail salon. dicure tub with bleach Onychomycosis Information for Patients

What is onychomycosis? Nail fungus infection, called onychomycosis (ON-ick-co-my-CO-sis), usually affects the toenails but also may occur on the fingernails. Most cases of onychomycosis are caused by the same fungus that is responsible for athlete’s foot. Surface View Side View Hyponychium Onychocomeal/ Proximal Nail Fold Onychodermal Band Eponychium Nail infections most commonly affect the toenails. True Cuticle Nail Plate Lunuta Nail Plate Lateral The fungus organisms usually invade the nail bed Nail Fold Distal Edge Nail Bed from the outside (distal) edge of the nail. Sometimes Eponychium/ Lunuta Cuticle the nail plate itself is the original site of infection. Proximal Nail Fold

Who gets onychomycosis? About 10% to 12% of people, overall, have onychomycosis. However, this is an average for the population. Actually, onychomycosis is more common in some groups of people than in others. For example, onychomycosis is seldom seen in children. When children get onychomycosis, it is usually because a teenager or adult in the household has athlete’s foot and onychomycosis. Also, onychomycosis is most common in older people; a large percentage of individuals more than 70 years of age have the infection. People who tend to get athlete’s foot infections also have a higher risk for onychomycosis of the toenails. Injuries to the toes—even minor injuries—also can increase the chances of getting onychomycosis. Onychomycosis is also more common in people with certain medical conditions: diabetes, psoriasis or other autoimmune disease, HIV/AIDS infection, and poor circulation in the feet and hands.

What are the signs and symptoms of onychomycosis? The most common signs and symptoms of onychomycosis are: • Brittleness of the nail(s) • Change in nail shape • Crumbling of the outside edges of the nails • Debris trapped under the nail • Loosening or lifting up of the nails at the outside edges • Loss of luster and shine • Thickening of the nail • White or yellow streaks on the nail These suggest the presence of an infection, but the proper treatment is chosen based on a firm diagnosis by a medical professional. The diagnosis can be made in the health care provider’s office by taking scrapings of the nail and examining the sample under a microscope to determine whether a fungus is present. The results of this test are immediate. Sometimes the health care provider will decide that more involved testing is necessary, and he or she will send the sample for a culture. Laboratory identification of the infecting organism by culture can take several weeks. Your clinician will determine the best method in your case.

How is onychomycosis treated? Prescription medications, either oral or topical (applied to the nail) offer the best chance to clear onychomycosis. Also available are non-drug therapies such as laser treatment. Your health care provider will discuss these with you and will make a treatment recommendation that is tailored to your needs. Nonprescription over-the-counter products and “folk” remedies (such as tea tree oil and hydrogen peroxide) generally do not work. However, many people—including many health professionals— think they might help support the activity of the prescription medications and may help prevent the recurrence of onychomycosis later on.

This two-sided handout developed by David Pariser, MD, Boni Elewski, MD, Phoebe Rich, MD, and Richard K. Scher, MD may be freely duplicated and distributed, without charge, to patients and parents. Other uses, such as inclusion in published materials or presentations, require proper attribution for the authors and permission from the publisher. Supported by an educational grant from Medicis, a division of Valeant Pharmaceuticals. © 2013 Global Academy for Medical Education, LLC. All Rights Reserved. Is treatment always effective? There is no “quick fix,” and not every medication will work for everyone. About 50% of patients experience a clearance of the fungus with the first treatment. If your infection does not clear completely, your health care provider may recommend a different medication. It is important to follow these recommendations. Remember, though, that nails grow slowly, and improvement can be seen only when the “new” nail grows in. For this reason, it may take several months to see clearing of onychomycosis. Fingernails grow faster than toenails, and nails in older individuals tend to grow more slowly than do those in younger people. It is also important to remember that even if the fungus is cleared, it is common for it to return. This does not mean that medical treatment is useless; it means that onychomycosis tends to be stubborn and requires attention over the long term.

How can new infections be prevented? The following tips can help prevent new infections:

At home: • Throw away old shoes, particularly sneakers, running shoes, or other types of athletic shoes that you have used for exercise or sports. • Use antifungal spray or powder in your shoes every day. • Apply antifungal creams to your feet periodically to slow the growth of athlete’s foot fungus (which can then invade the nails). • Treat all signs and symptoms of athlete’s foot immediately. • Do not share tools used for manicures and pedicures. • Do not use the same nail clippers and files on normal nails that are used on nails with a fungus infection. • If you see signs of a nail infection, treat it immediately; do not wait until it has progressed. • Wash and dry your hands thoroughly after contact with any fungal infection. • Take proper care of your nails. Keep toenails trimmed and clean. Nails should be cut or filed straight across (not rounded or in a V shape). • Wear properly fitting shoes with a wide enough toe box so that your toes are not cramped or hit up against the front of the shoe. (High heels and narrow-toed shoes cause trauma to the toes and can damage the natural skin seal between the nail itself and the skin underneath, allowing fungus to invade under the nail.) • Make sure that household members with athlete’s foot infections receive treatment and take proper precautions to avoid spreading the fungus to others.

Outside the home: • Do not walk barefoot in public facilities, such as around pools and in spas, locker rooms, and gyms. Wear water shoes or rubber sandals. • Bring your own instruments (especially clippers and emery boards) to the nail salon. • Make sure your manicurist/pedicurist washes the nail-soaking dish or pedicure tub with bleach between clients. Seminars in Cutaneous Medicine and Surgery Update on Onychomycosis: Effective Strategies for Diagnosis and Treatment CME Post-Test Answer Sheet Original Release Date: June 2013 • Most Recent Review Date: June 2013 Expiration Date: June 30, 2015 • Estimated Time to Complete Activity: 2.5 hours To get instant CME credits online, sign in to the Web site at http://uofl.me/onycho13. Upon successful completion of the online assessments, you can download and print your certificate of credit. If you have any questions or difficulties, please contact the University of Louisville School of Medicine Continuing Medical Education office at [email protected].

CME Questions: For each question or incomplete statement, choose the answer or completion that is correct. Circle the most appropriate response.

1. the type of organism implicated most 7. the definition of “complete cure,” commonly in onychomycosis cases in the as defined by the US Food and Drug United States are: Administration (FDA) for the evaluation A. Bacteria of clinical trial results, is: b. Dermatophytes a. Negative results on fungal culture, as well c. Nondermatophyte molds as a completely normal appearance of d. Yeasts the nail b. Negative results on potassium hydroxide 2. Candida species are the most common (KOH) preparation, as well as a completely cause of onychomycosis among: normal appearance of the nail a. Children b. Elderly patients c. Negative results on potassium hydroxide (KOH) preparation and on fungal culture, c. Immunocompromised patients as well as an almost completely normal d. Individuals with poor peripheral circulation appearance of the nail 3. pediatric patients who present with d. Negative results on potassium hydroxide onychomycosis almost always have: (KOH) preparation and on fungal culture, a. Compromised immune function as well as a completely normal appearance b. Diabetes of the nail c. Family history of tinea pedis d. Previous toenail injury 8. all of the following currently are approved by the US Food and Drug Administration for 4. the most common presentation of the treatment of onychomycosis except: onychomycosis is a. Ciclopirox a. Chronic mucocutaneous candidiasis b. Itraconazole b. Distal-lateral-subungual c. Laser therapy c. Proximal subungual d. Terbinafine pulse-dose therapy d. Superficial white

5. the current standard method for identifying 9. the methods approved to date by the the causative organism in onychomycosis is US Food and Drug Administration for the a. Nail culture “temporary increase of clear nail in b. Periodic-acid Schiff staining of nail onychomycosis” are: plate samples a. Iontophoresis c. Potassium hydroxide preparation of b. Laser systems subungual debris c. Photodynamic therapy systems d. Polymerase chain reaction analysis d. Topical therapy 6. Which one of the following statements concerning periodic-acid Schiff (PAS) 10. A potent inhibitor of CYP3A4, ______staining is true? must be used with caution when treating a. PAS staining showing septate hyphae onychomycosis in patients with congestive is diagnostic heart failure or other ventricular b. PAS staining showing yeast forms only is not dysfunction. conclusive evidence of infection a. Ciclopirox c. PAS staining alone does not confirm that b. Fluconazole organisms are present d. PAS staining ascertains the viability of c. Itraconazole organisms present d. Terbinafine Seminars in Cutaneous Medicine and Surgery Update on Onychomycosis: Effective Strategies for Diagnosis and Treatment CME Evaluation Form Original Release Date: June 2013 • Most Recent Review Date: June 2013 Expiration Date: June 30, 2015 • Estimated Time to Complete Activity: 2.5 hours

To get instant CME credits online, sign in to the Web site at http://uofl.me/onycho13. Upon successful completion of the online assessments, you can download and print your certificate of credit. If you have any questions or difficulties, please contact the University of Louisville School of Medicine Continuing Medical Education office at [email protected].

EVALUATION FORM Did participating in this educational activity improve your We would appreciate your answering the following questions in order to COMPETENCE in the professional practice gaps that are listed help us plan for other activities of this type. All information is confidential. on the left? Please print. Strongly Agree Agree Somewhat Agree Disagree Strongly Disagree 1 2 3 4 5 Name:______Please elaborate on your answer.______Specialty:______Degree: o MD o DO o PharmD o RPh o NP o RN o BS o PA ______o Other ______Did participating in this educational activity improve your Affiliation:______PERFORMANCE in the professional practice gaps that are listed Address:______on the left?

City:______State: ______ZIP:______Strongly Agree Agree Somewhat Agree Disagree Strongly Disagree 1 2 3 4 5 Telephone:______Fax:______Please elaborate on your answer.______E-mail:______Signature:______

CME Credit Verification Please identify a change that you will implement into practice as I verify that I have spent _____ hour(s)/_____ minutes of actual time a result of participating in this educational activity (new protocols, working on this CME activity. No more than 2.5 CME credits will be different medications, etc). issued for this activity. ______COURSE EVALUATION: Gaps This activity was created to address the professional practice gaps listed How certain are you that you will implement this change? below. Please respond regarding how much you agree or disagree that the following gaps were met: Strongly Agree Agree Somewhat Agree Disagree Strongly Disagree 1 2 3 4 5 • Clinicians do not adequately treat onychomycosis. Many clinicians regard onychomycosis as a condition that is principally What topics do you want to hear more about, and what issue(s) in cosmetic in nature and therefore do not treat appropriately. your practice will they address?______• Clinicians outside the podiatry specialty are not utilizing ______current literature on onychomycosis diagnosis and treatment. ______Because onychomycosis traditionally has been managed by podiatrists and, less so, by dermatologists, many clinicians in Were the patient recommendations based on acceptable practices other specialties and general practice have considered definitive in medicine? m Yes m No diagnosis and treatment of this infection to be outside the purview of their practices. If no, please explain which recommendation(s) were not based on acceptable practices in medicine.______• Physicians are not identifying new medications and other therapeutic modalities for effective and safe treatment of ______onychomycosis. ______

Did participating in this educational activity improve your Do you think the articles were without commercial bias? KNOWLEDGE in the professional practice gaps that are m Yes m No listed above? If no, please list the article(s) that was/were biased.______Strongly Agree Agree Somewhat Agree Disagree Strongly Disagree ______1 2 3 4 5 ______Please elaborate on your answer.______The University of Louisville thanks you for your participation in this CME activity. ______All information provided improves the scope and purpose of our programs ______and your patients’ care.