Understanding Onychomycosis Treatment: Mechanisms of Action and Formulation
Topical Antifungal Agents
Topical antifungal agents lack the systemic adverse effects or drug-drug interactions associated with fluconazole, itraconazole, and terbinafine, as described above, and generally feature a low incidence of serious local adverse effects. Historically, the main disadvantages of topical therapy were poor bioavailability— and, in turn, less efficacy compared to systemic agents—and the need for frequent debridement of the affected nails by a clinician and weekly removal of the lacquer by patients. Two newer topical agents, efinaconazole and tavaborole, have demonstrated improved efficacy compared with other topical agents and are not formulated as lacquers (thus, removal is not necessary).
Ciclopirox 8% Solution
Ciclopirox, a synthetic antifungal agent, has been available in the United States since 1996. It was the first topical medication approved by the FDA for the treatment of onychomycosis. Its mechanism of action is poorly understood. Leem and colleagues 4 investigated the activity of this agent against the yeast Saccharomyces cerevisiae and found that ciclopirox seemed to target proteins in the yeast that affected the replication and repair of DNA as well as cellular trans - port. These researchers proposed that ciclopirox inhibits cell growth and metabolism, possibly through several targets in the organism.
Efinaconazole
Efinaconazole is an azole antifungal agent, with a mechanism of action identical to that of the systemic triazole agents discussed above—ie, inhibition of 14-alpha demethylase, with resulting downstream disruption of fungal cell membranes. However, the systemic adverse effects that are problematic with itraconazole and fluconazole are not seen with this topical agent.
Efinaconazole shows in vitro activity against T. rubrum and Trichophyton mentagrophytes . No clinically significant evidence of drug resistance to efinaconazole has been observed.
In addition, efinaconazole has been shown to have low keratin affinity; Sugiura and colleagues 5 suggested that this property enhances efinaconazole’s nail penetration and contributes to its fungicidal activity. These investigators tested free-drug concentrations—in suspensions prepared from keratin samples— of efinaconazole, ciclopirox, and amorolfine (similar to ciclopirox, amorolfine is an agent in a lacquer formulation; amorolfine is not FDA-approved). The free-drug concentration of efinaconazole was 14.3%, compared to 0.7% for ciclopirox and 1.9% for amorolfine, respectively ( P <0.001). They also tested the penetrations of these three agents through full-thickness, T. rubrum–infected human nails. Efinaconazole’s fungicidal activity was comparable to that observed with amorolfine and superior to the fungicidal activity of ciclopirox. In another experiment in a guinea pig model with T. mentagrophytes onychomycosis, efinaconazole decreased the fungal burden significantly more than ciclopirox and amorolfine lacquers ( P <0.01). 5
Managing Onychomycosis: New and Emerging Treatments and Recurrence Prevention Strategies
This educational activity is designed for dermatologists, family practitioners, internists, nurse practitioners, physician assistants, and other clinicians who treat patients with onychomycosis.
Supported by educational grants from:
Valeant Pharmaceuticals North America LLC
Activity Information
EXPIRED
Original Release Date: June 2015
Latest Review Date: June 2015
Expiration Date: June 30, 2017
Estimated Time to Complete Activity: 2.5 hours
Method of Participation
Participants should read the activity information, review the activity in its entirety, and complete the online post-test and evaluation. Upon completing this activity as designed and achieving a passing score on the post-test you will be directed to a Web page that will allow you to receive your certificate of credit via email or you may print it out at that time.The online post-test and evaluation can be accessed at http://tinyurl.com/onycho15.Inquiries may be directed to Global Academy for Medical Education info@globlacademycme.com or (973) 290-8225.
Target Audience
This educational activity is designed for dermatologists, family practitioners, internists, nurse practitioners, physician assistants, and other clinicians who treat patients with onychomycosis.
Program Overview
With the introduction of more effective treatments—particularly the recently approved topical agents—clinicians in dermatology as well as other specialties and general primary care have a renewed interest in diagnosing and treating onychomycosis, an infection that is now recognized as clinically important but was once considered largely a cosmetic problem with minimal or no medical implications.
However, although efficacy with some treatments is good, the medications must be used consistently and correctly for several months before clinical evidence of improvement appears, and before patients perceive that treatment is working.
Treatment options currently approved in the United States for onychomycosis include topical and oral agents, as well as laser therapy. Oral agents must be chosen for their activity against the involved pathogens (dermatophytes, nondermatophytes, or yeast species, or combination infections). The currently approved systemic agents generally are safe for most patients, but concerns remain with respect to systemic side effects (for example, hepatotoxicity), particularly in pediatric patients, the elderly, and others with underlying medical conditions such as diabetes. The three agents currently approved for topical therapy are ciclopirox gel 0.77%, approved in 1999, and efinaconazole 10% topical solution and tavaborole topical solution, 5%, both approved in 2014. Other classes of topical antifungals are being evaluated both here and abroad. Clinicians must be able to effectively and safely use the currently approved agents, and must be prepared to evaluate the emerging data on medications now being investigated. Several laser devices are approved, and other types of lasers as well as other modalities (including photodynamic therapy) are being tested in clinical trials.
This supplement focuses on the efficacy and safety of onychomycosis treatments, particularly those recently approved, and provides an overview of emerging therapies. Mechanisms of action of drugs and devices also are presented to help clinicians tailor therapy according to individual patient clinical profiles. Management strategies for challenging patient populations are offered, and practical approaches to preventing recurrence are addressed— in particular, strategies for enhancing patient adherence to medication use and avoidance of sources of reinfection.
Learning Objectives
As a result of participating in this activity, participants should be better able to:
- Explain the benefits of early diagnosis and treatment of onychomycosis and the potential sequelae if this infection is untreated or is inadequately treated.
- Establish or improve practice protocols for identifying patients with onychomycosis, particularly in special populations (for example, the elderly, pediatric patients, immunocompromised patients, patients with psoriasis, and those with diabetes mellitus).
- Identify the mechanism of action for the currently available therapeutic options, including differences in formulation and associated efficacy, and use this knowledge to more effectively tailor treatment choices to individual patients.
- Incorporate or enhance monitoring for onychomycosis in patients in special, at-risk, or difficult-to-manage populations (for example, the elderly, pediatric patients, immunocompromised patients, patients with psoriasis, and those with diabetes mellitus).
- More effectively use currently available oral and topical medications to treat various patient populations.
- Discuss techniques, including obtaining good culture specimens, that permit more accurate diagnosis of the infecting organisms and the most appropriate choice of therapy.
- Review and, if necessary, improve patient education materials and teaching plans regarding the patient’s role in the treatment of onychomycosis and the prevention of recurrence to increase the chances of effective long-term management of this disease.
- Evaluate the results of clinical studies on new and emerging and available treatments for onychomycosis.
Accreditation Statements
Physicians
This activity has been planned and implemented in accordance with the Essential Areas and Policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint providership of The University of Louisville and Global Academy for Medical Education LLC.
The University of Louisville is accredited by the ACCME to provide continuing medical education for physicians. The University of Louisville Office of Continuing Medical Education & Professional Development designates this enduring material for a maximum of 2.5 AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.
Nurses
This program has been approved by the Kentucky Board of Nursing for 3.0 contact hours through the University of Louisville Hospital, provider number 4-0068-7-16-820. The Kentucky Board of Nursing approval of an individual nursing education provider does not constitute endorsement of program content. Participants must complete the entire activity, provide license, and complete the evaluation to receive contact hours.
Disclosure Declarations
As a provider accredited by the ACCME, the Office of CME & PD, School of Medicine, University of Louisville must ensure balance, independence, objectivity, and scientific rigor in all its sponsored educational activities. All planners, faculty, reviewers, and other persons that affected the content of this CME activity were required to submit a financial disclosure form from which relevant conflicts of interest were determined.
Faculty Disclosures
David M. Pariser, MD, Consultant: Anacor Pharmaceuticals, Inc., DUSA Pharmaceuticals, Inc., LEO Pharma Inc., and Valeant Pharmaceuticals North America LLC.
Nathaniel J. Jellinek, MD, Advisory Board: Valeant Pharmaceuticals.
Phoebe Rich, MD, Grant/Research: Anacor, Meiji Seika Pharma Co., Ltd., Topica Pharmaceuticals, Inc., and Valeant Pharmaceuticals.
Melodie S. Young, MSN, RN, A/GNP-c, has no relevant financial relationships to disclose.
CME Reviewer: Cindy England Owen, MD, Assistant Professor, Division of Dermatology, University of Louisville School of Medicine, has no relevant financial relationships to disclose.
The CME & PD Staff and Advisory Board have nothing to disclose with the exception of Dr. Douglas Coldwell, Speaker: Sirtex, Inc. and Consultant: DFine, Inc.
Global Academy for Medical Education Staff: Sylvia H. Reitman, MBA, DipEd; Shirley V. Jones, MBA; and Joanne Still, BA have no relevant financial relationships to disclose
Off Label/Investigational-Use Disclosure
This CME/CE activity discusses the off-label use of fluconazole for the treatment of onychomycosis and unapproved dosing schedules for itraconazole and terbinafine. Also discussed is the use in pediatric patients of medications approved for the treatment of onychomycosis in adults; currently, no medication is approved for the treatment of onychomycosis in pediatric patients
This continuing education supplement was developed from interviews with the faculty. The Guest Editors acknowledge the editorial assistance of Global Academy for Medical Education and Joanne Still, medical writer, in the development of this supplement. The manuscript was reviewed and approved by the Guest Editors as well as the Editors of Seminars in Cutaneous Medicine and Surgery. The ideas and opinions expressed in this supplement are those of the Guest Editors and do not necessarily reflect the views of the supporters, Global Academy for Medical Education, the University of Louisville, or the Publisher.
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Supplement to Seminars in Cutaneous Medicine and Surgery Supplement to Dermatology News
Copyright
Copyright © 2015 by Frontline Medical Communications Inc. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopy, recording, or any information storage and retrieval system, without written permission from the Publisher. Printed in the United States of America.
References
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2. Chang CH, Young-Xu Y, Kurth T, Orav JE, Chan AK. The safety of oral antifungal treatments for superficial dermatophytosis and onychomycosis: A meta- analysis. Am J Med . 2007;120:791-798.
3. Ghannoum MA, Rice LB. Antifungal agents: Mode of action, mechanisms of resistance and correlation of these mechanisms with bacterial resistance. Clin Microbiol Rev . 1999; 12:501-517.
4. Leem SH, Park JE, Kim IS, Chae JY, Sugino A, Sunwoo Y. The possible mechanism of action of ciclopirox olamine in the yeast Saccharomyces cerevisiae. Mol Cells. 2003; 15(1):55-61.
5. Sugiura K, Sugimoto N, Hosaka S, et al. The low keratin affinity of efinaconazole contributes to its nail penetration and fungicidal activity in topical onychomycosis treatment. Antimicrob Agents Chemother . 2014;58:3837-3842.
6. Carney C, Cantrell W, Warner J, Elewski B. Treatment of onychomycosis using a sub millisecond 1064-nm neodymium:yttrium-aluminum-garnet laser. J Am Acad Dermatol . 2013;69:578-582.
7. Vural E, Winfield HL, Shingleton AW, Horn TD, Shafirstein G. The effects of laser irradiation on Trichophyton rubrum growth. Laser Med Sci. 2008;23(4):349-353.
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9. Piraccini BM, Rech G, Tosti A. Photodynamic therapy of onychomycosis caused by Trichophyton rubrum . J Am Acad Dermatol. 2008;59(5 suppl):S75-S76.
10. Watanabe D, Kawamura C, Masuda Y, Akita Y, Tamada Y, Matsumoto Y. Successful treatment of toenail onychomycosis with photodynamic therapy. Arch Dermatol. 2008;144:19-21.
11. Donnelly RF, McCarron PA, Lightowler JM, Woolfson AD. Bioadhesive patch- based delivery of 5-aminolevulinic acid to the nail for photodynamic therapy of onychomycosis. J Control Release. 2005;103:381-392.
12. Harris F, Pierpoint L. Photodynamic therapy based on 5-aminolevulinic acid and its use as an antimicrobial agent. Med Res Rev . 2011;32(6):1292-1327. doi:10.1002/ med.20251.
13. Smijs TG, van der Haas RN, Lugtenburg J, et al. Photodynamic treatment of the dermatophyte Trichophyton rubrum and its microconidia with porphyrin photosen - sitizers. Photochem Photobiol . 2004;80:197-202.
14. Dai T, Fuchs BB, Coleman JJ, et al. Concepts and principles of photody - namic therapy as an alternative antifungal discovery platform. Front Microbiol . 2012;3:120. doi:10.3389/fmicb.2012.00120.
15. Gilaberte Y, Aspiroz C, Martes MP, Alcalde V, Espinel-Ingroff A, Rezusta A. Treatment of refractory fingernail onychomycosis caused by nondermatophyte molds with methylaminolevulinate photodynamic therapy. J Am Acad Dermatol. 2011;65:669-671.
16. Barsness M, Davis SP, Etheredge R, et al. Studies in drug transport vs. current in iontophoretic onychomycosis treatment. Conf Proc IEEE Eng Med Biol Soc . 2009;2009:289-294.
17. Amichai B, Nitzan B, Mosckovitz R, et al. Iontophoretic delivery of terbinafine in onychomycosis: A preliminary study. Br J Dermatol . 2010;162:46-50.
18. Murdan S. Enhancing the nail permeability of topically applied drugs. Expert Opin Drug Deliv. 2008;5:1267-1282.
19. Borovoy M, Tracy M. Noninvasive CO 2 laser fenestration improves treatment of onychomycosis. Clin Laser Mon. 1992;10:123-124.
20. Lim EH, Kim HR, Park YO, et al. Toenail onychomycosis treated with a fractional carbon-dioxide laser and topical antifungal cream. J Am Acad Dermatol . 2014; 70:918-923.
Disclosures
As a provider accredited by the ACCME, the Office of CME & PD, School of Medicine, University of Louisville must ensure balance, independence, objectivity, and scientific rigor in all its sponsored educational activities. All planners, faculty, reviewers, and other persons that affected the content of this CME activity were required to submit a financial disclosure form from which relevant conflicts of interest were determined.
David M. Pariser, MD, Consultant: Anacor Pharmaceuticals, Inc., DUSA Pharmaceuticals, Inc., LEO Pharma Inc., and Valeant Pharmaceuticals North America LLC.
Nathaniel J. Jellinek, MD, Advisory Board: Valeant Pharmaceuticals.
Phoebe Rich, MD, Grant/Research: Anacor, Meiji Seika Pharma Co., Ltd., Topica Pharmaceuticals, Inc., and Valeant Pharmaceuticals.
Melodie S. Young, MSN, RN, A/GNP-c, has no relevant financial relationships to disclose.
CME Reviewer: Cindy England Owen, MD, Assistant Professor, Division of Dermatology, University of Louisville School of Medicine, has no relevant financial relationships to disclose.
The CME & PD Staff and Advisory Board have nothing to disclose with the exception of Dr. Douglas Coldwell, Speaker: Sirtex, Inc. and Consultant: DFine, Inc.
Global Academy for Medical Education Staff: Sylvia H. Reitman, MBA, DipEd; Shirley V. Jones, MBA; and Joanne Still, BA have no relevant financial relationships to disclose.