A Guide To Treatments For Onychomycosis

By John Mozena, DPM

Onychomycosis is the number one diagnosed and treated disease by podiatrists today. While the disease was first recognized in the United States in 1928, it has only recently been brought under control with drugs that have been introduced in the last 10 years. With the advent of safer oral and topical medications, there has been a renewed focus on increasing efficacy rates. The current research seems to be centered on synergistic activity of oral and topical medications as well as different vehicles to add additional penetration of the medication. Onychomycosis is present in 2 to 3 percent of the population with the most common source of contamination coming from the patient’s own skin. Currently, 70 percent of the population has fungus recovered from the feet. Fifteen to 20 percent of people between the ages of 40 and 60 have onychomycosis, 32 percent of 60- to 70-year-olds have nail fungus and approximately 50 percent of those over 70 are afflicted. A 1965 U.S. study stated fungus can also be contagious throughout the patient’s own body and can also spread among individuals. In a study of 963 children cultured for onychomycosis, 263 (30.74 percent) were positive. The number of cases rose quickly with the age of the child, with only 25 percent of the patients being below the age of six. The question of treatment is always present due to the fact that onychomycosis has been considered a cosmetic problem in the past. This has led many physicians to falsely believe that this infection should be monitored and not treated. However, recent evidence shows this is not the case. Seventy-five percent of the people who have this infection exhibit psychosocial concerns. These people face the dilemma of not being able to go to the swimming pool, public shower areas or even wear open-toed sandals. More important is the fact that 48 percent of the people with onychomycosis have pain. The pain is intense enough to have these patients miss 1.8 days of work on average over a six-month period.1,2,3 Understanding Nail Anatomy And The Etiology Of Onychomycosis The anatomy of the nail area starts with the proximal nail fold known as the eponychial area. This is where nail growth begins. The growth cells extend to the distal end of the lanula. The nail itself consists of dorsal, intermediate and ventral layers. The dorsal layer is the horny zone and is made up of hard keratin. The ventral nail plate is held to the nail bed by a specialized onychodermal band known as the solehorn. The nail separates distally from the solehorn at the hyponychium. The medial and lateral ungual labial folds enclose the nail completely. The function of the nail is one of protection and sensory discrimination. The nail plate acts as a buttress that opposes the opposite force, placing pressure on the finger or toe. This increases the discrimination ability of the acral pulp and skin whenever the object is felt. Without the nail, the skin around the digit would deform and not allow for fine proprioception. With the advent of fungus infections, the intermediate layer hypertrophies and distorts the nail.4,5 Nail infections from fungus are believed to have four different entry ports, according to Zaisis.6 Distal subungual onychomycosis is the most common variety and accounts for 90 percent of onychomycosis. The disease begins with initial fungal penetration of the stratum corium from the hyponychial area or from the lateral nail fold. The most common cause of the organism is Trichophyton rubrum. Superficial white onychomycosis is the second most common type and accounts for 10 percent of onychomycosis. In this type, the organism Trichophyte metagraphytes directly invades the nail plate and creates a white crumbly appearance to the surface. Proximal subungual onychomycosis (commonly caused by T. rubrum) is the least common type, accounting for less than 1 percent of onychomycosis. The infection penetrates the proximal portion of the nail, resulting in hyperkeratosis and onycholysis. This type is usually associated with immunocompromised patients and the AIDS population. Finally, candidal onychomycosis, primarily caused by Candida albicans, occurs in less than 1 percent of onychomycosis infections.6,7 Several conditions can mimic onychomycosis and should be considered as a possible differential diagnoses. Some of these diagnoses include psoriasis, which causes pitting of the nails; leukonychia, which presents as white spots or bands that appear proximally and grow out distally; and lichen planus, which produces exaggerated longitudinal ridging or an angel wing deformity to the nail. Another mimicking disease is yellow nail syndrome, which is associated with primary lymphedema and chronic obstructive pulmonary disease. Other diseases that can mimic onychomycosis are chronic dermatitis, Darier’s disease, pityriasis rubra pilaris Bowen’s disease, eczema and malignant melanoma.8-11 Keys To Diagnosing Fungal Infection The KOH test is the standard for diagnosing a fungus infection in the nail. The presence of hyphae will indicate a positive test. Dermatophyte test mediums (DTMs) are also commonly used by podiatrists. Unfortunately, DTMs and KOH tests have many false negative and positive results. This false positive or negative rate can approach 50 percent. Fungal cultures have a much higher specificity but their sensitivity rates are not great. The best technique for determining if a fungus is present in the tissue is a histological biopsy with PAS stain. Although verifying the existence of fungus is not necessary, it can help with determining a treatment plan. Currently, the FDA recommends a fungal culture prior to using oral antifungals. Once you confirm a fungal infection in the nail, either clinically or by a diagnostic test, you can institute a treatment plan. What You Should Know About Debridement And Chemical Avulsion There are five basic ways to treat onychomycosis. You can treat the fungus with debridement, superficial surgical nail avulsion, topical medications, oral medications or a combination of oral and topical medications.12,13 Debridement is defined as removal of the devitalized or contaminated tissue. But is debridement of the nail actually treating the infection? The answer is no. Debridement relieves the pressure necrotic presence of the nail and provides for a better cosmetic appearance. However, it does nothing to treat the underlying causative organism. Debulking the nail does help in combination with other treatments in that it can decrease the fungal load of the nail itself.14 Surgical or chemical avulsion obviously eliminates the problem on the surface but several concerns arise with the avulsion. The first problem is one of reinfection as the nail regrows. The second problem that can arise is that the distal dorsal tuft of the distal phalanx can hypertrophy, preventing the nail from completing its full excursion past the hyponychium. This will lead to deformity of the toe and distal ingrown toenails, necessitating a matrixectomy for resolution of the problem.15,16 Taking A Closer Look At Ciclopirox In the early 1990s, the FDA stated no topical remedy could claim efficacy against onychomycosis. Ciclopirox nail lacquer 8%, which was introduced in 1999, is the only currently approved topical nail treatment effective in treating onychomycosis. Ciclopirox lacquer is approved for mild to moderate onychomycosis of the finger or toenails. It is a hydroxypridone with a unique mechanism of action. It works by chelating the polyvalent cations (Fe+3 or Al+3), resulting in the inhibition of metal dependent enzymes that degrade the toxic peroxides within the fungal cell. The package insert suggests applying the drug once a day for 48 weeks to the infected nails or until a clinical cure has been achieved. The manufacturer also suggests monthly debridements of the nail by a healthcare professional and weekly debridements by the patient to remove excessive fungal material. The drug has antibacterial and antiinflammatory activity as well as a wide spectrum of activity against fungus. The drug can be used as a conservative first-line drug or for patients who have physical or psychological concerns with oral medications. Although mycological cure rates have been good (47 to 86 percent), the clinical cure rates are approximately one-half to one-quarter that of the oral medications. Even with the lower cure rates, 90 percent of patients rate their onychomycosis as “improved” after using ciclopirox lacquer. Ciclopirox has the best safety profile of all current FDA approved drugs for onychomycosis.17-19 A Review Of Oral Medications In 1958, the first oral agent approved for onychomycosis came to the marketplace. Griseofulvin proved to be effective for superficial and fungal infections and is still used frequently for tinea capitas. Over time, griseofulvin proved to have low cure rates and a high relapse of greater than 75 percent within two years. Its safety profile was also a concern due to the presence of agranulocytosis in certain patients.20-21 The first oral azole became available in the early 1980s. Ketconazole was affected for dermatophyte and Candida but fell out of favor due to a hepatotoxicity rate of 1:10,000. It is still commonly used for tinea versicolor. With the advent of new triazoles and the allymines, an effective, safe oral antifungal medication was introduced. In 1995, itraconazole was approved for continuous therapy of onychomycosis. Since that time, pulse therapy of itraconazole has been introduced. Pulse therapy of itraconazole is 200 mg BID daily for one week and then one week out of each month for a period of three to four months. Itraconazole is a broad spectrum drug and is effective against dermatophytes, Candida and nondermatophytic molds. The clinical cure rate is 14 percent but the clinical response rate is around 70 to 80 percent. Itraconazole works by inhibiting ergosterol synthesis at the demethylation step, converting lanosterol to 14-dimethyl lanosterol. This demethylization step is dependent on cytochrome P-450 activation. Therefore, drugs associated with cytochrome P-450 may be associated with toxicity. Itraconazole is fungal-static where ciclopirox and terbinafine are fungicidal. The most common side effects of both itraconazole and terbinafine are gastrointestinal issues, cutaneous problems and nervous system concerns. Most recently, itraconazole has been implicated in cardiac dysfunction in certain patients. Adverse side effects occur in 9 percent of the cases. Itraconazole is indicated for onychomycosis of the fingernail and is the standard of care in treating onychomycosis of the toenails. The medication is most effective on a full stomach.2,21-23 Terbinafine is classified as an allylamine antifungal agent. This drug group was specifically invented to battle onychomycosis. The drug works much like the azoles, with the exception being that it blocks ergosterol synthesis by inhibiting squalene epoxidase. This step does not involve cytochrome P-450 so interactions are not an issue. The medication is not as broad spectrum as itraconazole. Although it has very good dermatophyte coverage, its coverage for nondermatophytic molds and Candida is weaker. Terbinafine was approved in 1996 for the treatment of onychomycosis of both fingernails and toenails. The dosing regimen is 250 mg for three months. Both itraconzaole and terbinafine are keratinophilic and lipophilic, allowing for short-term therapy. Previously, the older drugs had to be used for the entire growth of the nail, which could take up to a year. Fingernails grow at a rate of approximately 0.1 mm per day and toenails at a rate of 0.33 mm per day. This means treatment would require about a year for the traditional medications versus three months for the newer oral agents. Physicians at a four-month follow-up noted improvement in 81 percent of the patients using oral therapy and only 39 percent of patients on non-oral therapy. More unusual side effects with terbinafine include green vision and taste disturbances. Side effects occur in approximately 6 percent of the patients. The clinical cure rate is 37 percent and a clinical response rate is approximately 70 to 80 percent.14,21,23-26 A public health advisory was issued by the FDA in 2001 concerning the use of itraconazole capsules and terbinafine tablets in the treatment of onychomycosis. The advisory noted a small risk of developing congestive heart failure associated with the use of itraconazole. The FDA also noted that in rare cases, severe liver failure may be associated with the use of itraconazole or terbinafine. The FDA recommends you obtain fungus specimens for confirmation of the diagnosis. You should also ensure proper screening of these patients with a baseline blood test to evaluate liver function. You may also advise patients to have a second liver function test performed at the midpoint of therapy with an oral antifungal agent, although this is not mandatory. Fluconzaole is another drug that one can use to treat onychomycosis. It is an azole much like itraconazole and has activity against dermatophytes but is most effective against Candida. Unfortunately, fluconazole is not approved for onychomycosis but has been used experimentally at 300 mg weekly for one year. Its high cost has been a stumbling block for use.14,28,29 Among systemic antifungals, terbinafine, itraconazole and fluconazole are safe and efficient in children. The treatment and dosing is dependent on weight. For small children, you should first consider topical treatment. Should You Combine Orals And Topicals? The most recent treatment option for improving efficacy and decreasing the occurrence of side effects involves combination therapy of oral and topical agents.29 Preliminary studies show that synergistic activity may be more effective than either oral or topical therapy alone. In addition, the combination of oral and topical antifungals may result in drug penetration from both “inside out” and “outside in.” The topical medications accumulate in the nail plate and work their way into the nail bed while oral agents rapidly build in the nail bed. The combination use of ciclopirox nail lacquer and terbinafine is currently being evaluated in a multi-national, multi-center randomized and evaluator-blinded study. (See “Study Examines Combination Therapy For Onychomycosis” in News and Trends.) In a study using pulsed itraconazole and ciclopirox nail lacquer 8%, a good therapeutic response was noted in 88 percent of patients and a clinical cure rate of 41 percent was achieved. The complementary mode of action may be due to the different pathways of the drugs (biosynthesis of ergosterol versus chelation of the metal dependent ions). One suggested treatment plan involves using the ciclopirox nail lacquer daily or three times a week in combination with terbinafine every other day for four to 12 weeks or until the nail has cleared.30-32 It has been demonstrated that 22 percent of patients experience a relapse of onychomycosis when they are followed up three years after initial treatment. Since relapses are relatively common following oral therapy, topical therapy may prove useful for the prevention of relapse or reinfection of onychomycosis. They also may be used as a prophylactic measure in patients who are at a high risk for reinfection. What One Case Study Revealed On Combination Therapy One 54-year-old male fire chief came to our office with a secondary complaint of onychomycosis. His primary complaint was plantar fasciitis and multiple sclerosis. The patient reported tenderness caused by the thickness of the nail resulting from the fungal infection. We went over the treatment options, including debridement, avulsion, topical medications and oral medications. We also discussed combination therapy in light of the new literature and increased efficacy. After a full discussion of options, complications and the treatment regimen, he chose a combination of terbinafine and ciclopirox lacquer therapy. The patient underwent blood work, including a CBC and a liver panel, which were normal. The nail was also cultured and this showed T. rubrum was the causative organism. After three months of treatment, it was obvious from the pictures below that the patient’s nail was clearing and the infection was resolving. Final Notes Treating fungal nails is not without its hazards. Besides the traditional side effects that have been enumerated in the past, new problems have been appearing, including infected ingrown toenails due to the fact that the nail has become thinned.33-35 The role of the environment for fungus growth needs to be investigated further in the hopes of developing better material for shoes and socks to prevent fungus infections. Also, immunity defects allowing for fungus infections need to be researched. We are not there yet but we are closing in on the complex issue of onychomycosis.2,36Dr. Mozena is board-certified and is a Fellow of the American College of Foot and Ankle Surgeons. He has a private practice at the Town Center Foot Clinic in Portland, Ore. Editor’s Note: For related articles on onychomycosis, see “How To Treat Onychomycosis In Diabetic Patients” in the March 2003 issue or “Ten Pearls For Treating Difficult Nails” in the September 2002 issue, or check out the archives at www.podiatrytoday.com. CE Exam #111 Choose the single best response to each question listed below: 1. Which is the true statement? a) Onychomycosis is not contagious b) Children do not get onychomycosis c) Fifty percent of patients over 70 have onychomycosis d) Onychomycosis is cosmetic and does not require treatment 2. The nail acts to: a) Protect and provide sensory discrimination b) Prevent fungus infection of the nail bed c) Provide increased discrimination of objects d) Prevent the skin around the digit from deforming, allowing fine proprioception 3. Which of the following organisms do not cause onychomycosis? a) T. rubrum b) Candida albicans c) T. metagraphytes d) T. mycodium 4. Which is the false statement? a) Histological biopsy of the nail is unreliable. b) Fungal cultures are recommended prior to oral antifungal treatment. c) DTMs and KOH have many false negative and positive results. d) The pressure of hyphae indicates a positive KOH test. 5. Which of the following conditions do not resemble onychomycosis? a) Eczema b) Pityriasis rubra pilaris c) Yellow nail syndrome d) Eruptive plaqtineum 6. Which of the following is not considered a treatment for onychomycosis infection? a) Ciclopirox lacquer b) Debridement c) Avulsion d) Terbinafine and itraconazole 7. Which antifungal is broad spectrum? a) Ciclopirox lacquer b) Itraconazole c) Terbinafine d) a and b 8. Combination therapy is not performed by using: a) griseofulvin and fluconazole b) ciclopirox lacquer and terbinafine c) ciclopirox lacquer and itraconazole d) ciclopirox lacquer and fluconazole 9. Which of the following statements is false about oral and systemic antifungals? a) They can be used safely in children. b) They can have a synergistic effect with topicals. c) Patients who use them may have relapses after treatment. d) None of the above 10. Antifungals work by all methods described except: a) Blocking the synthesis of ergosterol b) Accelerating mitosis in proliferating cells c) Chelation of the metal dependent ions d) Complementary actions of topical and oral medications Instructions for Submitting Exams Fill out the postage-paid card that appears on the following page or log on to www.podiatrytoday.com and respond electronically. Within 60 days, you will be advised that you have passed or failed the exam. A score of 70 percent or above will comprise a passing grade. A certificate will be awarded to participants who successfully complete the exam. Responses will be accepted up to 12 months from the publication date.



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