PODI8511 Written assignment Topic 2

Review of the Evidence in Support of the Efficacy of Optimal Antimycotic Pharmacotherapy of Onychomycosis
Introduction Onychomycosis is a mycotic infection of the keratinized tissue of the nail plate. (1) Onychomycosis is the most common nail disorder in adults, accounting for up to 50% of all nail diseases. Predisposing factors may include increasing age, immunosuppression, poor peripheral circulation, trauma, and tinea pedis. (2) Onychomycosis can be caused by dermatophytes, yeasts, or nondermatophyte organisms. Dermatophytes, particularly Trichophyton rubrum and Trichophyton mentagrophytes, have been found to be amongst the most common organisms in onychomycosis. (1-2) Topical Agents In the past few decades new topical agents have been developed with proven efficacy. These include the midazoles (e.g. miconazole, econazole), allylamines (e.g. terbinafine) and amorolfine lacquer. Generally, these are not effective when used alone, except for treatment of distal white superficial onychomycosis. However, it may be helpful to combine them with oral treatment regimens. (3) One study on topical antimycotic nail penetration speculated that the low cure rate of topical was, indeed, due to inadequate exposure of the fungal cells to the drugs. (4) To overcome this barrier several studies have combined mechanical nail debridement with topical treatments (1;5-6), as discussed later in this review. One study found that for mild-to-moderate onychomycosis treated via monotherapy, amorolfine nail lacquer was generally considered the most cosmetically convenient topical agent. (7) Another study found that distal onychomycosis was successfully treated by amorolfine in 75.3% of cases. (8) Tea tree oil has been shown to exhibit antifungal characteristics when added topically to nails. The literature does give some theories as to how the oils exert their antimicrobial effects, however, little is known on the oils effects on human tissue. Tea tree oil is toxic if taken orally and sensitivity reactions are not uncommon when it is used topically. Toxicity

levels of tea tree oil need to be determined. (9) Oral agents Griseofulvin is a fungistatic agent effective only within the nail matrix. Therefore needs to be taken for about a year for effectiveness. Poor compliance, adverse effects (ranging from photosensitivity to hepatotoxicity and teratogenicity) and drug interactions has seen it take a backseat to more effective medications for onychomycosis. (3) Ketoconazole is a broad spectrum azole agent . It has significant adverse effects and drug interactions that limit its long-term use in patients with nail infections. Abnormal liver function tests occur in about 15% of patients, and severe hepatitis has been reported.This drug has also lost popularity amongst prescribers. (3) Terbinafine is often the initial treatment of choice for confirmed onychomycosis. (10) It is an allylamine derivative that decreases ergosterol synthesis, causing fungal cell death. Terbinafine is available in Australia and listed on the PBS for onychomycosis when found by microscopy and/or culture. If the culture is negative but the microscopy positive, and it is toenail disease, it is has been recommended as a reasonable treatment choice. (3) The recommended dosage is 250 mg/ day for three months for toenails. Terbinafine is relatively safe. Minor occasional side effects include nausea, headaches, urticaria and taste disturbance. Severe adverse effects include liver disease, neutropenia and allergic skin reactions. A full blood examination and liver function tests are recommended after a few weeks of treatment. (3) One study found terbinafine to be more effective than itraconazole in the treatment of toenail onychomycosis. (11) In two different studies patients reported significantly greater ease and convenience of treatment and higher overall satisfaction with continuous terbinafine therapy compared with pulse-dose itraconazole or pulse-dose terbinafine therapy. (12-13) Itraconazole is also a broad spectrum azole. It has been found to be effective and safe in the treatment onychomycosis. (14) It is not listed on the PBS for treating nail infections.Pulse dosing of 400 mg/day for seven days a week every four weeks is recommended, with a duration of two months for treatment of fungal finger- nails and three months for toenails. (3) Minor adverse effects include nausea, headache and urticaria. Serious adverse effects include abnormal liver function tests, adrenal suppression, gynaecomastia, and congestive cardiac failure. There are many drug interactions for itraconazole. These include warfarin, digoxin, cisapride, felodipine lipid-lowering agents and calcium channel blockers. (3;15) Fluconazole is an azole that prevents conversion of lanosterol to

ergosterol. It does not seem to persist as long in the nails as the other azoles, so treatment should continue until the infectionis seen to resolve. Intermittent fluconazole, taken once weekly or on alternate days, has been found to be an efficacious and well-tolerated onychomycosis treatment. (16) Long courses of treatment are needed, for example, nine to 12 months for toenails; therefore, cost may be an issue for some patients. (3) Adverse effects of this medication are minimal, especially with a weekly dose. Nausea, headaches and abnormal liver function tests have been reported but routine liver testing is not usually needed. (3) Combination Therapy Various combinations of topical, oral and mechanical methods have been employed to cure onychomycosis with good results. A topical antimycotic study found a combination of topical miconazole nitrate 2% and terbinafine tincture to have a high onychomycosis cure rate and low reported side-effects. (17) The use of topical agents such as amorolfine in combination with a systemic antifungal drug has been found to increase the cure rate of patients with onychomycosis and cost savings compared with oral therapy alone. (7) A study that combined terbinafine with aggressive debridement for the treatment of onychomycosis found complete, mycologic, and clinical cure rates were higher in the terbinafine plus debridement group com- pared with the terbinafine alone group. (18) Another study found that antifungal nail lacquer combined with mechanical debridement improved onychomycosis significantly more than debridement alone. None of the patients in the debridement-only group experienced mycological cure. (5) A similar study found 80% resolution in a study where patients used clotrimazole 1% cream and mechanical debridement together. (6) Conclusion From the review it appears that the most efficacious and recommended treatment for onychomycosis is continuous oral terbinafine treatment. Topical treatments appear to fail in monotherapy unless the complaint is superficial. Topical treatments have a higher efficacy when used with debridement methods and have had treatment success in combination with oral antimycotics. Containdications must be carefully assessed prior to any of these treatment regimes.

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study of fungal isolates from nails: The frequency of onychomycosis, fungal distribution, and antifungal susceptibility patterns Journal of the American Academy of Dermatology. 2000;43(4):641-8. 3. Howard A. Nail Infections MedicineToday. 2011;12(7).

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6. Davies KJ. Study to determine the efficacy of Clotrimazole 1% cream for the treatment of onychomycosis in association with the mechanical reduction of the nail plate. The Foot. 2006;16:1922 7. Bodman MA, Feder L, Nace A. Topical Treatments for Onychomycosis: A Historical Perspective. Journal of the American Podiatric Medical Association. 2003;93(2):136-141. 8. Zalacain A, Ruiz L, Ramis G, Novel V, Ogalla JM, Calvo MA, Vinuesa T. Podiatry care and amorolfine: An effective treatment of foot distal onychomycosis. The Foot.2006;16:149152. 9. Benger S, Townsend P, Ashford RL, Lambert P. An in vitro study to determine the minimum inhibitory concentration of Melaleuca alternifolia against the dermatophyte Trichophyton rubrum. The Foot. 2004;14:8691. 10. Wargon O. Nail disease: Is it fungal? If so, what should I do? MedicineToday. 2003;4(4) 11. Brautigam M, Terbinafine versus itraconazole: a controlled clinical comparison in onychomycosis of the toenails. J Am Acad Dermatol. 1998;38(5 Pt 3):53-6. 12. Warshaw EM, Bowman T, Bodman MA, Kim JJ, Silva S, Mathias SD. Satisfaction with Onychomycosis Treatment Pulse versus Continuous Dosing. J Am Podiatr Med Assoc. 2003;93(5):373-379. 13. Tosti A, Piraccini BM, Stinchi C, Venturo N, Bardazzi F, Colombo MD. Treatment of dermatophyte nail infections: an open randomized study comparing intermittent terbinafine therapy with continuous terbinafine treatment and intermittent itraconazole therapy. Am Acad Dermatol. 1996;34(4):595-

600. 14. Doncker PD. Itraconazole pulse therapy for onychomycosis and dermatomycoses: an overview. J Am Acad Dermatol.1997;37(6): 969-74 15. Neuvonen PJ Itraconazole interacts with felodipine. - J Am Acad Dermatol. 1995;33(1):134-5 16. Assaf RR, Elewski BE. Intermittent fluconazole dosing in patients with onychomycosis: Results of a pilot study. J Am Acad Dermatol. 1996;35:216-9. 17. Ricketti JC. Terbinafine/miconazole nitrate 2% tincture compound for the treatment of onychomycosis The Foot. 2001;11;21-23. 18. Jennings MB, Pollak R, Harkless LB, Kianifard F, Tavakkol A. Treatment of Toenail Onychomycosis with Oral Terbinafine Plus Aggressive Debridement IRON-CLAD, a Large, Randomized, Open-Label, Multicenter Trial. J Am Podiatr Med Assoc. 2006;96(6):465-473.