CHAPTER 3I ONYCHOMYCOSIS: There is a Cure
Barbara S. Scblefman, D.P.M.
Onychomycosis is the cause of 500/o of all nail 5. The immunosuppressed patient, where disturbances, with toenails being affected approxi- the body's ability to combat the infection mateiy 4 times as often as fingernails.' is compromised. Onychomycosis represents approximately one- 5. Postmenopausal women are affected, as third of all mycotic infections of the integument. estrogen appears to exerl a protective More than 48o/o of patients who are 70 years of age effect in younger women. Onychomycosis and oldeq and 320/o of 60 to 7}-year-old patients are seems to manifest itself in patients in their affected by the condition.'The overall incidence in 40s and 50s. the population is not known, but it is repofied to 'When comparing the stratum corneum of the be approximately 2 to 730/0.3 epidermis (skin) to the nail, one finds distinct The incidence of onychomycosis is on the rise keratins, with the presence of a high sulfur matrk today due to many factors. A growing proportion component in the nail plate. The fat content in nails of the population is elderly. \7ith the advent of is 0.1% to 70/o compared to 100/o in the stratum more advanced and broader antibiotics which kill corneum. The water content in nail is 70/o to 720/0, bacteria more effectively, fungi have proliferated. which is less than the corresponding value of 15- There is an increased use of antineopiastic 250/o for the stratum corneum. There no immunosuppressive drugs for organ transplants ^re sebaceous or eccrine glands in nails.T'B and AIDS patients. There is an increased propensity Onychomycosis is caused by dermatophytes for communal bathing places, recreational facilities, (90o/o), yeasts (60/o) and non-dermatophye molds health clubs etc., which provide an ideal setting for (4o/o).a Tinea unguium is ciinically defined as a fungal infections. In addition, occlusive footwear is dermatophyte infection of the nail plate. Of the more popular in the work place.' dermatophytes, Trichophl,ton tubtum (T. rubrum) Many factors will predispose a patient to is the offender in 900/o of the cases. Other dermato- onychomycosis. People in the following categories phytes causing onychomycosis include T. are more susceptible:5r' mentagrophltes, Microsporum gypseum or nanum, 7. Paiients with chronic Tinea pedis or and Epidermophyton floccosum or canis. Candida other foot infections. albicans accounts for 50-830/o of the Candida 2. Patients with advanced age who have species causing nail infections, although C. slower growth of the nail and decreased parapsilosis is emerging now as a main pathogen circulation. in various centers. Other species include C. lypoly- 3. Athletes where trauma to the nail weak- tica, C. fumata, and C. rugosa.e Yeasts are fungi that ens the seal between the nail plate and reproduce by budding.'0 Several non-dermatophye nail bed allowing fungal organisms to molds have been identified such as Scopulariopsis penetrate the nail unit. They also sweat brevicaulis, Aspergillus spp, Fusarium oxyspoftum, profusely. Runners are particularly prone Hendersonula toruloidea (Scytalidium dimidiatum), to onychomycosis. Scytalidium hyalinum, Acremonium tenuis, and 4. Exogenous heat/moisture which worsens Cephalosporium,3,'1 with Scopulariopsis and the condition as well as hyperhidrosis, as Scyalidium being the most prevalent. seen in anyone who wears shoes or Onychomycosis can be classified into 4 boots every day for 72 or more hours at different types: distal subungual onychomycosis, a time. People who wear sandals are less superficial white onychomycosis, proximal r,-r-rlnerable to fungi as their feet are subungual onychomycosis, and candidal ony- exposed to the air. chomycosis.10,1214 Distal Subungual Onychomycosis CHAPTER 31 l9l
(DSO) is the most common variety and accounts There are several conditions that often mimic for 90o/o of onychomycosis. The disease begins with onychomycosis.6''3 Included in the differential an initial fungal penetration of the stratum corneum diagnosis are: from the hyponychial area, or from the lateral nail 1. Psoriasis, which causes a pitting of the fold. Characteristics include a yellow-brown nail plate surface in the fingernails as discoloration of the nail plate, onycholysis, and well as the toenails. subungual hyperkeratosis without thickening of the 2. Leukonychia, which is a white spot or actual nail plate. The predominant organism is T. band that appears proximally and grows rubrum. There may be a genetic predisposition out with the nail, which is usually caused with an autosomal dominant pattern. by trauma. These spots cannot be Superficial \7hite Onychomycosis (SVO) is burred-off as in S\WO. the second most common type, and occurs in 3. Lichen planus, which is an inflammatory approximately 1.0o/o of cases of onychomycosis. In skin disease that involves the nails in this type, fungi directly invade the nail plate and 70o/o of affected patients. Both hands and create a white crumbly appearance to the surface. feet have onychorrhexis (exaggerated The initial lesions may be randomly dispersed over longitudinal ridging) and "angel wing the nail, but with time these will eventually deformity" (the central portion of the nail coalesce to encompass the entire surface of the is raised, and the lateral poftion is nail. mentagrophyes predorninating T. is the depressed). organism. Treatment consists of mechanical 4. Yellow-nail syndrome is a condition that debridement as well as topical anti-fungals. The exists in conjunction with includes leukonychia, which Primary differential diagnosis lymphedema and chronic obstructive whitens the nail plate, but cannot be scraped off. pulmonary disease. It presents with an Proximal Subungual Onychomycosis (PSO) is absence of cuticles, yellow pigmentation, least common type and accounts for less the an excessive curve in the nall, with than 7o/o of onychomycosis. The infection pene- cessation of nail growth.'5 trates the proximal portion of the nail, resulting in hyperkeratosis and onycholysis. This type is usually Mycological testing includes the use of a associated with AIDS and is caused by T. rubrum. Potassium Hydroxide Slide Mount (KOH) as well as A recent study by Elewski et a1.'0 showed that a culture. The KOH technique involves applying 87.7o/o of 52 patients with AIDS had PSO. Non-HIV 150/o to 30% potassium hydroxide, either in water or infected patients typically have DSO. Presentations dimethyl sulfoxide, to the test media and viewing of PSO, especially in all ten fingernails should the results under a microscope. Heat can be increase one's suspicion of AIDS. Treatment with applied during preparation The incorporation of zidor,.r:dine for HIV is not affected during concomi- chlorazol black or Parkers blue/black ink, mixed in tant administration of itraconazole 3 equal volumes with KOH, will highlight nail fungi. Candidal Onychomycosis, primarily caused Phase contrast microscopy or dark field illumina- by Candida albicans, occurs in less than 70/o of tion will also highlight nail fungi.'6 onychomycosis and presents as three recognized Fungal cultures include the use of Sabouraud's forms. The first is a candidal paronychia that results and/or mycosel media. Dermatoph),te test medium in swelling and ery,thema of the proximal and (DTM) includes an antifung al/ antlbiotic cyclohex- lateral nail folds, with secondary involvement of imide that inhibits the growth of bacterial and the nail plate. The second is the typical distal and saprophltic fungi. It contains phenol red as a pH lateral onychomycosis (DSO) occurring when there indicator, and only dermatophl'tes will turn the test is separation of the nail plate from the nail bed medium from yellow to red." False positive and with erosion of the nail plate. The third is chronic negative results are coflunon. mucocutaneous candidiasis (CMC), where the Cultures require an adeqtate specimen. This organism directly invades the nail plate, and the involves clipping the full thickness nail together proximal and laleral nail folds become increasingly with debris from the underside of the na1l, and/or thick, until the nail becomes totally dystrophic. scraping the debris from the nail bed. In the case of SVO, one can scrape the surface of the nail. 192 CHAPTER 31
Some ffaditional antifungal agents used to treat true for itraconazole, with the pulse dosing being dermatophye infections include the following.5 superior over continuous therapy, and four pulses seems to have a slightly better result three. Azoles (ketoconazole, clotrimazoTe, than Doubling dose itraconazole from 100 to miconazole, sulconazole, oxiconazole, the of 200mg/day results in a 1O-fold increase in nail drug econazole),with or without urea. 1eve1s.35 Overall, terbinafine appears \Whitfield's ointment to be the drug dermatophyte Potassium permanganate of choice in the treatment of infections. Terbinafine can immuno- Ciclopirox Olamine be used in compromised patients, Amorolfine including those with AIDS, in the treatment of dermatophyosis. Increasing the Allylamines (naftifine, terbinafine) dose to will bring cure rates up to the Organic acids (saiicylic, undecylenic) 500m9/day Thiocarbamate derivatives (tolnaftate) level of those in otherwise healthy patients.'6 Itraconazole is more effective against Candida Polyenes (nystatin)-not effective against albicans some non-dermatoph),te dermatophyes and molds than terbinafine, and should be used where indicated At the present time there are five oral anti- based on culture resu1ts."''t," Itraconazole should fungal medications which may be used to treat be used for CMC and should be continued until onychomycosis. The ideal drug would diffuse complete recovery.'6 The concentration of through the nail bed and be readily incorporated fluconazole found in nails is much higher than that into the nail matrix, would present with a high found in the case of terbinafine and itraconazole, clinical cure rate as well as a high mycologic cure indicating that fluconazole should be at least as rate, would provide a low incidence of relapse, effective as these drugs in the treatment of would be effective when used for shofi-term onychomycosis.43 Fluconazole is currently used in therapy, would have a 1ow incidence of side effects the treatment of onychomycosis as an off-label and few drug interactions, and would be cost indication, as clinical trials are still needed prior to effective. Table 1 presents details concerning the FDA approval, which is planned for the future. The five available drugs.3,a',13,18'21 Griseofulvin is safe but primary indication for griseofulvin is the treatment not highly effective. Ketoconazoie is also not highly of dermatophl,tosis in children.'6 Ketoconazole, effective, and has a potential for serious liver due to its hepatoxicity, is given for short courses toxicity. Ilraconazole is very effective and very safe, rather than long courses, negating its use in the but does have some seriotrs drug interactions due treatment of onychomycosis. to its affinity for the cytochrome P-450 errzyrne Itraconazole studies indicate that it has fewer system. Terbinafine is very effective and very safe side effects than terbinafine, but caution should be and has limited drug interactions. Fluconazole is exercised when patients are taking a drug which is very effective and very safe, but is also limited due metabolized by the cytochrome P-450 enzyme to its drug interactions due to the cyochrome P-450 system, as drug interactions with itraconazole or enzyme system. It is not currently FDA approved fluconazole are possible. A large post-marketing for the treatment of onychomycosis in the surueillance study of oral terbinafine in the United United States. Kingdom," involving 9879 patients, revealed a A review of various drug studies done in 74.5o/o "medical event" during or after the use of many different countries was performed. The oral terbinafine. Half of these may have been 1, Statistics are recorded in Table 2.1.3.6-1.e.11.1e.25 The related to terbinafine use. Of these patients, 0.7o/o reported data reflect studies done in more recent (74 patients) were classified as "serious," and only years, therefore, there are limited statistics on the five were assessed as possibly or probably related older drugs, griseofulvin and ketoconazole. Most of to terbinafine. Of these patieots, 48.50/o were using the studies target itraconazole and terbinafine. concomitant medications for an affay of medical Fewer studies have been done on fluconazole in problems. the treatment of onychomycosis. Short-term use of the oral anti-fungals has The overall success rate for terbinafine proven to be successful in the treatment of topical appears to be better with continuous use for three Tinea pedis. Ninety-three percent of patients months, rather than pulse dosing. The reverse is treated with one pulse of itraconazole were CHAPTER 31 r93 clinically cured and B4o/o were mycologically was noted may be due to poor penetration of the cured.'6 Another study comparing two-weeks of drug into the nail. Peripheral vascular disease with oral terbinafine (250m9/day) with itraconazole distal occlusion will prevent delivery of the anti- (100mg/day) reported a clinical slrccess rate of 940/o fungal agent to the nail matrix and bed, resulting in and 72o/0, respectively.aa The mycology was failr-rre. Thirdly, the patient, though clinically clear, negative in 86o/o and 550/0, respectively. Possibly may still have latent fungi or be reinfected and the increasing the itraconazole dose to 200m9/day infection will recur.a'z Patients whose nails do not would have produced identical results to grow or grow excessively slowly, do not generally terbinafine. respond well to oral treatment.l6 Some studies sug- A pharmacokinetic evaluation of treatment gest that longer treatment times may eliminate practices in 13 countries,'5'a6 not including the remissions and relapses, bringing the success rate United States, has shown that oral terbinafine is closer to 100%.11 more cost-effective than griseofulvin, ketoconazole, A prospective study involving 50 patients who or itraconazole in the treatment of onychomycosis. completed three months of terbinafine with a Again, sufficient data to evaluate fluconazole was minimum one-year follow-up, as well as 24 not available. The cost of treatment included patients who completed a trial of fluconazole, will the cost of the drug, the medicai management be presented. The results are truly exciting. inch-rding laboratory testing, and the management The newer oral anti-fungal agents, itracona- of adverse drug reaction costs. Terbinafine had the zo1e, terbinafine and fluconazole, appeat to be lowest cost per mycologic cure after one treatment more effective than the older agents, griseofulvin regimen. and ketoconazole. A variety of effective oraT anli- Obviously, the newer drugs have proven to fungal drLrgs are now available for use, and the be effective in the treatment of onychomycosis, but decision to use one drug or another may depend like all medication, success is not 7000/0. Reasons on several factors such as dosage schedule, adverse for treatment failures may inciude the following. In effects profile, sensitivity to drug or organism(s) some patients, only some of the affected nails were isolated, concomitant medical conditions or cleared, or only pafis of a nall were cleared and concurrent drugs, and cost-effectiveness. The new others were not. Fungi may persist along narrow drugs have an increased cure rate, shortened linear streaks that apparently foilow the longitu- period of treatment time, and increased safety. The dinal oriented nail bed epidermal ridges. This newer drugs, although appearing to be more could possibly reflect poor distribution of the drug expensive, may actually decrease costs due to in some areas of the nail that remained infected shorter treatment times, decreased side effects, and during treatment, and become a source of reinfec- increased efficacy. Ve now have a cure for tion a few months after treatment is stopped. onychomycosis. Secondly, cases where no clinical improvement 194 CHAPTER 31
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E o (d (g E o E 5 a -s) -9 _9 o 6 c O a o U) o o o o o o a o o .E .= o a ct) o 6 l (, c0 (n = rn (D f a= o LL I o :) l o D ) C o o o6 .a o o o N :+ @ N @ c! o C @ N o N od o s9 tr cc tr o -,i 6' z @ o z CO r) o o o N E, tr uJ uJ ul (f) F o uJ 6 uJ uJ Y Y I tt z o rI c{ o rq L IU () z6 E ! E o s9 X (, Y o o v uJ N z REFERENCES 28. De Cuyper C: Long-term evaluation of terbinafine 250 and 500 mg daily in a 16-r-eek oral treatment for toenail onychomycosis lletter). Br J Dermatol 735(J):756-157, 1996. Jones HE, Zaias N: Double-blincl, randomized comparison of 29 De Doncker P, DecrolrJ, Pierard GE, Roelant D, 'il/oestenborghs itraconazole capsules and placebo in onychomycosis of toenail. R, Jacqmin P, Odds F, Heremans A, Dockx P, Doseeuw D; Int J Dennatol 35(8)'589-590, 1996. Antifungal pulse therapy for onychomycosis. 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Chiritescu MM, Chiritescu ME, Scher RK: Newer systemic anti- 1996. fungal drugs for the treatment of onychomyc APPENDDG Naftifine: Naftin, Allergan Inc., Irvine CA Terbinafine: Lamisil, Novafiis Pharmaceutical, Cornmon Trade Names of Generic Drugs East Hanover NJ Oral Anti-Fungal Agents Undecylenic acid: Fungoid Tincture, Pedinol, Farmindale NY Gris-peg: Allergan, Inc., Iruine CA Tolnaftate: Tinactin, Schering Corp., Kenilworth NJ Fulvicin: Schering Corporation, Kenilworth NJ Nystatin: Mycostatin, Grisfulvin: Ofiho Pharmaceutical Corporation, Vestwood-Squibb, Buffalo NY Raritan NJ Miscellaneous Oral Agents Grisactin: \7yeth-Ayerst Laboratories, Philadelphia PA rWarfarin: Coumidin, Dupont Phanna, \Tilmington DE Nizoral: Janssen Pharmaceutica Inc., Titusville NJ Cimetidine:Tagamet, Smith Kline Beecham, Sporonox: Janssen Pharmaceutica Inc., Titusville NJ Phildelphia PA Lamisil: Novafiis Pharmaceutical Corp, East Hanover Nf Cyclosporin: Neoral, Sandimmune, Sandoz Diflucan: Pfizer Inc, New York, NY Pharmaceutical, East Hanover NJ Terfenadine: Seldane, Marion Merrell Dow, Kansas TopicaI Anti-Fungal Agents City MO Astemizole: Hismanal, Janssen Pharnaceutical Inc., Ketoconazole: Nizoral, Janssen Pharmaceutical Inc., NJ Titusville NJ Titusville Phenytoin: Dilantin, Parke-Davis, Morris Plains NJ Clotrimazole: Lotrimin, Schering Corp., Kerulworth NJ Miconazole: Micatin, Ortho Dermatological, Digoxin: Lanoxin, Burroughs \7ellcome/Glaxo Vellcome Inc., Research Triangle Park NC Raritan NJ Cisapride: Propulsid, Pharmaceutica Inc., Fungoid tincture and Fungoid Cream, Pedinol, Janssen Farmingdale NY Titusvile Nl Versed, Roche Laboratories, NJ Sulconazoie: Exelderm, \Westwood-Squibb, Midazolam: Nutley Buffalo NY Triazolam: Halcion, The Upjohn Company, Kalamazoo MI Oxconazole: Oxistat, Glaxo Wellcome Inc., Carbamazepine: Tegretol, Ciba Geneva Research Triangle Park NC Pharmaceuticals, Summit NJ Econazole: Spectazole, Ortho Dermatological, Zidovudine: Retrovir, Burroughs Vellcome/Glaxo Raritan NJ Research Triangle Park NC Ciclopiroxolamine: Loprox, Hoechst-Roussel, Vellcome, Inc., Lovastin: Zocot, Merck & Co, West Point PA Somerwille NJ Simvastatin: Mevacor, Merck & Co, 'West Point PA Amorolfine not ayallable or manufactured in the United States