Review DOI: 10.6003/jtad.1482r1 Treating Onychomycosis Sevim Harman Baysak,1 MD, Uğur Çelik,2*MD, Burhan Engin,2 MD, Yalçın Tüzün,2 MD Address: 1Dışkapı Resarch and Training Hospital, Department of Dermatology, Ankara, 2İstanbul University, Cerrahpaşa Medical Faculty, Department of Dermatology, İstanbul, Turkey E-mail: [email protected] * Corresponding Author: Dr Uğur Çelik, İstanbul University, Cerrahpaşa Medical Faculty, Department of Dermatology, İstanbul, Turkey. Published: J Turk Acad Dermatol 2014; 8 (2): 1482r1. This article is available from: http://www.jtad.org/2014/2/jtad1482r1.pdf Key Words: Onychomycosis, tinea unguium, treatment. Abstract Background: Onychomycosis means fungal infection of nails. Causative agents are yeasts and dermatophyte or nondermatophyte molds. Toenail onychomycosis mainly caused by dermatophytes while yeasts come into prominence for fingernails. Risk factors are genetic predisposition, age, swimming, tinea pedis, psoriasis, diabetes and immunodeficiency. It is important to consider differential diagnosis including trauma, eczema, psoriasis, lichen planus, onychogryphosis before starting antimycotic treatment. Although there are different clinical forms such as distal subungual, proximal subungual, white superficial, nondermatophytic and yeast onychomycosis, treatment options are similar. Topical therapies for onychomycosis are generally not effective so systemic antifungals are required. Introduction rubrum. In white superficial form, T. menta- grophytes takes over. Candida albicans is Onychomycosis is fungal infection of nails major yeast causing onychomycosis [1, 2, 3]. caused by yeasts, dermatophyte and nonder- matophyte molds. This term expresses infec- tion of nails with any fungal agent differently Diagnosis from the term tinea unguium that means only dermatophytic infection of nails. Onychomy- Nail dystrophies are caused not only by fun- cosis of toenails mainly caused by dermato- gal infections but also trauma, eczema, pso- phytes (so called tinea unguium) while yeasts riasis, lichen planus and onychogryphosis. It are main pathogens for fingernails [1, 2]. is important to mind differantial diagnoses Patients usually have concomitant tinea before starting antimycotic treatment. KOH pedis. Genetic predisposition, age, swimming, examination of scrapings is useful to observe psoriasis, diabetes and immunodeficiency are dermatophytic hyphae and spores. Nail cul- other risk factors for onychomycosis. The pre- ture on Sabouraud’s medium is helpful to de- velance is 4 to 18 percent and most of them termine causative agent but it takes four are toenail involvement. Tinea unguium has weeks and has one third false negative ratio. three clinical forms consisting of distal sub- The dermatophyte test medium (DTM) is an ungual, proximal subungual and white su- alternative culture and results are available perficial with the former is most frequent. The in seven days. Histopathological examination causative agent is mainly Trichophyton of the nail plate with PAS staining is more Page 1 of 6 (page number not for citation purposes) J Turk Acad Dermatol 2014; 8 (2): 1482r1. http://www.jtad.org/2014/2/jtad1482r1.pdf sensitive method for diagnosis but also more oral itraconazole for nondermatophyte ony- expensive one. Polymerase chain reaction test chomycosis and yeast onychomycosis. is also sensitive but not widely used [1, 4]. Griseofulvin Treatment Griseofulvin is the first approved antimycotic Onychomycosis may cause physical discomfort drug for onychomycosis treatment and is beside generating cosmetic worry. It may also effective only against dermatophytes [6, 7]. The increase the risk of bacterial infections. Treat- mechanism of action is arresting fungal cell ment is indicated for patients having history of mitosis by blocking the formation of mitotic cellulitis or predisposition such as venous in- spindle [5, 6]. It is ineffective against yeasts sufficiency, and also for patients having cos- and nondermatophyte molds [7]. Prolonged metic worry. There are different clinical forms administration, up to 18 months, is required such as distal subungual, proximal subun- because it takes a long time to reach gual, white superficial, nondermatophytic and therapeutic concentrations in nail plate [6, 8]. yeast onychomycosis, but treatment options Griseofulvin has lower clinical cure rates and are similar. Topical therapies for onychomyco- higher recurrence rates than terbinafin and sis are generally not effective so systemic anti- itraconazole [1, 7]. The daily dosage for adults fungals are required [1]. is 500-1000 mg [9]. In children, griseofulvin is the only licensed antimycotic drug and dosage Antifungal therapy aims mycological clearence is 10 mg/kg daily [6]. Gastrointestinal and clinical cure. Clinical improvement may complaints and headache are the most take several months particularly in toenails so common side effects. Hypersensitivity follow up period must be at least six months reactions and serious side effects such as after therapy. In patients with white superficial cytopenias and hepatotoxicity are rare. form, distal subungual form affecting < 50 % Hemogram and liver function tests must be of nail plate without matrix involvement and controlled during treatment. It may cause drug patients with intolerance to systemic therapy, interactions by it’s effects on cyp-450 enzyme topical therapy may be used. Systemic therapy [5, 7]. is indicated in proximal subungual form, distal subungual form affecting > 50 % of the nail Terbinafine with matrix involvement or affecting more than Terbinafine is the most effective oral two nails. Also we can switch to systemic ther- treatment for toenail onycomycosis [10]. It apy for the patients not responding to topical has fungicidal activity against dermatophytes therapy for six months [5, 6]. Criteria for treat- by inhibiting the enzyme squalen epoxidase ment success or failure are summarized in leading to accumulation of squalene in the table modified from study of Scher RK et al cytoplasm and lysis of the cell. It has also [Table 1] [4]. fungostatic activity against C. Albicans via Oral Therapy inhibition of ergosterol synthesis [6, 7]. Most frequently used drugs are oral terbi- Bioavailability is high as 70 % after oral nafine for dermatophyte onychomycosis and intake and it’s detectable in nail from 7 days Table 1. Criteria for Treatment Success and Failure Cure Noncure Clinically normal nails Positive mycology Remaining onycholysis or subungual Residual changes compatible with fungal in- hyperkeratosis < 10 % of nail plate, myco- fection affecting more than 10 % of nail plate logy negative Lateral hyperkeratosis or onycholysis Remaining nail thickening caused by other conditions, mycology negative Page 2 of 6 (page number not for citation purposes) J Turk Acad Dermatol 2014; 8 (2): 1482r1. http://www.jtad.org/2014/2/jtad1482r1.pdf of therapy up to 90 days after treatment. but hepatic function tests must be monitored Daily dosage is 250 mg during 6 weeks for during treatment. It is contraindicated in fingernails and 12 weeks for toenails [6]. patients with congestive cardiac failure and Terbinafine was compared with other one must pay attention when using antifungal agents in a meta analysis of 36 itraconazole in patients with arrhythmia [15, studies by Gupta et al. Terbinafine is found 16]. more effective than others for treatment of dermatophyte onychomycosis [11]. In L.I.ON. Fluconazole study with 496 patients, continuous Fluconazole is a hydrophilic antifungal drug terbinafine was significantly more effective that interferes with the synthesis of ergos- than intermittent itraconazole in the terol, like itraconazole does. It is effective treatment of toenail dermatophyte onycho- against dermatophytes and Candida spp. but mycosis [12]. Gupta et al and Sikder et al not approved for onychomycosis treatment in found intermittent terbinafine treatment as USA. Placebo controlled studies with flucona- effective as continuous terbinafine and more zole revealed cure rates of 36 to 100 %. It is efficacious than pulse itraconazole [13, 14]. Side effects are nausea, diarrhea, abdominal administered at the dose of 150 mg daily or pain, pruritus, skin rash and taste 300 mg weekly for up to 6 months [6, 7]. alterations. Serious side effects are rare and Scher et al reported that there was no signif- include hepatitis, agranulocytosis, acute icant difference in the efficacy of doses 150, generalized exanthematous pustulosis and 300 and 450 mg weekly for toenail onycomy- lupus erythematosus. Terbinafine is cosis [18]. Side effects are headache, nausea, metabolized by cytochrome P 450 enzymes so skin rashes, insomnia and palpitations. Drug interacted with rifampicin, cimetidine, interactions with oral hypoglicemic agents, cyclosporin, TCA antidepressants and beta cyclosporine and phenytoin are important is- blockers [5, 6, 7]. sues. Itraconazole Other Azoles Itraconazole is a triazole antifungal which has Other azoles including voriconazole, a broad spectrum of activity against posaconazole and ravuconazole also inhibit dermatopyhtes, nondermatophytes and 14-alfa demethylase enzyme and interfere yeasts. The mechanism of action is interfering with the ergosterol synthesis. Voriconazole is with the cell wall synthesis via inhibiting the effective against Scopulariopis brevicaulis, enzyme called 14-alpha demethylase which Fusarium spp and Scytalidium dimidiatum. transforms lanosterol to ergosterol. It is It may be the drug of choice for resistant rapidly absorbed