Advertisement

The Safety of Oral Antifungal Treatments for Superficial Dermatophytosis and Onychomycosis: A Meta-analysis

      Abstract

      Purpose

      We estimated the absolute risks of treatment termination and incidence of adverse liver outcomes among all commonly used oral antifungal treatments for superficial dermatophytosis and onychomycosis.

      Methods

      MEDLINE, EMBASE, and Cochrane Library were searched to identify randomized and nonrandomized controlled trials, case series, and cohort studies published before December 31, 2005. Two reviewers independently applied selection criteria, performed quality assessment, and extracted data. Treatment arms with the same regimen in terms of drug, type (continuous or intermittent), and dosage were combined to estimate the risk of an outcome of interest.

      Results

      We identified 122 studies with approximately 20,000 enrolled patients for planned comparison. The pooled risks (95% confidence intervals) of treatment discontinuation resulting from adverse reactions for continuous therapy were 3.44% (95% confidence interval [CI], 2.28%-4.61%) for terbinafine 250 mg/day; 1.96% (95% CI, 0.35%-3.57%) for itraconazole 100 mg/day; 4.21% (95% CI, 2.33%-6.09%) for itraconazole 200 mg/day; and 1.51% (95% CI, 0%-4.01%) for fluconazole 50 mg/day. For intermittent therapy, the pooled risks were as follows: pulse terbinafine: 2.09% (95% CI, 0%-4.42%); pulse itraconazole: 2.58% (95% CI, 1.15%-4.01%); intermittent fluconazole 150 mg/week: 1.98% (95% CI, 0.05%-3.92%); and intermittent fluconazole 300 to 450 mg/week: 5.76% (95% CI, 2.42%-9.10%). The risk of liver injury requiring termination of treatment ranged from 0.11% (continuous itraconazole 100 mg/day) to 1.22% (continuous fluconazole 50 mg/day). The risk of having asymptomatic elevation of serum transaminase but not requiring treatment discontinuation was less than 2.0% for all treatment regimens evaluated.

      Conclusion

      Oral antifungal therapy against superficial dermatophytosis and onychomycosis, including intermittent and continuous terbinafine, itraconazole, and fluconazole, was associated with a low incidence of adverse events in an immunocompetent population.

      Keywords

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to The American Journal of Medicine
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Vander Straten M.R.
        • Hossain M.A.
        • Ghannoum M.A.
        Cutaneous infectious dermatophytosis, onychomycosis, and tinea versicolor.
        Infect Dis Clin N Am. 2001; 17: 87-112
        • Elewsk B.E.
        • Charif M.A.
        Prevalence of onychomycosis in patients attending a dermatology clinic in northeastern Ohio for other conditions.
        Arch Dermatol. 1997; 133: 1172-1173
        • Ghannoum M.A.
        • Hajjeh R.A.
        • Scher R.
        • et al.
        A large-scale North American study of fungal isolates from nails: the frequency of onychomycosis, fungal distribution, and antifungal susceptibility patterns.
        J Am Acad Dermatol. 2000; 43: 641-648
        • Smith E.S.
        • Fleischer A.B.
        • Feldman S.T.
        • Williford P.M.
        Characteristics of office-based physician visits for cutaneous fungal infections: an analysis of 1990 to 1994 National Ambulatory Medical Care Survey Data.
        Cutis. 2002; 69: 191-202
        • Gupta A.K.
        • Ryder J.E.
        The use of oral antifungal agents to treat onychomycosis.
        Dermatol Clin. 2003; 21: 469-479
        • Ajit C.
        • Suvannasankha A.
        • Zaeri N.
        • Munoz S.J.
        Terbinafine-associated hepatotoxicity.
        Am J Med Sci. 2003; 325: 292-295
        • O’Sullivan D.P.
        • Needham C.A.
        • Bangs A.
        • et al.
        Postmarketing surveillance of oral terbinafine in the UK: report of a large cohort study.
        Br J Clin Pharmacol. 1996; 42: 559-565
        • Hall M.
        • Monka C.
        • Krupp P.
        • O’Sullivan D.
        Safety of oral terbinafine: results of a postmarketing surveillance study in 25,884 patients.
        Arch Dermatol. 1997; 133: 1213-1219
        • Gupta A.K.
        • Chwetzoff E.
        • Del Rosso F.
        • Baran R.
        Hepatic safety of itraconazole.
        J Cutan Med Surg. 2002; : 210-213
        • Garcia-Rodriguez L.A.
        • Castellsague A.D.
        • Perez-Gutthann S.
        • Stricker B.H.C.
        A cohort study on the risk of acute liver injury among users of ketoconazole and other antifungal drugs.
        Br J Clin Pharmacol. 1999; 48: 847-852
        • Alpsoy E.
        • Yilmaz E.
        • Basaran E.
        Intermittent therapy with terbinafine for dermatophyte toe-onychomycosis: a new approach.
        J Dermatol. 1996; 23: 259-262
        • Moher D.
        • Cook D.J.
        • Eastwood S.
        • et al.
        Improving the quality of reports of meta-analyses of randomised controlled trials: the QUOROM statement.
        Lancet. 1999; 354: 1896-1900
        • Epstein E.
        How often does oral treatment of toenail onychomycosis produce a disease-free nail?.
        Arch Dermatol. 1998; 134: 1551-1554
        • Bell-Syer S.E.M.
        • Hart R.
        • Crawford F.
        • et al.
        A systematic review of oral treatments for fungal infectious of the skin of the feet.
        J Dermatol Treat. 2001; 12: 69-74
        • Cribier B.J.
        • Paul C.
        Long-term efficacy of antifungals in toenail onychomycosis: a critical review.
        Br J Dermatol. 2001; 145: 446-452
        • Haugh M.
        • Helou S.
        • Boissel J.P.
        • Cribier B.J.
        Terbinafine in fungal infections of the nail: a meta-analysis of randomized clinical trials.
        Br J Dermatol. 2002; 147: 118-121
        • Crawford F.
        • Young P.
        • Godfrey C.
        • et al.
        Oral treatments for toenail onychomycosis.
        Arch Dermatol. 2002; 138: 811-816
        • Bell-Syer S.E.M.
        • Hart R.
        • Crawford F.
        • et al.
        Oral treatments for fungal infections of the skin of the foot.
        Cochrane Database Syst Rev. 2002; (CD003584)
        • Krob H.A.
        • Fleischer A.B.
        • D’Agostino R.
        • Feldman S.R.
        Terbinafine is more effective than itraconazole in treating toenail onychomycosis: results from a meta-analysis of randomized controlled trials.
        J Cutan Med Surg. 2003; : 306-311
        • Gupta A.K.
        • Ryder J.E.
        • Johnson A.M.
        Cumulative meta-analysis of systematic antifungal agents for the treatment of onychomycosis.
        Br J Dermatol. 2004; 150: 537-544
        • Chuang-Stein C.
        An application of the beta-binomial model to combine and monitor medical event rates in clinical trials.
        Drug Inf J. 1993; 27: 515-523
        • Daniel W.
        Probability distribution.
        in: Biostatistics: A Foundation for Analysis in the Health Sciences. 7th ed. Wiley & Sons, New York1999: 97
        • Agresti A.
        • Coull B.
        Approximate is better than ‘exact’ for interval estimation of binomial proportions.
        Am Stat. 1998; 52: 119-126
        • Castellsague J.
        • Garcia-Rodriguez L.A.
        • Duque A.
        • Perez S.
        Risk of serious skin disorders among users of oral antifungals: a population-based study.
        BMC Dermatol. 2002; 2: 14
        • Chitturi S.
        • Farrell G.C.
        Drug-induced liver disease.
        in: Schiff E.R. Sorell M.F. Maddrey W.C. Schiff’s Diseases of the Liver. 9th ed. Lippincott, Williams & Wilkins, Philadelphia2003: 1063
        • Ioannidis J.P.A.
        • Evans S.J.W.
        • Gotzsche P.C.
        • et al.
        Better reporting of harms in randomized trials: an extension of the CONSORT statement.
        Ann Intern Med. 2004; 141: 781-788

      Appendix

      Studies Included in Meta-analysis

        • Albanese G.
        • Di Cintio R.
        • Martini C.
        • Nicoletti A.
        Short therapy for tinea unguium with terbinafine: four different courses of treatment.
        Mycoses. 1995; 38: 211-214
        • Albreski D.A.
        • Gross E.G.
        The safety of itraconazole in the diabetic population.
        J Am Podiatr Med Assoc. 1999; 89: 339-345
        • Alpsoy E.
        • Yilmaz E.
        • Basaran E.
        Intermittent therapy with terbinafine for dermatophyte toe-onychomycosis: a new approach.
        J Dermatol. 1996; 23: 259-262
        • Aman S.
        • Akbar T.M.
        • Hussain I.
        • et al.
        Itraconazole pulse therapy in the treatment of disto-lateral subungual onychomycosis.
        J Coll Physicians Surg Pak. 2003; 13: 618-620
        • Arca E.
        • Tastan H.B.
        • Akar A.
        • et al.
        An open, randomized, comparative study of oral fluconazole, itraconazole and terbinafine therapy in onychomycosis.
        J Dermatolog Treat. 2002; 13: 3-9
        • Arenas R.
        • Dominguez-Cherit J.
        • Fernandez L.M.
        Open randomized comparison of itraconazole versus terbinafine in onychomycosis.
        Int J Dermatol. 1995; 34: 138-143
        • Arenas R.
        • Fernandez G.
        • Dominguez L.
        Onychomycosis treated with itraconazole or griseofulvin alone with and without a topical antimycotic or keratolytic agent.
        Int J Dermatol. 1991; 30: 586-589
        • Assaf R.R.
        • Elewski B.E.
        Intermittent fluconazole dosing in patients with onychomycosis: results of a pilot study.
        J Am Acad Dermatol. 1996; 35: 216-219
        • Avner S.
        • Nir N.
        • Henri T.
        Combination of oral terbinafine and topical ciclopirox compared to oral terbinafine for the treatment of onychomycosis.
        J Dermatolog Treat. 2005; 16: 327-330
        • Bahadir S.
        • Inaloz H.S.
        • Alpay K.
        • et al.
        Continuous terbinafine or pulse itraconazole: a comparative study on onychomycosis.
        J Eur Acad Dermatol Venereol. 2000; 14: 422-423
        • Baldari U.
        • Righini M.G.
        • Raccagni A.A.
        • et al.
        Comparative double blind, double dummy study on the efficacy and safety of fluconazole 100 mg/day versus terbinafine 250 mg/day in the treatment of dermatomycoses.
        G Ital Dermatol Venereol. 2000; 135: 229-235
        • Baran R.
        • Belaich S.
        • Beylot C.
        • et al.
        Comparative multicentre double-blind study of terbinafine (250 mg per day) versus griseofulvin (1 g per day) in the treatment of dermatophyte onychomycosis.
        J Dermatolog Treat. 1997; 8: 93-97
        • Baran R.
        • Feuilhade M.
        • Combernale P.
        • et al.
        A randomized trial of amorolfine 5% solution nail lacquer combined with oral terbinafine compared with terbinafine alone in the treatment of dermatophytic toenail onychomycoses affecting the matrix region.
        Br J Dermatol. 2000; 142: 1177-1183
        • Baudraz-Rosselet F.
        • Rakosi T.
        • Wili P.B.
        • Kenzelmann R.
        Treatment of onychomycosis with terbinafine.
        Br J Dermatol. 1992; 126: 40-46
        • Bonifaz A.
        • Carrasco-Gerard E.
        • Saul A.
        Itraconazole in onychomycosis: intermittent dose schedule.
        Int J Dermatol. 1997; 36: 70-72
        • Boonk W.
        • de Geer D.
        • de Kreek E.
        • et al.
        Itraconazole in the treatment of tinea corporis and tinea cruris: comparison of two treatment schedules.
        Mycoses. 1998; 41: 509-514
        • Bourlond A.
        • Lachapelle J.M.
        • Aussems J.
        • et al.
        Double-blind comparison of itraconazole with griseofulvin in the treatment of tinea corporis and tinea cruris.
        Int J Dermatol. 1989; 28: 410-412
        • Brautigam M.
        • Nolting S.
        • Schopf R.E.
        • Weidinger G.
        Randomised double blind comparison of terbinafine and itraconazole for treatment of toenail tinea infection.
        BMJ. 1995; 311: 919-922
        • Chen J.
        • Liao W.
        • Wen H.
        • et al.
        A comparison among four regimens of itraconazole treatment in onychomycosis.
        Mycoses. 1999; 42: 93-96
        • Chen X.
        • Hiruma M.
        • Shiraki Y.
        • Ogawa H.
        Combination therapy of once-weekly fluconazole (100, 150, or 300 mg) with topical application of ketoconazole cream in the treatment of onychomycosis.
        Jpn J Infect Dis. 2004; 57: 260-263
        • Cole G.W.
        • Stricklin G.
        A comparison of a new oral antifungal, terbinafine, with griseofulvin as therapy for tinea corporis.
        Arch Dermatol. 1989; 125: 1537-1539
        • De Backer M.
        • De Vroey C.
        • Lesaffre E.
        • et al.
        Twelve weeks of continuous oral therapy for toenail onychomycosis caused by dermatophytes: a double-blind comparative trial of terbinafine 250 mg/day versus itraconazole 200 mg/day.
        J Am Acad Dermatol. 1998; 38: S57-S63
        • De Bersaques J.
        • Bjerke J.R.
        • Borelli S.
        • et al.
        Comparison of oral fluconazole and topical clotrimazole in the treatment of fungal infections of the skin: European and American experience.
        Int J Dermatol. 1992; 31: 21-26
        • De Cuyper C.
        • Amblard P.
        • Austad J.
        • et al.
        Noncomparative study of fluconazole in the treatment of patients with common fungal infections of the skin.
        Int J Dermatol. 1992; 31: 17-20
        • De Doncker P.
        • Van Lint J.
        • Dockx P.
        • Roseeuw D.
        Pulse therapy with one-week itraconazole monthly for three or four months in the treatment of onychomycosis.
        Cutis. 1995; 56: 180-183
        • De Doncker P.R.
        • Scher R.K.
        • Baran R.L.
        • et al.
        Itraconazole therapy is effective for pedal onychomycosis caused by some nondermatophyte molds and in mixed infection with dermatophytes and molds: a multicenter study with 36 patients.
        J Am Acad Dermatol. 1997; 36: 173-177
        • De Keyser P.
        • De Backer M.
        • Massart D.L.
        • Westelinck K.J.
        Two-week oral treatment of tinea pedis, comparing terbinafine (250 mg/day) with itraconazole (100 mg/day): a double-blind, multicentre study.
        Br J Dermatol. 1994; 130: 22-25
        • Degreef H.
        • del Palacio A.
        • Mygind S.
        • et al.
        Randomized double-blind comparison of short-term itraconazole and terbinafine therapy for toenail onychomycosis.
        Acta Derm Venereol. 1999; 79: 221-223
        • Degreef H.
        • Marien K.
        • De Veylder H.
        • et al.
        Itraconazole in the treatment of dermatophytoses: a comparison of two daily dosages.
        Rev Infect Dis. 1987; 9: S104-S108
        • del Palacio Hernandez A.
        • Lopez Gomez S.
        • Gonzalez Lastra F.
        • et al.
        A comparative double-blind study of terbinafine (Lamisil) and griseofulvin in tinea corporis and tinea cruris.
        Clin Exp Dermatol. 1990; 15: 210-216
        • del Palacio A.
        • Van Cutsem J.
        • Lopez S.
        • et al.
        Double-blind randomized comparative study on Tinea manuum and Tinea pedis treated with itraconazole and griseofulvin.
        Actas Dermo-Sifiliogr. 1993; 84 (45-53): 1-2
        • Difonzo E.M.
        • Papini M.
        • Cilli P.
        • et al.
        A double-blind comparison of itraconazole and fluconazole in tinea pedis and tinea manuum.
        J Eur Acad Dermatol Venereol. 1995; 4: 148-152
        • Dobric I.
        • Pasic A.
        • Basta-Juzbasic A.
        Treatment of onychomycosis with oral terbinafine: an open clinical trial.
        Acta Dermatovenerol Croat. 1994; 2: 73-76
        • Drake L.
        • Babel D.
        • Stewart D.M.
        • et al.
        Once-weekly fluconazole (150, 300, or 450 mg) in the treatment of distal subungual onychomycosis of the fingernail.
        J Am Acad Dermatol. 1998; 38: S87-S94
        • Drake L.A.
        • Shear N.H.
        • Arlette J.P.
        • et al.
        Oral terbinafine in the treatment of toenail onychomycosis: North American multicenter trial.
        J Am Acad Dermatol. 1997; 37: 740-745
        • Elewski B.E.
        • Scher R.K.
        • Aly R.
        • et al.
        Double-blind, randomized comparison of itraconazole capsules vs. placebo in the treatment of toenail onychomycosis.
        Cutis. 1997; 59: 217-220
        • Evans E.G.
        • Sigurgeirsson B.
        Double blind, randomised study of continuous terbinafine compared with intermittent itraconazole in treatment of toenail onychomycosis.
        BMJ. 1999; 318: 1031-1035
        • Faergemann J.
        • Anderson C.
        • Hersle K.
        • et al.
        Double-blind, parallel-group comparison of terbinafine and griseofulvin in the treatment of toenail onychomycosis.
        J Am Acad Dermatol. 1995; 32: 750-753
        • Faergemann J.
        • Mork N.J.
        • Haglund A.
        • Odegard T.
        A multicentre (double-blind) comparative study to assess the safety and efficacy of fluconazole and griseofulvin in the treatment of tinea corporis and tinea cruris.
        Br J Dermatol. 1997; 136: 575-577
        • Farkas B.
        • Paul C.
        • Dobozy A.
        • et al.
        Terbinafine (Lamisil) treatment of toenail onychomycosis in patients with insulin-dependent and non-insulin-dependent diabetes mellitus: a multicentre trial.
        Br J Dermatol. 2002; 146: 254-260
        • Finzi A.
        • Cilli P.
        Italian multicentre trial comparing itraconazole with griseofulvin in the treatment of dermatomycoses.
        J Eur Acad Dermatol Venereol. 1992; 1: S15-S18
        • Fischbein A.
        • Haneke E.
        • Lacner K.
        • et al.
        Comparative evaluation of oral fluconazole and oral ketoconazole in the treatment of fungal infections of the skin.
        Int J Dermatol. 1992; 31: 12-16
        • Fraki J.
        • Heikkila H.T.
        • Kero M.O.
        • et al.
        An open-label, noncomparative, multicenter evaluation of fluconazole with or without urea nail pedicure for treatment of onychomycosis.
        Curr Ther Res Clin Exp. 1997; 58: 481-491
        • Galimberti R.
        • Kowalczuk A.
        • Flores V.
        • Squiquera L.
        Onychomycosis treated with a short course of oral terbinafine.
        Int J Dermatol. 1996; 35: 374-375
        • Ginter G.
        • De Doncker P.
        An intermittent itraconazole 1-week dosing regimen for the treatment of toenail onychomycosis in dermatological practice.
        Mycoses. 1998; 41: 235-238
        • Goodfield M.J.
        • Andrew L.
        • Evans E.G.
        Short term treatment of dermatophyte onychomycosis with terbinafine.
        BMJ. 1992; 304: 1151-1154
        • Goodfield M.J.
        • Rowell N.R.
        • Forster R.A.
        • et al.
        Treatment of dermatophyte infection of the finger- and toe-nails with terbinafine (SF 86-327, Lamisil), an orally active fungicidal agent.
        Br J Dermatol. 1989; 121: 753-757
        • Goodfield M.J.
        Clinical results with terbinafine in onychomycosis.
        J Dermatolog Treat. 1990; 1: 55-57
        • Goodfield M.J.D.
        • Evans E.G.V.
        Combined treatment with surgery and short duration oral antifungal therapy in patients with limited dermatophyte toenail infection.
        J Dermatolog Treat. 2000; 11: 259-262
        • Gupta A.K.
        • Gregurek-Novak T.
        Efficacy of itraconazole, terbinafine, fluconazole, griseofulvin and ketoconazole in the treatment of Scopulariopsis brevicaulis causing onychomycosis of the toes.
        Dermatology. 2001; 202: 235-238
        • Gupta A.K.
        • Konnikov N.
        • Lynde C.W.
        Single-blind, randomized, prospective study on terbinafine and itraconazole for treatment of dermatophyte toenail onychomycosis in the elderly.
        J Am Acad Dermatol. 2001; 44: 479-484
        • Gupta A.K.
        • Lynde C.W.
        • Konnikov N.
        Single-blind, randomized, prospective study of sequential itraconazole and terbinafine pulse compared with terbinafine pulse for the treatment of toenail onychomycosis.
        J Am Acad Dermatol. 2001; 44: 485-491
        • Gupta A.K.
        • Maddin S.
        • Arlette J.
        • et al.
        Itraconazole pulse therapy is effective in dermatophyte onychomycosis of the toenail: a double-blind placebo-controlled study.
        J Dermatolog Treat. 2000; 11: 33-37
        • Haneke E.
        • Abeck D.
        • Ring R.
        Safety and efficacy of intermittent therapy with itraconazole in finger- and toenail onychomycosis: a multicentre trial.
        Mycoses. 1998; 41: 521-527
        • Haneke E.
        • Tajerbashi M.
        • De Doncker P.
        • et al.
        Itraconazole in the treatment of onychomycosis: a double-blind comparison with miconazole.
        Dermatology. 1998; 196: 323-329
        • Haneke E.
        • Tausch I.
        • Brautigam M.
        • et al.
        Short-duration treatment of fingernail dermatophytosis: a randomized, double-blind study with terbinafine and griseofulvin.
        J Am Acad Dermatol. 1995; 32: 72-77
        • Hanifin J.M.
        • Tofte S.J.
        Itraconazole therapy for recalcitrant dermatophyte infections.
        J Am Acad Dermatol. 1988; 18: 1077-1080
        • Havu V.
        • Brandt H.
        • Heikkila H.
        • et al.
        A double-blind, randomized study comparing itraconazole pulse therapy with continuous dosing for the treatment of toe-nail onychomycosis.
        Br J Dermatol. 1997; 136: 230-234
        • Havu V.
        • Heikkila H.
        • Kuokkanen K.
        • et al.
        A double-blind, randomized study to compare the efficacy and safety of terbinafine (Lamisil) with fluconazole (Diflucan) in the treatment of onychomycosis.
        Br J Dermatol. 2000; 142: 97-102
        • Hay R.J.
        • Clayton Y.M.
        • Moore M.K.
        • Midgely G.
        An evaluation of itraconazole in the management of onychomycosis.
        Br J Dermatol. 1988; 119: 359-366
        • Hay R.J.
        • Clayton Y.M.
        • Moore M.K.
        • Midgely G.
        Itraconazole in the management of chronic dermatophytosis.
        J Am Acad Dermatol. 1990; 23: 561-564
        • Hay R.J.
        • Logan R.A.
        • Moore M.K.
        • et al.
        A comparative study of terbinafine versus griseofulvin in ‘dry-type’ dermatophyte infections.
        J Am Acad Dermatol. 1991; 24: 243-246
        • Hay R.J.
        • McGregor J.M.
        • Wuite J.
        • et al.
        A comparison of 2 weeks of terbinafine 250 mg/day with 4 weeks of itraconazole 100 mg/day in plantar-type tinea pedis.
        Br J Dermatol. 1995; 132: 604-608
        • Hofmann H.
        • Brautigam M.
        • Weidinger G.
        • Zaun H.
        Treatment of toenail onychomycosis.
        Arch Dermatol. 1995; 131: 919-922
        • Honeyman J.F.
        • Talarico F.S.
        • Arruda L.H.F.
        • et al.
        Itraconazole versus terbinafine (LAMISIL(registered trademark)): which is better for the treatment of onychomycosis?.
        J Eur Acad Dermatol Venereol. 1997; 9: 215-221
        • Iozumi K.
        • Hattori N.
        • Adachi M.
        • et al.
        Long-term follow-up study of onychomycosis: cure rate and dropout rate with oral antifungal treatments.
        J Dermatol. 2001; 28: 128-136
        • Jones H.E.
        • Zaias N.
        Double-blind, randomized comparison of itraconazole capsules and placebo in onychomycosis of toenail.
        Int J Dermatol. 1996; 35: 589-590
        • Khosravi A.R.
        • Mansouri P.
        Onychomycosis in Tehran, Iran: prevailing fungi and treatment with itraconazole.
        Mycopathologia. 2001; 150: 9-13
        • Kim J.A.
        • Ahn K.J.
        • Kim J.M.
        • Youn J.I.
        Efficacy and tolerability of itraconazole in patients with fingernail onychomycosis: a 6-week pilot study.
        Curr Ther Res Clin Exp. 1995; 56: 1066-1075
        • Korting H.C.
        • Schafer-Korting M.
        • Zienicke H.
        • et al.
        Treatment of tinea unguium with medium and high doses of ultramicrosize griseofulvin compared with that with itraconazole.
        Antimicrob Agents Chemother. 1993; 37: 2064-2068
        • Kuokkanen K.
        • Alava S.
        Fluconazole in the treatment of onychomycosis caused by dermatophytes.
        J Dermatolog Treat. 1992; 3: 115-117
        • Lecha M.
        • Alsina M.
        • Torres Rodriguez J.M.
        • et al.
        An open-label, multicenter study of the combination of amorolfine nail lacquer and oral itraconazole compared with oral itraconazole alone in the treatment of severe toenail onychomycosis.
        Curr Ther Res Clin Exp. 2002; 63: 366-379
        • Ling M.R.
        • Swinyer L.J.
        • Jarratt M.T.
        • et al.
        Once-weekly fluconazole (450 mg) for 4, 6, or 9 months of treatment for distal subungual onychomycosis of the toenail.
        J Am Acad Dermatol. 1998; 38: S95-S102
        • Mishra M.
        • Panda P.
        • Tripathy S.
        • et al.
        An open randomized comparative study of oral itraconazole pulse and terbinafine pulse in the treatment of onychomycosis.
        Indian J Dermatol Venereol Leprol. 2005; 71: 262-266
        • Montero-Gei F.
        • Perera A.
        Therapy with fluconazole for tinea corporis, tinea cruris, tinea pedis.
        Clin Infect Dis. 1992; : S77-S81
        • Montero-Gei F.
        • Robles-Soto M.E.
        • Schlager H.
        Fluconazole in the treatment of severe onychomycosis.
        Int J Dermatol. 1996; 35: 587-588
        • Nolting S.
        • Brautigam M.
        • Weidinger G.
        Terbinafine in onychomycosis with involvement by non-dermatophytic fungi.
        Br J Dermatol Suppl. 1994; 130: 16-21
        • Noppakun N.
        • Phuphaibool K.
        Treatment of dermatophytosis with new systemic antifungal agent, itraconazole.
        J Med Assoc Thai. 1992; 75: 99-103
        • Nozickova M.
        • Koudelkova V.
        • Kulikova Z.
        • et al.
        A comparison of the efficacy of oral fluconazole, 150 mg/week versus 50 mg/day, in the treatment of tinea corporis, tinea cruris, tinea pedis, cutaneous candidosis.
        Int J Dermatol. 1998; 37: 703-705
        • Nuijten S.T.
        • Schuller J.L.
        Itraconazole in the treatment of tinea corporis: a pilot study.
        Rev Infect Dis. 1987; 9: S119-S120
        • Odom R.
        • Daniel C.R.
        • Aly A.
        A double-blind, randomized comparison of itraconazole capsules and placebo in the treatment of onychomycosis of the toenail.
        J Am Acad Dermatol. 1996; 35: 110-111
        • Odom R.B.
        • Aly R.
        • Scher R.K.
        • et al.
        A multicenter, placebo-controlled, double-blind study of intermittent therapy with itraconazole for the treatment of onychomycosis of the fingernail.
        J Am Acad Dermatol. 1997; 36: 231-235
        • Panagiotidou D.
        • Kousidou T.
        • Chaidemenos G.
        • et al.
        A comparison of itraconazole and griseofulvin in the treatment of tinea corporis and tinea cruris: a double-blind study.
        J Int Med Res. 1992; 20: 392-400
        • Panconesi E.
        • Difonzo E.
        Treatment of dermatophytoses and pityriasis versicolor with itraconazole.
        Rev Infect Dis. 1987; 9: S109-S113
        • Parent D.
        • Decroix J.
        • Heenen M.
        Clinical experience with short schedules of itraconazole in the treatment of tinea corporis and/or tinea cruris.
        Dermatology. 1994; 189: 378-381
        • Pariser D.M.
        • Pariser R.J.
        • Ruoff G.
        • Ray T.L.
        Double-blind comparison of itraconazole and placebo in the treatment of tinea corporis and tinea cruris.
        J Am Acad Dermatol. 1994; 31: 232-234
        • Pavlotsky F.
        • Armoni G.
        • Shemer A.
        • Trau H.
        Pulsed versus continuous terbinafine dosing in the treatment of dermatophyte onychomycosis.
        J Dermatolog Treat. 2004; 15: 315-320
        • Piepponen T.
        • Blomqvist K.
        • Brandt H.
        • et al.
        Efficacy and safety of itraconazole in the long-term treatment of onychomycosis.
        J Antimicrob Chemother. 1992; 29: 195-205
        • Rakosi T.
        • Gerber M.
        Treatment of tinea with itraconazole: an open multicentre study.
        J Dermatolog Treat. 1995; 6: 35-38
        • Ramos-e-Silva M.
        • Marques S.A.
        • Gontijo B.
        • et al.
        Efficacy and safety of itraconazole pulse therapy: Brazilian multicentric study on toenail onychomycosis caused by dermatophytes.
        J Eur Acad Dermatol Venereol. 1998; 11: 109-116
        • Rigopoulos D.
        • Katoulis A.C.
        • Ioannides D.
        • et al.
        A randomized trial of amorolfine 5% solution nail lacquer in association with itraconazole pulse therapy compared with itraconazole alone in the treatment of Candida fingernail onychomycosis.
        Br J Dermatol. 2003; 149: 151-156
        • Rongioletti F.
        • Robert E.
        • Tripodi S.
        • Persi A.
        Treatment of onychomycosis with itraconazole.
        J Dermatolog Treat. 1992; 2: 145-146
        • Roseeuw D.
        • Willemsen M.
        • Kint R.T.
        • et al.
        Itraconazole in the treatment of superficial mycoses—a double-blind study vs. placebo.
        Clin Exp Dermatol. 1990; 15: 101-104
        • Sanmano B.
        • Hiruma M.
        • Mizoguchi M.
        • Ogawa H.
        Combination therapy consisting of week pulses of oral terbinafine plus topical application of terbinafine cream in the treatment of onychomycosis.
        J Dermatolog Treat. 2004; 15: 245-251
        • Saul A.
        • Bonifaz A.
        • Arias I.
        Itraconazole in the treatment of superficial mycoses: an open trial of 40 cases.
        Rev Infect Dis. 1987; 9: S100-S103
        • Savin R.
        Successful treatment of chronic tinea pedis (moccasin type) with terbinafine (Lamisil).
        Clin Exp Dermatol. 1989; 14: 116-119
        • Savin R.C.
        • Zaias N.
        Treatment of chronic moccasin-type tinea pedis with terbinafine: a double-blind, placebo-controlled trial.
        J Am Acad Dermatol. 1990; 23: 804-807
        • Scher R.K.
        • Breneman D.
        • Rich P.
        • et al.
        Once-weekly fluconazole (150, 300, or 450 mg) in the treatment of distal subungual onychomycosis of the toenail.
        J Am Acad Dermatol. 1998; 38: S77-S86
        • Schuller J.
        • Remme J.J.
        • Rampen F.H.
        • Van Neer F.C.
        Itraconazole in the treatment of tinea pedis and tinea manuum: comparison of two treatment schedules.
        Mycoses. 1998; 41: 515-520
        • Segal R.
        • Kritzman A.
        • Cividalli L.
        • et al.
        Treatment of Candida nail infection with terbinafine.
        J Am Acad Dermatol. 1996; 35: 958-961
        • Smith E.B.
        • Stein L.F.
        • Fivenson D.P.
        • Atillasoy E.S.
        The safety of terbinafine in patients over the age of 60 years: a multicenter trial in onychomycosis of the feet.
        Int J Dermatol. 2000; 39: 861-864
        • Smith S.W.
        • Sealy D.P.
        • Schneider E.
        • Lackland D.
        An evaluation of the safety and efficacy of fluconazole in the treatment of onychomycosis.
        South Med J. 1995; 88: 1217-1220
        • Stary A.
        • Sarnow E.
        Fluconazole in the treatment of tinea corporis and tinea cruris.
        Dermatology. 1998; 196: 237-241
        • Stengel F.
        • Robles-Soto M.
        • Galimberti R.
        • Suchil P.
        Fluconazole versus ketoconazole in the treatment of dermatophytoses and cutaneous candidiasis.
        Int J Dermatol. 1994; 33: 726-729
        • Svejgaard E.L.
        • Brandrup F.
        • Kragballe K.
        • et al.
        Oral terbinafine in toenail dermatophytosis.
        Acta Derm Venereol. 1997; 77: 66-69
        • Tang W.Y.M.
        • Chong L.Y.
        • Leung C.Y.
        • et al.
        Intermittent pulse therapy with itraconazole for onychomycosis.
        Mycoses. 2000; 43: 35-39
        • Tausch I.
        • Brautigam M.
        • Weidinger G.
        • Jones T.C.
        Evaluation of 6 weeks treatment of terbinafine in tinea unguium in a double-blind trial comparing 6 and 12 weeks therapy.
        Br J Dermatol. 1997; 136: 737-742
        • Tausch I.
        • Decroix J.
        • Gwiezdzinski Z.
        • et al.
        Short-term itraconazole versus terbinafine in the treatment of tinea pedis or manus.
        Int J Dermatol. 1998; 37: 140-142
        • Tosti A.
        • Piraccini B.M.
        • Stinchi C.
        • et al.
        Treatment of dermatophyte nail infections: an open randomized study comparing intermittent terbinafine therapy with continuous terbinafine treatment and intermittent itraconazole therapy.
        J Am Acad Dermatol. 1996; 34: 595-600
        • Tuzun Y.
        • Kotogyan A.
        • Oguz O.
        Terbinafine: efficacy and safety in the treatment of dermatophytosis.
        Int J Dermatol. 1992; 31: 720-721
        • van der Schroeff J.G.
        • Cirkel P.K.
        • Crijns M.B.
        • et al.
        A randomized treatment duration-finding study of terbinafine in onychomycosis.
        Br J Dermatol. 1992; 126: 36-39
        • van Hecke E.
        • Van Cutsem J.
        Double-blind comparison of itraconazole with griseofulvin in the treatment of tinea pedis and tinea manuum.
        Mycoses. 1988; 31: 641-649
        • Voravutinon V.
        Oral treatment of tinea corporis and tinea cruris with terbinafine and griseofulvin: a randomized double blind comparative study.
        J Med Assoc Thai. 1993; 76: 388-393
        • Walsoe I.
        • Stangerup M.
        • Svejgaard E.
        Itraconazole in onychomycosis.
        Acta Derm Venereol. 1990; 70: 137-140
        • Wang D.L.
        • Wang A.P.
        • Li R.Y.
        • Wang R.
        Therapeutic efficacy and safety of one-week intermittent therapy with itraconazole for onychomycosis in a Chinese patient population.
        Dermatology. 1999; 199: 47-49
        • Warshaw E.M.
        • Fett D.D.
        • Bloomfield H.E.
        • et al.
        Pulse versus continuous terbinafine for onychomycosis: a randomized, double-blind, controlled trial.
        J Am Acad Dermatol. 2005; 53: 578-584
        • Watson A.
        • Marley J.
        • Ellis D.
        • Williams T.
        Terbinafine in onychomycosis of the toenail: a novel treatment protocol.
        J Am Acad Dermatol. 1995; 33: 775-779
        • White J.E.
        • Perkins P.J.
        • Evans E.G.
        Successful 2-week treatment with terbinafine (Lamisil) for moccasin tinea pedis and tinea manuum.
        Br J Dermatol. 1991; 125: 260-262
        • Wishart J.M.
        A double blind study of itraconazole vs griseofulvin in patients with tinea pedis and tinea manus.
        N Z Med J. 1994; 107: 126-128
        • Wong C.K.
        • Cho Y.L.
        Very short duration therapy with oral terbinafine for fingernail onychomycosis.
        Br J Dermatol. 1995; 133: 329-331
        • Wu J.
        • Wen H.
        • Liao W.
        Small-dose itraconazole pulse therapy in the treatment of onychomycosis.
        Mycoses. 1997; 40: 397-400
        • Zaias N.
        • Serrano L.
        The successful treatment of finger Trichophyton rubrum onychomycosis with oral terbinafine.
        Clin Exp Dermatol. 1989; 14: 120-123