Oral antifungal agents for onychomycosis (1998)

Onychomycosis affects about 7–8% of the North American population.1Gupta AK Jain HC Lynde CW Watteel GN Summerbell RC Prevalence and epidemiology of unsuspected onychomycosis in patients visiting dermatologists' offices in Ontario, Canada—a multicenter survey of 2001 patients.Int J Dermatol. 1997; 36: 783-787Crossref PubMed Scopus (190) Google Scholar It is commonly more than a cosmetic issue since it can cause pain or discomfort and affect mobility as well as other activities of daily living.2Scher RK Onychomycosis is more than a cosmetic problem.Br J Dermatol. 1994; 130: 15Crossref PubMed Scopus (136) Google Scholar An important advance in its management is the development of oral antifungal agents and methods of their administration.Griseofulvin, the first promising oral antifungal agent for the treatment of onychomycosis and other dermatomycoses,3Gupta AK Sauder DN Shear NH Antifungal agents: an overview. Part I.J Am Acad Dermatol. 1994; 30: 677-698Summary Full Text PDF PubMed Scopus (178) Google Scholar was introduced 40 years ago. Surprisingly, the pharmacokinetics of griseofulvin in the nail have not been studied in detail. Griseofulvin has a low affinity for keratin, with drug concentrations in keratin declining in parallel with those in plasma.4Epstein WL Riegelman S Griseofulvin levels in stratum corneum.Arch Dermatol. 1972; 106: 344-348Crossref PubMed Scopus (82) Google Scholar, 5Meinhof W Kinetics and spectrum of activity of oral antifungals: the therapeutic implications.J Am Acad Dermatol. 1993; 29: S37-S41Summary Full Text PDF PubMed Scopus (41) Google Scholar A study4Epstein WL Riegelman S Griseofulvin levels in stratum corneum.Arch Dermatol. 1972; 106: 344-348Crossref PubMed Scopus (82) Google Scholar has shown that in many patients no drug was detectable in the stratum corneum within 48–72 h of stopping griseofulvin 500 mg twice a day for 25 days; however, drug remained in the plasma for about 6 days. Griseofulvin is thought to enter the nail via the nail matrix, and it needs to be given for as long as the diseased nail is growing out. Because of the slow rate at which toenails grow out (0·5-1·0 mm/month), for onychomycosis of the toes griseofulvin usually has to be given for 12–24 months. Meta-analysis shows a mycological cure rate of 24·5% (SE 6·7), with a relapse rate of 40% 3–12 months after end of therapy.6Gupta AK Pharmacoeconomic analysis of oral antifungal therapies used to treat dermatophyte onychomycosis of the toenails.Pliarmacoeconomics. 1998; 13: 1-15Crossref PubMed Scopus (265) Google Scholar Hence griseofulvin has been superseded by the newer oral antifungal agents for the treatment of onychomycosis, particularly of the toes.Introduced in 1980, ketoconazole was the first important azole for the treatment of onychomycosis.3Gupta AK Sauder DN Shear NH Antifungal agents: an overview. Part I.J Am Acad Dermatol. 1994; 30: 677-698Summary Full Text PDF PubMed Scopus (178) Google Scholar, 7Harris R Jones HE Artis WM Orally administered ketoconazole: route of delivery to the human stratum corneum.Antimicrob Ag Chemother. 1983; 24: 876-882Crossref PubMed Scopus (59) Google Scholar It is an imidazole with a high affinity for nail keratin. Ketoconazole has been detected in the distal nail within 11 days of the start of therapy,5Meinhof W Kinetics and spectrum of activity of oral antifungals: the therapeutic implications.J Am Acad Dermatol. 1993; 29: S37-S41Summary Full Text PDF PubMed Scopus (41) Google Scholar which suggests that it enters the nail plate via both the nail matrix and the nail bed. It is no longer preferred for the treatment of onychomycosis of the toes because, in the rare case, it has been associated with idiosyncratic, sometimes fatal, hepatotoxicity.3Gupta AK Sauder DN Shear NH Antifungal agents: an overview. Part I.J Am Acad Dermatol. 1994; 30: 677-698Summary Full Text PDF PubMed Scopus (178) Google ScholarThe newer generation of oral antifungal agents for the treatment of onychomycosis are terbinafine,8Gupta AK Shear NH Terbinafine: an update.J Am Acad Dermatol. 1997; 37: 979-988Summary Full Text Full Text PDF PubMed Scopus (116) Google Scholar itraconazole, and fluconazole. Itraconazole, a triazole, was first approved for the treatment of onychomycosis as a continuous regimen in Mexico in 1989.9De Doncker P Gupta AK Marynissen G Stoffels P Heremans A Itraconazole pulse therapy for onychomycosis and dermatomycoses: an overview.J Am Acad Dermatol. 1997; 37: 969-974Summary Full Text Full Text PDF PubMed Scopus (97) Google Scholar The concept of pulse therapy was soon introduced, because itraconazole reaches the distal end of the toenail within 2 weeks of starting therapy and persists in the nail plate for about 9–12 months from the start of therapy, even though it is present at low to negligible concentrations in the plasma within 7–14 days after the end of a week of treatment.9De Doncker P Gupta AK Marynissen G Stoffels P Heremans A Itraconazole pulse therapy for onychomycosis and dermatomycoses: an overview.J Am Acad Dermatol. 1997; 37: 969-974Summary Full Text Full Text PDF PubMed Scopus (97) Google Scholar, 10De Doncker P Decroix J Gierard GE et al.Antifungal pulse therapy for onychomycosis: a pharmacokinetic and pharmacodynamic investigation of monthly cycles of 1-week pulse therapy with itraconazole.Arch Dermatol. 1996; 132: 34-41Crossref PubMed Google Scholar Itraconazole pulse therapy was first approved for onychomycosis in 1993, in Finland. Fluconazole, the latest of the newer antifungal agents for the treatment of onychomycosis is also a triazole.Terbinafine, itraconazole, and fluconazole enter the nail plate via both the nail matrix and nail bed. Like itraconazole, terbinafine and fluconazole can be found at the distal end of the nail plate within a few weeks of start of therapy and persist in the nail for several months after withdrawal of therapy.11Schatz F Bräutigam M Dobrowolski E et al.Nail incorporation kinetics of terbinafine in onychomycosis patients.Clin Exp Dermatol. 1995; 20: 377-383Crossref PubMed Scopus (97) Google Scholar, 12Cauwenbergh G Degreef H Heykants J Woestenborghs R Van Rooy P Haeverans K Pharmacokinetic profile of orally administered itraconazole in human skin.J Am Acad Dermatol. 1988; 18: 263-268Summary Full Text PDF PubMed Scopus (228) Google Scholar, 13Scher RK. A placebo-controlled, randomized, double-blind trial of once-weekly fluconazole (150, 300, or 450 mg) in the treatment of distal subungual onychomycosis of the toenail. Presented at the 37th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), Toronto, Canada, September 28-October 1, 1997.Google Scholar They are also eliminated from the plasma within weeks of the end of treatment. This difference is associated with a high benefit to risk ratio. The persistence of drug in the nail plate may explain why the mycological cure rates (60–80%) for the newer agents are higher than that of griseofulvin.6Gupta AK Pharmacoeconomic analysis of oral antifungal therapies used to treat dermatophyte onychomycosis of the toenails.Pliarmacoeconomics. 1998; 13: 1-15Crossref PubMed Scopus (265) Google Scholar The pharmacokinetics of these newer agents has enabled shortening of treatment duration, which increases compliance. Another advantage is that, unlike griseofulvin, which has activity against dermatophytes only, the newer agents are also active in vivo against Candida species and some non-dermatophyte moulds. Pharmacoeconomic analyses of griseofulvin, terbinafine, and itraconazole (continuous or pulse) in the treatment of onychomycosis of the toes indicate that terbinafine and pulse therapy with itraconazole are the two most cost-effective treatments, with no significant difference between them.6Gupta AK Pharmacoeconomic analysis of oral antifungal therapies used to treat dermatophyte onychomycosis of the toenails.Pliarmacoeconomics. 1998; 13: 1-15Crossref PubMed Scopus (265) Google ScholarFor terbinafine the recommended treatment regimen for onychomycosis of the toes is 250 mg/day for 12 weeks. In a double-blind trial 6 weeks of treatment was compared with 12 weeks in patients in whom the proximal part of the toenails was not affected.14Tausch I Brautigam M Weidinger G Jones TC the Lagos V Study GroupEvaluation 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: 737-742Crossref PubMed Scopus (54) Google Scholar Among the patients who completed the study, the mycological cure rate at 48 weeks after the start of therapy in the 6-week group was 56% (34/61), compared with 82% (46/56) for the 12-week group. Responders did not differ from non-responders in age, weight, or degree of nail involvement. A trend towards better response was observed in those with a short duration of disease and with infection of toenails other than the big (first) toenail. Positive mycology at week 24 predicted therapeutic failure or relapse in 68% (25/37) patients. The investigators14Tausch I Brautigam M Weidinger G Jones TC the Lagos V Study GroupEvaluation 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: 737-742Crossref PubMed Scopus (54) Google Scholar suggest that one management approach would be to check mycological status 6 months after the start of therapy and then to repeat treatment for those with positive results.With itraconazole, despite the popularity of pulse therapy, there has been only one study that has compared pulse (200 mg twice daily for 1 week a month for 3 months) against continuous therapy (200 mg daily for 3 months). At month 12 after the start of therapy, mycological cure rates were 69% for pulse therapy (n=59) and 66% for continuous therapy (n=62). In patients with less than 75% nail-plate involvement, the mycological cure rates at month 12 were 75% for pulse therapy and 79% for continuous therapy. When more than 75% of the nail plate was affected, the corresponding figures were 66% and 60%, respectively.15Havu 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: 230-234Crossref PubMed Scopus (120) Google Scholar Although there were no significant differences, the investigators found a trend for superiority of the pulse over the continuous regimen. Furthermore, for onychomycosis of the toes, itraconazole pulse therapy requires exactly half the drug needed for the continuous regimen, thus making the former more cost-effective.The newer oral antifungal agents used alone, or in some cases in conjunction with topical antifungals or surgery, are providing the basis for effective treatment of onychomycosis of the toes in a large proportion of affected individuals. Efficacy can be improved if those unikely to respond to therapy can be identified, and efforts to do so and to find the most cost-effective manner of treating pedal onychomycosis are under way. Recurrence of disease still occurs in a high proportion of patients. It can be due to inadequate eradication of onychomycosis or reinfection. Hence once cure has been obtained it is prudent to counsel the patient about measures that will reduce the likelihood of reinfection.16Gupta AK Scher RK Management of onychomycosis: a North American perspective.Dermatol Ther. 1997; 3: 58-65Google Scholar Some strategies include avoidance of facilities with a high level of dermatophyte contamination (communal swimming pools, showers, changing facilities) discarding old shoes that may have a high density of fungal spores, and the judicious use of topical antifungal agents. Onychomycosis affects about 7–8% of the North American population.1Gupta AK Jain HC Lynde CW Watteel GN Summerbell RC Prevalence and epidemiology of unsuspected onychomycosis in patients visiting dermatologists' offices in Ontario, Canada—a multicenter survey of 2001 patients.Int J Dermatol. 1997; 36: 783-787Crossref PubMed Scopus (190) Google Scholar It is commonly more than a cosmetic issue since it can cause pain or discomfort and affect mobility as well as other activities of daily living.2Scher RK Onychomycosis is more than a cosmetic problem.Br J Dermatol. 1994; 130: 15Crossref PubMed Scopus (136) Google Scholar An important advance in its management is the development of oral antifungal agents and methods of their administration. Griseofulvin, the first promising oral antifungal agent for the treatment of onychomycosis and other dermatomycoses,3Gupta AK Sauder DN Shear NH Antifungal agents: an overview. Part I.J Am Acad Dermatol. 1994; 30: 677-698Summary Full Text PDF PubMed Scopus (178) Google Scholar was introduced 40 years ago. Surprisingly, the pharmacokinetics of griseofulvin in the nail have not been studied in detail. Griseofulvin has a low affinity for keratin, with drug concentrations in keratin declining in parallel with those in plasma.4Epstein WL Riegelman S Griseofulvin levels in stratum corneum.Arch Dermatol. 1972; 106: 344-348Crossref PubMed Scopus (82) Google Scholar, 5Meinhof W Kinetics and spectrum of activity of oral antifungals: the therapeutic implications.J Am Acad Dermatol. 1993; 29: S37-S41Summary Full Text PDF PubMed Scopus (41) Google Scholar A study4Epstein WL Riegelman S Griseofulvin levels in stratum corneum.Arch Dermatol. 1972; 106: 344-348Crossref PubMed Scopus (82) Google Scholar has shown that in many patients no drug was detectable in the stratum corneum within 48–72 h of stopping griseofulvin 500 mg twice a day for 25 days; however, drug remained in the plasma for about 6 days. Griseofulvin is thought to enter the nail via the nail matrix, and it needs to be given for as long as the diseased nail is growing out. Because of the slow rate at which toenails grow out (0·5-1·0 mm/month), for onychomycosis of the toes griseofulvin usually has to be given for 12–24 months. Meta-analysis shows a mycological cure rate of 24·5% (SE 6·7), with a relapse rate of 40% 3–12 months after end of therapy.6Gupta AK Pharmacoeconomic analysis of oral antifungal therapies used to treat dermatophyte onychomycosis of the toenails.Pliarmacoeconomics. 1998; 13: 1-15Crossref PubMed Scopus (265) Google Scholar Hence griseofulvin has been superseded by the newer oral antifungal agents for the treatment of onychomycosis, particularly of the toes. Introduced in 1980, ketoconazole was the first important azole for the treatment of onychomycosis.3Gupta AK Sauder DN Shear NH Antifungal agents: an overview. Part I.J Am Acad Dermatol. 1994; 30: 677-698Summary Full Text PDF PubMed Scopus (178) Google Scholar, 7Harris R Jones HE Artis WM Orally administered ketoconazole: route of delivery to the human stratum corneum.Antimicrob Ag Chemother. 1983; 24: 876-882Crossref PubMed Scopus (59) Google Scholar It is an imidazole with a high affinity for nail keratin. Ketoconazole has been detected in the distal nail within 11 days of the start of therapy,5Meinhof W Kinetics and spectrum of activity of oral antifungals: the therapeutic implications.J Am Acad Dermatol. 1993; 29: S37-S41Summary Full Text PDF PubMed Scopus (41) Google Scholar which suggests that it enters the nail plate via both the nail matrix and the nail bed. It is no longer preferred for the treatment of onychomycosis of the toes because, in the rare case, it has been associated with idiosyncratic, sometimes fatal, hepatotoxicity.3Gupta AK Sauder DN Shear NH Antifungal agents: an overview. Part I.J Am Acad Dermatol. 1994; 30: 677-698Summary Full Text PDF PubMed Scopus (178) Google Scholar The newer generation of oral antifungal agents for the treatment of onychomycosis are terbinafine,8Gupta AK Shear NH Terbinafine: an update.J Am Acad Dermatol. 1997; 37: 979-988Summary Full Text Full Text PDF PubMed Scopus (116) Google Scholar itraconazole, and fluconazole. Itraconazole, a triazole, was first approved for the treatment of onychomycosis as a continuous regimen in Mexico in 1989.9De Doncker P Gupta AK Marynissen G Stoffels P Heremans A Itraconazole pulse therapy for onychomycosis and dermatomycoses: an overview.J Am Acad Dermatol. 1997; 37: 969-974Summary Full Text Full Text PDF PubMed Scopus (97) Google Scholar The concept of pulse therapy was soon introduced, because itraconazole reaches the distal end of the toenail within 2 weeks of starting therapy and persists in the nail plate for about 9–12 months from the start of therapy, even though it is present at low to negligible concentrations in the plasma within 7–14 days after the end of a week of treatment.9De Doncker P Gupta AK Marynissen G Stoffels P Heremans A Itraconazole pulse therapy for onychomycosis and dermatomycoses: an overview.J Am Acad Dermatol. 1997; 37: 969-974Summary Full Text Full Text PDF PubMed Scopus (97) Google Scholar, 10De Doncker P Decroix J Gierard GE et al.Antifungal pulse therapy for onychomycosis: a pharmacokinetic and pharmacodynamic investigation of monthly cycles of 1-week pulse therapy with itraconazole.Arch Dermatol. 1996; 132: 34-41Crossref PubMed Google Scholar Itraconazole pulse therapy was first approved for onychomycosis in 1993, in Finland. Fluconazole, the latest of the newer antifungal agents for the treatment of onychomycosis is also a triazole. Terbinafine, itraconazole, and fluconazole enter the nail plate via both the nail matrix and nail bed. Like itraconazole, terbinafine and fluconazole can be found at the distal end of the nail plate within a few weeks of start of therapy and persist in the nail for several months after withdrawal of therapy.11Schatz F Bräutigam M Dobrowolski E et al.Nail incorporation kinetics of terbinafine in onychomycosis patients.Clin Exp Dermatol. 1995; 20: 377-383Crossref PubMed Scopus (97) Google Scholar, 12Cauwenbergh G Degreef H Heykants J Woestenborghs R Van Rooy P Haeverans K Pharmacokinetic profile of orally administered itraconazole in human skin.J Am Acad Dermatol. 1988; 18: 263-268Summary Full Text PDF PubMed Scopus (228) Google Scholar, 13Scher RK. A placebo-controlled, randomized, double-blind trial of once-weekly fluconazole (150, 300, or 450 mg) in the treatment of distal subungual onychomycosis of the toenail. Presented at the 37th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), Toronto, Canada, September 28-October 1, 1997.Google Scholar They are also eliminated from the plasma within weeks of the end of treatment. This difference is associated with a high benefit to risk ratio. The persistence of drug in the nail plate may explain why the mycological cure rates (60–80%) for the newer agents are higher than that of griseofulvin.6Gupta AK Pharmacoeconomic analysis of oral antifungal therapies used to treat dermatophyte onychomycosis of the toenails.Pliarmacoeconomics. 1998; 13: 1-15Crossref PubMed Scopus (265) Google Scholar The pharmacokinetics of these newer agents has enabled shortening of treatment duration, which increases compliance. Another advantage is that, unlike griseofulvin, which has activity against dermatophytes only, the newer agents are also active in vivo against Candida species and some non-dermatophyte moulds. Pharmacoeconomic analyses of griseofulvin, terbinafine, and itraconazole (continuous or pulse) in the treatment of onychomycosis of the toes indicate that terbinafine and pulse therapy with itraconazole are the two most cost-effective treatments, with no significant difference between them.6Gupta AK Pharmacoeconomic analysis of oral antifungal therapies used to treat dermatophyte onychomycosis of the toenails.Pliarmacoeconomics. 1998; 13: 1-15Crossref PubMed Scopus (265) Google Scholar For terbinafine the recommended treatment regimen for onychomycosis of the toes is 250 mg/day for 12 weeks. In a double-blind trial 6 weeks of treatment was compared with 12 weeks in patients in whom the proximal part of the toenails was not affected.14Tausch I Brautigam M Weidinger G Jones TC the Lagos V Study GroupEvaluation 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: 737-742Crossref PubMed Scopus (54) Google Scholar Among the patients who completed the study, the mycological cure rate at 48 weeks after the start of therapy in the 6-week group was 56% (34/61), compared with 82% (46/56) for the 12-week group. Responders did not differ from non-responders in age, weight, or degree of nail involvement. A trend towards better response was observed in those with a short duration of disease and with infection of toenails other than the big (first) toenail. Positive mycology at week 24 predicted therapeutic failure or relapse in 68% (25/37) patients. The investigators14Tausch I Brautigam M Weidinger G Jones TC the Lagos V Study GroupEvaluation 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: 737-742Crossref PubMed Scopus (54) Google Scholar suggest that one management approach would be to check mycological status 6 months after the start of therapy and then to repeat treatment for those with positive results. With itraconazole, despite the popularity of pulse therapy, there has been only one study that has compared pulse (200 mg twice daily for 1 week a month for 3 months) against continuous therapy (200 mg daily for 3 months). At month 12 after the start of therapy, mycological cure rates were 69% for pulse therapy (n=59) and 66% for continuous therapy (n=62). In patients with less than 75% nail-plate involvement, the mycological cure rates at month 12 were 75% for pulse therapy and 79% for continuous therapy. When more than 75% of the nail plate was affected, the corresponding figures were 66% and 60%, respectively.15Havu 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: 230-234Crossref PubMed Scopus (120) Google Scholar Although there were no significant differences, the investigators found a trend for superiority of the pulse over the continuous regimen. Furthermore, for onychomycosis of the toes, itraconazole pulse therapy requires exactly half the drug needed for the continuous regimen, thus making the former more cost-effective. The newer oral antifungal agents used alone, or in some cases in conjunction with topical antifungals or surgery, are providing the basis for effective treatment of onychomycosis of the toes in a large proportion of affected individuals. Efficacy can be improved if those unikely to respond to therapy can be identified, and efforts to do so and to find the most cost-effective manner of treating pedal onychomycosis are under way. Recurrence of disease still occurs in a high proportion of patients. It can be due to inadequate eradication of onychomycosis or reinfection. Hence once cure has been obtained it is prudent to counsel the patient about measures that will reduce the likelihood of reinfection.16Gupta AK Scher RK Management of onychomycosis: a North American perspective.Dermatol Ther. 1997; 3: 58-65Google Scholar Some strategies include avoidance of facilities with a high level of dermatophyte contamination (communal swimming pools, showers, changing facilities) discarding old shoes that may have a high density of fungal spores, and the judicious use of topical antifungal agents.