Piet De Doncker

Onychomycosis in children: Prevalence and treatment strategies

BACKGROUND Onychomycosis is observed less frequently in children than adults. Until recently management of onychomycosis in children included topical formulations, oral griseofulvin, and in some cases deferral of treatment. OBJECTIVE We attempted to determine the prevalence of onychomycosis in North American children 18 years old or younger attending our dermatology offices (three Canadian, two U.S.) and to report the groups experience using fluconazole, itraconazole, and terbinafine for onychomycosis. METHODS We undertook a prospective, multicenter survey in which all children, regardless of presenting complaint, were examined for onychomycosis by a dermatologist. In instances of clinical suspicion appropriate nail samples were obtained for light microscopy and culture. RESULTS A total of 2500 children under age 18 were examined in the five-center survey (1117 males and 1383 females, mean +/- S.E. age: 11.2 +/- 0.1 years). There was one child with fingernail and ten with mycologically confirmed toenail dermatophyte onychomycosis. The overall prevalence of onychomycosis was 0.44%. Considering those children whose primary or referring diagnosis was not onychomycosis or tinea pedis, the prevalence of onychomycosis was 0.16%. Outside the survey we have seen six other children with dermatophyte onychomycosis; these 17 cases form the basis for the remainder of the report. Of the 17 children, eight (47%) had concomitant tinea pedis infection, and in 11 (65%) a sibling, parent, or grandparent had onychomycosis or tinea pedis. Management included topical terbinafine (two patients: one cured, one failed therapy), topical ketoconazole (one patient: clinical improvement), oral fluconazole (two patients: one cured, one had Downs syndrome and was noncompliant), oral itraconazole (four patients: three cured with subsequent recurrence at follow-up in one patient, one lost to follow-up), oral terbinafine (five patients: four cured with subsequent recurrence at follow-up in one patient, one failed therapy). One child received no therapy following discussion with the parents, one was lost to follow-up and one was found to have asymptomatic hepatic dysfunction with hepatitis C at pretherapy bloodwork. CONCLUSION The prevalence of onychomycosis in our sample of North American children 18 years old or younger was 0.44% (n = 2500). In the subset of children whose primary or referring diagnosis was not onychomycosis, the prevalence of onychomycosis was 0.16%. Children with onychomycosis should be carefully examined for concomitant tinea pedis, and their parents and siblings checked for onychomycosis and tinea pedis. The newer oral antifungal agents fluconazole, itraconazole, and terbinafine may be effective and well-tolerated in the treatment of onychomycosis in this age group. These drugs should be carefully evaluated in a larger cohort of children with onychomycosis.

Antifungal Pulse Therapy for Onychomycosis: A Pharmacokinetic and Pharmacodynamic Investigation of Monthly Cycles of 1-Week Pulse Therapy With Itraconazole

BACKGROUND AND DESIGN In the treatment of onychomycosis, oral therapies have generally been given as a continuous-dosing regimen. For example, the suggested dose of itraconazole for the treatment of onychomycosis has thus far been 200 mg/d for 3 months. Based on the advances in our understanding of the pharmacokinetics of itraconazole, we investigated the efficacy and nail kinetics of intermittent pulse-dosing therapy with oral itraconazole in patients who were suffering from onychomycosis. Fifty patients with confirmed onychomycosis of the toenails, predominantly Trichophyton rubrum, were recruited and randomly assigned to three (n = 25) or four (n = 25) pulses of 1-week itraconazole therapy (200 mg twice daily for each month). Clinical and mycological evaluation of the infected toenails, and determination of the drug levels in the distal nail ends of the fingernails and toenails, were performed at the end of each month up to month 6 and then every 2 months up to 1 year. RESULTS In the three-pulse treatment group, the mean concentration of itraconazole in the distal ends of the toenails ranged from 67 (month 1) to 471 (month 6) ng/g, and in the distal ends of the fingernails, it ranged from 103 (month 1) to 424 (month 6) ng/g. At month 11, the drug was still present in the distal ends of the toenails at an average concentration of 186 ng/g. The highest individual concentrations of 1064 and 1166 ng/g were reached at month 6 for toenails and fingernails, respectively. At end-point follow-up, toenails in 84% of the patients were clinically cured with a negative potassium hydroxide preparation and culture in 72% and 80% of the patients, respectively. In the four-pulse treatment group, the mean concentration of itraconazole in the distal ends of the toenails ranged from 32 (month 1) to 623 (month 8) ng/g, and in the distal ends of the fingernails, it ranged from 42 (month 1) to 380 (month 6) ng/g. The highest individual concentrations of 1549 and 946 ng/g were reached at month 7 for toenails and at month 9 for fingernails, respectively. At month 12, the drug was still present in the distal ends of the toenails at an average concentration of 196 ng/g. At end-point follow-up, toenails in 76% of the patients were clinically cured with a negative potassium hydroxide preparation and culture in 72% and 80% of the patients, respectively. There were no significant intergroup differences between the three- and four-pulse treatment groups for the primary efficacy parameters. The drug was well tolerated with no significant side effects in either patient group. CONCLUSIONS Following pulse therapy with itraconazole (400 mg/d given for 1 week each month for 3 to 4 months), the drug has been detected in the distal ends of nails after the first pulse, and it has reached therapeutic concentrations with further therapy. After stopping the last pulse, the drug remains in the nail plate at levels above 300 ng/g for several months. Clinical cure rates between 76% and 84% and negative mycological examination findings between 72% and 80%, respectively, were observed in toenail onychomycosis. The data suggest that pulse therapy with itraconazole is an effective and safe treatment option for onychomycosis.

The treatment of aspergillosis and aspergilloma with itraconazole, clinical results of an open International study(1982-1987)

Summary: A total of 137 patients with aspergillosis or aspergilloma has been treated with 50 to 400 mg itraconazole daily during 11 to 780 days.

Itraconazole penetrates the nail via the nail matrix and the nail bed—an investigation in onychomycosis

Nail‐matrix kinetics were studied in 21 patients (19 with onychomycosis, two with tinea corporis) as soon as taking itraconazole (Sporanox®) 100 mg daily for up to 7 months. Itraconazole was detected in the distal nail as soon as 1 month after the start of therapy (42 ng/g in fingernails and 16 ng/g in toenails). During the course of treatment, this concentration rose and reached a mean of 160 ng/g in fingernail clippings and 197 ng/g in toenail clippings. Moreover, in fingernails of 12 out of 21 patients and in toenails of six out of 20 patients, itraconazole was detected in the distal nail clippings before full outgrowth of the fastest‐growing nail. In most patients, itraconazole was detected in the distal nail clippings earlier than would be expected if the drug were incorporated only via the nail matrix, indicating that in addition to the nail matrix, a second route of penetration into the nail exists, i.e. the nail bed.

CURRENT MANAGEMENT OF ONYCHOMYCOSIS: An Overview

Until recently pedal onychomycosis, particularly when it affected several nails or involved a large nail plate area, was often regarded as untreatable. The advent of new therapies such as itraconazole, terbinafine, and fluconazole has been a significant and welcome addition to the armamentarium of therapies at the disposal of the physician. These drugs appear in the nail plate within days of starting oral therapy, being taken up by both the nail matrix and the nail bed. The duration required for effective therapy has been reduced, while the efficacy rates and cost-effectiveness have increased compared with the older treatments, such as griseofulvin. Some of the newer agents appear to have a wider spectrum of activity. Thus far, the newer agent have exhibited a low risk to benefit ratio. I may be possible to combine oral therapies with topical and surgical treatments, thereby further increasing efficacy rates and the cost-effectiveness while decreasing adverse effects and duration of oral therapy.

Itraconazole pulse therapy for onychomycosis and dermatomycoses: An overview

BACKGROUND Itraconazole is a broad-spectrum antifungal agent that has been used to treat dermatomycosis and onychomycosis using continuous therapy. More recently the drug has been used as pulse dosing. OBJECTIVE Our purpose was to review the studies in which itraconazole pulse therapy (PT) has been administered in the management of dermatomycoses. RESULTS For tinea pedis and manuum, the recommended dosage is itraconazole 200 mg twice daily for 1 week (n = 220). A clinical response and mycologic cure rate of 90% +/- 4% and 76% +/- 6%, respectively, has been obtained. For tinea corporis/cruris, itraconazole 200 mg/day for 1 week (n = 354) resulted in a clinical response and mycologic cure rate of 90% +/- 4% and 77% +/- 6%, respectively. When three pulses of itraconazole are used to treat toenail onychomycosis (n = 1389), the clinical cure rate, clinical response, and mycologic cure rate at follow-up 12 months after the start of therapy were 58% +/- 10%, 82% +/- 3%, and 77% +/- 5%, respectively. With two pulses for onychomycosis of the fingernails, the clinical cure rate, clinical response, and mycologic cure rate at follow-up, 9 months after the start of therapy, were 78% +/- 10%, 89% +/- 6%, and 87% +/- 8%, respectively. CONCLUSION Itraconazole PT is effective and safe in the treatment of tinea pedis/manuum, tinea corporis/cruris, and onychomycosis.

New approaches to the treatment of onychomycosis

The purpose of this article is to review the pharmacologic properties of two newer agents, itraconazole and terbinafine, and to assess their clinical efficacy in onychomycosis. Both drugs are effective in treating infections caused by dermatophytes. Itraconazole appears to be more efficacious in infections caused by Candida species. The improved effectiveness of these agents is probably related to their rapid penetration into the nails and prolonged bioavailability at the site of infection.

Treatment of tinea capitis with itraconazole capsule pulse therapy

Abstract Background: The number of newly diagnosed cases of tinea capitis in children appears to be on the rise, particularly in urban centers. Objective: The purpose of this study was to assess the effectiveness, safety, and compliance of itraconazole pulse therapy for tinea capitis. Methods: Fifty subjects (48 children [less than 18 years of age] and 2 adults) with tinea capitis were treated with pulse itraconazole in a multicenter evaluation. Each pulse lasted 1 week, with 2 weeks between the first two pulses and 3 weeks between the second and third pulses. The decision to administer a second or third pulse was determined by the response of the subject at the time that the next pulse was due. During the 1-week pulse of active therapy, itraconazole (5 mg/kg/day) was dosed as follows: more than 40 kg, 200 mg per day (two capsules per day); 20 to 40 kg, 100 mg per day (one capsule per day); and 10 to 19 kg, 50 mg per day (one half of a capsule per day). The duration of the study was 12 weeks with mycologic evaluation at this time. Subjects who were classified as treatment failures at 12 weeks after the start of therapy were given the option of receiving an additional 1-week pulse of active therapy, with 3 weeks between successive pulses. Results: The causative organisms were Trichophyton tonsurans (41 subjects), T. violaceum (7), T. soudanense (1), and T. rubrum (1). Thirteen subjects were lost to follow-up, with 37 subjects (35 children and 2 adults) available for evaluation 12 weeks after the start of therapy. At this time, cure (clinical and mycologic) was observed in 30 (81%) of 37 subjects. When the tinea capitis was mild, cure was obtained after one pulse in two subjects and after two pulses in five subjects. With tinea capitis of moderate extent, complete cure was obtained after one pulse in one subject, two pulses in eight subjects, and after three pulses in seven subjects. When tinea capitis was severe, two and three pulses produced complete cure in one and six subjects, respectively. Of the seven subjects whose conditions failed to respond (three subjects with moderate disease and four subjects with severe disease), five subjects chose to receive extra itraconazole. Clinical and mycologic cure was observed after four pulses in four subjects and after five pulses in one subject. There were no associated clinical adverse effects with itraconazole therapy. Conclusion: With tinea capitis, itraconazole pulse therapy is effective and safe and is associated with high compliance. The pulse regimen enables the duration of treatment to be individualized, according to the extent of disease and its rate of resolution. (J Am Acad Dermatol 1998;39:216-9.)

The Use of Itraconazole to Treat Cutaneous Fungal Infections in Children

Background: Cutaneous mycoses such as tinea capitis, onychomycosis and some cases of tinea corporis/cruris, and tinea pedis/manus require oral antifungal therapy. There is relatively limited data regarding the use of the newer oral antifungal agents, e.g. itraconazole, in the treatment of these mycoses in children. Objective: We wished to determine the efficacy and safety of itraconazole continuous therapy in the management of cutaneous fungal infections in children. Methods: Children with cutaneous mycoses were treated with itraconazole in an open-label manner in 4 studies. For tinea capitis, the treatment regimens using itraconazole continuous therapy were: study 1, 3 mg/kg/day for 4 or 8 weeks; study 2, 5 mg/kg/day for 6 weeks, and study 3, 5 mg/kg/ day for 4 weeks. In a different trial, study 4, itraconazole continuous therapy 5 mg/kg/day was used to treat toenail onychomycosis (duration: 12 weeks), tinea corporis/ cruris (duration: 1 week) and tinea pedis/manus (duration: 2 weeks). Results: The efficacy rates at follow-up 12 weeks from the start of therapy in children with tinea capitis treated using the itraconazole continuous regimen were: clinical cure (CC) and mycological cure (MC) in study 1 (n = 10, Trichophyton violaceum all patients), CC 50%, MC 86%; in study 2 (n = 35, Microsporum canis 22 patients, Trichophyton sp. 12 patients), CC 82.8%, MC 80%, and in study 3 (n = 16, M. canis 11 patients, Trichophyton sp. 5 patients), (CC 66.7%, MC 78.5%. Itraconazole was also effective in the treatment of dermatomycoses in 24 children (study 4). The CC and MC rates at the follow-up 8 weeks from the start of therapy in children with dermatomycoses and 12 months in children treated for onychomycosis were: onychomycosis (n = 1, T. rubrum), CC 100%, MC 100%; tinea corporis (n = 12, M. canis 10 patients), CC 100%, MC 90%; tinea cruris (n = 3, Trichophyton sp. 2 patients), CC 100%, MC 100%; tinea manus (n = 1, T. rubrum), CC 100%, MC 100%, and tinea pedis (n = 7, T. rubrum), CC 100%, MC 100%). Adverse effects consisted of a cutaneous eruption in 1 (1.2%) of the 85 children, with mild, transient, asymptomatic elevation of liver function tests (less than twice the upper limit of normal) in 2 (3.4%) of 58 children in whom monitoring was performed. Conclusions: Itraconazole is effective and safe in the treatment of tinea capitis and other cutaneous fungal infections in children.

Use of topical ketanserin in the treatment of skin ulcers: A double-blind study

The use of a 2% ointment formulation of ketanserin, an S2-serotoninergic blocking agent, was investigated in a randomized double-blind clinical trial for its effect on the healing of wounds of patients with decubitus, venous, and ischemic skin ulcers. The result demonstrates a significant difference in favor of the ketanserin-treated group (35 patients) versus the placebo-treated group (37 patients) on the basis of two factors: formation of granulation tissue and epithelialization. In addition, a significant difference of 150% in the initial velocity of wound closure was observed in favor of the patients treated with ketanserin. This effect was persistent during the entire study period.