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Keywords:

  • Onychomycosis;
  • terbinafine;
  • pulse therapy

Summary

  1. Top of page
  2. Summary
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. References

We assessed the safety and efficacy of pulse therapy with terbinafine tablets in 55 patients with dermatophytic onychomycosis. One pulse consisted of oral terbinafine tablets (500 mg day−1) given for 1 week usually followed by a 3-week interval. This regimen was repeated twice. Topical 1% terbinafine cream was applied daily. Efficacy was assessed based on both clinical and mycological examinations 1 year after treatment initiation. We observed a complete cure in 41 patients (74.5%), marked improved in three patients (5.6%), slight improvement in three patients (5.6%) and drop out in six patients (10.7%). Two patients (3.6%) discontinued terbinafine because of gastrointestinal disturbance (one patient) and drug-induced eruption (one patient). No patient had abnormal laboratory findings, including liver function tests. In summary, a regimen of three pulses of terbinafine therapy given daily for 1 week in combination with topical application of terbinafine cream appears to be safe and effective in treating dermatophytic onychomycosis and offers advantages in convenience and cost-effectiveness compared with continuous dosing.


Introduction

  1. Top of page
  2. Summary
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. References

The improved safety and efficacy profile of recently developed antifungal agents such as terbinafine and itraconazole has led to increased treatment of dermatophyte onychomycosis. More dosing options for oral administration have become available with the development of intermittent therapy (pulse therapy) and short-duration therapy to replace long-term continuous oral administration.1–3

In Europe and North America, the standard terbinafine regimen for treatment of onychomycosis is 3-month therapy at a dose of 250 mg day−1. In contrast, in Japan, dermatophyte onychomycosis is usually treated with terbinafine given daily at a dose of 125 mg day−1 for 5 to 6 months. The pharmacokinetic properties of terbinafine are similar to those of itraconazole, which is widely administered using pulse therapy, and a few reports have described terbinafine pulse therapy for the treatment of dermatophyte onychomycosis.4–9 Recently, we reported a pilot study showing terbinafine pulse therapy to be effective in treatment of dermatophyte onychomycosis.10

We report herein the results of a trial designed to assess the clinical and mycological effects of three pulses of terbinafine therapy in combination with daily topical terbinafine cream for treatment of dermatophyte onychomycosis.

Patients and methods

  1. Top of page
  2. Summary
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. References

Study design

The study subjects were patients who visited the dermatology clinic at Juntendo University School of Medicine and affiliated hospitals between October 2004 and July 2005. Patients were eligible to participate if they were 20 years or older and had a diagnosis of dermatophytic onychomycosis of the fingernail or toenail based on clinical manifestations and confirmed by microscopic examination with KOH wet-mount or by mycological culture. Exclusion criteria were as follows: use of another oral antifungal agent within 6 months prior this study; presence of a serious underlying systemic conditions; pregnancy or possible pregnancy or lactation; use of medication that could interact with terbinafine, such as cimetidine, rifampicin and others;11 haematological count abnormalities or liver dysfunction; and being judged to be inappropriate for inclusion in this clinical trial. All patients provided written informed consent.

The most damaged fingernail was evaluated in cases with fingernail infection. With toenail infection, only the toenail with the highest degree of turbidity on the first to the third toe was evaluated. The degree of turbidity of an infected nail was scored by measuring the distance from the distal edge to the proximal edge of the involved area, with the distance from the distal edge of the nail bed to the proximal nail fold being defined as 10 (highest).

Age, gender and occupation of the patients were recorded. Patients were classified into two groups by occupation: blue-collar workers were those engaged in work that might cause strain in the toenails or fingernails, and white-collar workers were those engaged in clerical work.

Medical data collected for each patient included onychomycosis disease duration, anatomic site(s), clinical type (distal lateral subungual onychomycosis, proximal subungual onychomycosis, superficial white onychomycosis and total dystrophic onychomycosis), the number of affected nails (excluding the fifth toenail), severity of nail thickening (rated in the following four grades as 0: no thickening, 1: mild, 2: moderate and 3: severe), causative pathogen, underlying systemic diseases (e.g. diabetes, hypertension, collagen diseases, etc.) and the Scoring Clinical Index for Onychomycosis score.12

Treatment regimen

For 7 days, subjects took two 125 mg tablets of terbinafine immediately after a meal, twice daily, for a total dose of 500 mg day−1. An interval of approximately 3 weeks followed the 7-day dosing period. This regimen of 1-week dosing followed by 3-week period without oral dosing was defined as one pulse. This regimen was repeated twice. Topical 1% terbinafine cream was applied to the area surrounding the infected nails, interdigital area and planta on a daily basis. After completion of pulse therapy, patients were advised to continue topical application of 1% terbinafine cream until the final evaluation 12 months after discontinuing pulse therapy.

Patients were asked to visit hospital once a month. At each hospital visit, the affected nails were examined and photographed, and clippings from the affected nail were examined by direct microscopy. Laboratory tests, including liver function tests, were performed periodically.

Patients were not permitted to treat the nails with other oral antifungal agents, to use urea ointment and occlusive dressings or to file the affected nails during the study period. At the hospital visit, patients were asked about any adverse effects experienced since the last visit and were reminded not to use prohibited concomitant medications.

Evaluation of efficacy

Efficacy was evaluated 12 months after the start of treatment. The degrees of improvement were assessed as follows: (i) ‘complete cure’ was defined as regeneration of a healthy nail plate to replace the diseased nail; (ii) ‘marked improvement,’ defined as regeneration of a healthy nail plate in at least 70% of the affected nail; (iii) ‘improvement,’ defined as regeneration in 40–70% of the affected nail; (iv) ‘slight improvement,’ defined as regeneration in less than 40%; and (v) ‘no change’, defined as the absence of change or exacerbation of the disease condition or the side effect. The absence of fungal elements by direct microscopy was taken as evidence of mycological cure. Adverse events, both local and systemic, were recorded at each visit and their relation to the trial drugs was judged.

Results

  1. Top of page
  2. Summary
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. References

Patient demographics

Fifty-five patients with dermatophyte oncomycosis were enrolled in this trial. Of these, six patients failed to return to the clinic for the final evaluation after 1 year and were considered unevaluable. A total of 55 patients, 31 men and 24 women, were included in the efficacy analysis. Table 1 presents the patient demographics.

Table 1.   Background factors of patients (n = 55, October 2004–July 2005)
  1. DLSO, distal lateral subungual onychomycosis; SWO, superficial white onychomycosis; SCIO, the Scoring Clinical Index for Onychomycosis.

Gender
 Male31
 Female24
Age (year) (mean ± SD) (min–max)53.2 ± 11.8(28–76)
Occupation
 White-collar37
 Blue-collar16
 ND2
Underlying disease
 Without44
 With11
Duration of disease (year) (mean ± SD) (min–max)8.1 ± 7.9 (0.2–30)
Site of lesion
 Toe53
 Finger1
 Toe and finger1
Number of affected nails (mean ± SD) (min–max)3.4 ± 2.5 (1–10)
Clinical of lesion
 DLSO51
 SWO4
Severity of thickening (mean ± SD) (min–max)2.5 ± 0.7 (1–3)
SCIO (mean±SD) (min–max)22.0 ± 7.7 (1–30)
Pathogens
 Trichophyton rubrum20
 Trichophyton mentagrophytes6
 Contamination10
 Not isolated19
Turbidity (mean ± SD) (min–max)8.7 ± 1.4(5–10)

Treatment results

Forty-four patients (80.1%) showed complete cure or marked improvement (Table 2). Of these, 41 patients (74.5%) showed complete cure and three (5.6%) showed marked improvement. Slight improvement was seen in three patients (5.6%). No patient was rated as having ‘improvement’. Two patients (3.6%) were rated as having ‘no change’. Representative cases are illustrated in Fig. 1.

Table 2.   Results of terbinafine pulse therapy
OutcomeToenailFinger nailTotal
  1. Values are expressed as n (%).

Complete cure40 (74.1)2 (100)41 (74.5)
Marked improvement3 (5.6)0 (0)3 (5.6)
Improvement0 (0)0 (0)0 (0)
Slight improvement3 (5.6)0 (0)3 (5.6)
No change (side effect)2 (3.6)0 (0)2 (3.6)
Dropped out6 (11.1)0 (0)6 (10.7)
Total54 (100)2 (100)55 (100)
image

Figure 1.  (a) A 50-year-old housewife with toenail onychomycosis caused by Trichophyton mentagrophytes for 2.5 years. (b) Affected nails show improvement 2 months after start of treatment, following completion of two pulses of terbinafine therapy. (c) At the follow-up examination a year after start of treatment, the patient showed complete cure.

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Both patients assessed as having no change had discontinued treatment because of drug side effects. One experienced mild gastrointestinal symptoms 2 days after dosing, and the other experienced drug eruption after 1 week. Medication was discontinued immediately in both cases, and the complaints resolved for a few days, without any special treatment. No patients showed abnormal findings in any of the laboratory tests performed before, during and after pulse therapy.

Discussion

  1. Top of page
  2. Summary
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. References

The standard dose of terbinafine is 250 mg day−1 in Europe and North America, with continuous drug administered for 6 weeks for the treatment of fingernail onychomycosis and 12 weeks for toenail onychomycosis.13 In Japan, oral terbinafine is usually administered daily at a dose of 125 mg for 6 months for the treatment of dermatophyte onychomycosis.

Pulse therapy with itraconazole appears to be highly efficacious and resulted in good patient compliance.14 Terbinafine has a pharmacokinetic profile similar to that of itraconazole. When terbinafine is given orally at a dosage of 250 mg day−1 for 6–12 weeks, it persists in the nail plate for an additional 30–36 weeks at concentrations above the minimum inhibitory concentrations of several dermatophyte species.3 Researchers have hypothesized that pulse therapy with terbinafine should be effective for treatment of onychomycosis.4–9

Tosti et al. [5] reported that the mycological cure rate was 95% after daily administration of terbinafine 250 mg for 4 months, 80% after pulse therapy with terbinafine 500 mg for four cycles and 76% after pulse therapy with itraconazole 400 mg for four cycles, with no significant difference among the three groups. Alpsoy et al. [6] reported that a regimen with pulse therapy with terbinafine 500 mg for three cycles achieved good results similar to those achieved with the standard dosing regimen of 250 mg day−1 for 3 months. Sanmmano et al. [8] reported that combination of pulse therapy with terbinafine 250 mg and daily application of topical terbinafine cream achieved good results and provided good patient compliance.

Recently, we reported that pulse therapy with terbinafine was effective in treatment of dermatophyte onychomycosis, in a pilot study.10 The number of pulses, to a maximum of six, was determined based on the patient’s preference and on the extent of improvement in the affected nails. Two or more pulses were necessary for a good outcome. Treatment with terbinafine pulse therapy in combination with daily topical terbinafine cream led to a good outcome after three pulses, with a complete cure rate of 83.7%.10 Results in this pilot study were comparable to those reported with a conventional regimen of terbinafine 125 mg administered daily for 5.5 months.15

In this study, terbinafine pulse therapy in combination with topical application of terbinafine cream is at least as effective and safe as continuous dosing and offers the advantages of greater cost-effectiveness and patient convenience. We recommend combination therapy consisting of three pulses of 500 mg day−1 terbinafine and daily topical application of 1% terbinafine cream for the treatment of dermatophyte onychomycosis.

References

  1. Top of page
  2. Summary
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. References
  • 1
    Hiruma M, Matsushita A, Kobayashi M, Ogawa H. One week pulse therapy with itraconazole (200 mg day−1) for onychomycosis. Evaluation of treatment results according to patient background. Mycoses 2001; 44: 8793.
  • 2
    Gupta AK, Lynde CW, 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: 48591.
  • 3
    Faergemann J, Zehender H, Denouel J, Milleroux L. Levels of terbinafine in plasma, stratum corneum, dermisepidermis (without stratum corneum), sebum, hair and nails during and after 250 mg terbinafine orally once per day four weeks. Acta Derm Venereol 1993; 73: 3059.
  • 4
    Shuster S, Munro SC. Single dose treatment of fungal nail disease. Lancet 1992; 339: 1066.
  • 5
    Tosti A, Piraccini BM, Stinchi C, Venturo N. 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: 595600.
  • 6
    Alpsoy E, Yilmaz E, Basaran E. Intermittent therapy with terbinafine for dermatophyte toe-onychomycosis: a new approach. J Dermatol 1996; 23: 25962.
  • 7
    Warshaw EM, Carver SM, Zielke GR, Ahmed DDF. Intermittent terbinafine for toenail onychomycosis: is it effective? Result of a randomized pilot trial. Arch Dermatol 2001; 137: 1253.
  • 8
    Sanmano B, Hiruma M, Mizoguchi M, Ogawa H. Combination therapy consisting of 1-week pulse of oral terbinafine plus topical application of terbinafine cream in the treatment of onychomycosis. J Dermatol Treat 2004; 15: 17.
  • 9
    Zaias N, Rebell G. The successful treatment of Trichophyton rubrum nail bet (distal subungual) onychomycosis with intermittent pulse-dosed terbinafine. Arch Dermatol 2004; 140: 6915.
  • 10
    Nakano N, Hiruma M, Shiraki Y, Chen X, Porgpermdee S, Ikeda S. Combination of pulse therapy with terbinafine tablets (500 mg day−1 for 1 week + following 3 weeks interval) and topical terbinafine cream for the treatment of dermatophyte onychomycosis: a pilot study. J Dermatol 2006; 33: 7538.
  • 11
    Darkes MJ, Scott LJ, Goa KL. Terbinafine: a review of its use in onychomycosis in adults. Am J Clin Dermatol 2003; 4: 3965.
  • 12
    Sergeev AY, Gupta AK. The scoring clinical index for onychomycosis (SCIO Index). Skin Therapy Lett 2002; 7: 67.
  • 13
    Scher RK. Onychomycosis: therapeutic update. J Am Acad Dermatol 1999; 40: 216.
  • 14
    Terbinafine study group. Clinical evaluation of terbinafine tablets on onychomycosis: a double-blind comparative trial in comparison with griseofulvin tablets. Nishinihon J Dermatol 1994; 56: 80925 (in Japanese).
  • 15
    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: 2304.