STUDY

The Successful Treatment of Trichophyton rubrum

Nail Bed (Distal Subungual) Onychomycosis
With Intermittent Pulse-Dosed Terbinafine
Nardo Zaias, MD; Gerbert Rebell, MS
Background: The standard treatment of Trichophyton

rubrum nail bed onychomycosis (or distal subungual onychomycosis [DSO]) with daily terbinafine for 12 weeks
involves treating for a fixed period shorter than the time
required for complete replacement of the nail bed and
overlying nail plate by normal growth. The same total
amount of terbinafine pulse-dosed for approximately 12
months would treat the patient until normal replacement of the mycotic nail bed has occurred.
Objectives: To determine the effectiveness of intermit-

tent administration of oral terbinafine (250 mg/d for 7

consecutive days every 2-4 months) to cure DSO and to
determine the maximum effective treatment interval.
Design: A prospective, nonrandomized, open study of

sequential groups of office patients.

Setting: A private dermatology practice.
Methods: A sequence of 4 groups of office patients with
DSO (n=10-20 each) were treated with pulse-dosed terbinafine for 7 consecutive days at intervals of 2, 3, and 4
months, respectively. In each group, treatment was continued until the distally advancing new nail bed and nail

had completely removed the mycotic defect or failure of

fungistasis was detected.
Main Outcome Measurement: Results were determined by monthly evaluation. Cure was noted as complete replacement of the mycotic nail bed and overlying
nail plate (ascertained by monthly metric measurements of the mycosis-free nail bed and overlying nail place
distal to the proximal nail fold). Treatment failure was
noted when the mycosis-free proximal portion of the nail
bed failed to increase in correspondence with the distally directed movement of the nail bed and overlying nail.
Results: Thirty-nine (93%) of the 42 patients in the first

3 groups were cured (95% binomial confidence interval,

67%-100%) with no evidence of decrease in efficacy. However, the group of patients who received the 7-day pulse
treatment every 4 months experienced significantly more
failures (P.01), and cures dropped to 10 of 17 cases.
Conclusion: Terbinafine is an effective treatment for DSO
when pulse-dosed for 7 days every 3 months but not every 4 months.

Arch Dermatol. 2004;140:691-695

E UNDERTOOK THIS

independent, officebased, open pilot

study of our patients to answer 2
questions: (1) Is pulse-dosed oral terbinafine effective in treating Trichophyton rubrum nail bed onychomycosis (distal subungual onychomycosis [DSO])? and (2)
Under a 7-consecutive-day, 1-pulse-perday treatment regimen, what is the maximum effective interval between treatment pulses?
METHODS
From the Greater Miami Skin
and Laser Center and Mount
Sinai Medical Center, Miami
Beach, Fla. The authors have
no relevant financial interest in
this article.

SUBJECTS
We recruited patients with DSO sequentially
from our regular office practice. No attempts
to randomize the patients were made, and the
study groups were recruited and studied se-

(REPRINTED) ARCH DERMATOL / VOL 140, JUNE 2004

691

quentially. The criterion for patient selection

was culture-proven DSO invasion of 60% or
more of the nail bed of the great toes.

CME course available at

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Oral informed consent was obtained
from each patient. Signed consent forms
were not used, and institutional approval
of this study of human subjects was
not sought. A few subjects recruited
for the study did not return for their
first monthly postrecruitment examination;
these patients were dropped from the study
and are not included in the intent-to-treat
analysis.
The study population consisted of adults
of both sexes. The disease studied, DSO, once
acquired, is a lifelong infection with no record or incidence of spontaneous recovery and
may have a familial component bearing on susceptibility and infection.

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Direction of Nail and Nail Bed Growth

0 Months

Notch Made to Mark Junction

of Normal/Infected Nail Bed

g
min
For

Extent of Normal Nail Bed, mm

Proximal
Nail Fold

Direction of Mycotic Invasion Into Nail Bed

Nail Plate
Infected Stratum
Corneum of
Nail Bed

Matrix of
Nail Plate

Matrix of
Nail Bed
0

Hyponychium
2

10

11

12
11
10
9
8
7
6
5
4
3
2
1
0
0 1 2 3 4 5 6 7 8 9 10 11 12

12

Treatment Duration, mo

Scale, mm
Nonmycotic Nail Bed Present
Infected Stratum Corneum of Nail Bed

Figure 1. Graphic illustration of the Zaias and Drachman1 method of monitoring clinical effect and cure of a great toenail 12 mm long with 75% of the toenail bed
invaded by Trichophyton rubrum prior to treatment with pulse-dosed terbinafine. Before treatment, a reference notch is made in the nail plate to mark the proximal
border of the nail bed mycosis and the baseline measurements. Note the plot (right) of the size of normal nail bed present prior to treatment. The presence of
T rubrum nail bed onychomycosis should be confirmed microscopically and by culture.

TREATMENT GROUPS
The first 20 patients in this pilot study were treated with 250
mg of terbinafine daily for 7 consecutive days per month. Following this, we treated 10 patients by administering the 7-day
pulse of terbinafine every 2 months, and then 12 patients by
administering the pulse every 3 months, and finally 17 patients by administering the treatment pulse every 4 months. Since
the results obtained from this last group indicated that we had
achieved the objective of the study, the study was terminated.
Our plan was to recruit at least 10 patients into each study
group after the first until a significant increase in treatment failures indicated a loss of depot effect. Seven patients were added
to the final group to verify the increased failures observed in
the first 10 patients.
CLINICAL EXAMINATION AND EVALUATION
OF TREATMENT EFFECT
Rationale of the Method Used
In DSO, T rubrum invades the nail bed in a proximal direction,
and, because of the normal growth of the nail, the overlying nail
plate moves in the contrary (distal) direction (Figure 1).1 An
effective antifungal compound (such as terbinafine) given by
mouth stops the proximally directed invasion of the mycosis in
the nail bed. Because the nail bed moves distally at the same rate
as the overlying nail plate, the inactive mycotic lesion will be carried distally by normal growth and is eventually desquamated at
the hyponychium (Figure 2). The growing new nail and nail
bed proximal to the mycotic nail bed replace the retreating inactivated mycosis and eventually occupy the entire nail bed. At this
point the DSO is totally cured. (This cure should be verified by
negative findings under potassium hydroxide and culture analysis.)
While foci of lasting damage to the nail unit may remain (whether
from DSO or another cause), these cannot be attributed to the
antifungal treatment and do not constitute treatment failure. In
the case of the toenail of the large toe, the nail plate and underlying nail bed stratum corneum advance distally at a rate of close

(REPRINTED) ARCH DERMATOL / VOL 140, JUNE 2004

692

to 1 mm per month, and, depending on the size of the toenail,

the mycosis will be totally cured 8 to 14 months from the start of
treatment.
Examination Strategy
The strategy we used to monitor therapeutic effect was to measure the increase in new normal (nonmycotic) nail bed monthly
until it occupied the entire nail bed from the nail matrix to the
hyponychium. At this point, we considered the disease cured.
Baseline Measurements
Our measurement method was first characterized by Zaias and
Drachman.1 Before treatment, a notch was cut into the surface of
the nail plate to mark the most proximal margin of the nail bed
lesion as seen through the transparent nail plate (ie, to mark the
most proximal edge of the visible onychomycosis or a point safely
proximal to it) (Figure 1). This notch served to mark the location of the distal edge of the normal noninfected nail bed before
therapy. We also measured the distance in millimeters between
the reference notch and some fixed reference point such as the
proximal nail fold. This measurement provided a baseline measurement of the nonmycotic nail bed at the start of treatment.
The entire nail bed distal to the reference notch was considered mycotic. Because the goal of therapy was to completely remove this area by desquamation at the hyponychium
before discontinuing treatment, no attempt was made to monitor treatment effect by evaluating severity, improvement, or worsening in this mycotic area. The nail bed was therefore considered to be divided into 2 parts: the distal mycotic nail bed already
invaded by the fungus and the proximal normal nail bed not
yet invaded by the fungus.
The objective of treatment was to increase the nonmycotic portion to 100% of the nail bed and reduce the mycotic
portion to 0% (Figure 2B) while holding the fungus in a nongrowing and noninvasive state. The pulsed treatments with terbinafine were continued until this objective was accomplished, at which point potassium hydroxide and culture analyses

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Direction of Nail and Nail Bed Growth

3 Months

Proximal
Nail Fold

g
min
For

Matrix of
Nail Plate

Nail Plate
Infected Stratum
Corneum of
Nail Bed
Matrix of
Nail Bed
0

Hyponychium
2

10

11

Extent of Normal Nail Bed, mm

Notch Made to Mark Junction

of Normal/Infected Nail Bed

12
11
10
9
8
7
6
5
4
3
2
1
0
0 1 2 3 4 5 6 7 8 9 10 11 12

12

Treatment Duration, mo

Scale, mm

Nonmycotic Nail Bed Present

Infected Stratum Corneum of Nail Bed

Direction of Nail and Nail Bed Growth

Cured New Nail

Proximal
Nail Fold

g
min
For

Nail Plate
No Infected
Nail Bed

Matrix of
Nail Plate

Matrix of
Nail Bed
0

Hyponychium
2

10

11

Extent of Normal Nail Bed, mm

9 Months
12
11
10
9
8
7
6
5
4
3
2
1
0

Cured

0 1 2 3 4 5 6 7 8 9 10 11 12

12

Treatment Duration, mo

Scale, mm

Figure 2. Graphic illustrations of the Zaias and Drachman1 method of monitoring clinical effect and cure of a great toenail 12 mm long with 75% of the toenail bed
invaded by Trichophyton rubrum after treatment has begun with pulse-dosed terbinafine. A, At the third monthly examination, distal movement of the reference
notch and the addition of new nonmycotic nail bed proximal to the reference notch indicate satisfactory inactivation of the mycotic invasion of the nail bed. Note
that 3 mm of normal nail bed have been added after 3 months of successful treatment. This is a feature of successful treatment, regardless of the interval between
pulse doses or treatment regimen used. B, At the 9-month examination, normal mycosis-free nail bed has totally replaced the affected area, and complete cure of
the T rubrum onychomycosis has been achieved. A fungus-negative state should be present and confirmed microscopically and by culture.

were performed to confirm the absence of fungus, and the mycosis was recorded as cured. Since this is a systemic treatment,
the final evaluation included the examination of all nails to ensure that the patient was entirely free of onychomycosis before declaring cure.

mal border of the nail bed mycosis to the proximal nail fold)
continued to coincide with the measurement from the reference notch to the proximal nail fold; it increased steadily at a
rate of close to 1 mm per month, and its growth could be plotted as a straight line (graph insets in Figure 2).

Monthly Examinations and Determination of Cure

Evidence and Determination of Treatment Failure

During the course of treatment, all patients were examined

monthly, and at each examination the distance from the most
proximal edge of the nail bed lesion (as seen through the transparent nail plate) to the proximal nail fold was noted. When
treatment was effective in inactivating the mycosis, the extent
of the nonmycotic nail bed (as measured from the most proxi-

If, on any monthly examination, the measurement of new nonmycotic nail bed (ie, the measurement from the most proximal border of the nail bed mycosis as seen though the transparent nail plate to the proximal nail fold) failed to show an
increase over the previous month (ie, measured less than the
measured distance to the reference notch), the result was in-

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Individual Patient
14 Patients at Inception
7 Patients Experienced Treatment Failure
R
x

7-Day Treatment Pulse Administered

Zone of Cure (Fungus-Free Nail Bed)

12
11

8 of 14
Patients
Cured

10

Extent of Normal Nail Bed, mm

1 Failure at 6 mo
8
7
6

1 Failure at 6 mo

2 Failures at 5 mo

4
3

1 Failure at 4 mo

1 Failure at 2 mo

1 Failure at 1 mo

0
0
R
x

R
x

10

11

12

R
x

Treatment Duration, mo

Figure 3. Schematic plot of the patients of group 4 who received a 7-day pulse
of terbinafine every 4 months. The plot shows the month during treatment when
failure to maintain fungistasis was detected. Except for the increase in failures,
this plot does not differ from those of the other groups of patients in the study.
With respect to the extent of nail bed invaded by Trichophyton rubrum at the
beginning of treatment, 50 (85%) of the 59 patients had a totally mycotic nail
bed, and of the 15% who had less than total involvement (3 in each of the 3
groups treated at 1-month intervals), 3 patients (1 in each of the 3 groups
treated at 1-month intervals) had 50% rather than 60% of the nail bed
involved. However, there is no evidence that this biased the results.

terpreted as a treatment failure (ie, the treatment failed to prevent growth of the fungus in a proximal direction from the reference notch into the previously normal nonmycotic nail bed).
Treatment failure was also evident and confirmed by simple
inspection (using the reference notch as a guide) with or without measurement.
Under these circumstances, it was assumed that the patient would not attain complete replacement of the mycotic nail
bed with new nonmycotic nail bed because the fungus was still
actively invading the nail bed in a proximal direction, and so
the patient was removed from the study protocol. Alternative
treatment, after failure, was left to the judgment of the physician and the patient.
RESULTS

The monthly treatment group received 11 seven-day pulses

of 250-mg terbinafine (19250 mg); the 2-month-interval
group received 6 pulses (10 500 mg); the 3-monthinterval group received 4 pulses (7000 mg); and the
4-month-interval group received 3 pulses (5250 mg). For
comparison, under standard therapy, a patient with 12 mm
of mycotic nail bed would require 250 mg of terbinafine
per day for 12 weeks, for a total of 21000 mg of drug.
Treatment failure occurred in 2 (10%) of the 20 patients in the monthly pulse group; 1 (10%) of the patients
(REPRINTED) ARCH DERMATOL / VOL 140, JUNE 2004
694

in the every-2-months group; and 0 of the 12 patients in

the every-3-months group. Taken together, this 7% failure rate (3/42) is significantly better than the 41% failure
rate (7/17) that occurred in the every-4-months treatment
group (P.01; 95% confidence interval, 0%-15%).
We were also able to compare the results of the
monthly treatment group in the present study with those
of a group of 20 patients treated earlier with itraconazole
(200-mg pulse twice daily for 7 consecutive days each
month). The patients in the itraconazole group experienced 5 failures and 15 cures, as has already been reported.2
Although the number of patients per group in the
present study is small, statistically significant results were
obtained.3 The depot drug effect of terbinafine, and a cure
rate of at least 90% of patients treated with 250 mg of
terbinafine per day for 7 consecutive days every month,
was maintained when the interval between 7-day pulses
was increased to 2 and even to 3 months. However, when
the interval between pulses was increased to 4 months,
a significant increase in failures occurred (7/17, 41%;
P.01), indicating that the interval between pulse doses
had been increased beyond the limit of the depot effect
in some patients (Figure 3).
Additionally, Figure 3 shows that detection of treatment failure in all treatment groups can occur at any time
during the course of treatment but occurs mainly in the
first 6 months. No failures occurred after the first 6 months
of treatment in the present study.
COMMENT

The treatment of 42 patients with 250-mg, pulseddosed terbinafine for 1 week every 1 to 3 months cured
39 (93%) of 42 patients with a 95% confidence interval
of 68% to 100% cured. This confidence interval is
higher on the percentage scale than the interval of cure
rates reported for terbinafine in the large studies that
provide the research data for the regimen of 250 mg/d
for 12 weeks recommended by the drug manufacturer
and approved by the US Food and Drug Adminstration.4-7 The higher overall level of success we achieved
(if verified in larger studies and clinical practice) is an
advantage that we do not ascribe to pulsed therapy but
rather to the abandonment of the 12-week fixed treatment period in favor of treatment continued until the
mycotic portion of the nail bed is shed at the hyponychium, which is the regimen recommended by Zaias
and Drachman.1 The advantages we see in a pulseddose schedule of 1 week of treatment every 3 months
are reduced costs to patients and medical insurance
providers and the possibility of a decreased risk of adverse drug effects. The reduced-cost benefit is the result
of the reduction in total milligrams of terbinafine required to cure the initially infected nail bed.
Accepted for publication November 25, 2003.
Portions of this research were presented in a seminar
at the 20th World Congress of Dermatology; July 5, 2002;
Paris, France.
Corresponding author and reprints: Nardo Zaias, MD,
Greater Miami Skin and Laser Center and Mount Sinai MediWWW.ARCHDERMATOL.COM

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cal Center, 4302 Alton Rd, Suite 1005, Miami Beach, FL

33140 (e-mail: nardozaias@aol.com).
REFERENCES
1. Zaias N, Drachman D. A method for the determination of drug effectiveness in
onychomycosis. J Am Acad Dermatol. 1983;9:912-919.
2. Zaias N, Rebell G. Onychomycosis tested until nail is replaced by normal growth
or there is failure. Arch Dermatol. 2000;136:940.

3. Pocock ST. Clinical Trials: A Practical Approach. New York, NY: John Wiley &
Sons; 1983.
4. Drake LA, Shear NH, Arlette JP, et al. Oral terbinafine in the treatment of toenail infection: North American multicenter trial. J Am Acad Dermatol. 1997;37:740-745.
5. Brautigam M. Terbinafine vs itraconazole: a controlled clinical comparison in onychomycosis of the toenails. J Am Acad Dermatol. 1998;38:S53-S56.
6. De Backer M, DeVraey C, Scheys I, Keyser P. Twelve weeks of continuous oral terbinafine for toenail onychomycosis. J Am Acad Dermatol. 1998;38:S57-S63.
7. Evans EG, Sigurgeirrson B. Double-blind randomised study of continuous terbinafine compared with intermittent itraconazole in treatment of toenail onychomycosis. BMJ. 1999;318:1031-1035.

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