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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
had completely removed the mycotic defect or failure of rubrum nail bed onychomycosis (or distal subungual ony- chomycosis [DSO]) with daily terbinafine for 12 weeksinvolves treating for a fixed period shorter than the time Main Outcome Measurement: Results were deter-
required for complete replacement of the nail bed and mined by monthly evaluation. Cure was noted as com- overlying nail plate by normal growth. The same total plete replacement of the mycotic nail bed and overlying amount of terbinafine pulse-dosed for approximately 12 nail plate (ascertained by monthly metric measure- months would treat the patient until normal replace- ments of the mycosis-free nail bed and overlying nail place ment of the mycotic nail bed has occurred.
distal to the proximal nail fold). Treatment failure wasnoted when the mycosis-free proximal portion of the nail Objectives: To determine the effectiveness of intermit-
bed failed to increase in correspondence with the dis- tent administration of oral terbinafine (250 mg/d for 7 tally directed movement of the nail bed and overlying nail.
consecutive days every 2-4 months) to cure DSO and todetermine the maximum effective treatment interval.
Results: Thirty-nine (93%) of the 42 patients in the first
3 groups were cured (95% binomial confidence interval,
Design: A prospective, nonrandomized, open study of
67%-100%) with no evidence of decrease in efficacy. How- sequential groups of office patients.
ever, the group of patients who received the 7-day pulsetreatment every 4 months experienced significantly more Setting: A private dermatology practice.
failures (PϽ.01), and cures dropped to 10 of 17 cases.
Methods: A sequence of 4 groups of office patients with
Conclusion: Terbinafine is an effective treatment for DSO
DSO (n = 10-20 each) were treated with pulse-dosed ter- when pulse-dosed for 7 days every 3 months but not ev- binafine for 7 consecutive days at intervals of 2, 3, and 4 months, respectively. In each group, treatment was con-tinued until the distally advancing new nail bed and nail WEUNDERTOOKTHIS quentially.Thecriterionforpatientselection
was culture-proven DSO invasion of 60% or more of the nail bed of the great toes.
CME course available at
questions: (1) Is pulse-dosed oral terbin- www.archdermatol.com
afine effective in treating Trichophyton ru-brum nail bed onychomycosis (distal sub-ungual onychomycosis [DSO])? and (2) from each patient. Signed consent formswere not used, and institutional approval o f t h i s s t u d y o f h u m a n s u b j e c t s w a s n o t s o u g h t . A f e w s u b j e c t s r e c r u i t e d for the study did not return for theirfirst monthly postrecruitment examination;these patients were dropped from the study and are not included in the intent-to-treatanalysis.
SUBJECTS
of both sexes. The disease studied, DSO, once We recruited patients with DSO sequentially acquired, is a lifelong infection with no rec- from our regular office practice. No attempts ord or incidence of spontaneous recovery and to randomize the patients were made, and the may have a familial component bearing on sus- study groups were recruited and studied se- (REPRINTED) ARCH DERMATOL / VOL 140, JUNE 2004 2004 American Medical Association. All rights reserved.
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Direction of Mycotic Invasion Into 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
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 The first 20 patients in this pilot study were treated with 250 mg of terbinafine daily for 7 consecutive days per month. Fol-lowing this, we treated 10 patients by administering the 7-day Examination Strategy
pulse of terbinafine every 2 months, and then 12 patients byadministering the pulse every 3 months, and finally 17 pa- The strategy we used to monitor therapeutic effect was to mea- tients by administering the treatment pulse every 4 months. Since sure the increase in new normal (nonmycotic) nail bed monthly the results obtained from this last group indicated that we had until it occupied the entire nail bed from the nail matrix to the achieved the objective of the study, the study was terminated.
hyponychium. At this point, we considered the disease cured.
Our plan was to recruit at least 10 patients into each study group after the first until a significant increase in treatment fail- Baseline Measurements
ures indicated a loss of depot effect. Seven patients were addedto the final group to verify the increased failures observed in Our measurement method was first characterized by Zaias and Drachman.1 Before treatment, a notch was cut into the surface ofthe nail plate to mark the most proximal margin of the nail bed CLINICAL EXAMINATION AND EVALUATION
lesion as seen through the transparent nail plate (ie, to mark the OF TREATMENT EFFECT
most proximal edge of the visible onychomycosis or a point safelyproximal to it) (Figure 1). This notch served to mark the loca- Rationale of the Method Used
tion of the distal edge of the normal noninfected nail bed beforetherapy. We also measured the distance in millimeters between In DSO, T rubrum invades the nail bed in a proximal direction, the reference notch and some fixed reference point such as the and, because of the normal growth of the nail, the overlying nail proximal nail fold. This measurement provided a baseline mea- plate moves in the contrary (distal) direction (Figure 1).1 An
surement of the nonmycotic nail bed at the start of treatment.
effective antifungal compound (such as terbinafine) given by The entire nail bed distal to the reference notch was con- mouth stops the proximally directed invasion of the mycosis in sidered mycotic. Because the goal of therapy was to com- the nail bed. Because the nail bed moves distally at the same rate pletely remove this area by desquamation at the hyponychium as the overlying nail plate, the inactive mycotic lesion will be car- before discontinuing treatment, no attempt was made to moni- ried distally by normal growth and is eventually desquamated at tor treatment effect by evaluating severity, improvement, or wors- the hyponychium (Figure 2). The growing new nail and nail
ening in this mycotic area. The nail bed was therefore consid- bed proximal to the mycotic nail bed replace the retreating inac- ered to be divided into 2 parts: the distal mycotic nail bed already tivated mycosis and eventually occupy the entire nail bed. At this invaded by the fungus and the proximal normal nail bed not point the DSO is totally cured. (This cure should be verified by negative findings under potassium hydroxide and culture analysis.) The objective of treatment was to increase the nonmy- While foci of lasting damage to the nail unit may remain (whether cotic portion to 100% of the nail bed and reduce the mycotic from DSO or another cause), these cannot be attributed to the portion to 0% (Figure 2B) while holding the fungus in a non- antifungal treatment and do not constitute treatment failure. In growing and noninvasive state. The pulsed treatments with ter- the case of the toenail of the large toe, the nail plate and under- binafine were continued until this objective was accom- lying nail bed stratum corneum advance distally at a rate of close plished, at which point potassium hydroxide and culture analyses (REPRINTED) ARCH DERMATOL / VOL 140, JUNE 2004 2004 American Medical Association. All rights reserved.
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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 my- mal border of the nail bed mycosis to the proximal nail fold) cosis was recorded as cured. Since this is a systemic treatment, continued to coincide with the measurement from the refer- the final evaluation included the examination of all nails to en- ence notch to the proximal nail fold; it increased steadily at a sure that the patient was entirely free of onychomycosis be- rate of close to 1 mm per month, and its growth could be plot- ted 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 If, on any monthly examination, the measurement of new non- monthly, and at each examination the distance from the most mycotic nail bed (ie, the measurement from the most proxi- proximal edge of the nail bed lesion (as seen through the trans- mal border of the nail bed mycosis as seen though the trans- parent nail plate) to the proximal nail fold was noted. When parent nail plate to the proximal nail fold) failed to show an treatment was effective in inactivating the mycosis, the extent increase over the previous month (ie, measured less than the of the nonmycotic nail bed (as measured from the most proxi- measured distance to the reference notch), the result was in- (REPRINTED) ARCH DERMATOL / VOL 140, JUNE 2004 2004 American Medical Association. All rights reserved.
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in the every-2-months group; and 0 of the 12 patients in the every-3-months group. Taken together, this 7% fail-ure rate (3/42) is significantly better than the 41% failure rate (7/17) that occurred in the every-4-months treatment group (PϽ.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 eachmonth). The patients in the itraconazole group experi- enced 5 failures and 15 cures, as has already been re- Although the number of patients per group in the present study is small, statistically significant results wereobtained.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 pulseswas 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%; PϽ.01), indicating that the interval between pulse doseshad been increased beyond the limit of the depot effect in some patients (Figure 3).
Additionally, Figure 3 shows that detection of treat- ment failure in all treatment groups can occur at any time during the course of treatment but occurs mainly in thefirst 6 months. No failures occurred after the first 6 months 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 whenfailure 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 thebeginning of treatment, 50 (85%) of the 59 patients had a totally mycotic nail The treatment of 42 patients with 250-mg, pulsed- bed, and of the 15% who had less than total involvement (3 in each of the 3groups treated at Ͼ1-month intervals), 3 patients (1 in each of the 3 groups dosed terbinafine for 1 week every 1 to 3 months cured treated at Ͼ1-month intervals) had 50% rather than 60% of the nail bed 39 (93%) of 42 patients with a 95% confidence interval involved. However, there is no evidence that this biased the results.
of 68% to 100% cured. This confidence interval ishigher on the percentage scale than the interval of cure terpreted as a treatment failure (ie, the treatment failed to pre- rates reported for terbinafine in the large studies that vent growth of the fungus in a proximal direction from the ref- provide the research data for the regimen of 250 mg/d erence notch into the previously normal nonmycotic nail bed).
for 12 weeks recommended by the drug manufacturer Treatment failure was also evident and confirmed by simple and approved by the US Food and Drug Adminstra- inspection (using the reference notch as a guide) with or with- tion.4-7 The higher overall level of success we achieved (if verified in larger studies and clinical practice) is an Under these circumstances, it was assumed that the pa- advantage that we do not ascribe to pulsed therapy but tient would not attain complete replacement of the mycotic nail rather to the abandonment of the 12-week fixed treat- bed with new nonmycotic nail bed because the fungus was stillactively invading the nail bed in a proximal direction, and so ment period in favor of treatment continued until the the patient was removed from the study protocol. Alternative mycotic portion of the nail bed is shed at the hypo- treatment, after failure, was left to the judgment of the physi- nychium, which is the regimen recommended by Zaias and Drachman.1 The advantages we see in a pulsed-dose schedule of 1 week of treatment every 3 months are reduced costs to patients and medical insuranceproviders and the possibility of a decreased risk of ad- The monthly treatment group received 11 seven-day pulses verse drug effects. The reduced-cost benefit is the result of 250-mg terbinafine (19250 mg); the 2-month-interval of the reduction in total milligrams of terbinafine re- group received 6 pulses (10 500 mg); the 3-month- quired to cure the initially infected nail bed.
interval group received 4 pulses (7000 mg); and the4-month-interval group received 3 pulses (5250 mg). For Accepted for publication November 25, 2003. comparison, under standard therapy, a patient with 12 mm Portions of this research were presented in a seminar of mycotic nail bed would require 250 mg of terbinafine at the 20th World Congress of Dermatology; July 5, 2002; per day for 12 weeks, for a total of 21000 mg of drug.
Treatment failure occurred in 2 (10%) of the 20 pa- Corresponding author and reprints: Nardo Zaias, MD, tients in the monthly pulse group; 1 (10%) of the patients Greater Miami Skin and Laser Center and Mount Sinai Medi- (REPRINTED) ARCH DERMATOL / VOL 140, JUNE 2004 2004 American Medical Association. All rights reserved.
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cal Center, 4302 Alton Rd, Suite 1005, Miami Beach, FL 3. Pocock ST. Clinical Trials: A Practical Approach. New York, NY: John Wiley & 33140 (e-mail: [email protected]). 4. Drake LA, Shear NH, Arlette JP, et al. Oral terbinafine in the treatment of toenail in- fection: North American multicenter trial. J Am Acad Dermatol. 1997;37:740-745.
5. Brautigam M. Terbinafine vs itraconazole: a controlled clinical comparison in ony- chomycosis 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 ter- 1. Zaias N, Drachman D. A method for the determination of drug effectiveness in binafine for toenail onychomycosis. J Am Acad Dermatol. 1998;38:S57-S63.
onychomycosis. J Am Acad Dermatol. 1983;9:912-919.
7. Evans EG, Sigurgeirrson B. Double-blind randomised study of continuous ter- 2. Zaias N, Rebell G. Onychomycosis tested until nail is replaced by normal growth binafine compared with intermittent itraconazole in treatment of toenail onycho- or there is failure. Arch Dermatol. 2000;136:940.
mycosis. BMJ. 1999;318:1031-1035.
C ongratulations to the winner of our March quiz, Laxmisha Chan-
drashekar, MD, DNB, senior resident, Department of Dermatology and STD, Jawaharlal Institute of Postgraduate Medical Education and Research,Pondicherry, India. The correct answer to our March challenge was mycosis fun-goides. For a complete discussion of this case, see the Off-Center Fold sectionin the April ARCHIVES (Papadopoulos EJ, Jaffe ES, Elgart GW, Raffeld M, TurnerML. Periodic fever with dyshidrosis. Arch Dermatol. 2004;140:479-484).
Be sure to visit the Archives of Dermatology World Wide Web site (http: //www.archdermatol.com) to try your hand at the Interactive Quiz. We invitevisitors to make a diagnosis based on selected information from a case reportor other feature scheduled to be published in the following month’s print edi-tion of the ARCHIVES. The first visitor to e-mail our Web editors with the cor-rect answer will be recognized in the print journal and on our Web site andwill also receive a free copy of the The Art of JAMA II.
(REPRINTED) ARCH DERMATOL / VOL 140, JUNE 2004 2004 American Medical Association. All rights reserved.
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