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Oral antifungal agents for
onychomycosis

Onychomycosis affects about
7–8% of the North

American population.1 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.2

An important advance in its
management is the

development of oral
antifungal agents and methods of

their administration.

 

…

 

The newer generation
of oral antifungal agents for the

treatment of
onychomycosis are terbinafine,8 itraconazole,

and fluconazole.
Itraconazole, a triazole, was first

approved for the
treatment of onychomycosis as a

continuous regimen
in Mexico in 1989.9 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.9,10

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.11-13 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.6 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 costeffective

treatments, with
no significant difference between them.6

 

 

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.14 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

investigators14 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.15

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.16

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.

 

 

Aditya K Gupta,
*Richard K Scher

Division of Dermatology, Department of Medicine, Sunnybrook
Health

Science Center, University of Toronto, Ontario, Canada;

*Department of Dermatology, College of Physicians and
Surgeons,

Columbia University of New York, NY 10032, USA

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patients visiting dermatologists’ offices in Ontario,
Canada—a

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783–87.

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Dermatol 1994; 130 (suppl
43): 15.

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overview.

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Dermatol 1994; 30: 677–98.

4 Epstein WL, Riegelman S. Griseofulvin levels in stratum
corneum.

Arch Dermatol 1972; 106: 344–48.

5 Meinhof W. Kinetics and spectrum of activity of oral
antifungals: the

therapeutic implications. J Am Acad Dermatol 1993; 29:
S37–41.

6 Gupta AK. Pharmacoeconomic analysis of oral antifungal
therapies

used to treat dermatophyte onychomycosis of the toenails.

Pharmacoeconomics 1998; 13: 1–15.

7 Harris R, Jones HE, Artis WM. Orally administered
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8 Gupta AK, Shear NH.Terbinafine: an update. J Am Acad Dermatol

1997; 37: 979–88.

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10 De Doncker P, Decroix J, Giérard GE, et al. Antifungal
pulse therapy

for onychomycosis: a pharmacokinetic and pharmacodynamic

investigation of monthly cycles of 1-week pulse therapy with

itraconazole. Arch
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11 Schatz F, Bräutigam M, Dobrowolski E, et al. Nail
incorporation

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1995; 20: 377–83.

12 Cauwenbergh G, Degreef H, Heykants J,Woestenborghs R,

Van Rooy P, Haeverans K. Pharmacokinetic profile of orally

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13 Scher 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

14 Tausch
I, Bräutigam M,Weidinger G, Jones TC, the Lagos V Study

Group.
Evaluation 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: 737–42.

15 Havu V,
Brandt H, Heikkilä H, et al. A double-blind, randomized

study
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the
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230–34.

16 Gupta
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American
perspective. Dermatol Ther 1997; 3: 58–65.

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