Treatment with terbinafine in children

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Efficacy and tolerability of 8 weeks’ treatment with terbinafinein children with tinea capitis caused byMicrosporum canis:a comparison of three doses

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© 2004 European Academy of Dermatology and Venereology

155

ORIGINAL ARTICLE

JEADV

(2004)

18

, 155–159

Blackwell Publishing Ltd.

Efficacy and tolerability of 8 weeks’ treatment with terbinafine
in children with tinea capitis caused by

Microsporum canis

:
a comparison of three doses

D



Devliotou-Panagiotidou,

1



TH



Koussidou-Eremondi

2,

*

1

Department of Dermatology, Aristoteles University of Thessaloniki,

2

Mycological Laboratory of the State Hospital for Skin and Venereal Diseases,
Chalkidikis 51, GR-54644, Thessaloniki, Greece.

*

Corresponding author, tel. +30310 886300; fax +850762; E-mail: [email protected]

ABSTRACT

Background

Tinea capitis caused by

Microsporum canis

is the most common mycosis of the scalp in pre-
school and school-aged children in Greece.

Objective

To compare the efficacy, safety and tolerability of an 8-week course of oral terbinafine at different
doses.

Methods

Patients received oral terbinafine at doses ranging from 3.3 to 12.5 mg/kg/day for 8 weeks, as
follows: group A, terbinafine 3.3 to



6.0 mg/ kg/ day (40 patients); group B, terbinafine > 6.0 to 7.0 mg/ kg/ day
(23 patients); group C, terbinafine > 7.0 to 12.5 mg/kg/day (37 patients). Fungal microscopy and cultures
were performed 4 weeks before the start of the treatment, at the end of the treatment (week 8) and at a follow-
up visit at week 16.

Results

At week 8 mycological cure was achieved in one patient (2.7%) in group A, in 21 patients (91.3%)
in group B and in 34 patients (97.1%) in group C. At week 16 mycological cure was achieved in one patient
(2.7%) in group A, in 22 patients (95.7%) in group B and in 35 patients (100%) in group C

.

There was a
statistically significant difference (

P

< 0.0005) between dose level and efficacy of terbinafine at the end of the
treatment period and also at the follow-up visit at week 16. Five patients (three in group A and two in
group C) discontinued treatment because of adverse events.

Conclusions

The administration of terbinafine at a dose of either 6–7 or 7–12.5 mg/kg/day for 8 weeks is
safe and effective for the treatment in children of tinea capitis caused by

M. canis

.

Key words:

tinea capitis,

Microsporum canis

, terbinafine, children

Received: 26 August 2002, accepted 13 February 2003

Introduction

Studies on the epidemiology of tinea capitis in children in
Greece suggest that the most common causative agent is

Microsporum canis.

1–3

In other Western European countries
(the UK) and in the USA,

Trichophyton tonsurans

is the most
prevalent species,

4–7

while in Eastern Europe

T. mentagrophytes

is the most common species isolated.

8

Recently there has been
an increase of tinea capitis caused by

M. rivalieri

and

M.
audouinii

in the UK,

5

especially in the Black African and
Black Caribbean ethnic groups. A similar increase has been
seen with

T. soudanense

in Europe (France, Germany, Spain) in
Black immigrants from Africa.

9–11

In Italy the most prevalent
species is

M.

canis,

12

similar to that seen in Greece

.

The effectiveness of terbinafine in the treatment of tinea
capitis infection, especially when caused by

M. canis

, has been
shown to be variable.

13

The usual daily dose of terbinafine
administered is 62.5 mg for children weighing less than 20 kg,
125 mg for children weighing 20–40 kg and 250 mg for those
weighing more than 40 kg. This dosage regimen has been
tested in several studies for periods of between 2 and 12 weeks.

14,15

Trichophytic scalp infections caused by

T. violaceum

or

T.
soudanense

respond well to this dose regimen, while

Microsporum

infections, especially those caused by

M. canis

, need treatment
for longer periods to achieve acceptable cure rates.

16–19

The
authors of these studies highlight the need for further investiga-
tion into the most appropriate dose and duration of treatment
with terbinafine for tinea capitis in childhood caused by
156

Devliotou-Panagiotidou and Koussidou-Eremondi

© 2004 European Academy of Dermatology and Venereology

JEADV

(2004)

18

, 155–159

Microsporum

species.

13,16–20

This is particularly relevant as

M. canis

is the most common cause of tinea captis infection in
Greece, accounting for 88% of all cases.

1

In the present study a comparison was made between the
efficacy, safety and tolerability of an 8-week course of oral
terbinafine at different doses in children with tinea capitis
caused by

M. canis.

Subjects and methods

This was an open label study that included a total of 116
children with tinea capitis caused by

M. canis

. Patients were
enrolled in the study, with parental consent, between December
1998 and January 2001, with 100 in total being evaluable. Their
ages ranged from 2.5 to 9 years. The incidence in males was
higher than that in female subjects, with 61 boys infected
compared to 39 girls. The duration of infection ranged from
10 to 120 days. Immunocompromised children and those
receiving any systemic antifungal agents (within 3 months prior
to the start of treatment) or topical antifungal agents (within
14 days prior to the start of treatment) were excluded. The
majority of the children presented with ‘grey-patch ringworm’
tinea capitis (fig. 1) and only 16 children presented with kerion
(nine boys and seven girls). None of the children presented with
lymphadenopathy and concomitant microbial infection was
not observed. The size of the ‘tinea worm’ patches ranged from
1 to 6 cm.
The daily doses of terbinafine administered were based on
body weight as detailed in Table 1. The body weight of the
children ranged from 13 to 35 kg.
The patients formed three groups according to body weight
and daily dose of terbinafine received:
group A (

n

= 40) received 3.3 to



6.0 mg/ kg/day of terbinafine;
group B (

n

= 23) received > 6.0 to 7.0 mg/ kg/day of terbinafine;
group C (

n

= 37) received > 7.0 to 12.5 mg/ kg/day of terbinafine.
For the administration of terbinafine, the parents were
instructed to pulverize the tablets and divide the powdered drug
into equal quantities according to the weight of the children.
The powder was then mixed with honey or marmalade to aid in
swallowing. All patients were treated for 8 weeks.
As an adjunct to terbinafine therapy, parents were also
instructed to wash their children’s hair with zinc pyrithione
shampoo (Froika 1%) at least three times a week until the end
of the treatment period. This shampoo is an antimicrobial,
antiseborrheic agent with antifungal properties against

Pytiro-
sporum ovale

, used for removing scaling and dandruff from the
hair.

21,22

As exothrix fungal infections present with a large number of
arthroconidia on the hair surface, the most suitable method for
removing infected hair masses is by hair cutting.

23,24

Therefore,
parents were instructed to cut their children’s hair on, or 1 cm
around, the patches at the start and during week 4 of the treat-
ment period. In cases of kerion, parents were instructed to use
tweezers to remove from patches any infected hair that could be
detached without any resistance or pain, and also to cut the hair
around the patches as described previously.
Compliance was assessed by asking the parents at each
scheduled visit about the number of tablets taken.
The children were examined at visit 1 (4 weeks before com-
mencement of treatment), visit 2 (beginning of the treatment
period), visit 3 (week 8 at the end of the treatment period) and
visit 4 (week 16, the follow-up visit). Mycological examinations
were performed at each visit except for visit 2, and included
30% KOH preparation of scales and hair plus cultures in
Sabouraud dextrose agar medium containing chloramphenicol
and cycloheximide at 28

°

C for 3 weeks. Haematological and
biochemical profiles for renal and hepatic parameters were
performed before and after treatment at visits 2 and 3. Patients’
history and characteristics were noted before commencement
of treatment (visit 2).
The clinical status of tinea capitis was documented at visits 2,
3 and 4 as presence or absence of inflammatory signs including
oedema (kerion), size, desquamation, erythema, hair loss and
pruritus and assessed according to a four-point ordinal scale (where
0 = none, 1 = mild, 2 = moderate and 3 = severe). Efficacy was
assessed in terms of clinical evaluation (signs and symptoms)
and mycological outcome (microscopy/culture) and was categ-
orized in the following groups: cure, improvement and failure.
Cure was achieved if the patients had a negative microscopy and
culture, with a total score



2 for signs and symptoms. Improve-
ment was achieved if the patients had a positive microscopy and fig. 1 ‘Grey-patch ringworm’ tinea capitis.
Table 1 Terbinafine dose administered, dependent on body weight


Weight ( kg) Dose (mg)
< 20 62.5
20–40 125
> 40 250
< 20 125
20–40 250
> 40 500
Terbinafine dosing in children with tinea capitis due to

M. canis

157

© 2004 European Academy of Dermatology and Venereology

JEADV

(2004)

18

, 155–159

positive or negative culture, with a total score



2 for signs and
symptoms. Positive microscopy and culture with a total score
> 2 for signs and symptoms was categorized as failure.
Tolerability was assessed using a three-point scale: very good
(no signs and symptoms), moderate (transient side-effects) and
poor (adverse events which resulted in discontinuation of
therapy).
Data were analysed on an intention-to-treat basis. Other
statistical analyses included Student’s

t

-test or the Welch-test for
continuous variables, the

χ

2

-test for the qualitative variables
and the Binomial test for the comparisons of long-term efficacy.
Comparisons in efficacy between dosage regimens were made
using the

χ

2

-test. All tests were two-sided, with a significance
level of

P

< 0.05. The SPSS version 8 statistical package was used
to carry out the statistical analysis.

Results

The total terbinafine dose ranged from 3.3 to 12.5 mg/ kg/day.
Fourteen children (14%) received 62.5 mg/day, 57 (57%) received
125 mg/day and 29 (29%) received 250 mg/day. There was no
statistical difference between groups for daily dose, duration of
infection, age of the patients or male to female ratio (Table 2).
During the second week of treatment, three children in
group A and two in group C presented with a skin rash (urticaria
in two cases and confluent macular eruption in the other three
cases). All five patients withdrew from the study because of
these adverse events. One child from group A presented with
transient macular eruption in the eighth week of treatment.
However, treatment was not discontinued. Tolerability of
terbinafine was considered as ‘very good’ in 94 children (94%),
‘moderate’ in one child (1%) and ‘poor’ in the remaining five
children (5%).
Blood counts, renal and liver function tests were within normal
limits in the six patients with moderate or poor tolerability.
Furthermore, the results from the haematological and bio-
chemistry tests did not show any significant abnormalities in
the three dosage groups during visits 2 and 3.
Comparison of the clinical response at weeks 8 and 16 revealed
a statistically significant difference between the three dosage
groups (

P

< 0.0005) (Table 3). The percentage of patients achieving
cure at weeks 8 and 16, respectively, was 13.5% and 16.2% for
group A, 65.2% and 95.7% for group B, and 97.1% and 100%
for group C.
At week 8, cure (mycological cure) was achieved in one patient
(2.7%) in group A, in 21 patients (91.3%) in group B and in 34
patients (97.1%) in group C. At week 16, mycological cure was
achieved in one patient (2.7%) in group A, 22 patients (95.7%)
in group B and in 35 patients (100%) in group C. These data
demonstrate a statistically significant difference between dose
and efficacy of terbinafine at the end of the treatment period
(week 8) and at the follow-up visit at week 16 (

P

< 0.0005).

Discussion

The aim of our study was to compare the efficacy, safety and
tolerability of 8 weeks of treatment with terbinafine at different
doses in children infected by

M. canis

. Of the children treated
with a terbinafine dose of > 6.0 to 7.0 mg/ kg/ day (group B),
91.3% were mycologically cured at week 8 (end of treatment
period) and 95.7% were mycologically cured at week 16 (last
follow-up visit). Of the children treated with a terbinafine dose
of > 7.0 to 12.5 mg/kg/day (group C), 97.1% were mycologically
cured at the end of the treatment period and 100% were
mycologically cured at week 16 (follow-up visit). Children treated
with a terbinafine dose of 3.3 to



6 mg/ kg/ day (group A) had
poor mycological results; that is only 2.7% were cured at the end
of the treatment period and at the follow-up visit at week 16.
Table 2 Patient demographic data


Group A Group B Group C P-value
Terbinafine (mg/ kg/ day) ≤ 6 6–7 > 7
No. of patients 40 23 37
Duration of present
infection (days)
35.00 26.65 38.32 0.2 (NS)
Age (years) 5.65 4.78 5.42 0.08 (NS)
Male : Female (n) 27 : 13 11 : 12 23 : 14 0.3 (NS)
Table 3 Number and percentage of patients achieving mycological cure or satisfactory clinical response to the therapy (no signs and symptoms or signs and
symptoms ≤ 2) at weeks 8 and 16


Treatment end (week 8) Follow-up (week 16)
Clinical signs and
symptoms ≤≤≤ ≤ 2 Mycological cure
Clinical signs and
symptoms ≤≤≤ ≤ 2 Mycological cure
Group A, n (%) 5 (13.5) 1 (2.7) 6 (16.2) 1 (2.7)
Terbinafine (≤ 6 mg/ kg/day)
Group B, n (%) 15 (65.2) 21 ( 91.3) 22 (95.7) 22 (95.7)
Terbinafine (> 6–7 mg/ kg/day)
Group C, n (%) 34 ( 97.1) 34 (97.1) 35 (100) 35 (100)
Terbinafine (> 7 mg/ kg/day)
P-value < 0.0005 < 0.0005
158

Devliotou-Panagiotidou and Koussidou-Eremondi

© 2004 European Academy of Dermatology and Venereology

JEADV

(2004)

18

, 155–159

Previous studies have suggested that 4 weeks of treatment
with terbinafine is insufficient for

Microsporum

infections.

13,16–20

Two weeks of treatment was sufficient in most

Trichophyton

scalp infections (86%), but an acceptable cure rate in

M. canis

infections was achieved only after an additional 4 weeks of
treatment.

18

Other investigators have suggested that a 6-week
course of terbinafine is inadequate for tinea capitis due to

M. canis

and they have highlighted the need for further studies
with a longer duration of therapy.

17

In other analyses, however,
the complete cure rate seen in the shorter studies was not
exceeded with a longer duration of therapy.

19,20

It would seem
that with

Microsporum-

related tinea capitis, treatment duration
is not necessarily related to efficacy.

19

Other investigators have suggested that complete cure rates
are significantly correlated with a daily dose of terbinafine
according to body weight: children weighing 12.5–25 kg should
receive 125 mg/day, and those weighing over 25 kg should receive
250 mg/day.

25

In recent studies a significant linear relationship
(

P =

0.03) was observed between complete cure rates and the
weight-adjusted daily dose of terbinafine. Patients receiving
doses above the median (4.5 mg/kg) achieved higher cure rates,
irrespective of treatment duration.

19,20

In our study, terbinafine was administered for 8 weeks to all
children, but in three different dosage regimens according
to their weight. Treatment was well tolerated. Adverse events
occurred in only 5% of the patients and did not seem to be
related to the dose level or to treatment duration. Rashes were
not deemed to be an idiopathic reaction as skin eruptions
occurred 2–5 months after the onset of tinea capitis and id reac-
tions usually present 1–2 weeks after the primary infection.
Additionally, skin eruptions in these patients occurred during the
second week of treatment (typical time of onset for a drug-related
skin eruption) and resolved after treatment was discontinued.
This study demonstrates that the administration of terbinafine
at a dose of either 6.0–7.0 mg/kg/day or 7.0–12.5 mg/ kg/day
for 8 weeks in children with tinea capitis caused by

M. canis

is
safe and effective. In conclusion, based on the efficacy and safety
data in this study, the optimal dose of terbinafine in the treatment
of tinea capitis due to

M. canis

, in children, is 6.0–7.0 mg/ kg/
day for a duration of 8 weeks.

Acknowledgements

This study was supported by Novartis.

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