A prospective two-year assessment of miconazole resistance in Candida spp. With repeated treatment with 0.25% miconazole nitrate ointment in neonates and infants with moderate to severe diaper dermatitis complicated by cutaneous candidiasis


Blanco, D.; van Rossem, K.

Pediatric Dermatology 30(6): 717-724

2014


A petrolatum and zinc oxide-based ointment containing 0.25% miconazole nitrate is reported to be effective and well tolerated in the treatment of diaper dermatitis complicated by cutaneous candidiasis (DDCC). This prospective, multicenter, open-label, long-term, phase IV study investigated the potential resistance of Candida spp. to repeated topical use of 0.25% miconazole nitrate in infants age 15 months and younger with moderate to severe DDCC. For initial and recurring episodes of DDCC over the 2-year study period, subjects were treated with a 7-day course of 0.25% miconazole nitrate ointment (active components: miconazole nitrate 0.25%, zinc oxide 15%, and white petrolatum 81.35%) with a 7-day follow-up. Clinical and mycologic evaluations were conducted before treatment (day 0) and 7 days after treatment (day 14). Potential resistance to miconazole was defined using an arbitrary breakpoint of minimum inhibitory concentration of 2 μg/mL. There was no evidence of resistance to miconazole in Candida spp. after single or repeated treatment courses of 0.25% miconazole nitrate ointment. For the initial episode of DDCC, 83 of 168 subjects (49.4%) achieved a clinical cure, 77 (45.8%) achieved a mycologic cure, and 49 (29.2%) achieved an overall cure (clinical and mycologic). The overall cure rate for recurrent episodes of DDCC was similar to or numerically greater than rates observed for the initial episode. Treatment of DDCC with 0.25% miconazole nitrate ointment was effective and generally well tolerated. No evidence of the development of resistance to miconazole in Candida spp. was observed.

Pediatric
Dermatology
Vol.
30
No.
6
717-724,
2013
A
Prospective
Two-Year
Assessment
of
Miconazole
Resistance
in
Candida
Spp.
with
Repeated
Treatment
with
0.25%
Miconazole
Nitrate
Ointment
in
Neonates
and
Infants
with
Moderate
to
Severe
Diaper
Dermatitis
Complicated
by
Cutaneous
Candidiasis
Daisy
Blanco,
M.D.,*
and
Koen
van
Rossem,
M.D.t
*Institute
of
Dermatology,
Santo
Domingo,
Dominican
Republic,
tStiefel,
a
GSK
company,
Wavre,
Belgium
Abstract:
A
petrolatum
and
zinc
oxide-based
ointment
containing
0.25%
miconazole
nitrate
is
reported
to
be
effective
and
well
tolerated
in
the
treatment
of
diaper
dermatitis complicated
by
cutaneous
candidiasis
(DDCC).
This
prospective,
multicenter,
open-label,
long-term,
phase
IV
study
investigated
the
potential
resistance
of
Candida
spp.
to
repeated
topical
use
of
0.25%
miconazole
nitrate
in
infants
age
15
months
and
younger
with
moderate
to
severe
DDCC.
For
initial
and
recurring
episodes
of
DDCC
over
the
2-year
study
period,
subjects
were
treated
with
a
7-day
course
of
0.25%
miconazole
nitrate
ointment (active
components:
mico-
nazole
nitrate
0.25%,
zinc
oxide
15%,
and
white
petrolatum 81.35%)
with
a
7-day
follow-up.
Clinical
and
mycologic
evaluations
were
conducted
before
treatment
(day
0)
and
7
days
after
treatment
(day
14).
Potential
resistance
to
miconazole
was
defined
using
an
arbitrary
breakpoint
of
minimum
inhibitory
concentration
of
2
Eig/mL.
There
was
no
evidence
of
resistance
to
miconazole
in
Candida
spp.
after
single
or
repeated
treatment
courses
of
0.25%
miconazole
nitrate
ointment.
For
the
initial
episode
of
DDCC,
83
of
168 subjects
(49.4%)
achieved
a
clinical
cure,
77
(45.8%)
achieved
a
mycologic
cure,
and
49
(29.2%)
achieved
an
overall
cure
(clinical
and
mycologic).
The
overall
cure
rate
for
recurrent
episodes
of
DDCC
was
similar
to
or
numerically
greater
than
rates
observed
for
the
initial
episode.
Treatment
of
DDCC
with
0.25%
miconazole
nitrate
ointment
was
effective
and
generally
well
tolerated.
No
evidence
of
the
development
of
resistance
to
miconazole
in
Candida
spp.
was
observed.
Address
correspondence
to
Daisy
Blanco,
M.D.,
Instituto
DermatolOgico,
Calle
Federico
Veldsq,
Esq.
Albert
Thomas
Ensanche
Maria
Auxiliadora,
Santo
Domingo,
1009,
Dominican
Republic,
or
e-mail:
ClinicalTrials.gov
identifier:
NCT00702507.
DOI:
10.1111/pde.12107
2013Wiley
Periodicals,
Inc.
717
718
Pediatric
Dermatology
Vol.
30
No.
6
November/December
2013
Localized
infection
with
Candida
albicans
often
exacerbates
diaper
dermatitis
(1).
A
petrolatum
and
zinc
oxide—based
ointment
containing
0.25%
mico-
nazole
nitrate
is
reported
to
be
effective
and
well
tolerated
in
the
treatment
of
diaper
dermatitis
complicated
by
cutaneous
candidiasis
(DDCC)
(2-4).
There
were
significantly
fewer
positive
cul-
tures
of
C.
albicans
in
the
diaper-covered
skin
of
infants
treated
with
miconazole
nitrate—containing
ointment
than
in
those
who
were
not
treated
(5).
Systemic
or
cutaneous
side
effects
were
not
observed
in
hospitalized
infants,
even
after
multiple
topical
applications
of
the
ointment
to
inflamed
or
damaged
skin
(6).
Miconazole
nitrate
0.25%,
zinc
oxide
15%,
and
white
petrolatum
81.35%
(Vusion
Ointment,
Stiefel,
a
GSK
company,
Research
Triangle
Park,
NC)
was
the
first
antifungal
topical
formulation
approved
by
the
U.S.
Food
and
Drug
Administration
for
the
treat-
ment
of
documented
DDCC
in
immunocompetent
children
age
4
weeks
and
older
(7,8).
C.
albicans
resistance
to
azoles
is
rare
in
superficial
infections,
even
after
long-term
exposure
(9-11),
and
recent
evidence
has
shown
that
Candida
spp.
isolates
do
not
develop
resistance
to
miconazole
(12).
This
study
investigated
the
potential
development
of
resis-
tance
of
Candida
spp.
to
miconazole
in
neonates
and
infants
age
15
months
and
younger
with
moderate
to
severe
DDCC
after
repeated
topical
use
of
0.25%
miconazole
nitrate.
MATERIALS
AND
METHODS
This
prospective,
noncontrolled,
multicenter,
open-
label,
long-term,
phase
IV
study
(ClinicalTrials.
gov
identifier:
NCT00702507)
comprised
an
initial
treatment
phase
(7-day
treatment;
7-day
follow-up)
and
a
2-year
follow-up
phase,
with
visits
scheduled
every
6
months
or
at
recurrent
infection.
In
case
of
continuing
infection
after
the
initial
treatment
phase
or
recurrence
during
the
2-year
follow-up,
subjects
received
re-treatment
for
7
days
with
a
7-day
follow-up.
Subjects
were
enrolled
from
12
study
sites:
9
in
the
United
States
and
3
in
Latin
America.
Research
ethics
board
approval
was
obtained
from
all
participating
institutions,
and
parents
or
guardians
gave
informed
consent.
Subjects
Inclusion
criteria
were
age
15
months
or
younger,
clinical
evidence
of
diaper
dermatitis,
and
a
positive
potassium
hydroxide
(KOH)
result
for
pseudohyp-
hae
or
budding
yeast
at
the
baseline
visit
(day
0).
A
diaper
dermatitis
severity
index
score
(DDSIS)
was
calculated
as
the
sum
of
severity
grades
for
ery-
thema,
papules
or
pustules,
and
erosions
(where
an
overall
score
of
3-4
is
considered
moderate
and
a
score
of
5-8
is
considered
severe;
Table
S1).
The
overall
DDSIS
had
to
be
4
to
8
at
day
0,
including
an
overall
clinical
grade
of
2
or
more
for
erythema.
Subjects
wore
commercially
available
diapers
(day
and
night)
for
7
days
or
longer
before
enroll-
ment
(day
0)
and
during
the
course
of
the
2-year
study.
Exclusion
criteria
were
known
sensitivity
to
any
of
the
formulation
components,
skin-care
toiletry
prod-
ucts,
or
diapers;
the
presence
of
any
skin
condition,
human
immunodeficiency
virus,
or
chronic
illness
requiring
concurrent
therapy
or
that
may
have
confounded
the
evaluation
of
drug
efficacy
and
tolerability;
and
treatment
with
a
prescription
product
for
diaper
dermatitis
or
any
other
skin
condition
7
days
before
enrollment.
Chronic
antibiotic
therapy
did
not
exclude
a
subject
from
study
participation.
Interventions
In
the
initial
treatment
phase,
eligible
subjects
began
treatment
with
0.25%
miconazole
nitrate
ointment
(active
components:
miconazole
nitrate
0.25%,
zinc
oxide
15%,
and
white
petrolatum
81.35%)
(Barrier
Therapeutics
Inc.,
Princeton,
NJ
[acquired
by
Stiefel,
a
GSK
company]).
The
ointment
was
applied
topically
at
each
diaper
change
and
after
bathing.
Care
providers
(parents
or
legal
guardians)
were
instructed
not
to
apply
any
prescription
or
over-
the-counter
medications
for
diaper
dermatitis
other
than
the
study
drug
during
the
2-year
study.
They
were
also
instructed
not
to
apply
any
topical
products
(e.g.,
creams,
ointments,
lotions)
or
use
disposable
wash-
cloths
with
fragrance
or
alcohol
on
the
infant
during
the
initial
treatment
phase.
Determination
of
Minimum
Inhibitory
Concentration
Clinical
evaluations,
a
KOH
preparation,
and
a
culture
to
test
for
the
presence
of
Candida
spp.
in
involved
skin
were
conducted
at
baseline
(day
0)
and
at
the
7-day
posttreatment
follow-up
visit
(day
14).
All
positive
cultures
were
used
for
minimum
inhib-
itory
concentration
(MIC)
determination
and
species
classification.
Potential
resistance
to
miconazole
was
defined
using
an
arbitrary
breakpoint
of
MIC
of
2
µg/mL.
Blanco
and
van
Rossem:
Assessing
Miconazole
Resistance
in
Diaper
Dermatitis
719
Outcomes
Primary
endpoints
were
the
proportion
of
subjects
who
developed
Candida
spp.
resistance
to
miconazole
after
repeated
courses
of
treatment
and
the
percentage
of
subjects
who
had
an
overall
cure
at
the
test-of-cure
visit
(day
14)
for
the
initial
treatment
phase.
Overall
cure
was
defined
as
clinical
cure
(total
resolution
of
signs
and
symptoms;
equating
to
a
severity
score
of
zero
in
erythema,
papules,
pustules,
and
erosions)
and
microbiologic
cure
(mycologic
eradication:
KOH
and
culture
results
negative).
Secondary
endpoints
at
the
test-of-cure
visit
included
clinical
and
mycologic
cure
rates
and
DDSIS.
In
subsequent
episodes
of
DDCC,
endpoints
were
cure
rates
(overall,
clinical,
and
microbiologic).
Sample
Size
Based
on
experience,
approximately
70%
of
subjects
who
enrolled
on
day
0
with
a
positive
KOH
exami-
nation
were
expected
to
have
a
positive
culture
for
Candida
spp.
Therefore
approximately
300
subjects
were
screened
to
provide
approximately
200
eligible
candidates.
Statistical
Methods
Statistical
processing
was
performed
using
SAS,
version
9.1
(SAS
Institute,
Inc.,
Cary,
NC).
Resistance
During
follow-up,
potential
resistance
to
miconazole
in
Candida
spp.
after
treatment
with
0.25%
miconaz-
ole
nitrate
ointment—determined
according
to
labo-
ratory-derived
MIC
values—was
summarized
according
to
the
frequency
of
subjects.
After
treat-
ment
with
0.25%
miconazole
nitrate
ointment,
if
resistance
to
miconazole
was
found
in
Candida
spp.,
this
resistance
would
be
estimated,
taking
into
account
the
frequency
of
use
during
the
2-year
study.
The
predicted
probability
curve
and
95%
confidence
interval
(CI)
for
the
resistance
rate
were
calculated
using
logistic
regression,
with
the
number
of
treated
episodes
as
a
covariate.
Efficacy
Overall,
clinical
and
mycologic
cure
rates
for
the
initial
treatment
phase
at
the
test-of-cure
visit
and
over
time
were
summarized
with
frequency
counts,
percentages,
and
95%
CIs.
Safety
Adverse
events
(AEs)
reported
during
the
study
were
documented
according
to
the
number
of
subjects,
system
organ
class,
preferred
term,
severity,
serious-
ness,
and
relationship
to
the
study
drug.
RESULTS
Subjects
Between
May
2007
and
December
2010,
200
subjects
were
enrolled;
all
received
0.25%
miconazole
nitrate
ointment.
One
hundred
sixty-seven
had
positive
Candida
spp.
culture
and
KOH
at
baseline;
the
remaining
33
were
discontinued
from
the
study.
One
of
these
33
subjects
presented
with
a
positive
Candida
culture
and
KOH
at
a
subsequent
episode
of
DDCC
and
was
reenrolled
in
the
study.
One
hundred
fifty-
eight
subjects
completed
the
initial
treatment
phase,
and
nine
did
not.
Fig.
1
summarizes
subject
disposi-
tions
for
both
study
phases.
Table
1
shows
baseline
demographic
and
clinical
characteristics
for
the
modified
intention-to-treat
analysis
set
(n
=
168)
(all
subjects
who
received
the
study
drug
for
the
treatment
of
DDCC).
Primary
Analysis
After
single
or
repeated
treatment
courses
of
0.25%
miconazole
nitrate
ointment,
resistance
to
miconazole
in
Candida
spp.
did
not
develop
in
these
subjects.
Four
subjects
had
mycology
results
that
were
classified
as
potentially
resistant,
with
MIC
results
of
2
or
4
µg/mL.
In
all
four
cases
these
results
were
observed
at
day
14
of
the
initial
treatment
phase
and
related
to
species
not
identified
at
day
0
(C.
tropicalis,
C.
parapsilosis,
or
C.
guilliermondit),
but
C.
albicans
was
identified
in
all
samples
at
day
0,
with
subsequent
testing
at
day
14
showing
no
growth
in
or
susceptibility
to
C.
albicans.
Two
of
the
four
subjects
with
potentially
resistant
results
continued
treatment
for
an
additional
2
weeks
and
had
negative
cultures
when
tested
on
day
28.
For
the
initial
episode
of
DDCC,
49
of
168
subjects
(29.2%;
95%
CI
22.4%,
36.7%)
achieved
an
overall
cure.
Secondary
Analyses
In
the
initial
treatment
phase,
83
subjects
(49.4%;
95%
CI
41.6%,
57.2%)
achieved
a
clinical
cure,
and
77
(45.8%;
95%
CI
38.1%,
—53.7%)
achieved
a
720
Pediatric
Dermatology
Vol.
30
No.
6
November/December
2013
A
Screened
=
334)
Screen
failures
(n
=
134)
Enrolled*
and
treated
(n
=
200)
Positive
Candida
culture;
Negative
Candida
culture,
Negative
Candida
culture,
positive
KOH
negative
KOH
positive
KOH
(ti
=
167)
(n
=
1)
(n
=
32)
Did
not
complete
initial
treatment
Did
not
complete
initial
treatment
(n
=
1)
(n
=
32)
Re-enrolled
at
subsequent
episode
and
treated
(n
=
1)
Positive
Candida
culture,
positive
KOH
(n
=
1)
Discontinued
during
Completed Completed
2nd
initial
treatment
initial
treatment
initial
treatment
period
period
period
(n=
9
)
=
158)
(n
=
1)
Completed
initial
treatment
period
(n
=
159)
Recurrent
episodesm
(ti
=
54)
1
(n
=
39)
2
(n
=
11)
3
(n
=
3)
4
(n
=
1)
No
recurrent
episode
(n
=
105)
Completed
study
(n
=
78)
Did
not
complete
study
(n
=
27)
Completed
study
=
54
)
Did
not
complete
study
(n=0)
Figure
1.
Subject
disposition
in
(A)
the
initial
treatment
phase
and
(B)
the
follow-up
phase.
*Subjects
who
were
potassium
hydroxide
(KOH)
positive
but
with
unknown
culture
results.
1•Subjects
with
positive
culture
results
continued
treatment
for
7
days.
Subjects
with
negative
culture
results
were
discontinued
from
the
study
but
could
reenroll
at
their
next
episode.
§Numbers
refer
to
the
number
of
recurrent
episodes
(all
episodes,
not
just
positive
culture).
¶Subjects
had
a
KOH
test
and
a
culture
specimen
taken
before
each
treatment
and
at
the
7-day
posttreatment
follow-up
visit
(day
14).
B
Blanco
and
van
Rossem:
Assessing
Miconazole
Resistance
in
Diaper
Dermatitis
721
TABLE
1.
Baseline
Characteristics
of
the
Modified
Intention-to-Treat
Analysis
Group
0.25%
Miconazole
nitrate
ointment
(n
=
168)
Age,
(months)
Mean
±
(SD)
6.5
(3.8)
Median
6.0
Range
0-16*
Sex,
n
(%)
Male
77
(45.8)
Female
91
(54.2)
Race
or
ethnicity,
n
(%)
Black
13
(7.7)
Hispanic
109
(64.9)
White
25
(14.9)
Other
21
(12.5)
Location
of
investigational
site,
n
(%)
United
States
50
(29.8)
Latin
America
118
(70.2)
Fitzpatrick
skin
type,
n
(%)
I
(always
burns,
never
tans)
5
(3.0)
II
(usually
burns,
tans
with
difficulty)
20
(11.9)
III
(sometimes
mild
burn,
tan
average)
56
(33.3)
IV
(rarely
burns,
tans
with
ease)
69
(41.1)
V
(very
rarely
burns,
tans
very
easily)
10
(6.0)
VI
(no
burn,
tans
very
easily)
8
(4.8)
Number
of
previous
episodes
of
diaper
dermatitis
Mean
±
(SD)
1.4
(1.9)
Median
1.0
Range
0-14
SD,
standard
deviation.
*One
subject
was
16
months
old
and
was
included
in
the
modified
intention-to-treat
population.
mycologic
cure
(Table
2).
Whereas
mycologic
cure
rates
were
similar
between
the
U.S.
and
Latin
Amer-
ican
investigational
sites,
the
clinical
and
overall
cure
rates
were
higher
for
those
in
Latin
America.
This
result
was
attributed
to
one
investigational
site
that
had
overall
and
clinical
cure
rates
of
42.0%
(21/50)
and
66.0%
(33/50),
respectively.
The
mean
(standard
deviation)
DDSIS
decreased
from
5.7
±
1.2
at
day
0
to
1.0
±
1.4
at
day
14.
During
follow-up,
35
subjects
experienced
a
first
recurrent
episode
of
DDCC
and
presented
with
a
positive
KOH
and
nonnegative
Candida
culture.
Overall
(n
=
11,
31.4%),
clinical
(n
=
20,
57.1%),
and
mycologic
(n
=
16,
45.7%)
cure
rates
for
the
first
confirmed
recurrent
episode
were
similar
to
those
observed
for
the
initial
episode.
Ten
and
four
subjects
had
a
second
and
third
recurrent
episode,
respectively,
and
presented
with
positive
KOH
and
nonnegative
Candida
culture.
The
cure
rates
were
similar
to
or
better
than
those
seen
for
the
initial
episode.
One
subject
had
a
fourth
recurrent
episode;
clinical
cure
was
not
achieved
during
the
study,
although
myco-
logic
cure
was
achieved.
Table
2
summarizes
follow-
up
period
test-of-cure
rates
of
initial
and
recurrent
episodes.
Safety
During
the
initial
treatment
period,
94
AEs
were
reported
for
57
of
200
subjects;
none
were
serious,
and
all
but
one
were
mild
or
moderate
in
severity.
The
AEs
reported
most
frequently
were
nasopharyngitis
(n
=
19,
9.5%),
pyrexia
(n
=
18,
9.0%),
and
diarrhea
(n
=
8,
4.0%).
All
other
AEs
were
reported
for
fewer
than
2%
of
subjects.
All
but
two
AEs
were
unrelated
to
the
study
drug;
probably
related
contact
dermatitis
was
reported
for
one
subject
and
possibly
related
contact
dermatitis
for
another.
Both
subjects
were
discontinued
from
the
study
as
a
result.
Study
drug
application
during
the
initial
treatment
phase
was
discontinued
for
one
subject
because
of
mild
Candida
spp.
diaper
rash
that
was
unrelated
to
the
study
drug,
but
the
subject
continued
in
the
study.
TABLE
2.
Summary
of
Cure
Rates
of
Initial
Episode
with
0.25%
Miconazole
Nitrate
Ointment
and
Confirmed
Recurrent
Episodes
for
Subjects
Completing
the
Treatment
Course
(Modified
Intention-to-Treat
Analysis
Group)
Initial
episode
(n
=
168)
First
recurrence
(n
=
35)
Second
recurrence
(n=
10)
Third
recurrence
(n
=
4)
Fourth
recurrence
(n
=
1)
Overall
cure
Success,
n
(%)
49
(29.2)
11
(31.4)
5
(50)
2
(50)
0
(0)
95%
CI
for
success*
(22.4,
36.7)
(16.9,
49.3)
(18.7,
81.3)
(6.8,
93.2)
(0.0,
97.5)
Clinical
cure
Success,
n
(%)
83
(49.4)
20
(57.1)
5
(50)
3
(75)
0
(0)
95%
CI
for
cure*
(41.6,
57.2)
(16.9,
49.3)
(18.7,
81.3)
(6.8,
93.2)
(0.0,
97.5)
Mycologic
cure
Success,
n
(%)
77
(45.8)
16
(45.7)
7
(70)
3
(75)
1
(100)
95%
CI
for
success*
(38.1,
53.7)
(28.8,
63.4)
(34.8,
99.4)
(19.4,
99.4)
(2.5,
100)
Note:
Only
subjects
with
a
confirmed
case
of
diaper
dermatitis
(positive
KOH
and
nonnegative
Candida
culture)
at
day
0
of
each
episode
are
summarized
in
this
table.
CI,
confidence
interval.
*Exact
95%
CL.
722
Pediatric
Dermatology
Vol.
30
No.
6
November/December
2013
During
the
follow-up
period,
1,017
AEs
were
reported
for
137
subjects,
including
three
serious
AEs.
All
AEs
were
unrelated
to
the
study
drug.
TABLE
3.
Incidence
of
AEs
Reported
for
>
3%
of
Subjects
in
Initial
Treatment
Phase
or
Follow-up
Phase
(Safety
Population;
All
Subjects
Who
Received
Treatment)
System
organ
class
preferred
term,
n
(%)*1
During
treatment
phase
(n
=
200)
During
follow-up$
(n
=
168)
Subjects
with
>
1
AE
57
137
Ear
and
labyrinth
disorders
2
(1.0)
5
(3.0)
Ear
pain
2
(1.0)
5
(3.0)
Eye
disorders
1
(0.5)
14
(8.3)
Conjunctivitis
1
(0.5)
12
(7.1)
Gastrointestinal
disorders
11
(5.5)
50
(29.8)
Diarrhea
8
(4.0)
41
(24.4)
Vomiting
3
(1.5)
22
(13.1)
General
disorders
and
administration
site
conditions
19
(9.5)
79
(47.0)
Pyrexia
18
(9.0)
79
(47.0)
Infections
and
infestations
41
(20.5)
118
(70.2)
Acarodermatitis
0
(0.0)
5
(3.0)
Acute
sinusitis
1
(0.5)
5
(3.0)
Amoebiasis
0
(0.0)
8
(4.8)
Bronchitis
1
(0.5)
11
(6.5)
Diarrhea,
infectious
0
(0.0)
9
(5.4)
Ear
infection
2
(1.0)
11
(6.5)
Impetigo
2
(1.0)
8
(4.8)
Influenza
2
(1.0)
7
(4.2)
Nasopharyngitis
19
(9.5)
69
(41.1)
Otitis
media
acute
2
(1.0)
13
(7.7)
Pharyngitis
0
(0.0)
12
(7.1)
Pharyngotonsillitis
0
(0.0)
15
(8.9)
Respiratory
tract
infection
0
(0.0)
10
(6.0)
Rhinitis
2
(1.0)
14
(8.3)
Tonsillitis
1
(0.5)
28
(16.7)
Varicella
0
(0.0)
6
(3.6)
Viral
infection
1
(0.5)
10
(6.0)
Viral
rash
3
(1.5)
7
(4.2)
Injury,
poisoning,
and
procedural
complications
0
(0.0)
18
(10.7)
Arthropod
bite
0
(0.0)
6
(3.6)
Respiratory,
thoracic,
and
mediastinal
disorders
4
(2.0)
49
(29.2)
Asthma
1
(0.5)
16
(9.5)
Cough
1
(0.5)
26
(15.5)
Rhinitis,
allergic
0
(0.0)
6
(3.6)
Skin
and
subcutaneous
disorders
4
(2.0)
40
(23.8)
Dermatitis,
atopic
1
(0.5)
5
(3.0)
Dermatitis,
diaper
0
(0.0)
23
(13.7)
Notes:
One
subject
enrolled
was
discontinued
because
of
negative
baseline
culture
results.
The
same subject
was
later
reenrolled;
this
subject
was
counted
only
once.
Subjects
are
counted
only
once
at
each
level
of
summarization
(system
organ
class
or
preferred
term).
*MedDRA
version
10.1.
1
-
Counts
reflect
numbers
of
subjects
reporting
>
1
AE
classified
to
each
MedDRA
system
organ
class.
Subjects
were
counted
only
once.
$Subjects
were
considered
to
have
entered
the
follow-up
phase
if
they
completed
any
visit
more
than
1
day
after
the
last
date
of
treatment
in
the
initial
treatment
phase.
Table
3
summarizes
incidences
of
the
AEs
experi-
enced
by
3%
or
more
of
subjects
for
each
treatment
period.
DISCUSSION
This
study
demonstrated
that
no
resistance
to
0.25%
miconazole
nitrate
developed
during
treatment.
Based
on
the
low
MICs
obtained
in
this
study,
it
is
unlikely
that
any
potentially
resistant
results
observed
would
be
considered
resistant.
Four
poten-
tially
resistant
results
(MIC
of
2
or
4
gg/mL)
were
obtained
at
day
14.
These
were
all
related
to
Candida
species
that
were
not
identified
at
day
0,
whereas
C.
albicans
was
identified
in
all
samples
at
day
0
and
was
susceptible
or
eradicated
by
day
14.
In
the
two
subjects
who
continued
treatment
for
an
additional
2
weeks,
the
cultures
were
negative
at
day
28,
and
therefore
the
species
were
susceptible
after
treatment.
The
Clinical
and
Laboratory
Standards
Institute
has
not
determined
breakpoints
or
categorical
place-
ment
of
MICs
for
miconazole.
For
unknown
azoles,
the
susceptible
breakpoint
has
been
assumed
as
1
gg/mL.
Therefore,
for
miconazole,
an
arbitrary
breakpoint
of
1
µg/mL
was
considered
susceptible,
and
potential
resistance
was
considered
for
an
MIC
of
2
µg/mL
or
greater.
The
breakpoint
of
2
µg/mL
is
stringent
because
the
susceptibility
breakpoint
for
miconazole
is
reported
to
be
4
to
8
µg/mL
in
various
publications
(13-15).
This
stringency
should
therefore
ensure
robust
detection
of
potential
resistance.
The
overall
cure
rate
observed
in
this
study
was
consistent
with
results
previously
observed
in
the
phase
III
clinical
study
BT0100
USA/001,
in
which
26
of
112
subjects
(23.2%)
had
an
overall
cure
(data
on
file).
The
overall
cure
rates
for
the
first,
second,
and
third
recurrent
episodes
of
DDCC
were
similar
to
or
numerically
greater
than
the
rates
observed
for
the
initial
episode,
suggesting
that
repeated
treatment
with
0.25%
miconazole
nitrate
ointment
does
not
negatively
affect
efficacy.
The
stringent
criteria
for
clinical
cure
(total
resolution
of
signs
and
symptoms),
coupled
with
a
minimum
baseline
DDSIS
of
moderate
severity,
made
for
a
robust
determination
of
clinical
cure.
Also,
complete
resolution
of
erythema
(of
at
least
moderate
severity
at
baseline)
associated
with
candidal
infection
may
occur
beyond
the
time
of
clinical
assessment
at
7
days
after
a
7-day
treatment.
The
results
of
this
study
are
similar
to
those
obtained
in
the
pivotal
phase
3
study
of
topical
miconazole
nitrate
versus
placebo
in
DDCC
using
equally
strin-
gent
criteria
(3).
Blanco
and
van
Rossem:
Assessing
Miconazole
Resistance
in
Diaper
Dermatitis
723
AEs
reported
in
this
study
were
typical
for
this
population;
0.25%
miconazole
nitrate
ointment
was
generally
well
tolerated
and
did
not
raise
safety
concerns.
During
the
2-year
follow-up,
subjects
were
not
controlled
for
the
use
of
medications
for
other
indications,
which
may
have
had
some
effect
on
the
resistance
profile
of
the
individual
and
long-term
effect
of
the
study
drug.
Zinc
oxide
and
petrolatum
are
regarded
as
active
components
of
0.25%
miconazole
nitrate
ointment,
although
the
possible
contribution
of
these
compo-
nents
in
the
treatment
of
DDCC
in
combination
with
miconazole
is
unknown.
Comparative
studies
would
be
needed
to
investigate
the
possible
contributions
of
zinc
oxide
and
petrolatum
to
the
efficacy
and
resis-
tance
profile
of
the
ointment.
In
addition,
compara-
tive
resistance
profiles
of
other
azole-containing
ointments
may
provide
further
information
on
the
relative
suitability
of
using
miconazole-based
oint-
ments
for
the
treatment
of
DDCC.
In
conclusion,
no
evidence
of
development
of
resistance
of
C.
albicans
to
miconazole
was
observed
after
topical
use
of 0.25%
miconazole
nitrate
ointment
for
the
treatment
of
DDCC.
Overall
cure
rates
were
consistent
with
previous
investigations;
the
ointment
was
effective
and
patients
tolerated
it
well.
FUNDING
Stiefel,
a
GSK
company,
sponsored
this
study.
ACKNOWLEDGMENTS
Alessandra
Alio,
Manager,
Clinical
Development,
and
Joe
Eastman,
M.D.,
Medical
Affairs
Lead,
of
Stiefel,
a
GSK
company,
contributed
to
the
conduct
of
the
trial.
Daisy
Blanco,
M.D.,
was
the
principal
investigator.
The
authors
thank
the
clinical
study
manager,
Sandra
Mays,
and
the
principal
study
center
investigators:
Lewis
M.
Purnell,
M.D.,
David
Rodri-
guez,
M.D.,
Alicia
Barba,
M.D.,
William
Parker,
M.D.,
Paul
Darden,
M.D.,
Anne
Lucky,
M.D.,
Alfred
Lane,
M.D.,
John
Podgore,
D.O.,
Lawrence
Schachner,
M.D.,
Suephy
C.
Chen,
M.D.,
Sheila
Fallon
Friedlander,
M.D.,
Wilson
P.
Andrews
Jr.,
M.D.,
Manuel
Briones,
M.D.,
Charles
McKeever,
M.D.,
and
Zila
Espinosa,
M.D.
The
authors
thank
Annette
W.
Fothergill,
M.A.,
M.B.A.,
M.T.
(A.S.C.P.),
C.L.S.
(N.C.A.)
Technical
Director,
Fun-
gus
Testing
Laboratory,
University
of
Texas
Health
Science
Center,
San
Antonio,
Texas,
for
input
in
study
design,
MIC
determination,
and
related
assessments
of
resistance.
The
authors
thank
Annette
L.
Mathisen,
Ph.D.,
and
D.
Lowell
Stacy,
Ph.D.,
of
QST
Consul-
tations
Ltd.,
Allendale,
Michigan,
for
statistical
support
and
medical
writing
support,
respectively,
of
the
study.
The
authors
thank
Esther
Law,
Caudex
Medical,
Oxford,
UK
(supported
by
Stiefel,
a
GSK
company),
for
assistance
in
preparing
the
initial
draft
of
the
manuscript
and
collating
the
comments
of
the
authors
and
other
named
contributors.
SUPPORTING
INFORMATION
Additional
supporting
information
may
be
found
in
the
online
version
of
this
article:
Table
Sl.
Diaper
dermatitis
severity
scoring
system.
A
diaper
dermatitis
severity
index
score
(DDSIS)
was
calculated
as
the
sum
of
severity
grades
for
erythema,
papules
or
pustules,
and
erosions.
REFERENCES
1.
Leyden
JJ.
Diaper
dermatitis.
Dermatol
Clin
1986;4:23-28.
2.
Concannon
P,
Gisoldi
E,
Phillips
S
et
al.
Diaper
derm-
atitis:
a
therapeutic
dilemma.
Results
of
a
double-blind
placebo
controlled
trial
of
miconazole
nitrate
0.25%.
Pediatr
Dermatol
2001;18:149-155.
3.
Spraker
MK,
Gisoldi
EM,
Siegfried
EC
et
al.
Topical
miconazole
nitrate
ointment
in
the
treatment
of
diaper
dermatitis
complicated
by
candidiasis.
Cutis
2006;
77:113-120.
4.
Eichenfield
LF,
Bogen
ML.
Absorption
and
efficacy
of
miconazole
nitrate
0.25%
ointment
in
infants
with
diaper
dermatitis.
J
Drugs
Dermatol
2007;6:522-526.
5.
Pierard-Franchimont
C,
Letawe
C,
Pierard
GE.
Tribo-
logical
and
mycological
consequences
of
the
use
of
a
miconazole
nitrate-containing
paste
for
the
prevention
of
diaper
dermatitis:
an
open
pilot
study.
Eur
J
Pediatr
1996;155:756-758.
6.
Herrera
JC,
Regalado
E,
Alcantara
R
et
al.
Study
of
the
efficacy
and
the
absorption
of
miconazole
nitrate
in
infants
with diaper
dermatitis,
alone
or
associated
with
systemic
pathology,
Janssen
Research
Foundation
Clinical
Research
Report,
1989.
7.
Fallon
Friedlander
S,
Eichenfield
LF,
Leyden
J
et
al.
Diaper
dermatitis:
appropriate
evaluation
and
optimal
management
strategies.
In
association
with
Contemporary
Pediatrics
2009
[on-line].
http://www.modernmedicine.
com/modernmedicine/data/articlestandardllmodernmed-
icine/142009/590198/article.pdf
(accessed
March
15,
2012).
8.
Stiefel
Laboratories,
a
GSK
company,
Vusion
®
oint-
ment,
prescribing
information,
2011
[on-line].
http://
www.stiefel.com/content/dam/stiefel/globals/documents/
pdf/US_Vusion_Ointment.pdf
(accessed
May
24,
2012).
9.
Bennet
JE.
Antimicrobial
agents.
In:
Hardman
JG,
Limbird
LE,
Molinoff
PB
et
al.,
eds.
Goodman
and
Gilman's
the
pharmacological
basis
of
therapeutics.
New
York:
McGraw-Hill,
1996:1175-1190.
724
Pediatric
Dermatology
Vol.
30
No.
6
November/December
2013
10.
Vanden
Bossche
H,
Marichal
P,
Odds
FC
et
al.
Characterization
of
an
azole-resistant
Candida
glabrata
isolate.
Antimicrob
Agents
Chemother
1992;36:2602-
2610.
11.
Kerridge
D,
Fasoli
M,
Wayman
FJ.
Drug
resistance
in
Candida
albicans
and
Candida
glabrata.
Ann
N
Y
Acad
Sci
1988;544:245-259.
12.
Ghannoum
MA,
Herbert
J,
Isham
N.
Repeated
expo-
sure
of
Candida
spp.
to
miconazole
demonstrates
no
development
of
resistance.
Mycoses
2011;54:e175—e177.
13.
Dota
KFD,
Freitas
AR,
Consolaro
MEL
et
al.
A
challenge
for
clinical
laboratories:
detection
of
antifun-
gal
resistance
in
Candida
species
causing
vulvovaginal
candidiasis.
Lab
Med
2011;42:87-93.
14.
Fothergill
AW.
Miconazole:
a
historical
perspective.
Expert
Rev
Anti
Infect
Ther
2006;4:171-175.
15.
Girish
Kumar
CP,
Hanafy
AM,
ICatsu
M
et
al.
Molec-
ular
analysis
and
susceptibility
profiling
of
Candida
albicans
isolates
from
immunocompromised
patients
in
South
India.
Mycopathologia
2006;161:153-159.