Prophylactic treatment with miconazole in patients highly predisposed to fungal infection. A placebo-controlled double-blind study


Brincker, H.

Acta Medica Scandinavica 204(1-2): 123-128

1978


In a placebo-controlled double-blind study the prophylactic value of oral systemic treatment with the antimycotic agent miconazole was assessed in 30 highly predisposed patients receiving intensive cytostatic chemotherapy because of haematological malignancies. Patients colonized with Candida before treatment were not freed from this micro-organism by miconazole treatment. However, only 3 out of 6 initially non-colonized miconazole-treated patients became colonized during the study, against 10 out of 10 placebo-treated patients (p = 0.036). Seven out of 15 patients in the placebo group developed clinical mycosis, against only two out of 15 in the miconazole group. The miconazole-treated patients remained clinically free of mycosis for 252 out of 264 treatment days, while the placebo-treated patients remained free of mycosis for only 263 out or 338 treatment days (p = 0.0001). The results indicate that systemic miconazole treatment protects highly predisposed patients from colonization with Candida and prevents or postpones clinically established candidosis.

Acta
Med
Scand
204:
123-128,
1978
Prophylactic
Treatment
with
Miconazole
in
Patients
Highly
Predisposed
to
Fungal
Infection
A
Placebo-Controlled
Double-Blind
Study
Hans
Brincker
From
the
Department
of
Oncology
and
Radiotherapy,
Odense
Hospital,
Odense,
Denmark
ABSTRACT.
In
a
placebo-controlled
double-blind
study
the
prophylactic
value
of
oral
systemic
treat-
ment
with
the
antimycotic
agent
miconazole
was
as-
sessed
in
30
highly
predisposed
patients
receiv-
ing
intensive
cytostatic
chemotherapy
because
of
haematological
malignancies.
Patients
colonized
with
Candida
before
treatment
were
not
freed
from
this
micro-organism
by
miconazole
treatment.
How-
ever,
only
3
out
of
6
initially
non-colonized
miconazole-treated
patients
became
colonized
during
the
study,
against
10
out
of
10
placebo-treated
pa-
tients
(p
=0.036).
Seven
out
of
15
patients
in
the
placebo
group
developed
clinical
mycosis,
against
only
two
out
of
15
in
the
miconazole
group.
The
miconazole-treated
patients
remained
clinically
free
of
mycosis
for
252
out
of
264
treatment
days,
while
the
placebo-treated
patients
remained
free
of
mycosis
for
only
263
out
of
338
treatment
days
(p
=0.0001).
The
results
indicate
that
systemic
miconazole
treat-
ment
protects
highly
predisposed
patients
from
colo-
nization
with
Candida
and
prevents
or
postpones
clinically
established
candidosis.
Intensive
cytostatic
therapy
in
patients
with
haematological
malignancies
usually
induces
both
marked
granulocytopenia
and
immunosuppression.
These
two
factors
probably
constitute
the
main
reasons
for
the
high
incidence
of
fungal
infections
in
patients
submitted
to
this
type
of
therapy.
Miconazole,
a
broad-spectrum
antifungal
agent
(2)
belonging
to
the
class
of
imidazole
antimycotics,
is
widely
used
in
the
topical
treatment
of
mycoses.
Moreover,
its
systemic
use
has
been
reported
by
several
investigators
(3,
4,
5,
6,
7,
8,
9,
12,
13,
15,
17,
18,
20,
21,
23,
26).
Of
special
relevance
to
the
study
reported
here
are
successes
obtained
with
this
drug
in
the
treatment
of
mycoses
of
the
diges-
tive
tract
(22,
24,
25),
its
successful
use
as
an
oral
treatment
of
South
American
blastomycosis
(14),
and
uncontrolled
observations
(1,
11)
suggesting
the
usefulness
of
miconazole
in
highly
predisposed
pa-
tients
with
haematological
malignancies.
The
aim
of
this
study
was
to
investigate
the
latter
possibilities
by
means
of
a
placebo-controlled
double-blind
evaluation
of
miconazole's
ability
to
protect
highly
predisposed
patients
against
fungal
infections.
STUDY
POPULATION
AND
METHODS
Patients
(Table
I)
Thirty
patients
with
leukaemia
or
leukaemic
lymphoma
were
included
in
the
study
that
took
place
between
Aug.
1975
and
Feb.
1977.
All
were
highly
predisposed
to
fungal
infections
as
a
consequence
of
intensive
cytostatic
treat-
ment,
resulting
in
granulocyte
counts
below
1O00/µ1
for
several
days.
Only
patients
presenting
no
clinical
signs
of
fungal
in-
fection
were
eligible
for
the
study,
but
a
previous
oral
candidosis
did
not
rule
out
participation,
provided
that
this
infection
had
been
successfully
treated
before
the
patient
entered
the
trial.
Treatment
Eligible
patients
were
randomized
to
receive
either
a
placebo
or
miconazole,
500
mg
four
times
daily.
The
drug
was
given
as
tablets
of
250
mg
which
were
separately
packed
for
each
patient
in
sufficiently
large
amounts
to
ensure
double-blindness.
The
tablets
were
to
be
swal-
lowed
and
the
study
protocol
prescribed
this
treatment
to
be
continued
for
at
least
three
weeks
(maximum
25
days).
Patients
who
developed
signs
of
localized
candidosis
of
the
oral
and/or
oesophageal
mucosa
received
local
treat-
ment
with
amphotericin
B
while
the
treatment
with
the
placebo
or
miconazole
was
continued.
However,
in
pa-
tients
developing
signs
of
generalized
mycosis,
the
randomization
code
was
broken
for
the
patient
concerned
Acta
Med
Scand
204
124
H.
Brincker
Table
I.
Results
of
randomization
AML=acute
myeloid
leukaemia,
ALL=acute
lymphocytic
leukaemia
Miconazole
Placebo
group
group
p-value
Sex
(c37
8/7
8/7
n.s.*
Age
(below/over
54
y)°
8/7
7/8
n.s.**
Diagnosis
(myeloid/lymphoid)
12/3
10/5
n.
s.*
Myeloid
AML
primary
AML
relapse
Lymphoid
ALL
primary
ALL
relapse
Leukaemic
lymphoma
Very
poor
general
condition
Prior
buccal
mycosis
Incidence
of
colonization
Oral
Anal
Concurrent
antibiotics
Lowest
granulocyte
count
(below/above
48/µ1)°
66
)
12
2
0
3
1
1111
5
of
15
9
of
15
4
of
15
5
of
15
14
of
15
6/9
3
2
0
2
of
15
3
of
15
4
of
15
2
of
15
13
of
15
9/6
n
.
s.*
0.06*
n.s.*
n.
s
.*
n.s.*
n
.
s.**
n
Median
of
total
population.
*
Fisher
exact
probability
test:
n.s.=p>0.10.
**
Median
test:
n.s.=p>0.10.
and
she
or
he
was
then
given
systemic
therapy
with
amphotericin
B,
5-fluoro-cytosine
and/or
miconazole.
Concurrent
antimicrobial
treatment
was
given
in
27
of
the
patients
(Table
I)
because
of
suspected
or
verified
bacterial
infection.
This
treatment
consisted
of
a
triple
combination
of
tobramycin,
penicillin
V
and
sulfamethox-
azole/trimethroprim.
Prednisolone
was
given
in
all
eight
patients
with
lymphoproliferative
malignancies,
but
in
none
of
the
22
acute
myeloid
leukaemia
(AML)
patients.
Assessments
The
time
of
occurrence
of
possible
oral
as
well
as
systemic
mycotic
infections
was
carefully
registered
during
the
treatment
for
all
participating
patients.
Also,
cultures
were
taken
from
the
oral
cavity
and
the
anal
canal
(faeces)
of
all
patients
at
the
start
of
the
study
and
weekly
thereafter.
The
growth
on
the
culture
media
was
assessed
as
0
=no
growth,
F=a
few
colonies
(not
found
in
this
study),
S=
several
colonies,
M=
massive
growth.
A
patient
was
considered
to
be
colonized
by
fungi
as
soon
as
growth
was
observed
on
at
least
one
culture,
and
the
highest
degree
of
fungal
growth
on
the
cultures
was
used
as
a
measure
of
the
severity
of
this
colonization.
In
patients
developing
signs
of
fungal
infection,
cultures
were
also
taken
from
the
sputum,
urine
and
blood.
A
clinical
evaluation
was
performed
in
all
patients
every
day,
a
leukocyte
and
differential
count
at
least
twice
weekly,
a
chest
X-ray
was
taken
once
weekly,
and
serum
IgA,
IgG
and
IgM
were
determined
at
the
start
of
the
study
and
after
three
weeks.
Statistical
evaluations
The
Fisher
exact
probability
test
and
the
median
test
were
used
for
assessing
the
results
of
the
randomization
proce-
dure.
The
colonization
rate
during
the
treatment
was
evaluated
using
the
cultures
which
had
shown
the
most
pronounced
growth.
Since
it
was
found
that
colonization
with
Candida
species
took
place
after
a
mean
interval
of
about
1
1/2
weeks,
five
patients
(four
from
the
miconazole
and
one
from
the
placebo
group)
who
had
been
treated
for
less
than
a
fortnight
were
not
considered
for
the
analysis
of
this
aspect.
Therefore,
at
least
two
double
(i.e.
oral
and
anal)
cultures
were
available
from
each
patient
during
double-blind
treatment.
The
Fisher
exact
probability
test
was
used
to
compare
the
two
treatment
groups
regarding
1)
the
proportion
of
patients
who
became
colonized
during
the
treatment
and
who
had
shown
negative
cultures
at
the
start,
2)
the
greatest
cumulative
difference
between
the
two
groups
after
subdividing
the
populations
into
patients
who
became
positive,
who
remained
either
positive
or
negative,
and
who
had
yeasts
before
the
study
but
who
no
longer
showed
any
growth
on
the
cultures
during
the
study.
As
the
duration
of
treatment
was
not
entirely
similar
(though
not
reaching
the
5%
level
of
statistical
signifi-
cance)
between
the
two
treatment
groups,
it
was
consid-
ered
unfair
to
make
a
straight-forward
comparison
of
the
total
number
of
patients
who
became
infected
in
the
two
groups.
Two
approaches
were
used
to
correct
this
differ-
ence
in
the
duration
of
treatment
(which
was
also
the
duration
of
observation):
1)
The
total
number
of
protected
days
was
calculated
for
each
treatment
group
and
related
to
the
total
duration
of
the
observation.
The
intergroup
difference
was
assessed
by
means
of
the
)4
2
-test.
2)
The
total
duration
of
protection
for
each
patient
was
also
used
for
an
overall
assessment
of
the
infection
rate
in
each
treatment
group
by
means
of
the
actuarial
analysis
tech-
nique.
These
results
were
statistically
evaluated
by
means
of
Student's
t-test.
Two-tailed
probabilities
were
calcu-
lated
for
all
statistical
tests
used.
Arta
Med
Scand
204
Miconazole
in
fungal
infection
125
Table
II.
Reasons
for
stopping
treatment
before
3
weeks
ALL=acute
lymphocytic
leukaemia,
AML=acute
myeloid
leukaemia,
LL=leukaemic
lymphoma
Treatment
Trial
no.
Sex
Age
(y.)
Basic
disease
Treatment
stopped
on
day
Reason
Placebo
4
a
67
ALL
8
Systemic
candidosis
23
9
71
AML
17
Herpetic
stomatitis
24
a
77
ALL
14
Death
Miconazole
3
9
57
AML
20
Systemic
aspergillosis
5
8'
49
AML
18
Poor
condition
20
9
71
AML
14
Poor
condition
7
a
65
AML
12
Poor
condition
22
e
65
AML
9
Death
9
a
19
ALL
4
Poor
condition
29
9
57
ALL
18
Discharged
18
9
43
LL
16
Discharged
21
e
21
AML
5
Error
RESULTS
Results
of
the
randomization
procedure
(Table
I)
Though
the
two
treatment
groups
proved
to
be
comparable,
as
they
did
not
differ
significantly
for
any
characteristic,
the
active
drug
was
dis-
advantaged
by
a
somewhat
uneven
distribution:
more
patients
in
the
miconazole
group
had had
oral
candidosis
before
and
somewhat
more
patients
in
the
same
group
were
in
a
very
poor
condition,
probably
because
of
a
higher
number
of
relapse
cases
of
AML.
This
is
also
reflected
in
the
fact
that
nine
patients
in
the
miconazole
group
had
their
treatment
interrupted
within
three
weeks,
against
only
three
in
the
placebo
group
(Table
II).
Moreover,
the
anal
pretreatment
colonization
rate
tended
to
be
somewhat
higher
in
the
miconazole
than
in
the
placebo
group.
On
the
other
hand,
the
above
findings
were
partly
counterbalanced
by
a
somewhat
lower
granulocyte
level
in
the
placebo
patients.
Fungal
colonization
rate
As
explained
above,
25
patients
(11
treated
with
miconazole
and
14
controls)
were
considered
evaluable
as
they
had
been
treated
for
at
least
two
weeks.
The
degree
of
colonization
by
Candida
spp.
before
and
during
therapy
is
shown
in
Fig.
I.
Although
the
pretreatment
degree
of
colonization
is
somewhat
to
the
disadvantage
of
the
miconazole
patients,
especially
regarding
the
coprocultures,
this
pattern
is
reversed
during
treatment.
When
growth
on
culture
is
used
as
a
yes-or-no
phenome-
non,
it
is
found
that
only
three
out
of
six
initially
negative
(combined
data)
miconazole
patients
be-
came
positive
during
the
study,
against
all
ten
placebo
patients
(p=0.036).
Also,
if
the
patients
are
ranked
according
to
the
changes
observed
in
their
cultures
during
the
double-blind
treatment
(Table
III),
significantly
more
control
patients
are
colo-
nized
at
the
end
of
the
study
(p
=0.047).
Similar
trends
are
seen
when
the
oral
and
anal
cultures
are
considered
separately
but
these
differences
fail
to
reach
the
level
of
statistical
significance,
though
the
difference
regarding
the
coprocultures
was
nearly
significant
(p=0.090).
Occurrence
of
mycotic
infections
Two
patients
in
the
miconazole
group
developed
a
mycosis
after
15
(oral
candidosis)
and
20
days
(generalized
aspergillosis),
respectively.
Seven
placebo
patients
experienced
fungal
infections,
six
of
whom
developed
oral
candidosis
after
3-19
days
(median
14)
of
treatment
followed
by
a
generalized
candidosis
eight
days
later
in
one,
the
seventh
pa-
tient
developed
a
generalized
aspergillosis
on
day
19.
All
the
cases
of
oral
candidosis
responded
well
to
topical
application
of
amphotericin
B,
but
all
three
generalized
mycoses
were
fatal
despite
systemic
antifungal
treatment.
Neither
chest
X-rays
nor
cultures
from
sputum
and
urine
were
helpful
in
establishing
the
diagnosis
of
generalized
mycosis
in
these
patients
and
positive
blood
cultures
were
Acta
Med
Scand
204
80
20
o
S
S
S
II
co
100
a
O
a)
C
1
5
Oral
cultures
Anal
cultures
=
massive
growth
on
culture
=
several
colonies
Mi
=
miconazole
patients
so
P1
=
placebo
patients
40
Mi
PI
Before
treatment
Mi
PI
During
treatment
Mi
PI
Before
treatment
Mi
P
During
treatment
Combined
data
M
M
S
S
S
M
M
PI
Before
treatment
Mi
PI
During
treatment
126
H.
Brincker
Fig.
I.
Presence
of
Candida
species
in
cultures.
obtained
only
in
a
67-year-old
male
acute
lympho-
cytic
leukaemia
patient
who
died
of
generalized
candidosis.
Also,
possible
abnormalities
of
the
immunoglobulin
levels
did
not
correlate
with
the
occurrence
of
the
fungal
infections
(nor
with
the
colonization
rates).
Miconazole-treated
patients
had
been
followed
during
treatment
for
264
days
and
had
remained
clinically
free
of
mycosis
for
252
days.
In
contrast,
the
placebo-treated
patients,
who
had
been
fol-
lowed
for
338
days,
had
remained
free
of
such
dis-
eases
for
only
263
days.
This
difference
is
highly
significant
(p<0.0001).
Further,
according
to
the
results
of
the
actuarial
analysis
(Fig.
2),
the
percentage
of
patients
who
had
developed
a
clinical
mycosis,
was
significantly
higher
in
the
control
group
than
in
the
miconazole
group
after
14
and
19
days
of
treatment
(p<0.05).
The
latter
analysis
also
shows
that
one
quarter
of
the
control
patients
had
already
developed
a
mycosis
after
13-14
days,
whereas
this
occurred
about
one
week
later
in
the
miconazole
group.
However,
the
duration
of
the
treatment
was
too
short
to
determine
whether
miconazole
therapy
protects
a
certain
number
of
patients
from
mycotic
infections
or
only
postpones
the
occurrence
of
such
diseases.
In
order
to
rule
out
the
possibility
that
the
observed
difference
was
due
to
a
lower
granulocyte
count
in
the
control
group,
the
data
were
analyzed
separately
for
the
six
miconazole
patients
and
the
Table
III.
Colonization
rate:
changes
observed
during
double-blind
treatment
Patients
are
considered
positive
as
soon
as
fungal
growth
has
been
found
on
one
of
the
cultures
(either
oral
or
anal)
Positivation"
No
change
Negativation
Total
no.
of
evaluable
Group
before
—0
+
during
+before
+
during
before
—.
during
+
before
—'
during
pats.
Miconazole
3
4
3
11
Placebo
10
3
0
14
The
greatest
cumulative
difference
is
seen
here:
p
=0.047
(Fisher
exact
probability
test).
Acta
Med
Scand
204
Miconazole
in
fungal
infection
127
100
0
a
BO...,
:7;
a
"8
v.;
vi
60
_
"
8
a
40
miconazole
group
placebo
group
*
=
p
i
0.02
20_
0
4
9
Fig.
2.
Duration
of
protection
against
fungal
infections.
nine
control
patients
whose
granulocyte
counts
were
below
48/µ1.
All
the
patients
who
had
de-
veloped
a
clinical
mycosis
during
the
study
be-
longed
to
this
category
with
the
exception
of
one
patient
from
the
placebo
group
with
an
oral
candi-
dosis.
The
six
miconazole
patients
whose
granulo-
cyte
counts
were
below
48/µ1
had
been
protected
for
84
days
during
their
treatment,
which
had
lasted
for
a
total
of
96
days,
whereas
the
corresponding
nine
placebo
patients
had
remained
free
of
clinical
mycosis
for
only
144
of
their
207
treatment
days.
The
difference
between
these
two
groups
is
statisti-
cally
significant
(p
=0.001).
Side-effects
ascribable
to
the
miconazole
treat-
ment
were
not
seen
either
in
this
or
in
a
previous
study
(1).
DISCUSSION
The
results
of
this
double-blind
study
indicate
that
oral
systemic
miconazole
treatment
protects
high-
ly
predisposed
patients
from
colonization
with
Candida
spp.
Further,
such
patients
are
protected
by
this
treatment
against
clinical
infections
with
Candida,
or
the
occurrence
of
such
infections
is
postponed.
These
data
were
obtained
even
though
14
19
24
Duration
(days)
of
treatment
the
randomization
procedure
had
slightly
dis-
advantaged
the
active
drug
except
for
the
absolute
granulocyte
count,
which
tended
to
be
lower
in
the
control
group.
However,
it
was
found
that
the
latter
factor
could
not
explain
the
overall
results.
In
the
dose
employed,
the
effect
of
the
miconazole
treatment
appears
to
be
prophylactic
rather
than
curative,
since
it
was
found
that
patients
who
were
colonized
with
Candida
at
the
beginning
of
the
treatment
were
not
freed
from
this
micro-organism
more
often
than
similar
patients
treated
with
a
placebo
(Table
III).
Whether
the
pro-
tective
effect
of
miconazole
is
directed
against
types
of
fungus
other
than
Candida
remains
to
be
examined.
The
importance
of
the
protective
effect
of
miconazole
demonstrated
in
this
study
is
quite
ob-
vious
since
a
period
of
prolonged
granulocytopenia
usually
is
inevitable
during
chemotherapeutic
in-
duction
of
remission
in
acute
leukaemias.
Further,
the
ease
of
administration
and
the
low
rate
of
side-
effects
of
miconazole
compare
very
favourably
with
other
antimycotics
intended
for
systemic
use.
As
the
effect
of
the
treatment
was
more
marked
on
the
anal
than
on
the
oral
cultures,
and
as
the
tablets
used
in
this
study
were
swallowed
by
the
*
Acta
Med
Scand
204
128
H.
Brincker
patients,
it
may
be
speculated
that
still
more
effi-
cient
prophylaxis
could
be
achieved
if
this
type
of
treatment
were
supplemented
with
a
concomitant
topical
treatment
of
the
oral
mucosa.
In
one
open
study,
systemic
treatment
with
miconazole
tablets
together
with
topical
oral
application
of
amphoteri-
cin
B
was
used
and
the
results
suggested
an
additive
effect
(11).
Also,
since
the
digestive
tract
is
gener-
ally
considered
to
be
an
important
site
of
entry
for
systemic
candidosis
in
highly
predisposed
patients
(10,
16,
19),
one
could
expect
that
a
longer-lasting
treatment
in
patients
who
remain
highly
pre-
disposed
for
a
long
period
of
time
may
significantly
prevent
the
occurrence
of
systemic
candidosis.
Fi-
nally,
it
must
be
borne
in
mind
that
the
systemic
use
of
prophylactic
miconazole
treatment
may
have
ecologic
consequences
which
cannot
be
assessed
at
present.
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