Aerosolized pentamidine versus i.v. pentamidine for secondary prophylaxis of Pneumocystis carinii pneumonia


Lidman, C.; Tynell, E.; Berglund, O.; Lindbäck, S.

Infection 21(3): 146-149

1993


The efficacy and toxicity of aerosolized pentamidine was evaluated in 78 AIDS patients given 60 mg biweekly as secondary prophylaxis against Pneumocystis carinii pneumonia (PCP). Patients were monitored for clinical progression and mortality and were compared to 42 historical controls given 200-300 mg i. v. pentamidine biweekly. The relapse rates did not differ markedly between the two groups, and the PCP-free rates in survivors were at 12 months 0.83 and 0.77, respectively. Seventy-one new AIDS-defining events and 25 deaths were recorded in patients on aerosolized pentamidine compared to 29 AIDS events and two deaths in patients on intravenous pentamidine. Recurrent PCP contributed to death in only one case of the aerosolized pentamidine group. PCP is not a serious clinical problem in immunodeficient patients taking pentamidine prophylaxis by either route compared to the progression of clinical HIV disease and death.

Originalia
C.
Lidman,
E.
Tynell,
0.
Berglund,
S.
Lindback
Aerosolized
Pentamidine
versus
i.
v.
Pentamidine
for
Secondary
Prophylaxis
of
Pneumocystis
carinii
Pneumonia
Summary:
The
efficacy
and
toxicity
of
aerosolized
pentamidine
was
evaluated
in
78
AIDS
patients
given
60
mg
biweekly
as
secondary
prophylaxis
against
Pneumocystis
carinii
pneumonia
(PCP).
Patients
were
monitored
for
clinical
progression
and
mortality
and
were
compared
to
42
historical
controls
given
200-300
mg
i.
v.
pentamidine
biweekly.
The
relapse
rates
did
not
differ
markedly
between
the
two
groups,
and
the
PCP
-free
rates
in
survivors
were
at
12
months
0.83
and
0.77,
respectively.
Seventy-one
new
AIDS
-defining
events
and
25
deaths
were
recorded
in
patients
on
aerosolized
pentamidine
compared
to
29
AIDS
events
and
two
deaths
in
patients
on
intravenous
pentamidine.
Recurrent
PCP
contributed
to
death
in
only
one
case
of
the
aerosolized
pentamidine
group.
PCP
is
not
a
serious
clinical
problem
in
immunodeficient
patients
taking
pentamidine
prophylaxis
by
either
route
compared
to
the
progression
of
clinical
HIV
disease
and
death.
Zusammenfassung:
Sekundar-Prophylaxe
der
Pneumo-
cystis
carinii-Pneumonie
mit
Pentamidin
alter
Vernebler
oder
i.
v.
Bei
78
AIDS-
Patienten
wurde
eine
Sekundar-
Prophylaxe
gegen
die
Pneumocystis
carinii-
Pneumonie
(PCP)
mit
Pentamidin
in
einer
Dosis
von
60
mg
alle
zwei
Wochen
durchgefiihrt.
Dabei
wurde
die
Wirksam-
keit
und
Toxizitat
der
fiber
Vernebler
als
Aerosol
ver-
abreichten
Form
gepriift.
Die
Patienten
wurden
hin-
sichtlich
klinischer
Progression
und
Mortalitat
ausge-
wertet.
Die
Ergebnisse
wurden
mit
42
historischen
Kontrollen
verglichen,
bei
denen
alle
zwei
Wochen
200-300
mg
Pentamidin
i.
v.
verabreicht
worden
war.
Die
beiden
Gruppen
unterschieden
sich
nicht
wesent-
lich
in
den
Rezidivraten.
Bei
den
Patienten,
die
12
Mo-
nate
iiberlebten,
waren
die
PCP-freien
Raten
0,83
und
0,77
in
den
beiden
Gruppen.
Bei
Patienten,
die die
Ae-
rosol
-Form
erhielten,
waren
71
neue
AIDS-definieren-
de
Episoden
und
25
Todesfalle,
bei
den
i.
v.
behandel-
ten
Patienten
29
Episoden
und
zwei
Todesfalle
aufge-
treten.
In
nur
einem
Fall
der
Studiengruppe
war
ein
PCP-Rezidiv
fiir
den
Tod
mit
verantwortlich.
Bei
bei-
den
Applikationsformen
von
Pentamidin
stellt
die
PCP
bei
immundefizienten
HIV-infizierten
Patienten,
die
die
Prophylaxe
durchfiihren,
verglichen
mit
der
Pro-
gression
der
durch
HIV-
verursachten
Krankheit
und
Mortalitat,
kein
wesentliches
Problem
dar.
Introduction
Pneumocystis
carinii
pneumonia
(PCP)
develops
in
60
to
80%
of
patients
with
HIV
infection,
of
whom
more
than
50%
experience
a
recurrence
[1,2].
The
recurrence
rate
can
be
reduced
if
chemoprophylaxis
is
given.
Trimethoprim-sulfamethoxazole,
dapsone,
sulfadoxine-
pyrimethamine,
parenteral
and
aerosolized
pentamidine
have
shown
prophylactic
efficacy
[3-9].
Treatment
or
prophylaxis
with
sulfones
and
sulfonamides
can
be
associated
with
a
high
frequency
of
adverse
reactions,
leading
to
withdrawal
of
the
drug
[10-13].
This
may
limit
their
use
in
HIV
-infected
patients
with
severe
immunodeficiency
and
in
patients
with
concomitant
multiple
drug
therapies.
In
this
study
we
report
on
the
efficacy
and
adverse
reactions
as
well
as
clinical
progression
and
mortality
rates
in
patients
given
prophylactic
treatment
with
low
-dose
aerosolized
pentamidine
studied
prospectively
and
in
patients
given
i.
v.
pentamidine
studied
retrospectively.
Patients
and
Methods
Patients:
Seventy-eight
patients
with
one
to
three
previous
episodes
of
PCP
(Table
1)
were
enrolled
from
December
1988
to
December
1989
in
a
prospective
study
on
aerosolized
pentamidine
as
PCP
prophylaxis.
All
were
men
except
two.
The
mean
age
was
40.5
(range
24-75)
years
and
the
risk
categories
were
homosexuality
in
65,
blood
transfusions
in
seven,
i.
v.
drug
use
in
four
and
unknown
in
two.
The
mean
CD4
+
cell
count
(
±
95%
confidence
interval
limits)
was
81
(59-104)
x
10
6
/
1
.
Twenty-seven
of
78
patients
who
entered
the
study
had
38
AIDS
-defining
diagnoses
in
addition
to
PCP
(Table
1)
and
44
patients
were
receiving
treatment
with
zidovudine,
with
a
median
dose
of
400,
range
200-1200,
mg
daily.
Fourteen
patients
were
started
on
zidovudine,
with
a
median
dose
of
400
(400-1200)
mg
daily,
and
36
of
all
patients
on
aerosolised
pentamidine
discontinued
zidovudine
during
the
follow-up.
For
comparison
we
included
42
patients
with
one
to
four
previous
episodes
of
PCP
(Table
1)
given
i,
v.
pentamidine
as
PCP
prophylaxis
from
November
1987
to
June
1990.
Three
patients
were
female
and
the
mean
age
in
the
group
was
40
(range
23-81)
years.
Risk
categories
were
homosexuality
in
35,
transfusions
in
5
and
i.
v.
drug
use
in
two.
The
mean
CD4
+
cell
count
(
±
95%
confidence
interval
limits)
was
77
(51-102)
x
10
6
/I.
At
the
start
of
the
study
15
patients
had
21
AIDS
-defining
diagnoses
other
than
PCP
(Table
1).
Twenty-four
patients
were
Received:
24
August
1992/Revision
accepted:
17
February
1993
Dr.
C.
Lidman,
M.
D.,
Dr.
0.
Berglund,
M.
D.,
Associate
Professor,
Dr.
S.
Liridback,
M.
D.,
Department
of
Infectious
Diseases,
Huddinge
Hospital,
Huddinge,
S-141
86,
Sweden;
Dr.
Elsa
Tynell,
Department
of
Infectious
Diseases,
Danderyd
Hospital,
Danderyd,
S-18288,
Sweden.
16
1
146
Infection
21
(1993)
No.
3
©
MMV
Medizin
Verlag
GmbH
Mfinchen,
Munchen
1993
C.
Lidman
et
al.:
Aerosolized
and
i.
v.
Pentamidine
receiving
treatment
with
zidovudine.
The
median
dose
was
800,
range
200-1200,
mg
daily.
Eight
patients
were
placed
on
zidovudine
therapy
(median
dose
800,
range
400-1200
mg
daily),
but
11
patients
in
the
intravenous
pentamidine
group
discontinued
the
drug
during
the
follow-up
period.
Pentamidine
treatments:
Aerosolized
pentamidine,
300
mg
initia;ly
and
then
60
mg
twice
every
month,
was
nebulized
through
the
Acorn
22
mizer
system.
A
bronchodilatator
was
used
if
needed.
I.
v.
pentamidine
was
given
as
a
2-4
h
infusion
(4
mg/kg
bw)
twice
every
month.
Follow-up:
The
patients
were
monitored
either
until
2
months
after
the
last
treatment
or
for
patients
on
aerosolized
pentamidine
prophylaxis
on
February
28,
1991.
The
median
follow-up
period
was
11.4
(2-26)
months
for
patients
on
aerosolized
pentamidine.
The
last
day
of
follow-up
was
June
18
1990,
for
patients
on
i.
v.
pentamidine
prophylaxis.
In
that
group
the
median
follow-up
period
was
5.9
(2-17)
months.
AIDS
-defining
events
and
statistics:
AIDS
-diagnoses
were
defined
according
to
the
1987
CDC
-criteria
[14].
Distinction
between
verified
and
presumed
AIDS
diagnosis
was
not
made
in
calculations
except
for
PCP.
All
recurrent
episodes
of
PCP
were
verified
with
sputum
sample
or
bronchoalveolar
lavage
positive
for
P.
carinii.
No
chemoprophylaxis
other
than
pentamidine
and
antifungal
agents
was
used
in
patients
with
previously
diagnosed
Candida
oesophagitis.
For
statistical
analysis
we
used
Chit,
Student's
t
-test,
log
rank
and
Kaplan
-Meier
life
table
estimate.
Results
AIDS
and
PCP
During
the
study
eight
patients
in
the
aerosolized
pentamidine
group
developed
recurrence
of
PCP,
which
was
proved
by
positive
sputum
or
bronchoalveolar
lavage.
The
proportion
of
PCP
-free
patients
among
survivors
at
6,
12
and
18
months
was
0.97,
0.83
and
0.83,
respectively.
A
total
of
71
AIDS
-defining
events
was
noted
in
46
patients
during
the
follow-up
period
(Table
2).
In
the
i.
v.
pentamidine
group
four
patients
had
a
verified
recurrence
of
PCP.
The
proportion
of
PCP
-free
patients
among
survivors
at
6
and
12
months
was
0.98
and
0.77,
respectively.
Twenty-nine
new
AIDS
-defining
events
were
recorded
in
21
patients
during
the
follow-up
period
(Table
2).
Mortality
Twent-five
patients
died
in
the
aerosolized
pentamidine
group,
compared
to
two
patients
in
the
i.
v.
pentamidine
group.
In
the
former
group
PCP
was
the
cause
of
death
in
one
patient
and
P.
carinii
was
found
at
autopsy
in
another
patient
who
died
from
gastrointestinal
bleeding.
Disseminated
P.
carinii
infection
was
not
seen
in
11/25
of
the
patients
on
aerosolized
pentamidine
who
were
autopsied.
The
proportions
of
surviving
patients
were
0.86,
0.69
and
0.57
at
6,
12
and
18
months,
respectively.
In
the
i.
v.
pentamidine
group
these
proportions
were
0.96
and
0.92
at
6
and
12
months,
respectively.
Table
1:
AIDS
-defining
diagnoses
in
78
patients
given
aerosolized
pentamidine
and
in
42
patients
given
intravenous
pentamidine
as
PCP
prophylaxis
at
the
beginning
of
the
study.
..A11
)S
..,-
111=
42
1
PCP
63
24
2
PCP
11
10
3-4
PCP
4
8
Candida
esophagitis
10
3
CMV
retinitis
6
6
CMV
gastrointestinal'
2
1
Mycobacteriosis
(disseminated)
6
4
HSV
(disseminated)
1
1
Cryptococcal
meningitis
1
Histoplasmosis
(disseminated)
1
Tuberculosis
(extrapulmonary)
1
Kaposi's
sarcoma
9
5
Wasting
syndrome
2
°
CMVgastrointestinal
=
cytomegalovirus
in
histology
o
denum.
:olon
or
duo
-
Table
2:
Additional
AIDS
-defining
diagnoses
during
follow-up
in
78
patients
given
aerosolized
pentamidine
and
in
42
patients
given
intravenous
pentamidine
as
secondary
PCP
prophylaxis.
Ljr.)111
,
u
,
=421
P(
Candida
esophagitis
4
6
CMV
retinitis
16
3
CMV
gastrointestinal'
4
3
Mycobacteriosis
(disseminated)
12
5
HSV
(disseminated)
1
Cryptococcal
meningitis
Toxoplasmosis
(cerebral)
4
2
Cryptosporidiosis
Kaposi's
sarcoma
2
CNS
lymphoma
AIDS
dementia
complex
2
Wasting
syndrome
5
1
CMVgastrointestinal
=
cytomegalovirus
infection
in
histology
of
colon
or
duodenum.
Adverse
Reactions
to
Pentamidine
Adverse
reactions
were
reported
in
61/78
(78%)
of
the
patients
on
aerosolized
pentamidine
and
in
206
(13.7%)
of
1207
treatments.
The
adverse
reactions
were
cough
(n
=
145),
nausea
(n
=
30),
metallic
taste
(n
=
24),
dyspnea
(n
=
15),
vomiting
(n
=
8)
and
vertigo
(n
=
8).
Four
patients
discontinued
the
aerosolized
pentamidine
prophylaxis
because
of
adverse
reactions.
All
four
experienced
one
to
two
days
of
intensive
nausea
with
or
without
repeated
vomiting
in
association
with
treatments.
Pneumothorax
was
seen
in
three
patients.
One
episode
occurred
in
a
patient
with
recurrent
PCP
and
one
in
a
patient
who
had
P.
carinii
in
a
sputum
sample.
Drug
toxicities
were
reported
in
17/42
(40%)
patients
in
the
i.
v.
Infection
21
(1993)
No.
3
C
MMV
Medizin
Verlag
GmbH
Miinchen,
Munchen
1993
147
/
17
C.
Lidman
et
al.:
Aerosolized
and
i.
v.
Pentamidine
pentamidine
group
and
in
relation
to
44
of
459
(10%)
of
the
infusions.
Adverse
reactions
consisted
of
local
rash
and
pruritus
localized
to
the
infusion
site
(n
=
17),
nausea
(n
=
11),
rhinitis
(n
=
9),
vomiting
(n
=
3),
hypoglycaemia
(n
=
2)
and
one
case
each
of
chest
pain,
facial
paresthesia,
generalized
dermatitis
and
increase
in
serum-creatinine.
Three
patients
discontinued
the
i.
v.
prophylaxis
because
of
adverse
reactions
possibly
related
to
treatment.
One
patient
had
recurrent
hypoglycaemia
during
i.
v.
pentamidine
infusions,
one
patient
had
a
rise
in
serum
creatinine
and
one
had
generalised
dermatitis.
Discussion
About
80%
of
the
patients
treated
with
aerosolized
or
parenteral
pentamidine
as
secondary
prophylaxis
had
remained
free
from
relapse
after
12
months.
A
similar
figure
has
been
reported
from
other
studies
on
aerosolized
pentamidine
[4,9,15]
and
parenteral
pentamidine
[16].
A
dose
-response
for
aerosolized
pentamidine
was
indicated
by
Leoung
et
al.
[9],
and
recently
it
was
reported
that
600
mg
weekly
had
100%
efficacy
together
with
a
low
frequency
(18%)
of
adverse
reactions
[17].
The
12
cases
of
PCP
acquired
during
pentamidine
prophylaxis
were
usually
mild
and
contributed
to
death
of
only
one
or
two
patients.
Since
100
new
AIDS
-defining
events
and
27
deaths
were
observed,
one
may
conclude
that
both
regimens
have
sufficient
efficacy
from
a
practical
clinical
point
of
view.
Thus,
further
efforts
should
concentrate
on
the
prevention
of
AIDS
-defining
events
other
than
PCP
and/or
the
immunodeficiency
per
se.
Low
-dose
trimethoprim-sulfamethoxazole
daily
[4]
or
three
times
weekly
[18]
is
probably
the
most
practical,
economical
and
efficient
prophylaxis
one
can
offer
these
patients.
For
patients
who
cannot
tolerate
sulfones,
aerosolized
pentamidine
is
a
suitable
candidate
among
several
second
-line
alternatives
due
to
its
low
systemic
toxicity.
In
the
present
study
we
found
a
similar
efficacy
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more
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were
observed
in
the
aerosolized
pentamidine
group.
However,
intolerable
adverse
reactions
were
more
frequent
in
the
i.
v.
pentamidine
group.
The
existence
of
disseminated
P.
carinii
infection,
though
not
observed
in
our
patients,
would
make
i.
v.
administration
recommendable,
as
would
conditions
in
which
the
risk
of
nosocomial
airborne
spread
of
tuberculosis
exists
[19].
The
observed
difference
in
survival
favouring
the
i.
v.
pentamidine
group
may
be
explained
by
the
differences
in
observation
time.
The
two
groups
had
comparable
baseline
CD4
+
cell
counts,
and
the
deaths
in
the
aerosolized
pentamidine
group
were
not
caused
by
disseminated
P.
carinii
infection
or
attributable
to
severe
pulmonary
disease
caused
by
the
inhalation.
The
survival
estimate
in
the
aerosolized
pentamidine
group
at
18
months
was
similar
to
that
reported
by
Girard
et
al.
[3]
for
patients
given
zidovudine
or
zidovudine
and
aerosolized
pentamidine.
Aerosolized
pentamidine
had
neither
a
positive
effect
nor
a
negative
effect
on
survival
in
that
study.
Until
similar
differences
in
survival
between
patients
on
aerosolized
versus
those
on
i.
v.
pentamidine
have
been
observed
by
others
we
prefer
not
to
speculate
on
the
clinical
significance
of
our
findings.
In
summary,
in
view
of
the
severe
immunodeficiency
and
the
rapid
clinical
progression
observed
in
our
patients,
we
found
that
either
form
of
pentamidine
prophylaxis
was
tolerable
and
efficient.
Further
prevention
of
clinical
HIV
disease
should
concentrate
on
the
immunodeficiency
and
other
AIDS
-defining
diagnoses.
Acknowledgement
This
study
has
been
supported
by
the
Swedish
Medical
Research
Council
grant
(B91
-16H-9592-01)
and
the
Swedish
Physicians
against
AIDS
Research
Foundation.
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A.
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K.,
Wardlaw,
L.,
Adams,
M.,
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Current
and
Upcoming
Supplements
of
Infection
Cefotaxime
Efficacy
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Safety
A
Decade
of
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Guest
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H.
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Neu,
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H.
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7/91
(appeared
in
February
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Cooperation
between
Antibiotics
and
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New
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with
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Modifying
Activity
in
Humans
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K
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G.
Pulverer,
S.
Ringoir,
Suppl.
1/92
(appeared
in
July
1992)
GM-CSF
and
Infection
Guest
Editors:
B.
H.
Belohradsky,
M
Weiss,
Suppl.
2/92
(appeared
in
December
1992)
International
Consensus
Discussion
on
Clinical
Evaluation
of
Drug
Efficacy
in
UTI
I
Guest
Editors:
M
Ohkoshi,
K
G.
Naber,
Suppl.
3/92
(appeared
in
December
1992)
UTIs
in
the
90s
Pathogenesis
and
Management
Editors:
T.
Bergan,
W.
Marget,
Suppl.
4/92
(appeared
in
December
1992)
Roxithromycin
(appearing
in
October
1993)
International
Consensus
Discussion
on
Clinical
Evaluation
of
Drug
Efficacy
in
UTI
II
(appearing
in
late
1993)
Special
Addendum
to
Appear
in
a
Regular
Issue
Borreliosis
in
Europe
(about
12
articles)
(appearing
in
winter
1993/94)
NEW
POCKETBOOKS
INFECTION
Progress
in
Infectious
Diseases
Sulbactam
Combinations
(appearing
in
June
1993)
DM
28,90,
ISBN
3-8208-1207-5
Lyme-Borreliose
(in
German;
appeared
in
January
1993)
DM
39,80,
ISBN
3-8208-1198-2
Infection
21
(1993)
No.
3
t
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Medizin
Verlag
GmbH
Munchen,
Munchen
1993
149
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19