Download Reduction of Bacterial Resistance with Inhaled

ORIGINAL ARTICLE
Reduction of Bacterial Resistance with Inhaled Antibiotics in the
Intensive Care Unit
Lucy B. Palmer and Gerald C. Smaldone
Pulmonary, Critical Care and Sleep Division, Department of Medicine, State University of New York at Stony Brook, Stony Brook,
New York
Abstract
Rationale: Multidrug-resistant organisms (MDRO) are the
dominant airway pathogens in the intensive care unit (ICU) and
present a major treatment challenge to intensivists. Aerosolized
antibiotics (AA) result in airway concentrations of drug 100-fold
greater than the minimal inhibitory concentration of most bacteria
including MDRO. These levels, without systemic toxicity, may
eradicate MDRO and reduce the pressure for selection of new
resistant organisms.
Objectives: To determine if AA effectively eradicate MDRO in the
intubated patient without promoting new resistance.
New drug resistance to AA was not seen. Compared with AA,
resistance to systemic antibiotics significantly increased in placebo
patients (P = 0.03). Compared with placebo, AA significantly reduced
Clinical Pulmonary Infection Score (mean 6 SEM, 9.3 6 2.7 to 5.3 6
2.6 vs. 8.0 6 23 to 8.6 6 2.10; P = 0.0008).
Conclusions: In chronically intubated critically ill patients, AA
successfully eradicated existing MDRO organisms and reduced the
pressure from systemic agents for new respiratory resistance.
Clinical trial registered with www.clinicaltrials.gov (NCT 01878643).
Keywords: nebulizer; intubated; Clinical Pulmonary Infection
Score; pneumonia
Methods: In a double-blind placebo-controlled study, critically ill
intubated patients were randomized if they exhibited signs of
respiratory infection (purulent secretions and Clinical Pulmonary
Infection Score >6). Using a well-characterized aerosol delivery
system, AA or saline placebo was given for 14 days or until
extubation. The responsible clinician determined administration of
systemic antibiotics for ventilator-associated pneumonia and any
other infection.
Measurements and Main Results: AA eradicated 26 of 27
organisms present at randomization compared with 2 of 23
organisms with placebo (P , 0.0001). AA eradicated the original
resistant organism on culture and Gram stain at end of treatment in
14 out of 16 patients compared with 1 of 11 for placebo (P , 0.001).
For respiratory infections, intensivists are
faced with a clinical conundrum: the use of
systemic antibiotics is the main driving force
for antimicrobial resistance, and to reduce
mortality, guidelines recommend increasing
At a Glance Summary
Scientific Knowledge on the Subject: The intensive care
unit is a haven for multidrug-resistant organisms. They
frequently arise in the respiratory tract and they are difficult
to eradicate. Routine treatment with broad-spectrum
systemic antibiotics can lead to further resistance and
superinfection.
What This Study Adds to the Field: Inhaled antibiotics can
eradicate these organisms and prevent further development of
resistance.
use of broad-spectrum antibiotics driving
resistance (1–6).
We hypothesized that aerosolized
antibiotics (AA), which achieve local
concentrations in the airway routinely
100-fold greater than the minimal
inhibitory concentration, will eradicate
resistant bacteria in the proximal airways
without systemic toxicity or furthering
bacterial resistance (7–10). We deliberately
( Received in original form December 9, 2013; accepted in final form March 10, 2014 )
Author Contributions: L.B.P. and G.C.S. jointly conceived and performed this study. They wrote the manuscript and can independently take responsibility for
its content.
Correspondence and requests for reprints should be addressed to Lucy B. Palmer, M.D., Department of Medicine, Pulmonary, Critical Care and Sleep Division,
State University of New York at Stony Brook, Stony Brook, NY 11794-8172. E-mail: [email protected]
Am J Respir Crit Care Med Vol 189, Iss 10, pp 1225–1233, May 15, 2014
Copyright © 2014 by the American Thoracic Society
Originally Published in Press as DOI: 10.1164/rccm.201312-2161OC on March 19, 2014
Internet address: www.atsjournals.org
Palmer and Smaldone: Inhaled Antibiotics in the ICU
1225
ORIGINAL ARTICLE
studied patients at high risk for resistant
organisms.
Methods
This study was a double-blind, randomized,
placebo-controlled single-center trial.
Patients requiring mechanical ventilation
were candidates for the study if they met
the following inclusion criteria: 18 years old
or greater, intubated and mechanically
ventilated, and expected to survive at
least 14 days. All patients enrolled were
considered high risk for multidrug-resistant
organisms (MDRO) in the respiratory tract.
They all had at least three of the four known
risk factors for MDRO: (1) greater than
5 days of hospitalization, (2) prior use of
systemic antibiotics in the past 90 days, (3)
high frequency of resistance in the patient’s
hospital, and (4) immunosuppression (11).
Exclusion criteria included pregnancy,
use of immunosuppressive agents except
steroids, neutropenia (,1,000 white blood
cells [WBC] per milliliter), history of
allergy to study drugs, or subjects whose
primary diagnosis was communityacquired pneumonia. Patients with
nosocomial infection after treatment of
community-acquired pneumonia were
not excluded. All subjects enrolled had
informed consent approved by the Human
Investigations Committee.
Study candidates were initially placed
in an observational cohort (Figure 1).
Patients were eligible for enrollment if they
had increased purulent sputum with
organisms present on Gram stain, and their
Clinical Pulmonary Infection Score (CPIS)
was greater than or equal to 6 (includes
points for fever, leukocytosis, radiographic
changes, hypoxemia, purulence of sputum,
Gram stain, and cultures), criteria that we
have used previously for treatment trials
of respiratory infection (12, 13). After
informed consent, patients who entered the
treatment cohort were randomized to
placebo or AA by the four-block method
by a masked pharmacist. The physician
clinically responsible for the patient chose
all systemic antibiotics given before and
during the treatment period. Clinical
staff was masked to treatment arms. Five
patients in the placebo group left the
study shortly after enrollment (withdrew
or transferred to another facility). They
had received fewer than two doses of
drug and no data were available for
analysis.
AA selection was determined on the
basis of the Gram stain of their sputum.
Patients with gram-positive bacteria were
treated with vancomycin HCL, 120 mg every
8 hours. Those with gram-negative
organisms were treated with gentamicinsulfate, 80 mg every 8 hours, or amikacin,
400 mg every 8 hours. Both vancomycin and
aminoglycoside were used if both types of
organism were present. Placebo consisted of
2 ml of normal saline. Medication or placebo
was nebulized via an AeroTech II nebulizer
Figure 1. Flow chart for patient recruitment, enrollment, and analysis. AA = aerosolized antibiotics; CPIS = Clinical Pulmonary Infection Score.
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American Journal of Respiratory and Critical Care Medicine Volume 189 Number 10 | May 15 2014
ORIGINAL ARTICLE
(Biodex Medical Systems, Shirley, NY).
Patients were pretreated with albuterol
to prevent bronchospasm. During
administration, patients were all on assist
control so irregular breathing patterns, such
as intermittent mandatory ventilation, were
avoided. The ventilator was set to nebulize
only during inspiration with ventilator
humidification bypassed (humidification
significantly reduces nebulizer efficiency
[7]). Aerosol treatment was given every 8
hours for 14 days or until the patient was
extubated.
Sputum cultures were taken early in the
morning at baseline and weekly before
the first aerosol treatment. Sputum volume
was quantified daily Monday through Friday
by intermittent suction over 4 hours with
no added saline (12).
Acute Physiology and Chronic Health
Evaluation (APACHE) score at time of
randomization defined clinical severity of
illness. Vital signs, CPIS score, and adverse
events were tracked on a daily basis. MDR at
our hospital at the time of the study was
defined as follows: gram-positive MDROs
were oxacillin-resistant Staphylococcal
aureus and vancomycin-resistant
Enterococcus; gram-negative MDROs
were amikacin/gentamicin resistant, or
ceftazidine resistant, amikacin/gentamicin
susceptible. Cultures and Gram stains of
these samples were analyzed at the end
of treatment (EOT) to determine if the
organisms present at randomization were
eliminated and if newly resistant organisms
to drug administered appeared. An “isolate”
is a positive culture of an organism.
“Eradication” of an organism is defined
as no growth in culture and no visible
organisms seen on Gram stain of an
organism identified at randomization.
Sputum was streaked onto culture media in
three sectors consecutively and the growth
was classified by growth factor (grade 1–4)
(14). This provides a semiquantitative
representation of the number of organisms
in a culture: the greater the colonies of
growth on a plate, the higher the growth
factor.
Statistics
This was a pilot study examining the
microbiologic effects of AA. Continuous
variables were described using means and
standard deviations. Wilcoxon rank sum
test was used to test for group difference
between nonparametric continuous
variables. Fisher exact test was used for
Table 1: Demographic and Clinical Data
Demographics
AA
Placebo
Sex, N (%)
Male
14 (58.3)
13 (72.2)
Female
10 (41.7)
5 (27.8)
Mean age, yr (mean 6 SD)
57.7 6 23.1 60.6 6 18.2
Ethnicity, N (%)
White
21 (87.5)
18 (100)
Other
3 (12.5)
0 (0)
Clinical information
N (%)
N (%)
Major diagnoses leading to mechanical ventilation
Multitrauma, N (%)
6 (25)
4 (22)
Surgical intervention, N (%)
7 (29.2)
3 (17)
Sepsis, N (%)
3 (12.5)
0 (0)
Gastrointestinal, N (%)
1 (4.2)
2 (11)
Neurologic insult, N (%)
2 (8.3)
3 (17)
Cardiac, N (%)
1 (4.2)
1 (6)
Pneumonia, N (%)
0 (0)
1 (6)
Respiratory arrest, N (%)
1 (4.2)
1 (6)
Chronic obstructive pulmonary disease, N (%)
3 (12.5)
2 (11)
ETOH withdrawal, N (%)
0 (0)
1 (6)
APACHE score, mean 6 SD
20.96 6 5.8 14.4 6 5.5
Ventilation days before randomization,
29.4 6 20.1 32.3 6 18
mean 6 SD
CPIS at randomization, mean 6 SD
9.3 6 2.7
8.0 6 2.1
Volume of sputum at randomization (ml/4 hr),
6.9 6 4.7
8.9 6 0.69
mean 6 SD
Subjects on SA at randomization, mean 6 SD
24 (100)
18 (100)
Subjects on targeted antibiotics at
16 (66)
14 (77)
randomization, mean 6 SD
Randomization arms, N (%)
Gram-negative
12 (50)
9 (50)
Gram-positive
10 (41.7)
7 (38.9)
Both
2 (8.3)
2 (11.1)
P Value
0.517*
0.6616†
0.247*
0.0007†
0.624‡
0.5†
0.12†
1.000*
0.51*
1.000*
1.000*
1.000*
Definition of abbreviations: AA = aerosolized antibiotics; APACHE = Acute Physiology and Chronic
Health Evaluation; CPIS = Clinical Pulmonary Infection Score; ETOH = alcohol; SA = systemic
antibiotics.
*Fisher exact test.
†
Unpaired t test.
‡
Wilcoxon signed rank test.
Table 2: Bacterial Isolates from Tracheal Aspirates at Randomization
AA
Gram-positive bacteria
Methicillin-sensitive Staphylococcus aureus
Methicillin-resistant Staphylococcus aureus
Streptococcus agalactiae
Gram-negative bacteria
Pseudomonas sp.
MDR* Pseudomonas aeruginosa
Acinetobacter sp.
MDR* Acinetobacter sp.
Enterobacter sp.
MDR* Enterobacter sp.
Escherichia coli
Klebsiella pneumoniae
Citrobacter freundii
Stenotrophomonas maltophilia
Placebo
3
5
1
2
7
0
1
6
0
8
0
1
1
1
0
0
2
3
1
3
1
0
0
2
1
1
Definition of abbreviations: AA = aerosolized antibiotics; MDR = multidrug resistant.
Details are shown in Table 3, serial cultures in Figure 2.
*MDR gram-negative defined as resistance to ceftazidime or amikacin/gentamicin.
Palmer and Smaldone: Inhaled Antibiotics in the ICU
1227
1228
MRSA
Proteus, Klebsiella R
Acinetobacter sp. R–ACG
Pseudomonas R–C MRSA
Acinetobacter sp.
R–ACG, MSSA
Acinetobacter sp. R–CG
MRSA
MSSA, Escherichia coli
Acinetobacter sp. R–C
4
5
6
7
8
Pseudomonas R–C
Acinetobacter sp. R–C
Pseudomonas,
Pseudomonas
R–C, Proteus
MSSA
Acinetobacter sp. R–ACG,
Enterococcus
MSSA, Enterobacter R–C
Streptococcus
MRSA
14
15
16
17
18
19
naf, cefx
metr, imip, van, linz,
cefa
cefp
cefp, cefx
cefp, linz, van
cefp
gent, van, cip
van, cefp
imip, pip/taz
gati, van
cefx, van, azit
cefp, gati
amp
imip
van, imip, pip/taz
van
pip/taz, gent, imip
imip
gati
imip, linz, van, cefp
cip, metr, gent, mero
metr, van
amk, cefz, metr, van
Antibiotic
Pretherapy
naf, cefx
metr, imip, van,
linz, cefa
cefp
cefp, cefx
cefp, linz, van
cefp
pip/taz, cip
van, cefp, imip
cefp
azt, ery, van
cefx, van
cefp, imip, rif, van
van
pip/taz, van, naf, azt
amp, cefp, pip/taz
imip, van
van, pip/taz
gent, imip, mero
imip
gati
cip, metr, gent
amp, cefp, metr,
van, mero
imip, linz, van
amk, cefz, metr, van
Antibiotic
during Therapy
18
17
14
15
16
13
9
10
11
12
6
7
8
5
4
2
3
1
Placebo
Patient #
Pseudomonas sp.
R–AG 14
Acinetobacter sp.
Stenotrophomonas
Pseudomonas sp. R–C,
Enterobacter
Pseudomonas sp.,
Stenotrophomonas
Klebsiella R–C,
Citrobacter sp. R–C,
MRSA
Escherichia coli
Nl Flora
Enterobacter R–C
MRSA
MRSA, Acinetobacter
sp. R–ACG
MSSA, Acinetobacter
sp. R–ACG
MRSA
Enterobacter R–C
MRSA
Acinetobacter sp.
R–ACG,
MRSA, Klebsiella
Pseudomonas sp.
MSSA Klebsiella R–C
Organisms*
van, gent, cefp
van, pip/taz, cefp
van, pip/taz
pip/taz, cefp
van, cip, gati
clin, dox, gati, cip
pip/taz, metr,
cefp, van
van, gent
cefp, van
azt, metr, van
azt, imp, van
gati
amp, cefp, van
cefp, van
Antibiotic
Pretherapy
metr
van, gent, cefp
cip
bact, van
cefp
pip/taz, van, gent
azt, metr, van
imip
cefp, van, mero,
imip
cip, cefp
gati
cip
van, mero
imip, van
rif, imp, van
gati
pip/taz, van
cefp, van
Antibiotic
during Therapy
Definition of abbreviations: AA = aerosolized antibiotics; amk = amikacin; azt = aztreonam; cefp = cefepime; cefx = ceftriaxone; cefz = ceftazidime; cip = ciprofloxacin; clin = clindamycin;
dox = doxycycline; gati = gatifloxacin; gent = gentamicin; imip = imipenem; linz = linezolid; mero = meropenem; metr = metronidazole; MRSA = methicillin-resistant Staphylococcus aureus;
MSSA = methicillin-sensitive Staphylococcus aureus; naf = nafcillin; pip/taz = piperacillin/tazobactam; van = vancomycin.
*The organisms’ resistance that qualified these organisms as multidrug resistant is indicated by the following abbreviations: A = amikacin; C = ceftazidime; G = gentamicin; R = resistant.
22
23
24
20
21
MRSA Acinetobacter
sp. R–C
Klebsiella
MSSA
MRSA
13
9
10
11
12
Pseudomonas R–C
Acinetobacter R–CG
Pseudomonas R–AG
Organisms*
2
3
1
AA
Patient #
Table 3: Organisms at Randomization and Systemic Antibiotics before and during Aerosol Therapy
ORIGINAL ARTICLE
American Journal of Respiratory and Critical Care Medicine Volume 189 Number 10 | May 15 2014
ORIGINAL ARTICLE
Table 4: Microbiologic Response
Aerosolized Antibiotics
Placebo
P Value*
96% (26/27)
88% (14/16)
9% (2/23)
9% (1/11)
,0.0001
,0.0001
No. of randomization organisms eradicated†
No. of patients with eradication of resistant organisms
*Fisher exact test.
†
Resistant and nonresistant organisms.
testing for differences between percentages in
categorical variables. Unpaired t tests were
used for parametric continuous variables. The
significance level was fixed at an a level of P
less than 0.05. All analyses were performed
using SPSS 15 (SPSS, Inc., Chicago, IL) and
Prism (GraphPad, La Jolla, CA).
Results
Table 2 for AA and placebo. Some patients
had more than one isolate. Typical
respiratory pathogens were distributed
throughout both groups with 20 out of 27
isolates defined as MDR for AA and 10 out
of 23 isolates defined as MDR for placebo.
Table 3 demonstrates the organisms at
randomization for each patient and the
systemic antibiotics that were given by the
physician responsible for their care.
Patients
Microbiologic Effects
The final study sample consisted of 42 men
and women ranging in age from 19.0 to 92.0
years. The demographic and clinical data at
the time of randomization of the two groups
are shown in Table 1. Demographics were
similar in the two groups. The APACHE
scores in the two groups were significantly
different, with the severity of illness
being greater in the AA group (20.96 6
5.8 vs. 14.1 6 5.5; P , 0.0007). All other
parameters listed in Table 1 including
systemic antibiotic appropriateness (defined
by susceptibility and at least 5 d of treatment)
were similar in the two groups.
Bacterial isolates cultured from tracheal
aspirates at randomization are listed in
Table 4 demonstrates the effects of AA
versus placebo aerosols on eradication of
bacteria detected at randomization. The
data are analyzed for the effect of active
versus placebo arm on numbers of isolates
at randomization and by the number of
patients with MDRO organisms. For the
AA group, 26 of the 27 bacterial isolates
cultured at randomization were eradicated
(e.g., no growth and no organisms on Gram
stain) but only 2 of 23 to placebo (P ,
0.0001). Analysis of antimicrobial effects
specifically on MDRO revealed that 14 of
16 patients treated with AA had eradication
of resistant organisms compared with 1 out
of 11 with placebo aerosol (P , 0.0001).
New resistance to systemic antibiotics
is documented in Table 5. These isolates
were not seen at randomization. In the AA
group one organism each in 2 of 16 patients
emerged versus 6 of 11 in the placebo
group (P = 0.03).
The effect of AA versus placebo on the
growth of bacteria during treatment is
shown in Figure 2. Thirty-eight of 42
patients had serial cultures. The vertical
axis is the “growth factor” of a given
isolate, the symbols are individual isolates
at the indicated times. This figure
demonstrates marked reduction in
bacterial growth of all cultures during
treatment with AA (Figure 2A) compared
with placebo (Figure 2B). No AA patients
developed resistance to the AA
administered. Nine of the 11 eradicated
isolates were undetectable in the first to
fourth weeks post-EOT. Different symbols
are used for emergence of new resistance
to systemic agents.
Clinical Effects
Table 6 shows the clinical effect of
treatment on CPIS, volume of secretions,
and systemic WBC count. To determine if
Table 5: Systemic Antibiotics and New Resistance during Aerosol Therapy
Patients with
New Resistance
during Treatment
AA (n = 16)
2 (13%)
Placebo (n = 11)
6 (55%)
P value*
Patients
Aerosolized
Treatment
Systemic
Treatment
1
2
1
2
3
Gentamicin
Vancomycin
Placebo
Placebo
Placebo
4
5
Placebo
Placebo
6
Placebo
Piperacillin/tazobactam
Cefepime
Imipenem
Imipenem
Cefepime, meropenem,
vancomycin
Cefepime, gentamicin
Vancomycin,
piperacillin/tazobactam
Meropenem, vancomycin
Organism
VRE
Enterobacter sp.
PA
PA
Acinetobacter sp.
PA
Klebsiella pneumoniae, MRSA
Enterobacter sp.
0.03
Definition of abbreviations: AA = aerosolized antibiotics; MRSA = methicillin-resistant staphylococcus aureus; PA = Pseudomonas aeruginosa; VRE =
vancomycin-resistant enterococcus.
Data from patients with serial cultures throughout the study.
*Fisher exact test.
Palmer and Smaldone: Inhaled Antibiotics in the ICU
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ORIGINAL ARTICLE
24 vs. placebo, 2 of 18; P = 0.43). Deaths
were the result of multiorgan system
failure.
Discussion
Figure 2. Bacterial growth from tracheal aspirates obtained at time of randomization, mid treatment (Mid
Tx), and at end of treatment (EOT) for (A) aerosolized antibiotics (AA) and (B) placebo. Growth is quantified
using a graded scale of 0–4 from semiquantitative cultures: multidrug-resistant gram-negative
organisms (filled circles), nonresistant gram-negative organisms (open circles), resistant gram-positive
organisms (filled squares), nonresistant gram-positive organisms (open squares), and newly resistant
organisms on treatment (X). Some patients had multiple isolates. At Mid Tx all the isolates with
zero growth represent organisms detected at randomization that did not grow in isolates sampled
at Mid Tx. At EOT the isolates with zero growth represent organisms detected at randomization and
Mid Tx that did not grow in samples obtained at EOT. There was a clear difference in pattern of
bacterial growth between AA and placebo. Two AA isolates demonstrated persistent growth at EOT:
one methicillin-resistant Staphylococcus aureus (filled square) that was not eradicated by AA but had
no gram-positive cocci on Gram stain, and one persistent Acinetobacter (filled circle) with organisms
present on Gram stain. More newly resistant organisms were seen in the placebo group (Table 5).
the CPIS effects were primarily caused by
changes in bacterial growth in cultures
(a potential in vitro effect), we reanalyzed the
CPIS score with removal of the points for
culture and Gram stain. Treatment effects
on this modified CPIS score with AA were
still robust (P , 0.001). Other parameters
of infection including volume
of secretions (P , 0.05) and the systemic
WBC (P , 0.028) were significantly
reduced with AA.
1230
Total ventilator days were decreased
with AA but not significantly (AA vs.
placebo, 12.9 6 2.1 vs. 13.5 = 2.1; P =
0.078).
Nephrotoxicity was monitored by
serial creatinine assessment. No effects
were seen (AA: mean 6 SD, randomization,
0.84 6 0.73; end of study, 0.93 6 1.26; P ,
0.67) (placebo: randomization, 0.79 6 0.55;
end of study, 0.73 6 0.44; P = 0.50). Mortality
differences were not significant (AA, 6 of
This study shows that inhaled antibiotics
can eradicate a chronic pool of MDRO
found in the sputum of patients in the
intensive care unit (ICU). These effects
were demonstrated in a typical tertiary
care ICU environment in a population
of patients difficult to wean while receiving
numerous courses of antibiotics (Table 3)
(e.g., patients who harbor MDRO in
hospital).
Our patients were not merely
colonized. In addition to being critically ill
as indicated by their APACHE score, they
had signs and symptoms of respiratory
infection demonstrated by their CPIS
score, their high volume of secretions,
and their need for systemic antibiotics.
Similar amounts of appropriate systemic
antibiotics were given in both groups.
New resistance to the AA was not
seen. However, there was evidence
of continuous pressure creating new
resistance from systemic agents that was
significantly higher in the placebo patients
and mitigated by the use of AA.
Our main endpoints were
microbiologic. Our clinical observations
were consistent with those seen in our
previous studies. We have found that
AA can decrease ventilator-associated
pneumonia (VAP) and other signs and
symptoms of respiratory infection, facilitate
weaning, and reduce use of systemic
antibiotics. No new resistance to AA
was seen (7, 13). In the present study,
we deliberately attempted to treat MDRO
from the onset of therapy. Our data
suggest that AA reduce the pool of
MDRO in the ICU environment.
Microbial eradication in AA was
associated with a significant decrease in
signs of respiratory infection quantified by
CPIS. At the time of randomization both
groups averaged a CPIS greater than 7,
a value consistent with a high likelihood
of deep lung infection, rather than
colonization, influencing the responsible
clinician to use systemic antibiotics.
Treatment with AA was associated with
a significant drop in CPIS suggesting a low
post-treatment risk for deep lung infection.
American Journal of Respiratory and Critical Care Medicine Volume 189 Number 10 | May 15 2014
ORIGINAL ARTICLE
Table 6: Clinical Response
AA (n = 24)
CPIS*
CPIS w/o culture data‡
Volume per 4 hrx
Systemic white blood countjj
9.3
7.5
6.9
17.1
6
6
6
6
Randomization
Placebo (n = 18)
P Value
AA (n = 24)
6
6
6
6
0.5000†
0.9152†
0.12
0.18
5.3
4.9
1.1
13.3
2.7
2.1
4.7
1.9
8.0
7.1
8.9
12.6
2.1
2.6
0.69
1.2
6
6
6
6
EOT
Placebo (n = 18)
P Value
6
6
6
6
0.0008†
0.0546†
,0.001
0.726
2.6
2.2
1.3
1.3
8.6
6.3
6.3
13.9
2.6
2.0
4.3
1.5
Definition of abbreviations: AA = aerosolized antibiotics; CPIS = Clinical Pulmonary Infection Score; EOT = end of treatment.
*P , 0.0001.
†
Mann-Whitney test.
‡
P , 0.0001.
x
P , 0.0500.
jj
P , 0.0280.
Wilcoxon analyses: AA randomization versus AA EOT,*,‡,x,jj; placebo randomization versus placebo EOT, not significant for any parameters in table.
CPIS for the placebo group was unchanged
despite equivalent use of appropriate
systemic antibiotics. Therefore, differences
in treatment effect are attributable to AA
treatment, not systemic antibiotic effect.
AA may facilitate reduction in use of
systemic agents. This new concept needs to
be tested in future studies.
We do not believe our results were
caused by differences in systemic antibiotics
between groups. In Table 7 we summarize
all the antibiotics used for each patient
before and after aerosol therapy was
instituted and compared with antibiotic
days per patient. By inspection, the
distribution of antibiotic coverage between
groups seems to be broad in gram-positive
and gram-negative coverage for MDRO.
Quantification of these results by
antibiotics per day in the 2 weeks before
randomization and during the treatment
period demonstrated no significant
difference between the two groups.
American Thoracic Society guidelines
from 2005 recommend inhaled antibiotics
for VAP caused by MDRO only when
intravenous antibiotics have failed (11).
Since those guidelines were written
there have been numerous retrospective,
prospective, and three randomized
controlled trials using these agents as
adjuncts or as primary therapy to treat
VAP caused by highly resistant organisms
(13, 15–26). Few provide data on eradication
of organisms or details of the delivery
device and expected aerosol deposition.
Lu and coworkers (15) compared systemic
antibiotics with the same antibiotics
delivered by inhalation for VAP. Treatment
with systemic antibiotics led to increased
resistance to the drugs given, whereas
AA did not (7). None of the reported
studies of inhaled antibiotics were designed
to eliminate a chronic pool of resistant
organisms.
Our approach to therapy with inhaled
antibiotics has been previously described
(7, 12, 13). It is important to note that the
device used was well characterized for
particle size, efficiency, and deposition with
demonstrated high concentrations of drug
in airway secretions (7). Thus, we could
carefully control the conditions of delivery
ensuring highest concentrations of
antibiotic in the airways.
Limitations
Our microbiologic response endpoints
included presence of organisms on Gram
stain and semiquantitative culture of
tracheal aspirates, not a formal quantitative
culture. However, for microbiologically proved
Table 7: Systemic Antibiotic Days
Patients
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
Mean
SD
P value
Palmer and Smaldone: Inhaled Antibiotics in the ICU
Preantibiotic Days
per Patient
Aerosolized
Antibiotics
Placebo
32
43
28
26
0
1
28
3
29
0
4
5
11
10
7
20
15
23
2
0
20
9
11
29
14.83
12.51
17
6
30
21
0
5
0
28
12
13
12
20
3
10
0
23
37
0
13.17
11.42
0.7287
During Antibiotic Days
per Patient
Aerosolized
Antibiotics
Placebo
40
23
21
30
1
10
30
2
8
31
15
20
33
6
18
21
12
8
10
6
26
5
12
28
17.33
10.99
24
1
19
30
4
25
11
30
2
2
10
20
36
9
15
6
11
8
14.61
10.81
0.4159
1231
ORIGINAL ARTICLE
pneumonia, it has been shown that Gram
stains without organisms have a negative
predictive value of 94% for respiratory
infection and correlate with less than 105 CFU/
ml from cultures of tracheal aspirates (27–29).
The eradication of bacteria at EOT
could be attributed to in vitro suppression
of bacterial growth (as opposed to death of
bacteria) by high concentrations of
antibiotic in the sputum. However, the
absence of organisms on Gram stain with
AA confirms a very low bacterial burden.
Furthermore, although our protocol was
not designed to follow serial cultures after
the EOT, in the AA group, cultures in
the first and fourth weeks post-treatment
were available in nine patients (11 isolates).
In 9 of the 11 isolates defined at EOT as
“eradicated,” bacteria were undetectable
in both culture and Gram stain. In an
earlier study in tracheostomy patients
treated with AA for Pseudomonas aeruginosa
tracheobronchitis, recurrence of colonization
took 3 weeks post-treatment in most
patients (12). Finally, in previous work
we have shown that AA facilitates
extubation supporting an important
clinical effect that would not occur if
resistance to AA treatment emerged
during therapy. These observations led
us to the current study, a first attempt
to further define AA as direct therapy
for MDRO. Future studies should be
designed to confirm these observations.
They should include both respiratory and
nonrespiratory sites to determine overall
effect on antibiotic resistance in the ICU.
The difference in baseline APACHE
scores between the AA and placebo groups
at randomization was unexplained, with AA
more severely ill by this criterion. Although
the reason for this is not known, our
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