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R E S E A R C H Open Access
Nebulized antibiotics for ventilator-associated
pneumonia: a systematic review and meta-analysis
Fernando G Zampieri
1,2,3*†
, Antonio P Nassar Jr
1,2,4†
, Dimitri Gusmao-Flores
1,5,6
, Leandro U Taniguchi
2,7
,
Antoni Torres
8
and Otavio T Ranzani
1,8,9,10
Abstract
Introduction: Nebulized antibiotics are a promising new treatment option for ventilator-associated pneumonia.
However, more evidence of the benefit of this therapy is required.
Methods: The Medline, Scopus, EMBASE, Biological Abstracts, CAB Abstracts, Food Science and Technology
Abstracts, CENTRAL, Scielo and Lilacs databases were searched to identify randomized controlled trials or matched
observational studies that compared nebulized antibiotics with or without intravenous antibiotics to intravenous
antibiotics alone for ventilator-associated pneumonia treatment. Two reviewers independently collected data and
assessed outcomes and risk of bias. The primary outcome was clinical cure. Secondary outcomes were microbiological
cure, ICU and hospital mortality, duration of mechanical ventilation, ICU length of stay and adverse events. A mixed-effect
model meta-analysis was performed. Trial sequential analysis was used for the main outcome of interest.
Results: Twelve studies were analyzed, including six randomized controlled trials. For the main outcome analysis, 812
patients were included. Nebulized antibiotics were associated with higher rates of clinical cure (risk ratio (RR) = 1.23; 95%
confidence interval (CI), 1.05 to 1.43; I
2
=34%;D
2
= 45%). Nebulized antibiotics were not associated with microbiological
cure (RR = 1.24; 95% CI, 0.95 to 1.62; I
2
= 62.5), mortality (RR = 0.90; CI 95%, 0.76 to 1.08; I
2
= 0%), duration of mechanical
ventilation (standardized mean difference = −0.10 days; 95% CI, −1.22 to 1.00; I
2
= 96.5%), ICU length of stay (standardized
mean difference = 0.14 days; 95% CI, −0.46 to 0.73; I
2
= 89.2%) or renal toxicity (RR = 1.05; 95% CI, 0.70 to 1.57; I
2
= 15.6%).
Regarding the primary outcome, the number of patients included was below the information size required for a definitive
conclusion by trial sequential analysis; therefore, our results regarding this parameter are inconclusive.
Conclusions: Nebulized antibiotics seem to be associated with higher rates of clinical cure in the treatment
of ventilator-associated pneumonia. However, the apparent benefit in the clinical cure rate observed by
traditional meta-analysis does not persist after trial sequential analysis. Additional high-quality studies on this
subject are highly warranted.
Trial registration number: CRD42014009116. Registered 29 March 2014
Introduction
Ventilator-associated pneumonia (VAP) is an important
infection that develops in approximately one-third of
patients who are mechanically ventilated for more
than 48 hours [1,2]. VAP has caused great concern for
physicians and managers because it is associated with high
morbidity, mortality [3] and healthcare system costs [4].
One of the cornerstones of VAP management is antibiotic
treatment, which currently presents a major challenge
because of the emergence of resistant pathogens, a lack of
new drugs and high associated costs.
Nebulized antibiotics have been used to treat respiratory
tract infections for the last 70 years [5,6]. Many theoretical
advantages of nebulized antibiotic therapy have been
proposed, such as higher drug levels at the infection site
and fewer systemic side effects [7]. These potential
benefits would therefore enhance the antimicrobial
therapy and reduce adverse effects [8]. However, clinical
* Correspondence: fgzampieri@gmail.com
†
Equal contributors
1
Cooperative Network for Research - AMIB-Net, Associação de Medicina
Intensiva Brasileira, São Paulo, Brazil
2
Emergency Medicine Discipline, Faculty of Medicine, University of São Paulo,
São Paulo, Brazil
Full list of author information is available at the end of the article
© 2015 Zampieri et al.; licensee BioMed Central. This is an Open Access article distributed under the terms of the Creative
Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and
reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain
Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article,
unless otherwise stated.
Zampieri et al. Critical Care (2015) 19:150
DOI 10.1186/s13054-015-0868-y
and technical issues regarding the use of nebulized antibi-
otics, primarily the best approach to deliver the drug to
the lungs, have become barriers to the proper study of this
technique [7-11].
There has been a resurgence in interest in this type of
antibiotic administration in recent years because of the
appearance of multidrug-resistant (MDR) pathogens
[8,12]. Relapse and recurrence after initial treatment are
also common, and monotherapy with nebulized antibiotics
could be an alternative treatment. It is difficult to achieve
microbiological eradication for certain pathogens, includ-
ing MDR pathogens in VAP [13]. Because MDR pathogens
are frequently only susceptible to older antibiotics associ-
ated with significant side effects (such as renal failure),
nebulized therapy represents an interesting approach to
decrease the toxicity of these drugs in critically ill patients.
Nevertheless, with the exception of colistin, there are no
experimental data that support the idea that nebulized
antibiotics reduce systemic toxicity [11]. Adjunctive com-
bined therapy (inhaled and intravenous) has also been sug-
gested to maximize therapy [14]. Clinicians have a positive
view of nebulized antibiotics; in a recent survey, 70% of
physicians reported that adjunctive nebulized antibiotics
could increase the effectiveness of VAP treatment [6].
Therefore, we sought to review the currently available
evidence regarding the use of nebulized antibiotics for
VAP treatment because there is no evidence supporting
their use in the clinical practice. Studies that compared
the use of nebulized antibiotics, with or without systemic
(intravenous) therapy, with systemic therapy alone were
included. We hypothesized that nebulized antibiotics
would improve the clinical response success rate in the
treatment of VAP.
Methods
Literature search
Studies were identified through a standardized search of
Medline (via OvidSP), Scopus, CENTRAL (Cochrane
Central Register of Controlled Trials), EMBASE, Biological
Abstracts, CAB Abstracts, Food Science and Technology
Abstracts (via OvidSP), Lilacs (Literatura Latino-Americana
edoCaribeemCiênciasdaSaúde) and Scielo (Scientific
Electronic Library Online) databases. A sensitive search
strategy was used, which combined the following keywords:
“ventilator associated pneumonia”,“VAP ”,“hospital
acquired pneumonia”,“HAP”or “nosocomial pneumonia”
and “inhaled”,“inhalation”,“aerolized”,“aerolised”,
“nebulized”or “nebulised”. The references in the included
studies and personal files were also searched. The search
strategy was restricted to randomized clinical trials and
observational studies with matched groups (cohort studies
with comparable groups or case–control studies) per-
formed in adult subjects and published prior to 29 March
2014. We excluded care series and reports. There was no
language restriction. The titles and abstracts were assessed
for eligibility, and full-text copies of all of the articles
deemed potentially relevant were retrieved. A standardized
eligibility assessment was independently performed by two
reviewers (APN and FGZ). We selected the larger study in
cases of studies that reported data in more than one
publication. Disagreements were resolved by consensus.
The PRISMA statement was used for guidance [15],
and the meta-analysis was registered in the PROSPERO
database (CRD42014009116). Ethical approval was not
required for this work.
Study selection
Studies that fulfilled the following criteria were included:
1) compared nebulized antibiotics with or without intra-
venous antibiotics with intravenous antibiotics only in
the treatment of patients with an established diagnosis
of VAP; and 2) reported at least one of the following
outcomes: clinical cure, microbiological cure, mortality,
mechanical ventilation duration and ICU length of stay.
Data extraction and quality assessment
A data extraction sheet was developed. Two authors
(APN and FGZ) independently extracted the following data
from the included studies: year of publication, country,
study design, number of patients designated to nebulized or
intravenous-only antibiotics, microbiological cure criteria,
clinical cure criteria, severity score, mechanical ventilation
duration, ICU length of stay, microbiological and clinical
cure rates, mortality and adverseevents.Theauthorsofthe
included studies were contacted by email to complete the
missing data that were required for study characterization.
A maximum of four contacts was attempted per study over
aperiodof6months.
Two of the authors (APN and FGZ) assessed the risk
of bias in the individual trials using the Cochrane risk of
bias tool [16] for randomized clinical trials and the
Newcastle-Ottawa Scale for cohort and case–control
studies [17]. For the outcomes in each of the included
randomized clinical trials, the risk of bias was reported
as “low risk”,“unclear risk”,or“high risk”in the following
domains, according to the Cochrane risk of bias tool:
random sequence generation; allocation concealment;
blinding of participants and personnel; blinding of outcome
assessment; incomplete outcome data; selective reporting;
or other bias. Disagreements were resolved by consensus
with a third author (OTR).
Outcome measurements
The primary outcome was clinical cure, as it was defined
by each study author. The secondary outcomes were
microbiological cure, mortality (considering the longest
follow-up reported by the authors), ICU length of stay,
duration of mechanical ventilation and adverse events.
Zampieri et al. Critical Care (2015) 19:150 Page 2 of 12
Statistical analysis
A random-effects (DerSimonian-Laird) model was
employed because of the anticipated variability between
the trials regarding patient samples and medical interven-
tions. A constant continuity correction of 0.5 was used for
handling zero-event studies to include all selected studies
in the analysis and minimize bias. The differences observed
between the treatment groups are expressed as the relative
risk (RR) for categorical variables and the standardized
mean differences (SMDs) for continuous variables, both
with 95% confidence intervals (CIs). Heterogeneity was
assessed by the I
2
statistic and was classified as low (<25%),
moderate (25 to 50%) or high (>50%). We also used funnel
plotsforthemainoutcomesinordertoassesspubli-
cation bias. An a priori subgroup analysis was performed
separately analyzing randomized controlled trials and
observational studies for all outcome measurements.
We explored heterogeneity for study characteristics
(randomized controlled trials versus observational studies)
with meta-regression for the primary outcome. We
assessed post hoc if using a different method for random-
effects (Biggerstaff-Tweedie) for the main outcome would
produce different results. Biggerstaff-Tweedie may be the
most appropriate method when only a limited number of
studies are available [18].
A trial sequential analysis (TSA) was performed using
the required information size to construct sequential
monitoring boundaries. The boundaries were established
to limit the global type error to 5% and were calculated
with the O’Brien-Fleming function, which considered a
power of 80% to detect a 20% increase in clinical cure rate
and a 37.5% incidence of failure of VAP treatment, as sug-
gested by a recent meta-analysis [19]. The heterogeneity for
information size calculation was set using the D
2
measure.
D
2
is the relative variance reduction when the model is
changed from a random-effects to a fixed-effect model, and
its interpretation is similar to that of I
2
because it is a pro-
portion. However, it is advisable to use D
2
instead of I
2
for
therequiredsamplesizeinformation[20].Alloftheobser-
vational studies were included in the TSA as high bias. The
analyses were performed using R project software, version
3.1.1, with R Studio, version 0.98.1049, and the meta
package (version 3.1-1) by Guido Schwazer (http://cran.r-
project.org/web/packages/meta/meta.pdf). TSA was per-
formed using TSA software, version 0.9 beta (Copenhagen
Trial Unit, Copenhagen, Denmark).
Results
Study characteristics
Of the 1,921 references initially identified, 33 full-text
articles were assessed for eligibility, and 12 studies
were selected for the analysis [21-32] (Figure 1).
Table 1 summarizes the details of the included studies.
There were six observational studies and six randomized
clinical trials. Two randomized controlled trials and one
observational study were multicenter studies [21,26,28].
Acinetobacter spp., Pseudomonas spp. and Klebsiella spp.
were the most isolated bacteria. The most common nebu-
lized antibiotics administered were colistin (nine studies)
and aminoglycosides (seven studies). Eleven studies com-
pared adjunctive nebulized antibiotics with intravenous
antibiotics, and only one compared nebulized antibiotics
alone with intravenous antibiotics [27].
The clinical and microbiological cure criteria and
adverse events assessed are presented in Table 2. The
clinical cure criteria were similar among the studies,
with the exception of one study that focused on
whether patients were extubated in the 10 days after
treatment [26]. One study did not define clinical cure;
however, it compared the clinical pulmonary infection
score at randomization and at the end of treatment.
Because the score was presented as a continuous variable,
it was not included in the pooled analysis [30]. Renal
toxicity was the most common adverse event assessed
(seven out of twelve studies).
Study quality
Observational studies were considered high quality
according to the Newcastle-Ottawa Scale. Five randomized
Figure 1 Study flowchart. i.v., intravenous; VAP, ventilator-associated
pneumonia.
Zampieri et al. Critical Care (2015) 19:150 Page 3 of 12
Table 1 Study characteristics and quality assessment
Study, year Country Number of patients
(inhaled ± intravenous
antibiotic/intravenous only)
Isolated bacteria (n) Nebulizer device Inhaled antibiotic
given (daily dose)
Quality
assessment
Observational
studies
Newcastle-
Ottawa Scale
Doshi, 2013 [21] USA 44/51 Acinetobacter (61),
Pseudomonas (53),
ESBL Enterobacteria (11)
Jet or vibrating
mesh nebulizer
Colistin 150-300 mg 7
Ghannam, 2009 [22] USA 16/16 Pseudomonas (22),
Klebsiella (5),
Stenotrophomonas (3),
Serratia (2), E. coli (1),
Acinetobacter (1)
Jet nebulizer Gentamicin 300-400 mg,
Amikacin 200-300 mg,
Tobramycin 600-900 mg
or Colistin 300 mg
9
Kalin, 2012 [23] Turkey 29/15 Acinetobacter (10) Device not
described.
Nebulization
with oxygen
flow of 8 l/min
Colistin 300 mg 9
Kofteridis, 2010 [24] Greece 43/43 Acinetobacter (66),
Klebsiella (12),
Pseudomonas (8)
Not described Colistin 150 mg 9
Korbila, 2010 [29] Greece 78/43 Acinetobacter (92),
Pseudomonas (17),
Klebsiella (4)
Ultrasonic nebulizer Colistin 150 mg 9
Tumbarello, 2013 [31] Italy 104/104 Acinetobacter (128),
Pseudomonas (52),
Klebsiella (28)
Jet or ultrasonic
nebulizer
Colistin 225 mg 9
Randomized
controlled trials
Cochrane
risk of bias
Hallal, 2007 [25] USA 5/5 Pseudomonas (9),
Acinetobacter (3),
Staphylococcus (3)
Jet nebulizer Tobramycin 600 mg High
Le Conte, 2000 [26] France 21/17 Pseudomonas (16),
Haemophilus (6),
Enterobacter (4),
E. coli (3), Klebsiella (1)
Balloon with a valve
connected to the
endotracheal tube
Tobramycin 2.5 mg/kg High
Lu, 2011 [27] France 20/20 Pseudomonas (40) Vibrating nebulizer Ceftazidime 120 mg/kg
or Amikacin 25 mg/kg
High
Niederman, 2012 [28] France/Spain/USA 47
a
/22 Pseudomonas (24),
E. coli (14), Klebsiella (10),
Acinetobacter (7)
Vibrating mesh
nebulizer
Amikacin 800 mg Low
Palmer, 2014 [30] USA 24/18 Staphylococcus (18),
Acinetobacter (12),
Pseudomonas (9),
Klebsiella (5),
Jet nebulizer Vancomycin 360 mg
and/or Gentamicin
240 mg or Amikacin
1200 mg
High
Zampieri et al. Critical Care (2015) 19:150 Page 4 of 12
Table 1 Study characteristics and quality assessment (Continued)
Enterobacter (4),
Other (9)
b
Rattanaumpawan, 2010 [32] Thailand 51/49 Acinetobacter (65),
Pseudomonas (34),
Klebsiella (20), E. coli (7),
Enterobacter (3),
Stenotrophomonas (2)
Jet or ultrasonic
nebulizer
Colistin 150 mg High
1 mg colistin = 13,333 IU.
a
21 patients randomized to inhaled amikacin 400 mg every 12 hours and 26 patients randomized to inhaled amikacin 400 mg every 24 hours.
b
Proteus (2), E. coli (2), Stenotrophomonas (2),
Enterococcus (1), Streptococcus (1), and Citrobacter (1). ESBL, extended spectrum beta-lactamase.
Zampieri et al. Critical Care (2015) 19:150 Page 5 of 12
Table 2 Clinical and microbiological cure criteria, and adverse events assessment in included studies
Study, year Clinical cure criteria Microbiological cure criteria Adverse events assessed
Observational studies
Doshi, 2013 [21] Resolution of initial signs and symptoms of infection,
including normalization of white blood cell count and
temperature, by the end of therapy.
Eradication of the MDR pathogen
on subsequent respiratory cultures
NA
Ghannam, 2009 [22] Improved clinical parameters (fever defervescence,
suctioning requirements, symptoms and signs of
pneumonia), ventilator parameters and laboratory
findings (improved blood gases, normalization of
white blood cell count), and/or receding pulmonary
infiltrates on a chest radiograph at the end of therapy.
Eradication of causative organisms in
patients in whom a follow-up culture
was obtained at the end of therapy.
Renal dysfunction (doubling of serum creatinine
in patients with pretreatment (baseline) creatinine
clearance of ≥30 ml/minute or an increase in
creatinine by ≥1 mg/dl at the end of therapy in
patients with pretreatment creatinine clearance
<30 ml/minute)
Kalin, 2012 [23] Resolution of symptoms and signs of VAP at the
end of the therapy
Eradication of MDR A. baumannii on
follow-up culture
Renal toxicity (RIFLE criteria)
Kofteridis, 2010 [24] Resolution of presenting symptoms and signs of
infection by the end of colistin treatment
Eradication of the pathogen at the
end of antimicrobial therapy or at
discharge from ICU
Renal toxicity (serum creatinine value >2 mg/dl;
reduction in the calculated creatinine clearance of
50%, compared with the value at the start of
treatment; or as a decline in renal function that
prompted renal replacement therapy; increase of
150% of the baseline creatinine, a reduction in the
calculated creatinine clearance of 50% relative to
the value at therapy initiation in patients with
pre-existing renal dysfunction), bronchoconstriction,
cough, apnea, or chest tightness, and arterial
hypoxemia.
Korbila, 2010 [29] Normalization of temperature and tracheal secretions,
together with a return to baseline of the white blood
cell count and the C-reactive protein level, and the
improvement in chest X-ray appearances, by the end
of treatment.
NA NA
Tumbarello, 2013 [31] Resolution of all signs and symptoms of pneumonia and
improvement or lack of progression of all chest radiograph
abnormalities when colistin was discontinued
Disappearance of the infecting
bacterium from post-treatment
respiratory samples
Acute kidney injury (a greater than twofold
increase in serum creatinine or a ≥50% decrease
in the glomerular filtration rate or oliguria (output
<0.5 ml/kg/hour) for ≥12 hours)
Randomized controlled trials
Hallal, 2007 [25] Extubation within the study period, improving of MODS,
resolution of fever, pulmonary infiltrates and physical
signs of pneumonia.
NA Doubling of the serum creatinine concentration
or an increase of creatinine above 2 mg/dl at
any time
a
Le Conte, 2000 [26] Extubation within 10 days NA Respiratory tolerance (described in results section
as hypoxemia during nebulization) and evolution
of serum creatinine
Lu, 2011 [27] Reduction of clinical and biological signs of infection,
decrease in modified clinical pulmonary infection score
below 6, significant lung CT re-aeration, and lower
respiratory tract specimens either sterile or with
nonsignificant concentrations of P. aeruginosa
Eradication of P. aeruginosa in a
lower respiratory specimens after
8 days of antimicrobial therapy
Bronchospasm, hypoxemia, obstruction of
expiratory filter
Zampieri et al. Critical Care (2015) 19:150 Page 6 of 12
Table 2 Clinical and microbiological cure criteria, and adverse events assessment in included studies (Continued)
Niederman, 2012 [28] Complete or partial resolution of signs and symptoms
of pneumonia, improvement or lack of progression of
abnormalities on chest X-ray, and no additional
intravenous antibiotics since completion of treatment
Confirmed eradication of the original
pathogen or presumed eradication
in patients with complete or partial
resolution of pneumonia
Septic shock, seizures and bronchospasm.
Palmer, 2014 [30] NA No growth in culture and no visible
organisms seen on Gram-stain of
an organism identified at randomization
New resistant to antimicrobial therapy
Rattanaumpawan, 2010 [32] Complete resolution of all signs and symptoms
of pneumonia, and improvement or lack of
progression of all abnormalities on the chest
radiograph
Eradication or presumed eradication
after antimicrobial treatment
Renal impairment (a rise of 2 mg/dl in
the serum creatinine level of patients
with previously normal renal function
or a doubling of the baseline serum
creatinine level in patients with
pre-existing renal insufficiency),
bronchospasm.
a
This was among the definitions of treatment failure in the trial. CT, computed tomography; MDR, multidrug resistant; MODS, multiple organ dysfunction score; NA, not available; RIFLE, Risk, Injury, Failure, Loss, and
End-stage kidney disease; VAP, ventilator-associated pneumonia.
Zampieri et al. Critical Care (2015) 19:150 Page 7 of 12
controlled trials were considered to have a high risk of bias
as assessed by the Cochrane risk of bias tool (Table 1).
Assessment of each risk of bias is presented in Figure 2.
Outcomes
Clinical cure was assessed in 11 studies totaling 812
patients. Nebulized antibiotics were associated with
higher rates of clinical cure (RR = 1.23; 95% CI, 1.05
to 1.43; I
2
= 34%; D
2
= 45%) (Figure 3). The Biggertaff-
Tweedie model produced similar results (RR = 1.21;
95% CI, 1.19 to 1.22; I
2
= 34%; D
2
= 35%). Within the
subgroup analysis according to study design (randomized
controlled trial versus observational) there was a presence
of heterogeneity (Figure 3); however, the difference in
the effect of nebulized antibiotics by study design
was not significant in the meta-regression (P= 0.517).
A bubble plot for the meta-regression is shown in
Additional file 1 (Figure S1). A funnel plot for the
clinical cure analysis is shown in Additional file 1
(FigureS2).TheTSAresultsareshowninFigure4.
Considering the boundaries defined in the methods
section, our meta-analysis was insufficiently powered to
detect an increase in treatment success with a 5% alpha
error limit (information size required 1,895 patients).
Microbiological cure was assessed in eight studies that
enrolled a total of 609 patients. The effects of nebulized
antibiotics on the microbiological cure were uncertain
(RR = 1.24; 95% CI, 0.95 to 1.62; I
2
= 62.5%) (Figure 5).
The funnel plot for the microbiological cure analysis is
presented in Additional file 1 (Figure S3) [22,30].
Mortality was assessed in 10 studies that enrolled
817 patients. Nebulized antibiotics were not associ-
ated with a lower mortality rate compared with the
control groups (RR = 0.90; 95% CI, 0.76 to 1.08; I
2
=0%)
(Figure 6).
The total duration of mechanical ventilation (six studies,
496 patients) and ICU length of stay (six studies, 498
patients) were not affected by nebulized antibiotic use
(SMD = −0.10 days; CI 95%, −1.22 to 1.00; I
2
= 96.5% and
SMD = 0.14 days and CI 95% to 0.46-0.73; I
2
=89.2%,
respectively). Both outcomes had high levels of hetero-
geneity. The forest plots are shown in Additional file 1
(Figure S4 and Figure S5, respectively).
Renal toxicity was assessed in six studies that enrolled
476 patients. Nebulized antibiotics were not associated
with an increased risk of renal toxicity (RR = 1.05; 95% CI,
0.70 to 1.57; I
2
= 15.6%) (Additional file 1: Figure S6).
There were insufficient data available for pooling the risk
of other adverse outcomes, such as bronchospasm.
Discussion
The main finding of the present study was that VAP
treatment with nebulized antibiotics might be associated
with higher rates of clinical cure. However, a robust
analysis aimed at identifying the required information
size necessary to detect a significant difference (TSA)
demonstrated that our meta-analysis was underpowered
for its main clinical outcome. There were no differences
regarding the other secondary outcomes, including micro-
biological cure, mortality or renal toxicity.
Nebulized antibiotics could represent an attractive
alternative for VAP treatment, mainly for cases caused
by MDR Gram-negative bacteria, because the two most
commonly administered intravenous antibiotics (colistin
and aminoglycosides) in this scenario do not have
adequate lung penetration [33-35]. In contrast, clinical
studies in patients with VAP have also confirmed high
sputum concentrations of nebulized antibiotics [28].
Despite the good rationale for nebulized antibiotics, there
has been a lack of evidence in the current literature to
support their use. A recent meta-analysis has suggested
nebulized colistin may be effective in the treatment of
respiratory infections in ICU patients [36]. However,
this meta-analysis included studies of patients with
infections other than VAP (such as tracheobronchitis
and non-ventilated ICU-acquired pneumonia) and evalu-
ated the role of one specific antibiotic. This meta-analysis
concluded colistin has a beneficial effect in the treatment
Figure 2 Risk of bias and a summary are presented as the
judgment of the review authors regarding risk of bias for each
item included in the study.
Zampieri et al. Critical Care (2015) 19:150 Page 8 of 12
Figure 4 Trial sequential analysis results. RR, relative risk.
Figure 3 Forest plot for clinical cure. Pfor overall effect = 0.009. CI, confidence interval; RR, relative risk.
Zampieri et al. Critical Care (2015) 19:150 Page 9 of 12
of these respiratory infections, but they did not perform
any method to correct the type I error secondary to
multiple data analyses [37]. The merits of our meta-
analysis are that it has focused specifically on VAP,
evaluated a broader range of antibiotics, and included
amorerobustdataanalysis.Additionally,weincluded
six trials instead of only one in the previous meta-analysis
[36], showing the importance of other antibiotics as
inhaled options to treat VAP patients.
Several issues deserve further attention. For example,
a deeper understanding of the optimal method for
delivering the drug is a crucial next step that could
not be assessed in this meta-analysis. There are many
factors which may impact on delivery of inhaled particles
to lung parenchyma. First, not all types of nebulizers
deliver aerosol particles with the same efficiency. Vibrating
mesh and ultrasonic nebulizers have appeared to be more
efficient in drug delivery than jet nebulizers, because
the latter generates aerosol by superimposing a highly
turbulent flow to the inspiratory flow coming from
the ventilator [11]. This mechanism is associated with
lesser deposition of particles in lung parenchyma [38].
Second, spontaneous ventilator modes are associated with
high turbulent inspiratory flow and, consequently, delivery
of aerosol particles mostly in proximal airways. Ventilator-
patient asynchrony may also reduce drug delivery to the
Figure 6 Forest plot for mortality. Pfor overall effect = 0.252. CI, confidence interval; RR, relative risk.
Figure 5 Forest plot for microbiological cure. Pfor overall effect = 0.116. CI, confidence interval; RR, relative risk.
Zampieri et al. Critical Care (2015) 19:150 Page 10 of 12
lung [39]. Third, ventilator and circuit connections should
have smooth inner surfaces and should not have obtuse
angles which impair aerosol drug delivery [11]. For
the same reason, heat and moisture exchanges should
be removed before inhaled therapy [9]. Additionally,
antibiotic doses ignoring the inevitable extra-pulmonary
deposition may also impact on therapy efficacy [11]. It
may be possible that the lack of a clear positive effect
found in this meta-analysis could be a consequence of
suboptimal delivery of nebulized therapy.
Another important issue is whether inhaled antibiotics
should be used as adjunctive therapies or alone for the
treatment of VAP. In an experimental model of pneu-
monia caused by Pseudomonas, nebulized colistin pro-
vided high drug lung tissue concentrations, whereas
intravenous colistin generated undetectable levels in
lung tissue [40]. The only included study that directly
addressed this question and that was included in this
meta-analysis found no differences in the clinical or
microbiological cure rates between nebulized mono-
therapy and intravenous antibiotic regimens [27]. On
the other hand, an interesting study from the same
group showed that nebulized colistin combined with an
intravenous aminoglycoside in the treatment of VAP
causedbyMDRpathogensisaseffectiveasintraven-
ous combination of a beta-lactam and aminoglycoside
or quinolone in the treatment of VAP caused by suscep-
tible pathogens [41].
Additionally, our study highlights some important
points regarding the role of nebulized antibiotics in
the management of VAP. The available studies are
highly heterogeneous and are often associated with
high risk of bias. These limitations are reflected in
our analysis. We included observational studies and
randomized controlled trials, representing a strategy
that is sometimes questioned but may have advan-
tages that could outweigh the disadvantages because
the addition of more information can aid in clinical
decisions [42]. Other strengths of this analysis include
the extensive literature review that was performed,
which included databases that are typically not
searched in systematic reviews. Therefore, the risk of
not including a pertinent study was reduced [43].
Finally, the use of a robust statistical analysis with
TSA precluded us from making overly optimistic con-
clusions [37].
Conclusion
Nebulized antibiotics might be useful for the treatment
of VAP; however, the available evidence is of low quality
and is highly heterogeneous. The apparent benefit in the
clinical cure rate observed in traditional meta-analyses
does not persist after TSA. Further high-quality trials in
this subject are therefore warranted.
Key messages
Nebulized antibiotics may be beneficial for the
treatment of VAP.
However, high heterogeneity and the small number
of enrolled patients in the available studies preclude
any optimistic conclusions regarding the benefits of
nebulized antibiotics.
High-quality trials analyzing the value of nebulized
antibiotics for VAP treatment are warranted.
Additional file
Additional file 1: Figure S1. Bubble plot for metaregression. No impact
of study type in the results was observed. Figure S2. Funnel plot for
clinical cure. Figure S3. Funnel plot for microbiological cure. Figure S4.
Forest plot for length of mechanical ventilation. Pfor overall effect = 0.864.
Figure S5. Forest plot for length of ICU stay. Pfor overall effect = 0.651.
Figure S6. Forest plot for renal injury. Pfor overall effect = 0.823.
Abbreviations
CI: confidence interval; MDR: multidrug-resistant; RR: relative risk;
SMD: standardized mean difference; TSA: trial sequential analysis;
VAP: ventilator-associated pneumonia.
Competing interests
The authors declare that they have no competing interests.
Authors’contributions
LUT, OTR and DGF conceived the study concept and helped draft the
manuscript. FGZ and APN performed the search queries, reviewed the
articles, assessed their quality, extracted the data, performed the statistical
analyses and drafted the manuscript. OTR and AT participated in the design
and coordination of the study and critically revised the manuscript. All of the
authors read and approved the manuscript.
Acknowledgement
This work was performed by AMIB-Net, Associação de Medicina Intensiva
Brasileira (AMIB).
Author details
1
Cooperative Network for Research - AMIB-Net, Associação de Medicina
Intensiva Brasileira, São Paulo, Brazil.
2
Emergency Medicine Discipline, Faculty
of Medicine, University of São Paulo, São Paulo, Brazil.
3
Intensive Care Unit,
Hospital Alemão Oswaldo Cruz, São Paulo, Brazil.
4
Adult Intensive Care Unit,
A.C. Camargo Cancer Center, São Paulo, Brazil.
5
Intensive Care Unit, University
Hospital Prof. Edgar Santos, Universidade Federal da Bahia, Rua Augusto
Viana, Salvador 40110-910, Brazil.
6
Programa de Pós-graduação em Medicina
e Saúde (PPgMS) - Faculdade de Medicina da Bahia, Universidade Federal da
Bahia, Salvador, Brazil.
7
Research and Education Institute (IEP), Hospital
Sirio-Libanes, São Paulo, Brazil.
8
Institut Clinic de Pneumologia i Cirurgia
Toràcica, Servei de Pneumologia, UVIR, Universitat de Barcelona, IDIBAPS,
CIBERES, Barcelona, Spain.
9
Amil Critical Care Group, Hospital Paulistano, São
Paulo, Brazil.
10
Respiratory Intensive Care Unit, Pulmonary Division, Heart
Institute, Hospital das Clínicas, University of São Paulo, São Paulo, Brazil.
Received: 22 December 2014 Accepted: 9 March 2015
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