Cochrane Database of Systematic Reviews

Aerosolised antibiotics for the management of healthcare-

associated pneumonia (HCAP) and ventilator-associated
pneumonia (VAP) (Protocol)

Enuh HA, Enuh CU, Ezedunukwe IR, Diaz KT, Nfonoyim J

Enuh HA, Enuh CU, Ezedunukwe IR, Diaz KT, Nfonoyim J.

Aerosolised antibiotics for the management of healthcare-associated pneumonia (HCAP) and ventilator-associated pneumonia (VAP).
Cochrane Database of Systematic Reviews 2015, Issue 3. Art. No.: CD011617.
DOI: 10.1002/14651858.CD011617.

www.cochranelibrary.com

Aerosolised antibiotics for the management of healthcare-associated pneumonia (HCAP) and ventilator-associated pneumonia (VAP)
(Protocol)
Copyright 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
 TABLE OF CONTENTS
HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
APPENDICES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9

Aerosolised antibiotics for the management of healthcare-associated pneumonia (HCAP) and ventilator-associated pneumonia (VAP) i
(Protocol)
Copyright 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
[Intervention Protocol]

Aerosolised antibiotics for the management of healthcare-

associated pneumonia (HCAP) and ventilator-associated
pneumonia (VAP)

Hill A Enuh1 , Collins U Enuh2 , Ifeanyi R Ezedunukwe3 , Keith T Diaz4 , Jay Nfonoyim4

1
Department of Internal Medicine, Richmond University Medical Center, Staten Island, New York, USA. 2 Department of Anaesthesi-
ology, University of Abuja Teaching Hospital, Abuja, Nigeria. 3 Internal Medicine, Lagos University Teaching Hospital, Lagos, Nigeria.
4 Department of Pulmonary Critical Care, Richmond University Medical Center, Staten Island, New York, USA

Contact address: Hill A Enuh, Department of Internal Medicine, Richmond University Medical Center, Staten Island, New York,
USA. Enuh2010@yahoo.com.

Editorial group: Cochrane Acute Respiratory Infections Group.

Publication status and date: New, published in Issue 3, 2015.

Citation: Enuh HA, Enuh CU, Ezedunukwe IR, Diaz KT, Nfonoyim J. Aerosolised antibiotics for the management of healthcare-
associated pneumonia (HCAP) and ventilator-associated pneumonia (VAP). Cochrane Database of Systematic Reviews 2015, Issue 3.
Art. No.: CD011617. DOI: 10.1002/14651858.CD011617.

Copyright 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

ABSTRACT

This is the protocol for a review and there is no abstract. The objectives are as follows:

To assess the benefits and harms of aerosolised antibiotics, comparing aerosolised versus systemic antibiotics, aerosolised antibiotics
versus placebo and the addition of aerosolised to systemic antibiotics versus systemic antibiotics alone.

BACKGROUND facility; patients that have recently received chemotherapy, wound

Description of the condition
Ventilator-associated pneumonia (VAP) is a subgroup of hospital-
acquired pneumonia (HAP), which is defined as pneumonia that
occurs 48 to 72 hours after endotracheal intubation. HAP refers to
pneumonia that occurs 48 hours or more after hospital admission
and that is thought not to be incubating in the patient at the time
of admission. Healthcare-associated pneumonia (HCAP), on the
other hand, is defined as pneumonia that occurs in one or more of
these categories of people: patients admitted to an acute care centre
for a period of two or more days within the last 90 days of hospital
contact; patients that reside in a nursing home or long-term care
care or intravenous antibiotic therapy within the past 30 days of
infection; and patients who have visited a haemodialysis clinic or
a hospital (ATS/IDSA 2005). In 2005, HCAP was added as a
type of pneumonia in the American Thoracic Society/Infectious
Disease Society of America (ATS/IDSA) guidelines, to recognise
patients at high risk of developing multidrug-resistant pathogens
(File 2014). The term HAP is often used to represent both VAP
and HCAP (Tedja 2010).
VAP is one of the most common infections affecting intubated
and mechanically ventilated patients. It is categorized as early or
late onset VAP. Early onset VAP is defined as pneumonia emerg-
ing within 96 hours of admission and after the initial 48 hours,
while late onset VAP develops after 96 hours of hospitalisation.
Pneumonia in individuals who received antibiotics or who were

Aerosolised antibiotics for the management of healthcare-associated pneumonia (HCAP) and ventilator-associated pneumonia (VAP) 1
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Copyright 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
admitted to hospital in the last 90 days is also classified as late
onset pneumonia (Abu-Salah 2011).
The aetiology of HAP, VAP and HCAP can be polymicrobial and
most commonly involves a broad range of bacterial pathogens
and less commonly nosocomial viral or fungal infections in im-
munocompetent patients, or a single pathogen. The common
causative pathogens are the aerobic gram-negative bacilli such as
Pseudomonas aeruginosa (P. aeruginosa), Klebsiella pneumoniae (K.
pneumoniae), Escherichia coli (E. coli) and Acinetobacter species
or gram-positive cocci such as Staphylococcus aureus (S. aureus),
principally methicillin-resistant S. aureus (MRSA). Early onset
VAP has low risk factors for multidrug-resistant bacteria. The
causative pathogens include Streptococcus pneumoniae (S. pneumo-
niae), Haemophilus influenzae (H. influenzae), MRSA and gram-
negative bacteria. Multidrug-resistant pathogens are usually re-
sponsible for late onset VAP and include P. aeruginosa, Acinetobac-
ter spp, K. pneumoniae, Legionella pneumophilia (L. pneumophilia),
Stenotrophomonas maltophilia, Burkholderia cepacia, and MRSA
(Abu-Salah 2011; Chastre 2002; Tedja 2010). Other risk factors
for developing multidrug-resistant pathogens include antibiotic
use in the last 90 days, increased incidence of antibiotic resistance
in the hospital or community, HCAP risk factors and immuno-
suppression. HCAP is included in the spectrum of HAP and VAP
and patients with HCAP need therapy for multidrug-resistant
pathogens. Most of the principles for the treatment of HAP, VAP
and HCAP overlap (Kollef 2008; Tedja 2010).
HAP and VAP are the second most common nosocomial infections
and the leading cause of nosocomial infection in the intensive care
unit (ICU). They are the principal cause of death related to a noso-
comial infection. HAP increases morbidity and mortality, length
of hospital stay and costs in the ICU (MacIntyre 2007; Rotstein
2008). Patients receiving mechanical ventilation are at the greatest
risk of acquiring nosocomial pneumonia. VAP occurs in 5% to
70% of intubated and mechanically ventilated patients and the
incidence rises with prolonged periods of ventilation (Smaldone
2004). The risk of VAP is greatest in the early stage of a hospital
stay and is projected to be 3% per day during the first five days
of ventilation, 2% per day from the 5th to the 10th day of venti-
lation and, finally, 1% after the 10th day (ATS/IDSA 2005). Al-
most 300,000 patients acquire VAP in the United States annually,
which is an incidence rate of 10 cases per 1000 hospital admis-
sions (ATS/IDSA 2005; Dhand 2007a). The overall incidence is
approximately 350,000 cases per annum and the mortality rate
ranges from 24% to 50%, however it can be as high as 76% in
some specific conditions or when the causative organism is a high-
risk pathogen. Mortality as high as 20% to 70% has been reported
(Chastre 2002; Smaldone 2004). The time of onset of pneumonia
is an important epidemiological variable for outcomes in patients
with HAP and VAP. Early onset is usually associated with a better
prognosis and is more likely to be antibiotic-sensitive. Late onset
HAP and VAP are mostly caused by multidrug-resistant pathogens
and associated with the highest mortality among nosocomial in-
Aerosolised antibiotics for the management of healthcare-associated pneumonia (HCAP) and ventilator-associated pneumonia (VAP)
(Protocol)
Copyright 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
fections (ATS/IDSA 2005).
The pathogenesis of HAP and VAP is alleged to result from bac-
terial access through the compromised defensive barrier of the air-
ways. It entails the invasion of the microbes into the lower res-
piratory tract with subsequent colonisation and overwhelming of
the hosts defence system (ATS/IDSA 2005). Different mecha-
nisms have been postulated in the development of VAP. Firstly, the
placement of the endotracheal tube compromises the glottis and
laryngeal structures that protect the airways from oropharyngeal
contents. Microaspiration of the oropharyngeal content around
the cuff may still occur despite the use of protective cuffed endo-
tracheal tube. This is the primary route of bacterial entry into the
trachea. Also, impaired oesophageal and gastric motility in supine
patients may cause reflux of gastric contents into the pharynx,
which plays a role in aspiration pneumonia (MacIntyre 2007).
Other researchers suggest that bacteria, encased in a biofilm, which
have colonised the endotracheal tube, could result in embolisation
into the alveoli during suctioning or bronchoscopy. In addition,
the combination of injured airways and diminished host defences
results in infectious tracheobronchitis. This in turn spreads into
the alveoli, culminating in VAP. Haematogenous spread from in-
fected intravenous access or bacterial translocation from the gut
are uncommon (ATS/IDSA 2005; MacIntyre 2007).
A clinical diagnosis of HAP, VAP and HCAP can be difficult be-
cause the clinical findings are non-specific (Rotstein 2008; Tedja
2010). HAP, VAP and HCAP should be suspected by the pres-
ence of new or progressive radiographic pulmonary infiltrate in
patients with at least two of these criteria: a temperature above
38.3C or below 36.6 C, a leucocyte count greater than 12,000/
ml or less than 4000/ml, or purulent tracheobronchial secretions
(Arnold 2012). The presence of all four criteria increases the diag-
nostic specificity but decreases the sensitivity by 50% (Sutherland
1995). A microbiological diagnosis entails the qualitative culture
of endotracheal secretions, which is often used in place of invasive
diagnostic testing. The use of invasive bronchial aspirate/broncho-
alveolar lavage in the diagnosis of HAP and VAP remains con-
tentious and has not led to improved clinical outcomes, therefore
it is not recommended (Arnold 2012; Rotstein 2008).
Description of the intervention
The extensive use of systemic antibiotics in the critically ill may
account for the increased incidence of evolving multidrug-resis-
tant strains, secondary infections, systemic toxicity, hospital stay
and costs (Smaldone 2004). In the last three decades, progress has
been made towards minimising patients exposure to systemic an-
tibiotics in the management of VAP and thus decreasing the emer-
gence of antibiotic resistance. Instillation of antibiotics via the en-
dotracheal tube and aerosolised antibiotics have been empirically
used in the last three decades (Palmer 2008). The increasing inci-
dence of HCAP and VAP caused by multidrug-resistant micro-or-
ganisms in recent years led to the development of potentially use-
2
ful aerosolised antibiotics. Treatment of pneumonia with systemic in the mortality rate (Czosnowski 2009; Ioannidou 2007). Em-
antibiotics, particularly the aminoglycosides, has been reported phasis is placed on the potential contribution of good adjunc-
to achieve poor penetration of the lung parenchyma. The min- tive therapy to systemic antibiotic treatment. A combination of
imum inhibitory concentrations (MIC) of the active antibiotics aerosolised and systemic antibiotics will decrease the requirement
used predominantly for gram-negative multidrug-resistant bacilli for systemic antimicrobial agents as well as the duration of therapy.
are remarkably elevated. The excessive increase in the dose of in- Most recent studies support the use of aerosolised antimicrobial
travenous antibiotics needed in order to achieve an effective con- agents as an adjuvant or rescue therapy in the treatment of VAP
centration for multidrug-resistant strains may result in systemic and HCAP due to multidrug-resistant pathogens resistant to other
toxicity (Luyt 2009). forms of systemic antibiotics (Arnold 2012; Luyt 2009).
The purpose of aerosolised antibiotic delivery to the lower res-
piratory tract is to attain an adequate concentration of the an-
timicrobial at the lung tissue level and a low circulating serum
level, thereby minimising systemic drug toxicity in the patient How the intervention might work
(Luyt 2009). Aerosolised delivery of antibiotics accomplishes an
In theory, nebulisation of aerosolised antibiotics has the advantage
extremely high local drug concentration within the lung alve-
of homogenous distribution of the drug along the airways, thus
oli and high MIC values, thus decreasing the advent of resistant
achieving adequate antibiotic concentrations for a sufficient du-
strain organisms when compared to systemic antibiotics (Palmer
ration. The limitation to achieving these potential benefits with
2009). Inhaled antibiotics achieve a superior concentration, i.e.
a conventional nebuliser is that during mechanical ventilation a
about 200-fold greater in respiratory secretions compared to sys-
significant quantity of antimicrobial aerosols are retained in the
temic circulation. In the critically ill patient with ventilator-asso-
breathing circuits of the ventilator and proximal tracheobronchial
ciated trachea-bronchitis (VAT), aerosolized antibiotics have been
tree, thus limiting the drug concentration available at the target
proven to decrease the progression and development of VAP, bac-
sites (Goldstein 2002; Luyt 2009). Conventional nebulisers may
terial resistance and the volume of tracheal secretions, as well as
therefore be inadequate for achieving sufficient drug deposition
other signs and symptoms of respiratory tract infection (Abu-Salah
in the alveolar compartment. However, the use of modern neb-
2011; Palmer 2008).
ulisers has great potential for the management of patients with
Some of the limitations of the routine use of aerosolised antibiotics
VAP and HCAP. Through a process whereby a vibratory mesh
alone in the management of VAP and HCAP include a lack of
or plate is combined with multiple apertures, antibiotic particles
rationale for the initiation of therapy, concern regarding the devel-
can be generated as aerosols (Arnold 2012). The nebulised drug is
opment of bacterial resistance, a lack of a proper delivery system,
well distributed in the lung parenchyma, with high tracheal and
ambiguity about the optimal site of antibiotic delivery, absence of
alveolar concentrations but low serum concentration. Parenchy-
appropriate medication formulations and difficulty in establishing
mal lung penetration may therefore be better with the new-gen-
clinical endpoints for successful therapy in the critically ill. Con-
eration devices (Luyt 2009). In intubated and mechanically ven-
cern was raised about aerosolised antibiotics leading to an increased
tilated patients, factors that affect the operation of the nebuliser
risk of pneumonia due to resistant micro-organisms when these
include nebuliser output, aerosol particulate size, constituents of
antibiotics were used as a prophylaxis, rather than as a treatment
the inhaled gas, ventilator parameters and the disease condition
(ATS/IDSA 2005; Palmer 1998; Smaldone 2004). These draw-
of the lungs (Dhand 1997; Dhand 2004a; Dhand 2007a; Dhand
backs led to the use of adjuvant aerosolised antimicrobials in the
2007b).
treatment of VAP and HCAP. However, the use of systemic antibi-
There are three different nebuliser designs: jet, ultrasonic and vi-
otics is not without adverse effects, which may include Clostridium
brating-mesh or plate nebulisers. Jet nebulisers generate aerosol
difficile (C. difficile) infection, nephrotoxicity and bone marrow
particles using high-pressure air or oxygen either during inspira-
suppression. A growing concern related to aerosolised antibiotics
tion alone or continuously. During operation, the solution con-
is the possible severe bronchospasm associated with their delivery.
centration increases and its temperature decreases, both of which
Preservatives in the drug formulations, such as disodium ethylene-
influence the nebuliser output and particulate size. Other impor-
diaminetetraacetic acid (EDTA) or benzalkonium chloride, could
tant drawbacks to the conventional jet nebuliser include a lack of
cause bronchoconstriction or airway hyper-responsiveness. This is
power source, inopportunely long treatment time, the requirement
common with colistin administration and can be reduced by use
for equipment setup and cleaning, and substantial discrepancies
of a preservative-free drug solution designed for inhalation and
in the functioning of the various nebulisers of same and different
pre-treatment with a short-acting bronchodilator (Dhand 2007a).
brands (Dhand 2007a; Dhand 2008; Luyt 2009; Rau 2002).
The utilization of aerosolised antimicrobials as an adjuvant to in-
Ultrasonic nebulisers have a greater output compared to jet nebu-
travenous antibiotics for patients with multidrug-resistant VAP
lisers but generate larger-sized particles. The drug production and
caused by gram-negative bacteria has shown beneficial results, with
particulate size depend on the vibration amplitude and frequency,
encouraging clinical response, bacterial eradication and reduction
respectively. However, the major disadvantages are cost, bulkiness

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Copyright 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
and inadequacy in nebulising the drug suspension (Dhand 2008;
Luyt 2009).
Vibrating-mesh/aperture plate nebulisers, as the name implies,
use a vibrating mesh or plate with manifold apertures to generate
aerosolised particles. This newer generation of nebulisers has nu-
merous advantages over the conventional nebuliser. They have a
higher rate of nebulisation: about three times greater output than
jet nebulisers. In contrast with ultrasonic nebulisers, the temper-
ature of the solution is constant during operation, and proteins
and peptides can be nebulised with minimal risk of denaturation
(Dhand 2002; Dhand 2004b; Dhand 2007a). A vibrating mesh
nebuliser can function with either a battery pack or an electric
source, making them portable, and they are quieter than the con-
ventional jet nebuliser (Dhand 2008; Luyt 2009).
Why it is important to do this review
The definitive balance between the benefits and harms associated
with the use of aerosolised, systemic and adjuvant aerosolised an-
tibiotics in the management of HCAP and VAP is not yet clear.
With the development of modern nebulisers, it is possible that
aerosolised antibiotics could be effectively delivered to mechani-
cally ventilated patients (Arnold 2012; Luyt 2009). This treatment
modality could result in measurable changes in the clinical indices
of patients with VAP or HCAP, especially those with multidrug-
resistant strains. However, there is limited evidence to support this.
A systematic review of the available evidence is needed to justify
the use of this intervention.
OBJECTIVES
To assess the benefits and harms of aerosolised antibiotics, com-
paring aerosolised versus systemic antibiotics, aerosolised antibi-
otics versus placebo and the addition of aerosolised to systemic
antibiotics versus systemic antibiotics alone.
METHODS
Criteria for considering studies for this review
Types of studies
We will include randomised controlled trials (RCTs). We will ex-
clude non-RCTs.
Aerosolised antibiotics for the management of healthcare-associated pneumonia (HCAP) and ventilator-associated pneumonia (VAP)
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Copyright 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Types of participants
We will include all individuals with HCAP and VAP.
Types of interventions
We will include studies comparing aerosolised antibiotics versus
placebo, aerosolised antibiotics versus systemic antibiotics, and
aerosolised adjuvant antibiotics with systemic antibiotics versus
systemic antibiotics alone.
Types of outcome measures
Primary outcomes
1. Mortality.
2. Severe adverse reactions from aerosolised antibiotics (for
example, bronchospasm) and systemic antibiotics (for example,
development of C. difficile, nephrotoxicity and bone marrow
suppression).
Secondary outcomes
1. Length of ICU stay in days.
2. Length of hospital stay in days.
3. Length of mechanical ventilation in days.
4. Duration until resolution of pneumonia.
5. Time until micro-organism clearance from the aspirate and
the bacterial load of the aspirate.
6. VAP rate per thousand ventilator days.
7. Development of antibiotic resistance.
Search methods for identification of studies
Electronic searches
We will identify trials from searches of the following databases:
Cochrane Acute Respiratory Infections Group Trials
Register;
Cochrane Central Register of Controlled Trials
(CENTRAL) in The Cochrane Library;
MEDLINE (Ovid);
EMBASE (Ovid);
CINAHL (EBSCOhost).
The proposed MEDLINE strategy is shown in Appendix 1. We
will combine this with the Cochrane highly sensitive search strat-
egy for identifying randomised trials and adapt this for use in
the other databases. We will also conduct a search of ClinicalTri-
als.gov (http://clinicaltrials.gov) and the World Health Organiza-
tion (WHO) International Clinical Trials Registry Platform (IC-
TRP) (www.who.int/ictrp/en/). We will search all databases from
4
their inception to the present and we will not impose any restric-
tion on the language of publication.
Searching other resources
We will check the reference lists of all primary studies and review
articles for additional references. We will search relevant manu-
facturers websites for trial information. We will search for errata
or retractions from the included studies, published in PubMed (
www.ncbi.nlm.nih.gov/pubmed) and report the date this was done
within the review.
Data collection and analysis
Two review authors (HE, KD) will independently appraise all
identified citations to establish their relevance for inclusion in the
review. We will review studies for relevance based on study design
and types of participants, interventions and outcome measures.
We will resolve disagreements by discussion. We will give reasons
for excluding potentially relevant trials in the Characteristics of
excluded studies table.
Selection of studies
Two review authors (IE, HE) will independently screen the titles
and abstracts of all potential studies for inclusion identified as a re-
sult of the search and code them as retrieve (eligible or potentially
eligible or unclear) or do not retrieve. We will retrieve the full-
text study reports and two review authors (JN, CE) will indepen-
dently screen the full text of the studies for inclusion. We will give
reasons for the exclusion of ineligible studies. We will identify and
exclude duplicates and collate multiple reports of the same study
so that each study rather than each report is the unit of interest in
the review. We will record the selection process in sufficient detail
to complete a PRISMA flow diagram.
Data extraction and management
We will design a data extraction form for study characteristics and
outcome data, which we will pilot on at least one study in the
review. If there are eligible studies, one review author (KD) will
extract the following study characteristics:
1. Methods: study design, total duration of study, details of
any run-in period, number of study centres and locations, study
setting, withdrawals and date of study.
2. Participants: total number (N), mean age, age range, gender,
severity of condition, diagnostic criteria, baseline lung function,
smoking history, inclusion criteria and exclusion criteria.
3. Interventions: intervention, comparison, concomitant
medications and excluded medications.
4. Outcomes: primary and secondary outcomes specified and
collected and time points reported.
Aerosolised antibiotics for the management of healthcare-associated pneumonia (HCAP) and ventilator-associated pneumonia (VAP)
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Copyright 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
5. Notes: funding for trial and notable conflicts of interest of
trial authors.
Two review authors (KD, HE) will independently extract outcome
data from the included studies. We will note in the Characteristics
of included studies table if outcome data were not reported in
a usable way. We will resolve disagreements by consensus or by
involving a third review author (JN). One review author (CE)
will transfer the data into Review Manager (RevMan 2014). We
will double-check that data are entered correctly by comparing the
data presented in the systematic review with the study reports. A
second review author (IE) will spot-check study characteristics for
accuracy against the trial report.
Assessment of risk of bias in included studies
Two review authors (KD, CE) will independently assess the risk
of bias for each study using the criteria outlined in the Cochrane
Handbook for Systematic Reviews of Interventions (Higgins 2011).
We will resolve any disagreements by discussion. We will assess the
risk of bias according to the following domains.
1. Random sequence generation.
2. Allocation concealment.
3. Blinding of participants and personnel.
4. Blinding of outcome assessment.
5. Incomplete outcome data.
6. Selective outcome reporting.
7. Other bias.
We will grade each potential source of bias as high, low or un-
clear and provide a quote from the study report together with a
justification for our judgement in the Risk of bias table. We will
summarise the Risk of bias judgements across different studies for
each of the domains listed. We will consider blinding separately
for different key outcomes, where necessary. Where information
on risk of bias relates to unpublished data or correspondence with
a trialist, we will note this in the Risk of bias table.
When considering treatment effects, we will take into account the
risk of bias for the studies that contributed to that outcome.
Measures of treatment effect
We will analyse dichotomous data as an odds ratio (OR) and
continuous data as a mean difference (MD) or standardised MD
(SMD). We will enter data presented as a scale with a consistent
direction of effect. We will undertake a meta-analysis only where
this is meaningful, that is if the treatments, participants and un-
derlying clinical question are similar enough (homogeneous) for
pooling to make sense. We will describe skewed data reported as
medians and interquartile ranges. We will include only the rele-
vant arms where multiple trial arms are reported in a single trial.
We will summarise time-to-event data, i.e. clinical course duration
(for example, length of ICU stay in days, duration of resolution
of pneumonia), using a survival analysis method. The time is an-
ticipated to start from when treatment begins and end when the
5
event of interest (resolution of symptoms or death) is reached. We
will express the intervention effect as a hazard ratio. We do not
anticipate censored patients, but if available we will include them
in the analysis.
If we obtain O-E and V in a trial, we will enter them directly into we will contact the Cochrane Acute Respiratory Infections Group.
RevMan 2014 using the log rank approach and use a fixed-effect
model for meta-analysis. O is the observed number of events;
E is the expected number of events in the experimental group
and V is the variance. If trial investigators have analysed the data
using a Cox proportional hazards model, we will perform a generic
inverse analysis. We will use either a random-effects model or a
fixed-effect model in the meta-analysis.
Unit of analysis issues
We will group together studies with similar units of analysis. We
will not pool studies with different units of analysis.
Dealing with missing data
We will contact investigators or study sponsors in order to verify
key study characteristics and to obtain missing numerical outcome
data, where possible (for example, when a study is identified as an
abstract only). Where this is not possible and the missing data are
thought to introduce serious bias, we will explore the impact of
including such studies in the overall assessment of results using a
sensitivity analysis.
Assessment of heterogeneity
We will use the I statistic to measure heterogeneity among the tri-
als in each analysis. If we identify substantial heterogeneity we will
report it and explore possible causes using pre-specified subgroup
analyses (i.e. type of antibiotics and different models of nebuliser).
We will consider an I value of 75% to 90% as substantial hetero-
geneity.
Assessment of reporting biases
If we pool more than 10 trials, we will create and examine a funnel
plot to explore possible small study biases
Aerosolised antibiotics for the management of healthcare-associated pneumonia (HCAP) and ventilator-associated pneumonia (VAP)
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Copyright 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Data synthesis
We will summarise all eligible studies and extract the data into
RevMan 2014. The review authors will recheck all the entries. We
will resolve disagreements by discussion. If no consensus is reached,
We will use a fixed-effect model and perform a sensitivity analysis
with the random-effects model.
Subgroup analysis and investigation of heterogeneity
We plan to carry out the following subgroup analyses.
1. Type of antibiotics (amikacin, colistin etc).
2. Different models of nebuliser (jet, ultrasonic and vibrating-
mesh or plate nebulisers).
We plan to use the following outcomes in subgroup analyses.
1. Mortality.
2. Length of mechanical ventilation.
3. Serious adverse reactions.
We will use the formal test for subgroup interactions in RevMan
2014.
Sensitivity analysis
If the number of studies and data available allow, we will perform
sensitivity analysis by using one or all of the following strategies.
1. We will remove studies with high risk of bias to see if there
is any effect on the results of the meta-analysis.
2. We may re-analyse studies with missing data using a
reasonable range of missing values
Summary of findings Table
We will include outcomes for any mortality benefit and severe
adverse reactions from aerosolised antibiotics in a Summary of
findings table. We will use GRADE (Higgins 2011) to assess the
quality of the body of evidence of these outcomes.
ACKNOWLEDGEMENTS
We are grateful to Clare Dooley, Assistant Managing Editor of the
Cochrane Acute Respiratory Infections Group.
6
 REFERENCES
Additional references
Abu-Salah 2011
Abu-Salah T, Dhand R. Inhaled antibiotic therapy for
ventilator-associated tracheobronchitis and ventilator-
associated pneumonia: an update. Advances in Therapy
2011;28(9):72847. [DOI: 10.1007/s12325-011-0051-z]
Arnold 2012
Arnold H, Sawyer A, Kollef M. Use of adjunctive aerosolized
antimicrobial therapy in the treatment of pseudomonas
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Indicates the major publication for the study

APPENDICES

Appendix 1. MEDLINE (Ovid) search strategy

1 exp Pneumonia/
2 (pneumon* or bronchopneumon* or pleuropneumon* or tracheobronchit* or tracheo bronchit*).tw.
3 (vap or hap or hcap).tw.
4 Respiratory Tract Infections/
5 (respiratory infection* or respiratory tract infection*).tw.
6 exp Ventilators, Mechanical/
7 ventilat*.tw.
8 intubation/ or intubation, intratracheal/
9 intubat*.tw.
10 exp Drug Resistance, Bacterial/
11 drug resistance, multiple/ or drug resistance, multiple, bacterial/
12 (bacteria* adj2 ((multidrug or multi-drug or multiple drug or antibiotic) adj2 resistan*)).tw.
13 (mdr or mdro).tw.
14 or/1-13
15 exp Anti-Bacterial Agents/
16 (antibiotic* or antibacterial* or anti-bacterial* or antimicrobial* or anti-microbial*).tw.
17 Amikacin/
18 Colistin/
19 Vancomycin/
20 exp Gentamicins/
21 (amikacin* or colistin* or vancomycin* or gentamicin* or gentamycin*).tw,nm.
22 or/15-21
23 exp aerosols/ or suspensions/
24 exp Nebulizers and Vaporizers/
25 Administration, Inhalation/
26 (aerosol* or nebuliz* or nebulis* or vapor* or vapour* or atomis* or atomiz* or volatil* or spray* or inhal*).tw.
27 or/23-26
Aerosolised antibiotics for the management of healthcare-associated pneumonia (HCAP) and ventilator-associated pneumonia (VAP) 8
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Copyright 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
28 22 and 27
29 14 and 28

CONTRIBUTIONS OF AUTHORS
All authors contributed to the drafting of this protocol.

DECLARATIONS OF INTEREST
Hill Enuh: no financial or other interest to be disclosed.
Collins U Enuh: no financial or other interest to be disclosed
Keith T Diaz: no financial or other interest to be disclosed.
Ifeanyi R Ezedunukwe: no financial or interest to be disclosed.
Jay Nfonoyim: no financial or other interest to be disclosed.

SOURCES OF SUPPORT

Internal sources
None, Other.

External sources
None, Other.

Aerosolised antibiotics for the management of healthcare-associated pneumonia (HCAP) and ventilator-associated pneumonia (VAP) 9
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Copyright 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.