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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


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
Description of the condition type of pneumonia in the American Thoracic Society/Infectious
Ventilator-associated pneumonia (VAP) is a subgroup of hospital- Disease Society of America (ATS/IDSA) guidelines, to recognise
acquired pneumonia (HAP), which is defined as pneumonia that patients at high risk of developing multidrug-resistant pathogens
occurs 48 to 72 hours after endotracheal intubation. HAP refers to (File 2014). The term HAP is often used to represent both VAP
pneumonia that occurs 48 hours or more after hospital admission and HCAP (Tedja 2010).
and that is thought not to be incubating in the patient at the time VAP is one of the most common infections affecting intubated
of admission. Healthcare-associated pneumonia (HCAP), on the and mechanically ventilated patients. It is categorized as early or
other hand, is defined as pneumonia that occurs in one or more of late onset VAP. Early onset VAP is defined as pneumonia emerg-
these categories of people: patients admitted to an acute care centre ing within 96 hours of admission and after the initial 48 hours,
for a period of two or more days within the last 90 days of hospital while late onset VAP develops after 96 hours of hospitalisation.
contact; patients that reside in a nursing home or long-term care 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
(Protocol)
Copyright 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
admitted to hospital in the last 90 days is also classified as late fections (ATS/IDSA 2005).
onset pneumonia (Abu-Salah 2011). The pathogenesis of HAP and VAP is alleged to result from bac-
The aetiology of HAP, VAP and HCAP can be polymicrobial and terial access through the compromised defensive barrier of the air-
most commonly involves a broad range of bacterial pathogens ways. It entails the invasion of the microbes into the lower res-
and less commonly nosocomial viral or fungal infections in im- piratory tract with subsequent colonisation and overwhelming of
munocompetent patients, or a single pathogen. The common the hosts defence system (ATS/IDSA 2005). Different mecha-
causative pathogens are the aerobic gram-negative bacilli such as nisms have been postulated in the development of VAP. Firstly, the
Pseudomonas aeruginosa (P. aeruginosa), Klebsiella pneumoniae (K. placement of the endotracheal tube compromises the glottis and
pneumoniae), Escherichia coli (E. coli) and Acinetobacter species laryngeal structures that protect the airways from oropharyngeal
or gram-positive cocci such as Staphylococcus aureus (S. aureus), contents. Microaspiration of the oropharyngeal content around
principally methicillin-resistant S. aureus (MRSA). Early onset the cuff may still occur despite the use of protective cuffed endo-
VAP has low risk factors for multidrug-resistant bacteria. The tracheal tube. This is the primary route of bacterial entry into the
causative pathogens include Streptococcus pneumoniae (S. pneumo- trachea. Also, impaired oesophageal and gastric motility in supine
niae), Haemophilus influenzae (H. influenzae), MRSA and gram- patients may cause reflux of gastric contents into the pharynx,
negative bacteria. Multidrug-resistant pathogens are usually re- which plays a role in aspiration pneumonia (MacIntyre 2007).
sponsible for late onset VAP and include P. aeruginosa, Acinetobac- Other researchers suggest that bacteria, encased in a biofilm, which
ter spp, K. pneumoniae, Legionella pneumophilia (L. pneumophilia), have colonised the endotracheal tube, could result in embolisation
Stenotrophomonas maltophilia, Burkholderia cepacia, and MRSA into the alveoli during suctioning or bronchoscopy. In addition,
(Abu-Salah 2011; Chastre 2002; Tedja 2010). Other risk factors the combination of injured airways and diminished host defences
for developing multidrug-resistant pathogens include antibiotic results in infectious tracheobronchitis. This in turn spreads into
use in the last 90 days, increased incidence of antibiotic resistance the alveoli, culminating in VAP. Haematogenous spread from in-
in the hospital or community, HCAP risk factors and immuno- fected intravenous access or bacterial translocation from the gut
suppression. HCAP is included in the spectrum of HAP and VAP are uncommon (ATS/IDSA 2005; MacIntyre 2007).
and patients with HCAP need therapy for multidrug-resistant A clinical diagnosis of HAP, VAP and HCAP can be difficult be-
pathogens. Most of the principles for the treatment of HAP, VAP cause the clinical findings are non-specific (Rotstein 2008; Tedja
and HCAP overlap (Kollef 2008; Tedja 2010). 2010). HAP, VAP and HCAP should be suspected by the pres-
HAP and VAP are the second most common nosocomial infections ence of new or progressive radiographic pulmonary infiltrate in
and the leading cause of nosocomial infection in the intensive care patients with at least two of these criteria: a temperature above
unit (ICU). They are the principal cause of death related to a noso- 38.3C or below 36.6 C, a leucocyte count greater than 12,000/
comial infection. HAP increases morbidity and mortality, length ml or less than 4000/ml, or purulent tracheobronchial secretions
of hospital stay and costs in the ICU (MacIntyre 2007; Rotstein (Arnold 2012). The presence of all four criteria increases the diag-
2008). Patients receiving mechanical ventilation are at the greatest nostic specificity but decreases the sensitivity by 50% (Sutherland
risk of acquiring nosocomial pneumonia. VAP occurs in 5% to 1995). A microbiological diagnosis entails the qualitative culture
70% of intubated and mechanically ventilated patients and the of endotracheal secretions, which is often used in place of invasive
incidence rises with prolonged periods of ventilation (Smaldone diagnostic testing. The use of invasive bronchial aspirate/broncho-
2004). The risk of VAP is greatest in the early stage of a hospital alveolar lavage in the diagnosis of HAP and VAP remains con-
stay and is projected to be 3% per day during the first five days tentious and has not led to improved clinical outcomes, therefore
of ventilation, 2% per day from the 5th to the 10th day of venti- it is not recommended (Arnold 2012; Rotstein 2008).
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- Description of the intervention
sions (ATS/IDSA 2005; Dhand 2007a). The overall incidence is
The extensive use of systemic antibiotics in the critically ill may
approximately 350,000 cases per annum and the mortality rate
account for the increased incidence of evolving multidrug-resis-
ranges from 24% to 50%, however it can be as high as 76% in
tant strains, secondary infections, systemic toxicity, hospital stay
some specific conditions or when the causative organism is a high-
and costs (Smaldone 2004). In the last three decades, progress has
risk pathogen. Mortality as high as 20% to 70% has been reported
been made towards minimising patients exposure to systemic an-
(Chastre 2002; Smaldone 2004). The time of onset of pneumonia
tibiotics in the management of VAP and thus decreasing the emer-
is an important epidemiological variable for outcomes in patients
gence of antibiotic resistance. Instillation of antibiotics via the en-
with HAP and VAP. Early onset is usually associated with a better
dotracheal tube and aerosolised antibiotics have been empirically
prognosis and is more likely to be antibiotic-sensitive. Late onset
used in the last three decades (Palmer 2008). The increasing inci-
HAP and VAP are mostly caused by multidrug-resistant pathogens
dence of HCAP and VAP caused by multidrug-resistant micro-or-
and associated with the highest mortality among nosocomial in-
ganisms in recent years led to the development of potentially use-

Aerosolised antibiotics for the management of healthcare-associated pneumonia (HCAP) and ventilator-associated pneumonia (VAP) 2
(Protocol)
Copyright 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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

Aerosolised antibiotics for the management of healthcare-associated pneumonia (HCAP) and ventilator-associated pneumonia (VAP) 3
(Protocol)
Copyright 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
and inadequacy in nebulising the drug suspension (Dhand 2008; Types of participants
Luyt 2009). We will include all individuals with HCAP and VAP.
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- Types of interventions
merous advantages over the conventional nebuliser. They have a We will include studies comparing aerosolised antibiotics versus
higher rate of nebulisation: about three times greater output than placebo, aerosolised antibiotics versus systemic antibiotics, and
jet nebulisers. In contrast with ultrasonic nebulisers, the temper- aerosolised adjuvant antibiotics with systemic antibiotics versus
ature of the solution is constant during operation, and proteins systemic antibiotics alone.
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 Types of outcome measures
source, making them portable, and they are quieter than the con-
ventional jet nebuliser (Dhand 2008; Luyt 2009).
Primary outcomes
1. Mortality.
2. Severe adverse reactions from aerosolised antibiotics (for
Why it is important to do this review example, bronchospasm) and systemic antibiotics (for example,
development of C. difficile, nephrotoxicity and bone marrow
The definitive balance between the benefits and harms associated
suppression).
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 Secondary outcomes
aerosolised antibiotics could be effectively delivered to mechani-
1. Length of ICU stay in days.
cally ventilated patients (Arnold 2012; Luyt 2009). This treatment
2. Length of hospital stay in days.
modality could result in measurable changes in the clinical indices
3. Length of mechanical ventilation in days.
of patients with VAP or HCAP, especially those with multidrug-
4. Duration until resolution of pneumonia.
resistant strains. However, there is limited evidence to support this.
5. Time until micro-organism clearance from the aspirate and
A systematic review of the available evidence is needed to justify
the bacterial load of the aspirate.
the use of this intervention.
6. VAP rate per thousand ventilator days.
7. Development of antibiotic resistance.

Search methods for identification of studies


OBJECTIVES
To assess the benefits and harms of aerosolised antibiotics, com-
paring aerosolised versus systemic antibiotics, aerosolised antibi- Electronic searches
otics versus placebo and the addition of aerosolised to systemic We will identify trials from searches of the following databases:
antibiotics versus systemic antibiotics alone. Cochrane Acute Respiratory Infections Group Trials
Register;
Cochrane Central Register of Controlled Trials
(CENTRAL) in The Cochrane Library;
METHODS
MEDLINE (Ovid);
EMBASE (Ovid);
CINAHL (EBSCOhost).
Criteria for considering studies for this review 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-
Types of studies als.gov (http://clinicaltrials.gov) and the World Health Organiza-
We will include randomised controlled trials (RCTs). We will ex- tion (WHO) International Clinical Trials Registry Platform (IC-
clude non-RCTs. TRP) (www.who.int/ictrp/en/). We will search all databases from

Aerosolised antibiotics for the management of healthcare-associated pneumonia (HCAP) and ventilator-associated pneumonia (VAP) 4
(Protocol)
Copyright 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
their inception to the present and we will not impose any restric- 5. Notes: funding for trial and notable conflicts of interest of
tion on the language of publication. trial authors.
Two review authors (KD, HE) will independently extract outcome
data from the included studies. We will note in the Characteristics
Searching other resources of included studies table if outcome data were not reported in
We will check the reference lists of all primary studies and review a usable way. We will resolve disagreements by consensus or by
articles for additional references. We will search relevant manu- involving a third review author (JN). One review author (CE)
facturers websites for trial information. We will search for errata will transfer the data into Review Manager (RevMan 2014). We
or retractions from the included studies, published in PubMed ( will double-check that data are entered correctly by comparing the
www.ncbi.nlm.nih.gov/pubmed) and report the date this was done data presented in the systematic review with the study reports. A
within the review. second review author (IE) will spot-check study characteristics for
accuracy against the trial report.

Data collection and analysis Assessment of risk of bias in included studies


Two review authors (HE, KD) will independently appraise all Two review authors (KD, CE) will independently assess the risk
identified citations to establish their relevance for inclusion in the of bias for each study using the criteria outlined in the Cochrane
review. We will review studies for relevance based on study design Handbook for Systematic Reviews of Interventions (Higgins 2011).
and types of participants, interventions and outcome measures. We will resolve any disagreements by discussion. We will assess the
We will resolve disagreements by discussion. We will give reasons risk of bias according to the following domains.
for excluding potentially relevant trials in the Characteristics of 1. Random sequence generation.
excluded studies table. 2. Allocation concealment.
3. Blinding of participants and personnel.
4. Blinding of outcome assessment.
Selection of studies
5. Incomplete outcome data.
Two review authors (IE, HE) will independently screen the titles 6. Selective outcome reporting.
and abstracts of all potential studies for inclusion identified as a re- 7. Other bias.
sult of the search and code them as retrieve (eligible or potentially We will grade each potential source of bias as high, low or un-
eligible or unclear) or do not retrieve. We will retrieve the full- clear and provide a quote from the study report together with a
text study reports and two review authors (JN, CE) will indepen- justification for our judgement in the Risk of bias table. We will
dently screen the full text of the studies for inclusion. We will give summarise the Risk of bias judgements across different studies for
reasons for the exclusion of ineligible studies. We will identify and each of the domains listed. We will consider blinding separately
exclude duplicates and collate multiple reports of the same study for different key outcomes, where necessary. Where information
so that each study rather than each report is the unit of interest in on risk of bias relates to unpublished data or correspondence with
the review. We will record the selection process in sufficient detail a trialist, we will note this in the Risk of bias table.
to complete a PRISMA flow diagram. When considering treatment effects, we will take into account the
risk of bias for the studies that contributed to that outcome.
Data extraction and management
We will design a data extraction form for study characteristics and Measures of treatment effect
outcome data, which we will pilot on at least one study in the We will analyse dichotomous data as an odds ratio (OR) and
review. If there are eligible studies, one review author (KD) will continuous data as a mean difference (MD) or standardised MD
extract the following study characteristics: (SMD). We will enter data presented as a scale with a consistent
1. Methods: study design, total duration of study, details of direction of effect. We will undertake a meta-analysis only where
any run-in period, number of study centres and locations, study this is meaningful, that is if the treatments, participants and un-
setting, withdrawals and date of study. derlying clinical question are similar enough (homogeneous) for
2. Participants: total number (N), mean age, age range, gender, pooling to make sense. We will describe skewed data reported as
severity of condition, diagnostic criteria, baseline lung function, medians and interquartile ranges. We will include only the rele-
smoking history, inclusion criteria and exclusion criteria. vant arms where multiple trial arms are reported in a single trial.
3. Interventions: intervention, comparison, concomitant We will summarise time-to-event data, i.e. clinical course duration
medications and excluded medications. (for example, length of ICU stay in days, duration of resolution
4. Outcomes: primary and secondary outcomes specified and of pneumonia), using a survival analysis method. The time is an-
collected and time points reported. ticipated to start from when treatment begins and end when the

Aerosolised antibiotics for the management of healthcare-associated pneumonia (HCAP) and ventilator-associated pneumonia (VAP) 5
(Protocol)
Copyright 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
event of interest (resolution of symptoms or death) is reached. We Data synthesis
will express the intervention effect as a hazard ratio. We do not We will summarise all eligible studies and extract the data into
anticipate censored patients, but if available we will include them RevMan 2014. The review authors will recheck all the entries. We
in the analysis. will resolve disagreements by discussion. If no consensus is reached,
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 We will use a fixed-effect model and perform a sensitivity analysis
model for meta-analysis. O is the observed number of events; with the random-effects model.
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 Subgroup analysis and investigation of heterogeneity
inverse analysis. We will use either a random-effects model or a We plan to carry out the following subgroup analyses.
fixed-effect model in the meta-analysis. 1. Type of antibiotics (amikacin, colistin etc).
2. Different models of nebuliser (jet, ultrasonic and vibrating-
mesh or plate nebulisers).
Unit of analysis issues We plan to use the following outcomes in subgroup analyses.
We will group together studies with similar units of analysis. We 1. Mortality.
will not pool studies with different units of analysis. 2. Length of mechanical ventilation.
3. Serious adverse reactions.
We will use the formal test for subgroup interactions in RevMan
2014.
Dealing with missing data
We will contact investigators or study sponsors in order to verify
key study characteristics and to obtain missing numerical outcome Sensitivity analysis
data, where possible (for example, when a study is identified as an If the number of studies and data available allow, we will perform
abstract only). Where this is not possible and the missing data are sensitivity analysis by using one or all of the following strategies.
thought to introduce serious bias, we will explore the impact of 1. We will remove studies with high risk of bias to see if there
including such studies in the overall assessment of results using a is any effect on the results of the meta-analysis.
sensitivity analysis. 2. We may re-analyse studies with missing data using a
reasonable range of missing values

Assessment of heterogeneity
Summary of findings Table
We will use the I statistic to measure heterogeneity among the tri-
als in each analysis. If we identify substantial heterogeneity we will We will include outcomes for any mortality benefit and severe
report it and explore possible causes using pre-specified subgroup adverse reactions from aerosolised antibiotics in a Summary of
analyses (i.e. type of antibiotics and different models of nebuliser). findings table. We will use GRADE (Higgins 2011) to assess the
We will consider an I value of 75% to 90% as substantial hetero- quality of the body of evidence of these outcomes.
geneity.

Assessment of reporting biases ACKNOWLEDGEMENTS


If we pool more than 10 trials, we will create and examine a funnel We are grateful to Clare Dooley, Assistant Managing Editor of the
plot to explore possible small study biases Cochrane Acute Respiratory Infections Group.

Aerosolised antibiotics for the management of healthcare-associated pneumonia (HCAP) and ventilator-associated pneumonia (VAP) 6
(Protocol)
Copyright 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
REFERENCES

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File 2014
2011;28(9):72847. [DOI: 10.1007/s12325-011-0051-z]
File T, Bartlet J, Thomer A. Treatment of hospital-acquired,
Arnold 2012 ventilator-associated, and healthcare-associated pneumonia
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aeruginosa and Acinetobacter baumannii ventilator-
Goldstein 2002
associated pneumonia. Respiratory Care 2012;57(8): Goldstein I, Wallet F, Nicolas-Robin A, Ferrari F, Marquette
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CH, Rouby J. Lung deposition and efficiency of nebulized
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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.