Cochrane Database of Systematic Reviews

Antibiotics for hospital-acquired pneumonia in children

(Protocol)

Jiang L, Mu D, Zhang L, Gui G, Duan Y, Wan C

Jiang L, Mu D, Zhang L, Gui G, Duan Y, Wan C.

Antibiotics for hospital-acquired pneumonia in children.
Cochrane Database of Systematic Reviews 2016, Issue 6. Art. No.: CD012239.
DOI: 10.1002/14651858.CD012239.

www.cochranelibrary.com

Antibiotics for hospital-acquired pneumonia in children (Protocol)

Copyright © 2016 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
 TABLE OF CONTENTS
HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
APPENDICES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8

Antibiotics for hospital-acquired pneumonia in children (Protocol) i

Copyright © 2016 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
[Intervention Protocol]

Antibiotics for hospital-acquired pneumonia in children

Lucan Jiang1 ,2,3,4 , Dezhi Mu5 , Lingli Zhang1,2,3 , Ge Gui1,2,3,4 , Yanjun Duan6 , Chaomin Wan5

1 Department of Pharmacy, West China Second University Hospital, Sichuan University, Chengdu, China. 2 Key Laboratory of Birth
Defects and Related Diseases of Women and Children, Sichuan University, Ministry of Education, Chengdu, China. 3 Evidence-Based
Pharmacy Center, West China Second University Hospital, Sichuan University, Chengdu, China. 4 West China School of Pharmacy,
Sichuan University, Chengdu, China. 5 Department of Pediatrics, West China Second University Hospital, Sichuan University, Chengdu,
China. 6 Department of Pharmacy, University of Nebraska Medical Center, Omaha, Nebraska, USA

Contact address: Lingli Zhang, Department of Pharmacy, West China Second University Hospital, Sichuan University, No. 17, Section
Three, Ren Min Nan Lu AvenueRoad, Chengdu, Sichuan, 610041, China. zhlingli@sina.com.

Editorial group: Cochrane Acute Respiratory Infections Group.

Publication status and date: New, published in Issue 6, 2016.

Citation: Jiang L, Mu D, Zhang L, Gui G, Duan Y, Wan C. Antibiotics for hospital-acquired pneumonia in children. Cochrane
Database of Systematic Reviews 2016, Issue 6. Art. No.: CD012239. DOI: 10.1002/14651858.CD012239.

Copyright © 2016 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 compare different antibiotics in order to identify effective and safe antibiotic drug therapies for children with hospital-acquired
pneumonia (HAP) (including ventilator-associated pneumonia (VAP) and HAP without mechanical ventilation).

BACKGROUND of hospital-acquired infection in ICUs (Richards 2000; Vincent

2009). Although nearly 90% of episodes of HAP occur during me-
chanical ventilation in ICU patients, it is often difficult to identify
Description of the condition the exact incidence of VAP because of possible overlap with other
lower respiratory tract infections, such as infectious tracheobron-
Hospital-acquired pneumonia (HAP) or nosocomial pneumonia
chitis in mechanically ventilated patients (ATS 2005). Depending
is a type of pneumonia that develops at least 48 hours after being
on the case definition of pneumonia and the population under
admitted to hospital and that was not present at the time of hos-
evaluation, the exact incidence varies widely (Eggimann 2003).
pital admission (NICE 2014). Ventilator-associated pneumonia
Data published by the National Nosocomial Infection Surveillance
(VAP) is a subtype of HAP. VAP is a lung infection diagnosed in
program indicates that in paediatric ICUs, VAP is the second most
patients undergoing mechanical ventilation for at least 48 hours
frequent cause of nosocomial infection (Cernada 2013; Richards
(ATS 2005). HAP and VAP are serious diseases that are often dif-
1999). As such, VAP constitutes 20% of nosocomial infection in
ficult to treat in clinical practice and remain an important cause
paediatric ICUs, with rates of six episodes per 1000 ventilator days
of morbidity and mortality (Song 2008).
(Cernada 2013).
It is estimated that HAP has a rate of 5 to 10 per 1000 hospital
admissions (ATS 2005). For patients in the intensive care unit
(ICU), the incidence of HAP increases significantly; in both Eu-
rope and the United States, pneumonia is the most frequent cause
Antibiotics for hospital-acquired pneumonia in children (Protocol) 1
Copyright © 2016 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Description of the intervention
Compared with community-acquired pneumonia (CAP), HAP
and VAP are more likely to be infections caused by colonised bac-
teria and multi-drug resistant (MDR) pathogens (ATS 2005). The
pathogens commonly associated with HAP/VAP are aerobic gram-
negative bacilli, such as Pseudomonas aeruginosa (P. aeruginosa), Es-
cherichia coli (E. coli), Klebsiella pneumoniae (K. pneumoniae), and
Acinetobacter species. For patients with HAP and VAP, the time
of onset of pneumonia is important for specific pathogens and
outcomes as an epidemiologic variable and risk factor. Early-onset
HAP and VAP, occurring within the first four days of hospitalisa-
tion, generally have a better prognosis, and the pathogens are more
likely to be antibiotic-sensitive bacteria, such as Streptococcus pneu-
moniae (S. pneumoniae), Haemophilus influenzae (H. influenzae),
Staphylococcus aureus (S. aureus), E. coli and K. pneumoniae; while
late-onset HAP and VAP (five days or more of hospitalisation) are
more likely to be caused by MDR pathogens (including S. aureus,
P. aeruginosa, K. pneumoniae and Enterobacter spp et al), and results
in increased patient mortality and morbidity. The number of pa-
tients with HAP caused by MDR pathogens such as methicillin-
resistantS. aureus (MRSA), P. aeruginosa and Acinetobacter spp et
al shows an increasing trend. However, colonisation and infection
with MDR pathogens is more likely to happen in patients with
early-onset HAP who have received prior antibiotics or who have
had prior hospitalisation within the previous 90 days; these pa-
tients, they should be treated similar to patients with late-onset
HAP or VAP. According to the ATS guideline (ATS 2005), the
key decision in initial empiric therapy is whether the patient has
risk factors for MDR organisms rather than the time of onset of
HAP/VAP (Selim 2010). Other risk factors for MDR pathogens
include (ATS 2005):
1. antimicrobial therapy in the preceding 90 days;
2. current hospitalisation of five days or more;
3. high frequency of antibiotic resistance in the community or
in the specific hospital unit;
4. immunosuppressive disease and/or therapy;
5. presence of risk factors for healthcare-associated pneumonia
(HCAP).
Empiric therapy is defined as the use of antibiotics before the
confirmation of a definitive diagnosis of infection, and where the
patient would face greater risk by observation than by treatment
(Kim 1989). In contrast, the primary objective of directed ther-
apy is to help confirm a suspected diagnosis, involving a specific
treatment of pre-determined duration (Kim 1989). The follow-
ing statement explains the principles determining antimicrobial
use for HAP: “Choose empiric antimicrobial wisely (broad-spec-
trum), start early, hit hard with an appropriate dosing schedule,
de-escalate rapidly (narrow spectrum) and stop abruptly (post ad-
equate duration)” (Morrow 2009). The ATS guideline indicates
that individual empirical antibiotic selection should be based on
the risk for MDR pathogens (Selim 2010). Inappropriate initial
antimicrobial therapy refers to drugs not covered by the target
Antibiotics for hospital-acquired pneumonia in children (Protocol)
Copyright © 2016 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
pathogen, or pathogen resistance to the antimicrobial drug. The
most important independent factor that affects mortality in HAP
is inappropriate initial empiric therapy and the delayed application
of antibiotics (Masterton 2008; Torres 2009). Therefore, once the
diagnosis of bacterial HAP/VAP is established, even when bacteria
are not found in respiratory secretions, there is a need for imme-
diate broad-spectrum antimicrobial drugs (Torres 2009). The ini-
tial empirical antibiotic selection should cover possible common
bacteria, the patient should be treated and observed for the first
three days, and then a decision should be made on whether to
continue or change to other options according to the therapeutic
response. Once pathogens are specific, treatment should immedi-
ately be changed to sensitive, targeted narrow-spectrum antimicro-
bial drugs (Torres 2009). In addition, all antibiotics for HAP/VAP
should be selected according to the local epidemiological data.
How the intervention might work
Pneumonia is the leading cause of mortality in children below the
age of five (WHO 2015). Identifying pathogens in children with
pneumonia is not easy, and to meet public health goals of reducing
childhood mortality caused by pneumonia, appropriate antibiotic
administration is employed in most instances (Lodha 2013). As
appropriate antimicrobial treatment for patients with HAP will
significantly improve prognosis, more rapid identification of in-
fection and accurate selection of antimicrobial agents for patients
are vital clinical goals we should focus on (Chastre 2002; Kollef
2003).
Why it is important to do this review
A guideline published in 2005 by the American Thoracic Soci-
ety and Infectious Diseases Society of America recommended an-
tibiotics specifically for adults with HAP (ATS 2005). The latest
edition of Therapeutic Guidelines does not address children with
HAP (only listing paediatric doses in an adult framework) (NICE
2014). Also, antibiotic administration is at the core of treatment
of HAP in children, and its optimal management remains contro-
versial. Therefore, it is important to know what the best manage-
ment is for HAP in children.
OBJECTIVES
To compare different antibiotics in order to identify effective and
safe antibiotic drug therapies for children with hospital-acquired
pneumonia (HAP) (including ventilator-associated pneumonia
(VAP) and HAP without mechanical ventilation).
2
METHODS
Criteria for considering studies for this review
Types of studies
We will include all randomised controlled trials (RCTs) comparing
antibiotic treatment regimens for children with HAP (including
VAP and HAP without mechanical ventilation).
Types of participants
We will include children up to (not including) 18 years of age with
HAP (including VAP and HAP without mechanical ventilation)
diagnosed by clinical and/or radiological features and/or quantita-
tive culture of respiratory specimens. We will also include studies
of children with suspected HAP/VAP. The participants must have
signs and symptoms of a pneumonia infection, including: fever;
leukocytosis (increased numbers of white blood cells); and/or pu-
rulent tracheal secretions. We will exclude data from children with
immune suppression or dysfunction related to primary diagnoses.
We will exclude data from children at-risk due to disorders such as
cystic fibrosis, primary ciliary dyskinesia, congenital heart disease,
etc. We will also exclude data from neonates.
Types of interventions
We will include studies comparing one antibiotic regimen with
another antibiotic regimen or placebo. We will also include tri-
als evaluating monotherapy versus combination therapy. We will
classify antibiotic groups as follows.
1. β-lactams.
2. Lincosamides.
3. Glycopeptide antibiotics.
4. Quinolones.
5. Aminoglycosides.
6. Macrolides.
7. Antibacerial oxazolidinone agents.
8. Anti anaerobic antibiotics fungi: e.g. Flagyl.
Types of outcome measures
Primary outcomes
1. Clinical cure. The definition of clinical cure is symptomatic
and involves clinical recovery by the end of treatment.
2. Treatment failure rates. The definition of treatment failure
is the presence of any of the following: development of chest
indrawing, convulsions, drowsiness or inability to drink at any
time, respiratory rate above the age-specific cut-off point on
Antibiotics for hospital-acquired pneumonia in children (Protocol)
Copyright © 2016 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
completion of treatment, or oxygen saturation of less than 90%
(measured by pulse oximetry) after completion of the treatment.
Loss to follow-up or withdrawal from the study at any time after
recruitment will indicate failure in the analysis.
3. Mortality rate.
Secondary outcomes
The clinically relevant outcome measures will be as follows.
1. Relapse rate: defined as children declared ’cured’, but
developing recurrence of disease at follow-up in a defined period.
2. Length of hospital stay: duration of total hospital stay (from
day of admission to discharge) in days.
3. Need for change in antibiotics: children requiring change in
antibiotics from the primary regimen.
4. Attributable adverse events and/or any events requiring
discontinuation of the trial antibiotic.
Search methods for identification of studies
Electronic searches
We will identify trials from searches of the following databases:
1. Cochrane Acute Respiratory Infections Group Trials
Register;
2. Cochrane Central Register of Controlled Trials
(CENTRAL) in the Cochrane Library;
3. MEDLINE (Ovid);
4. Embase.com;
5. LILACS;
6. Chinese Biomedical Literature Database (CBM).
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 sensitivity- and precision-
maximising version (2008 revision) 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
their inception to the present and we will not impose any restric-
tion on the language of publication.
Searching other resources
We will contact authors/experts in the field for unpublished and
ongoing trials. We will also check the reference lists of retrieved
studies. We will not apply any language restrictions.
3
Data collection and analysis
Selection of studies
Two review authors (LJ, GG) will independently screen titles and
abstracts for inclusion of all the potential studies we identify as a
result of the search.
We will retrieve the full-text study reports/publication and two
review authors (LJ, CW) will independently screen the full-text
and identify studies for inclusion, and identify and record reasons
for exclusion of the ineligible studies. We will resolve any disagree-
ment through discussion or, if required, we will consult a third
review author (LZ). 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 (BMJ 2009) and ’Characteristics of excluded studies’
table.
Data extraction and management
Two review authors (LJ, GG) will independently extract data using
pre-designed forms. We will resolve discrepancies through consen-
sus or, if required, we will consult a third review author (DM). The
extracted data will include the following information: details of
source, eligibility, methods, participants, interventions, outcomes
and results.
If any included studies involve both children and adults, we will
extract data separately for children. If any of the information above
is inadequate, we will contact the authors of the primary study to
provide further details and clarification.
If any included studies are not in English or Chinese, we will
contact translators with relevant language skills to help us extract
the necessary data.
Assessment of risk of bias in included studies
Two review authors (LJ, YD) will independently assess risk of bias
according to the following domains using the criteria outlined in
the Cochrane Handbook for Systematic Reviews of Interventions (
Higgins 2011). We will resolve disagreements by discussion among
co-authors.
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 unclear
and provide a quote from the study report, together with a jus-
tification for our judgement in the ’Risk of bias’ tables. We will
Antibiotics for hospital-acquired pneumonia in children (Protocol)
Copyright © 2016 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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 contribute to that outcome.
Assesment of bias in conducting the systematic
review
We will conduct the review according to this published protocol
and report any deviations from it in the ’Differences between pro-
tocol and review’ section of the systematic review.
Measures of treatment effect
For dichotomous data, we will present results as summary risk
ratios (RRs) or odds ratio (ORs) with 95% confidence intervals
(CIs); we will also use the RR to measure time-to-event data.
We will use the mean difference (MD) for measuring continuous
data. For trials that measure the same outcome, but use different
methods, we will use the standardised mean difference (SMD) to
combine results.
Unit of analysis issues
We will include cluster-randomised trials and cross-over trials
along with individually-randomised trials. In this systematic re-
view, we will treat each group or cluster in cluster-randomised trials
as the unit of analysis; we will use the intracluster correlation coeffi-
cient (ICC) to estimate the relative variability within and between
clusters, according to the relevant section of the Cochrane Hand-
book for Systematic Reviews of Interventions (Higgins 2011). For
cross-over trials with binary outcomes, we will adopt the Becker-
Balagtas approach to combine cross-over trials with parallel trials
for meta-analysis (Stedman 2011). For cross-over trials with con-
tinuous outcomes, each individual will act as the unit of analysis
and we will conduct approximate paired analyses (Higgins 2011).
Dealing with missing data
We will conduct intention-to-treat analyses, when data on indi-
viduals are missing, such as when randomised participants are ex-
cluded from the analysis. We will follow recommendations in the
Cochrane Handbook for Systematic Reviews of Interventions regard-
ing strategies for dealing with missing data (Higgins 2011). These
are:
1. whenever possible, we will contact the original investigators
to request missing data;
2. we will make explicit the assumptions of any methods used
to cope with missing data: for example, that the data are assumed
4
missing at random, or that missing values were assumed to have
a particular value such as a poor outcome;
3. we will perform sensitivity analyses to assess how sensitive
results are to reasonable changes in the assumptions that are
made; and
4. we will address the potential impact of missing data on the
findings of the review in the discussion section.
The minimum number of contact attempts we will try will be
three.
Assessment of heterogeneity
We will assess heterogeneity among studies in two ways. Firstly, we
will assess heterogeneity at face value: heterogeneity in population,
interventions, or outcomes. Secondly, we will use a Chi2 test (P ≤
0.10 is considered to be consistent with statistical heterogeneity)
and the I2 statistic to assess presence of statistical heterogeneity (>
50% is substantial heterogeneity, > 75% is considerable hetero-
geneity; Higgins 2011).
Assessment of reporting biases
We will use funnel plots to detect small-study effects including
publication bias, if we find a sufficient number of studies. We will
assess funnel plot asymmetry visually. If asymmetry is suggested
by a visual assessment, we will perform exploratory analyses to
investigate it.
Data synthesis
We will carry out statistical analysis using the Review Manager
software (RevMan 2014). We will use fixed-effect meta-analysis
for combining data where it is reasonable to assume that studies
are estimating the same underlying treatment effect: i.e. where tri-
als are examining the same intervention, and the trials’ popula-
tions and methods are judged sufficiently similar. If there is clin-
ical heterogeneity sufficient to expect that the underlying treat-
ment effects differ between trials, or if statistical heterogeneity is
detected (I2 statistic > 0%), we will use random-effects meta-anal-
ysis to produce an overall summary, if an average treatment effect
across trials is considered clinically meaningful. The random-ef-
fects summary will be treated as the average of the range of possible
treatment effects and we will discuss the clinical implications of
treatment effects differing between trials. If the average treatment
effect is not clinically meaningful, we will not combine trials. If
Antibiotics for hospital-acquired pneumonia in children (Protocol)
Copyright © 2016 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
we use random-effects analyses, the results will be presented as the
average treatment effect with 95% confidence intervals, and the
estimates of I2 statistic. If appropriate, a Network meta-analyses
would be considered.
GRADE and ’Summary of findings’ table
We will create a ’Summary of findings’ table using the following
outcomes: clinical cure, treatment failure rates, relapse rate, need
for change in antibiotics, mortality rate, length of hospital stay
and adverse events reported. We will use the five GRADE con-
siderations (study limitations, consistency of effect, imprecision,
indirectness and publication bias) to assess the quality of a body
of evidence as it relates to the studies which contribute data to the
meta-analyses for the prespecified outcomes (GRADE 2004). We
will use methods and recommendations described in Section 8.5
and Chapter 12 of the Cochrane Handbook for Systematic Reviews
of Interventions (Higgins 2011) using GRADEproGDT software
(GRADEproGDT 2015). We will justify all decisions to down- or
up-grade the quality of studies using footnotes and we will make
comments to aid the reader’s understanding of the review where
necessary.
Subgroup analysis and investigation of heterogeneity
We will perform a subgroup analysis of:
1. early-onset HAP versus late-onset HAP (HAP without
mechanical ventilation);
2. early-onset VAP versus late-onset VAP.
Sensitivity analysis
We will perform a sensitivity analysis of the impact of high risk of
bias on the outcome of the meta-analysis.
ACKNOWLEDGEMENTS
The methods section of this protocol is based on a standard tem-
plate developed by the Cochrane Airways Group and adapted by
the Cochrane Acute Respiratory Infections Group. Many thanks
to all authors’ affiliated Institutions and organisations, and thanks
to the Co-ordinating Editors, Referees and Editors of the Cochrane
Acute Respiratory Infections Group for their comments and en-
couragement.
5
 REFERENCES
Additional references
ATS 2005
American Thoracic Society. Guidelines for the management
of adults with hospital-acquired, ventilator-associated,
and healthcare-associated pneumonia. American Journal
of Respiratory and Critical Care Medicine 2005;171(4):
388–416.
BMJ 2009
Moher D, Liberati A, Tetzlaff J, Altman DG, The PRISMA
Group. Preferred Reporting Items for Systematic Reviews
and Meta-Analyses: The PRISMA Statement. BMJ 2009;
339:2535.
Cernada 2013
Cernada M, Aguar M, Brugada M, Gutiérrez A, López
JL, Castell M, et al. Ventilator-associated pneumonia in
newborn infants diagnosed with an invasive bronchoalveolar
lavage technique: a prospective observational study.
Pediatric Critical Care Medicine 2013;14(1):55–61.
Chastre 2002
Chastre J, Fagon JY. Ventilator-associated pneumonia.
American Journal of Respiratory and Critical Care Medicine
2002;165(7):867-903.
Eggimann 2003
Eggimann P, Hugonnet S, Sax H, Touveneau S, Chevrolet
JC, Pittet D. Ventilator-associated pneumonia: caveats for
benchmarking. Intensive Care Medicine 2003;29:2086-9.
GRADE 2004
GRADE Working Group. Grading quality of evidence and
strength of recommendations. BMJ 2004;328(7454):1490.
GRADEproGDT 2015 [Computer program]
McMaster University (developed by Evidence Prime, Inc.).
GRADEproGDT: GRADEpro Guideline Development
Tool [www.guidelinedevelopment.org]. Hamilton:
McMaster University (developed by Evidence Prime, Inc.),
2015.
Higgins 2011
Higgins JPT, Green S (editors). Cochrane Handbook for
Systematic Reviews of Interventions Version 5.1 [updated
March 2011]. The Cochrane Collaboration, 2011.
Available from www.cochrane-handbook.org.
Kim 1989
Kim JH, Gallis HA. Observations on spiraling empiricism:
its causes, allure, and perils, with particular reference to
antibiotic therapy. American Journal of Medicine 1989;87
(2):201-6.
Kollef 2003
Kollef MH. Treatment of ventilator-associated pneumonia:
get it right from the start. Critical Care Medicine 2003;31
(3):969–70.
Lodha 2013
Lodha R, Kabra SK, Pandey RM. Antibiotics for
community-acquired pneumonia in children. Cochrane
Antibiotics for hospital-acquired pneumonia in children (Protocol)
Copyright © 2016 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Database of Systematic Reviews 2013, Issue 6. [DOI:
10.1002/14651858.CD004874.pub4]
Masterton 2008
Masterton RG, Galloway A, French G, Street M, Armstrong
J, Brown E, et al. Guidelines for the management of
hospital-acquired pneumonia in the UK: report of the
working party on hospital-acquired pneumonia of the
British Society for Antimicrobial Chemotherapy. Journal of
Antimicrobial Chemotherapy 2008;62(1):5–34.
Morrow 2009
Morrow BM, Argent AC, Jeena PM, Green RJ. Guideline
for the diagnosis, prevention and treatment of paediatric
ventilator-associated pneumonia. South African Medical
Journal 2009;99(4 Pt 2):255–67.
NICE 2014
National Institute for Health and Care Excellence.
Diagnosis and management of community- and hospital-
acquired pneumonia in adults. National Clinical Guideline
Centre 2014.
RevMan 2014 [Computer program]
The Nordic Cochrane Centre, The Cochrane Collaboration.
Review Manager (RevMan). Version 5.3. Copenhagen:
The Nordic Cochrane Centre, The Cochrane Collaboration,
2014.
Richards 1999
Richards MJ, Edwards JR, Culver DH, Gaynes RP.
Nosocomial infections in pediatric intensive care units in the
United States. National Nosocomial Infections Surveillance
System. Pediatrics 1999;103(4):e39.
Richards 2000
Richards MJ, Edwards JR, Culver DH, Gaynes RP.
Nosocomial infections in combined medical-surgical
intensive care units in the United States. Infection Control
and Hospital Epidemiology 2000;21(8):510–5.
Selim 2010
Selim AG, Balalis G, Bhaskar B, van Driel ML. Antibiotics
for ventilator-associated pneumonia. Cochrane Database
of Systematic Reviews 2010, Issue 9. [DOI: 10.1002/
14651858.CD004267.pub3]
Song 2008
Song JH, Asian Hospital Acquired Pneumonia Working
Group. Treatment recommendations of hospital-acquired
pneumonia in Asian countries: first consensus report by the
Asian HAP Working Group. American Journal of Infection
Control 2008;36(4 Suppl):83–92.
Stedman 2011
Stedman MR, Curtin F, Elbourne DR, Kesselheim AS,
Brookhart MA. Meta-analyses involving cross-over trials:
methodological issues. International Journal of Epidemiology
2011;40(6):1732–4.
Torres 2009
Torres A, Ewig S, Lode H, Carlet J, European HAP Working
Group. Defining, treating and preventing hospital acquired
6
 pneumonia: European perspective. Intensive Care Medicine
2009;35(1):9–29.
Vincent 2009
Vincent JL, Rello J, Marshall J, Silva E, Anzueto A, Martin
CD, et al. International study of the prevalence and
outcomes of infection in intensive care units. JAMA 2009;
302(21):2323–9.
WHO 2015
World Health Statistics 2015. http://apps.who.int/iris/
bitstream/10665/170250/1/9789240694439_eng.pdf?ua=
1&ua=1.
∗
Indicates the major publication for the study

APPENDICES

Appendix 1. Detailed search strategies

exp Pneumonia/ OR (pneumon* or bronchopneumon* or pleuropneumon* or tracheobronchit* or tracheo bronchit*).tw. OR (vap or
hap or hcap).tw. OR Respiratory Tract Infections/ OR (respiratory infection* or respiratory tract infection*).tw. OR exp Ventilators,
Mechanical/ OR ventilat*.tw. OR intubation/ OR intubation, intratracheal/ OR intubat*.tw. OR exp Drug Resistance, Bacterial/ OR
drug resistance, multiple/ OR drug resistance, multiple, bacterial/ OR (bacteria* adj2 ((multidrug or multi-drug or multiple drug or
antibiotic) adj2 resistan*)).tw. OR (mdr or mdro).tw.
AND
exp Anti-Bacterial Agents/ OR (antibiotic* or antibacterial* or anti-bacterial* or antimicrobial* or anti-microbial*).tw. OR Amikacin/
OR Colistin/ OR Vancomycin/ OR exp Gentamicins/ OR (amikacin* or colistin* or vancomycin* or gentamicin* or gen-
tamycin*).tw,nm.
AND
exp Infant/ OR exp Child/ OR exp Adolescent/ OR exp Minors/ OR exp Puberty/ OR exp Pediatrics/ OR exp Schools/ OR (Infant* OR
infancy OR Newborn* OR Baby* OR Babies OR Neonat* OR Preterm* OR Prematur* OR Postmatur* OR Child* OR Schoolchild*
OR School age* OR Preschool* OR Kid or kids OR Toddler* OR Adoles* OR Teen* OR Boy* OR Girl* OR Minors* OR Pubert*
OR Pubescen* OR Prepubescen* OR Paediatric* OR Paediatric* OR Peadiatric* OR Nursery school* OR Kindergar* OR Primary
school* OR Secondary school* OR Elementary school* OR High school* OR Highschool*)
AND
((randomized controlled trial or controlled clinical trial).pt. or randomized.ab. or randomised.ab. or placebo.ab. or drug therapy.fs. or
randomly.ab. or trial.ab. or groups.ab.) not (exp animals/ not humans.sh.)

CONTRIBUTIONS OF AUTHORS

Roles and responsibilities

Task Responsible

Protocol stage: draft the protocol Lucan Jiang, Lingli Zhang

Antibiotics for hospital-acquired pneumonia in children (Protocol) 7

Copyright © 2016 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
(Continued)

Review stage: select which trials to include (2 + 1 arbiter) Lucan Jiang, Ge Gui, Chaomin Wan

Review stage: extract data from trials (2 + 1 arbiter) Lucan Jiang, Ge Gui, Dezhi Mu

Review stage: enter data into RevMan Lucan Jiang, Ge Gui

Review stage: carry-out the analysis Yanjun Duan, Lingli Zhang

Review stage: interpret the analysis Yanjun Duan, Chaomin Wan

Review stage: draft the final review Lucan Jiang, Dezhi Mu, Lingli Zhang

Update stage: update the review Lucan Jiang, Lingli Zhang

DECLARATIONS OF INTEREST
Lucan Jiang: no known conflicts of interest.
Dezhi Mu: no known conflicts of interest.
Lingli Zhang: National Natural Science Foundation of China（No. 81373381&#65289. The grant of National Natural Science
Foundation of China has no role in study design, data collection and analysis or preparation of this review.
Ge Gui: no known conflicts of interest.
Yanjun Duan: no known conflicts of interest.
Chaomin Wan: no known conflicts of interest.

SOURCES OF SUPPORT

Internal sources
• Sichuan University, China.

External sources
• Natural Science Foundation of China, China.
Evidence based establishment of evaluation index system for paediatric rational drug use in China (No. 81373381)

Antibiotics for hospital-acquired pneumonia in children (Protocol) 8

Copyright © 2016 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.