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764
Lower respiratory tract infections in mechanically ventilated patients are a frequent cause of antibiotic treatment in
intensive-care units. These infections present as severe sepsis or septic shock with respiratory dysfunction in
intubated patients. Purulent respiratory secretions are needed for diagnosis, but distinguishing between pneumonia
and tracheobronchitis is not easy. Both presentations are associated with longlasting mechanical ventilation and
extended intensive-care unit stay, providing a rationale for antibiotic treatment initiation. Dierentiation of
colonisers from true pathogens is dicult, and microbiological data show Staphylococcus aureus and Pseudomonas
aeruginosa to be of great concern because of clinical outcomes and therapeutic challenges. Key management issues
include identication of the pathogen, choice of initial empirical antibiotic, and decisions with regard to the
resolution pattern.
Introduction
In the Extended Prevalence of Infection in Intensive
Care II (EPIC II) study,1 which looked at 1265 intensivecare units (ICUs) in 75 countries, 51% of adults
admitted to ICUs were infected, and the respiratory
tract was the focus of infection in 64% of cases. Airway
infection in intubated patients is the main reason for
antibiotic prescription in medical ICUs. Because no
gold standard exists for the diagnosis of respiratory
tract infections in intubated patients,2 prescription of
antibiotics for patients with purulent respiratory
secretions is common clinical practice in the ICU
setting. The panel shows the clinical challenges in
management of respiratory tract infections in ventilated
patients with a hypothetical clinical scenario. In this
Review we discuss ventilator-associated respiratory
infections (VARIs) in adult patients, with an emphasis
on diagnosis, microbiological causes, and management.
Clinical challenge
Key messages
Review
A
Colonisation
VAT
VAP
B
VAT
Colonisation
VAP
Early VAP
Colonisation
VAP
VAT
VARI
Epidemiology
The epidemiology of respiratory infections in the ICU
varies, dependent on whether the patient is mechanically
ventilated with a tracheostomy or an endotracheal tube.
The role of the biolm is important in patients who are
tracheostomised.12,13 Aspiration constitutes the main
pathophysiological event. Avoidance of an articial airway
is the best method of prevention of respiratory infection.
By contrast with community-acquired pneumonia,
respiratory infections in mechanically ventilated patients
are heterogeneous. The dierence between a patient who
has undergone intra-abdominal or cardiac surgery, or
trauma, and a medical patient, is hard to establish.
Although the attributable mortality of VAP is
controversial, this condition prolongs mechanical
ventilation and length of stay in the ICU.14 The overall
765
Review
We believe that prevention trials and recommendations should no longer focus on VAP rates only.
Measures associated with improved outcomes
(especially in patients mechanically ventilated for a
short time) and reduced costs should also be
implemented. Investigators of a Spanish multicentre
cohort study26 reported that full VAP prevention care
bundle compliance was associated with an incidence
risk ratio of 078 (95% CI 015099) and a reduction
of both median ICU length of stay from 10 days to
6 days and duration of ventilation from 8 days to 4 days.
Key interventions were oral care, cu pressure
maintenance, hand hygiene before articial airway
manipulation, and strategies to avoid hypersedation.
Prolongation of ICU stay is associated with increased
(preventable) health-care costs27 and emphasises the
interest in the prioritisation of prevention measures,
which have shown potential cost reductions (rather
than rate reductions only).
Pathogens
Fewer than ten organisms are implicated in most VARI
cases and a substantial proportion are polymicrobial
infections.28 Increasingly, respiratory pathogens are
Gram-negative bacteria. The EU-VAP study28 identied
Staphylococcus aureus and Pseudomonas aeruginosa as
the pathogens isolated most often in patients with VAP.
Organisms such as methicillin-susceptible S aureus,
Haemophilus inuenza, and Streptococcus pneumoniae
are common causes of early-onset VAP in trauma
patients, but the infection improves quickly (within
3 days) when adequate treatment is promptly started.
Authors of a secondary analysis of the EU-VAP study
reported that elderly ICU patients with VAP had
increased rates of Enterobacteriaceae compared with
younger age groups.29 The table details the top three
causative pathogens of VAP reported in seven
studies28,3035 published during the past decade. Figure 2
shows the median onset of VAP for each pathogen.
Antibiotic resistance
ESKAPE pathogens
Nosocomial infections are often caused by ESKAPE
pathogens (Enterococcus faecium, S aureus, Klebsiella
pneumoniae, Acinetobacter baumannii, P aeruginosa, and
Enterobacter species).36 Sandiumenge and colleagues37
reported S aureus, P aeruginosa, and A baumannii to be
the three main causes of infection in patients in ICUs.
Enteroccus spp and Candida spp, on the other hand,
should be interpreted as oral contaminants. The risk of
multidrug-resistant pathogens causing VAP is mainly
determined by comorbidity and previous exposure to
more than two antibiotics.37 The increased mortality of
VAP due to multidrug resistance as compared with
drug susceptible pathogens is attributable to more
severe comorbidity and the presence of organ failure.38
Resistant ESKAPE VAP mortality was twice that of
www.thelancet.com/respiratory Vol 2 September 2014
Review
Findings
Koulenti et al (2009)28*
Esperatti et al (2010)30
P aeruginosa 240%
MSSA 140%
MRSA 90%
Kollef et al (2005)31
MSSA 285%
P aeruginosa 212%
MRSA 190%
Lee MS et al (2013)32
MRSA 245%
Pseudomonas spp 140%
Klebsiella spp 119%
S aureus 172%
Haemophilus inuenzae 134%
Enterobacter spp 93%
Rosenthal V et al (2012)34
Bekaert M et al (2011)35
P aeruginosa 262%
MSSA 97%
A baumannii 82%
MRSA
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op
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ph
to
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St
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ia
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as
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rb
au
alt
gin
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RS
A
M
Ac
Ps
eu
d
om
En
te
on
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ae
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cte
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ce
SS
ae
14
12
10
8
6
4
2
0
St
pn rept
or em eum oco
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M op
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Table: Top three pathogens of VAP reported in seven studies published during the past decade
Ha
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P aeruginosa
An increased frequency of multidrug-resistant
P aeruginosa strains has been reported in the past
decade.48 In the ICU, these infections are a key issue for
infection management, especially VAP.49 In developing
countries, resistance rates to several antibiotic classes are
high (eg, uoroquinolones 46%, piperacillintazobactam
40%, and carbapenems 43%).42 Patients at risk of
P aeruginosa infection should receive combination
treatment with two drugs at pneumonia onset because of
the probability of wrong initial treatment, which has
been associated with signicantly increased mortality.50
However, when susceptible, one drug has similar
outcomes to that of two, and simplication of the
treatment regimen can be implemented after
susceptibility is established.50 For empirical treatment
choice, prescribers should bear in mind factors associated
with isolation of multidrug-resistant P aeruginosa. These
factors include admission to hospital from chronic care
facilities,51 old age, diabetes, long-term treatment in
hospital,5153 use of invasive devices,51,54,55 recent surgery,53
extended ICU stay, extended ventilation periods, and
higher illness severity scores.55,56,38
Candida spp airway colonisation could promote
pneumonia development, especially when caused by
P aeruginosa, perhaps linked to the biolm environment
in the articial airway.5760 In episodes with clinical
suspicion of VAP, Candida spp airway colonisation has
been associated with increased mortality risk (odds ratio
[OR] 172).58 Yeasts have been reported to be an
independent risk factor for identication of multidrugresistant microorganisms (OR 179). Whether Candida
airway colonisation should be a variable aecting
selection of VAP empirical treatment is not clear.58
Crossinfection could also contribute to emergence of
multidrug-resistant P aeruginosa strains.55,61 Previous
antibiotic exposure plays a key part in acquisition of
multidrug-resistant strains.6163 Aminoglycoside ex768
Review
A baumannii
A baumannii is a non-fermentative Gram-negative
bacilli that has caused large outbreaks in contaminated
ICUs. The pathogen has dierent risk factors to
P aeruginosa and no virulence factors. Independent risk
factors for A baumannii pneumonia in intubated
patients include acute respiratory distress syndrome,
head trauma, large volume pulmonary aspiration,78
presence of tracheostomy,79 and extended ICU stay.80 An
extended antibiotic course is a frequent risk factor for
A baumannii infections. The presence of a resistant
phenotype that often implicates carbapenems is of great
concern; rates of carbapenem resistance of up to 66%
have been reported.42 For carbapenem-resistant strains,
high doses of nebulised colistin have been associated
with good resolution and short periods of hospital
admission.81 High doses of colistin can purportedly be
delivered by nebulisation without substantial systemic
exposure because, even in the presence of severe lung
infection, colistin does not easily cross the alveolar
capillary membrane.81
Management
VAP
Administration of antibiotics should not be delayed in
pneumonia management because inadequate treatment
increases mortality and, in survivors, increases healthcare costs. The use of broad-spectrum antibiotics as
initial empirical treatment has been advocated;
however, concerns remain about resistance. The most
eective strategy against development of resistance
should be prompt and unequivocal killing of the
microbes, thereby defeating resistance before it starts.
Additionally, the de-escalation strategy that allows the
use of broad-spectrum antibiotics as initial empirical
treatment, maximisation of the odds of appropriate
antibiotic treatment associated with early de-escalation,
use of a more strict spectrum coverage after pathogen
identication, and minimisation of exposure and risk
of resistance emergence have shown benet on clinical
outcomes in ventilated patients.82,83 The so-called right
rst time idea and short duration of treatment
whenever possible represents the two-step strategy for
VAP management.
The best diagnostic method for VAP (invasive vs noninvasive sampling techniques) is unknown. From their
meta-analysis, Shorr and colleagues84 concluded that the
use of invasive strategies did not aect mortality, but did
aect antibiotic use, leading to modications in the
antibiotic regimen in more than half of patients. By
www.thelancet.com/respiratory Vol 2 September 2014
VAT
Use of antibiotics in VAT is more controversial than it
is in VAP. Only 24% of prescribers routinely gave
antibiotics for VAT in a survey and 24% stated a
preference for an antibiotic course of less than 7 days,
although only 26% thought that VAT should not be
treated with antibiotics.88 Nseir and colleagues89
reported reduced mortality rates and more days without
mechanical ventilation when VAT was treated with
intravenous antibiotics (45% of the cohort were patients
with COPD). However, several methodological
limitations should be considered as this study was
unblinded and underpowered, with high risk of crosscontamination, some unbalanced distribution in
severity of diseases, and an absence of adequate risk
analysis. Palmer and colleagues90 reported a decrease of
VAP development rates, faster weaning from the
ventilator, reduced use of systemic antibiotics, and
reduction of bacterial resistance when nebulised
antibiotics were given for VAT compared with no
antibiotics in a double-blind, randomised, placebocontrolled study. Dallas and colleagues10 reported that
patients diagnosed with VAT had much the same
outcomes to those with VAP, suggesting that
antimicrobial treatment might also be appropriate for
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NO
Narrow spectrum
antibiotics
YES
Broad spectrum
antibiotics
Areas of uncertainty
Favourable
Clinical response
De-escalate
Combination therapy to monotherapy
Change to narrower spectrum
according to culture results
Stop antibiotic if culture negative
Delayed
Review
Conclusions
Respiratory infections in mechanically ventilated
patients present in the form of severe sepsis or septic
shock in intubated patients. Purulent respiratory
secretions are needed for diagnosis, but dierentiation
between pneumonia and tracheobronchitis on the basis
of clinical ndings is a challenge. Both presentations
are associated with extended ventilation and ICU stay,
providing the rationale for treatment. Key VARI
management issues include identication of the
pathogen, initial antibiotic choice, and resolution pattern
and criteria. New opportunities for research include
roles for biomarkers, early causal diagnosis with
molecular diagnostic techniques, and optimisation and
customisation of treatment.
Contributors
JR reviewed the literature and conceived, organised, wrote, and gave
nal approval to the manuscript. DK and TL reviewed the literature
and organised and wrote the report.
Declaration of interests
JR has served on Speakers Bureaux and advisory boards for Pzer and
received grant research support from Sano Pasteur, Kenta, and
Cubist, and the Spanish Health Ministry (FISS11/1122). TL and DK
declare no competing interests.
References
1
Vincent JL, Rello J, Marshall J, et al, for the EPIC II Group of
Investigators. International study of the prevalence and outcomes
of infection in intensive care units. JAMA 2009; 302: 232329.
2
Klompas M. Does this patient have ventilator-associated
pneumonia? JAMA 2007; 297: 158393.
3
Klompas M. What can we learn from international ventilatorassociated pneumonia rates? Crit Care Med 2012; 40: 330304.
4
Niederman MS. Hospital-acquired pneumonia, health careassociated pneumonia, ventilator-associated pneumonia, and
ventilator-associated tracheobronchitis: denitions and challenges
in trial design. Clin Infect Dis 2010; 51 (suppl 1): S1217.
5
Improving surveillance for ventilator-associated events in adults.
http://www.cdc.gov/nhsn/PDFs/pscManual/10-VAE_FINAL.pdf
(accessed April 13, 2014).
6
Stevens JP, Kachniarz B, Wright SB, et al. When policy gets it
right: variability in U.S. hospitals diagnosis of ventilatorassociated pneumonia. Crit Care Med 2014; 42: 497503.
7
Pugin J, Auckenthaler R, Mili N, Janssens JP, Lew PD, Suter PM.
Diagnosis of ventilator-associated pneumonia by bacteriologic
analysis of bronchoscopic and nonbronchoscopic blind
bronchoalveolar lavage uid. Am Rev Respir Dis 1991;
143: 112129.
8
Luna CM, Blanzaco D, Niederman MS, et al. Resolution of
ventilator associated pneumonia: prospective evaluation of the
clinical pulmonary infection score as an early clinical predictor for
outcome. Crit Care Med 2003; 31: 67682.
9
Parks NA, Magnotti LJ, Weinberg JA, et al. Use of the clinical
pulmonary infection score to guide therapy for ventilatorassociated pneumonia risks antibiotic overexposure in patients
with trauma. J Trauma Acute Care Surg 2012; 73: 5258.
10 Dallas J, Skrupky L, Abebe N, Boyle WA 3rd, Kollef MH.
Ventilator-associated tracheobronchitis in a mixed surgical and
medical ICU population. Chest 2011; 139: 51318.
11 Martin-Loeches I, Papiol E, Almansa R, Lpez-Campos G,
Bermejo-Martin JF, Rello J. Intubated patients developing
tracheobronchitis or pneumonia have distinctive complement
system gene expression signatures in the pre-infection period:
a pilot study. Med Intensiva 2012; 36: 25763.
12 Solomon DH, Wobb J, Buttaro BA, Truant A, Soliman AM.
Characterization of bacterial biolms on tracheostomy tubes.
Laryngoscope 2009; 119: 163338.
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