REVIEW

CURRENT
OPINION Hospital-acquired pneumonia and ventilator-
associated pneumonia: recent advances in
epidemiology and management
François Barbier a,b, Antoine Andremont b,c, Michel Wolff b,d, and
Lila Bouadma d

Purpose of review
The recent evidence is reviewed on clinical epidemiology, trends in bacterial resistance, diagnostic tools
and therapeutic options in hospital-acquired pneumonia (HAP), with a special focus on ventilator-associated
pneumonia (VAP).
Recent findings
The current incidence of VAP ranges from two to 16 episodes for 1000 ventilator-days, with an attributable
mortality of 3–17%. Staphylococcus aureus (with 50–80% of methicillin-resistant strains), Pseudomonas
aeruginosa and Enterobacteriaceae represent the most frequent pathogens in HAP/VAP. The prevalence of
carbapenemase-producing Gram-negative bacilli (GNB) and the emergence of colistin resistance are
alarming. Procalcitonin seems to have a good value to monitor the response to treatment. Rapid molecular
tests for the optimization of empirical therapy will be available soon. Recent studies support the use of a
high-dosing regimen of colistin in HAP/VAP caused by extensively drug-resistant GNB. Linezolid may
probably be preferred to vancomycin for a subset of methicillin-resistant S. aureus HAP/VAP. Given the
scarcity of novel antimicrobial drugs, different approaches such as bacteriophage therapy or
immunotherapy warrant further clinical evaluations.
Summary
HAP/VAP is a major cause of deaths, morbidity and resources utilization, notably in patients with severe
underlying conditions. The development of new diagnostic tools and therapeutic weapons is urgently
needed to face the epidemic of multidrug-resistant pathogens.
Keywords
acute respiratory distress syndrome, antimicrobial resistance, mechanical ventilation, nosocomial
infections

INTRODUCTION published data on clinical epidemiology, trends

Hospital-acquired pneumonia (HAP) is a pulmonary in bacterial resistance, diagnostic methods and
infection that develops in patients hospitalized for
more than 48 h, either in the ICU or in other wards a
Service de Réanimation Médicale, Hôpital de la Source, Centre Hos-
[1,2]. Ventilator-associated pneumonia (VAP), a sub-
pitalier Régional d’Orléans, Orléans, bUniversité Paris-Diderot Sorbonne
set of HAP that occurs in mechanically ventilated Paris-Cité, cLaboratoire de Bactériologie, Hôpital Bichat-Claude
patients more than 48 h after tracheal intubation, is Bernard, Hôpitaux Universitaires Paris-Nord Val-de-Seine, Assistance
the most frequent ventilator-associated compli- Publique-Hôpitaux de Paris and dService de Réanimation Médicale et
cation (VAC) [1,2]. HAP/VAP represents a major des Maladies Infectieuses, Hôpital Bichat-Claude Bernard, Hôpitaux
Universitaires Paris-Nord Val-de-Seine, Assistance Publique-Hôpitaux
cause of deaths, morbidity and resources utilization
de Paris, Paris, France
in hospitalized patients, most notably in those with
& & Correspondence to Lila Bouadma, MD, PhD, Service de Réanimation
severe underlying conditions [1,3,4,5 ,6,7 ]. The Médicale et des Maladies Infectieuses, Groupe Hospitalier Bichat-
adequacy of empirical antimicrobial therapy is Claude Bernard, 46, rue Henri Huchard, 75018 Paris, France. Tel:
strongly predictive of hospital survival [3], making +33 1 40 25 81 22; fax: +33 1 40 25 87 82; e-mail: lila.bouadma@
the definition of patients at risk for multidrug-resist- bch.aphp.fr
ant (MDR) pathogens a pivotal challenge [1,8–10]. Curr Opin Pulm Med 2013, 19:216–228
In this short review, we summarize the recently DOI:10.1097/MCP.0b013e32835f27be

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 HAP and VAP Barbier et al.

of VAP in ARDS patients has not been confirmed

KEY POINTS &
by recent studies [13 ,31–43]. Early tracheostomy

HAP/VAP are the most common acquired infections in (i.e. within the first 7 days of mechanical ven-
critically ill patients, and are responsible for high tilation) in patients with predictable weaning
morbidity and mortality in this population. difficulties does not appear as an independent pre-
dictor of VAP when compared with late tracheos-

The main concern on antimicrobial resistance currently &
tomy or prolonged tracheal intubation [22,44 ,45].
relates to GNB, with the worldwide spread of
carbapenemase-producing strains and the emergence Other potential risk factors have been recently
of colistin resistance. suggested, such as etomidate use for tracheal intu-
bation or energetic deficit during the early ICU

Molecular assays directly applicable on respiratory course (at least for Staphylococcus aureus VAP)
samples are urgently needed, both to improve the
[46,47], whereas steroids (for trauma patients) or
adequacy of empirical therapy and to spare broad-
spectrum drugs. statin use could be protective [48,49].
Nonventilator-associated HAPs dramatically

A few novel drugs in the pipeline remain to be fully increase both the hospital length of stay and the
assessed in HAP/VAP caused by MDR pathogens. cost of care, and are associated with an overall

New therapeutic approaches such as phage therapy mortality of 27–51% [11,50,51], the poorer pro-
and immunotherapy warrant clinical evaluation in gnosis being reported in the elderly. Subsequent
this context. functional disability and accelerated cognitive
impairment in aged patients surviving bacterial
sepsis may increase the social burden of this noso-
comial event [52]. The crude mortality of VAP
therapeutic strategies in HAP, with a special focus & & &&
ranges from 22 to 60% [7 ,13 ,14 ,53]. Although
on VAP. the prognostic weight of underlying conditions pre-
vails in many cases, the occurrence of VAP is associ-
ated with a two-fold increase of the likelihood of
CURRENT CLINICAL EPIDEMIOLOGY: THE in-ICU death, most notably for patients with
BURDEN OF HOSPITAL-ACQUIRED inadequate empirical therapy [3]. The directly
PNEUMONIA AND VENTILATOR- attributable mortality is 6–9%, but varies from 3
ASSOCIATED PNEUMONIA to 17% depending on patient subgroups [4,5 ]. In
&

The incidence of HAP ranges from five to more than addition, survivors experience poorer outcome than
20 cases per 1000 hospital admissions [1,11]. Out- ICU patients who do not develop VAP, with signifi-
side the ICU, highest rates are observed in the cantly longer durations of mechanical ventilation,
&
elderly, immunocompromised hosts, surgical ICU stay and hospitalization [7 ]. The absolute
patients and those receiving enteral feeding through increase in hospitalization costs is estimated to be
40 000 USD per episode [7 ].
&
a nasogastric tube [1]. Almost one-third of HAPs are
ICU-acquired, with VAP accounting for 90% of
cases. Overall, VAP occurs in 9–40% of intubated
patients and represents the most frequent ICU- THE ALARMING SITUATION OF
& &&
acquired infection [12,13 ,14 ]. Recent surveys BACTERIAL RESISTANCE
from large healthcare networks reported a pooled The bacterial epidemiology of VAP (Table 2) [54]
incidence density of VAP ranging from two to depends on a panel of factors including mechanical
&&
16 episodes per 1000 ventilator-days [14 ,15]. The ventilation duration, length of hospital and ICU
daily incidence of VAP peaks between day 5 and day stays, previous exposure to antimicrobials, local
9 of mechanical ventilation, whereas the cumulative epidemiology and potential epidemic phenomenon
incidence appears as roughly proportional to mech- in a given ICU [1]. Rapid changes in the oropharyn-
&
anical ventilation duration [13 ,16,17]. The main geal flora of intubated patients (even in the absence
other risk factors for VAP and corresponding pre- of antibiotic exposure) represent a key determi-
&
ventive measures are exposed in Table 1 [17–42]. nant [55 ], as microaspirations of pharyngeal
Patients with the acute respiratory distress syn- secretions constitute the leading physiopatho-
drome (ARDS) are especially at risk, as a likely result logical mechanism of VAP. Early-onset VAP (within
of prolonged mechanical ventilation and heavy the first 4 days of mechanical ventilation) usually
sedation requirement, with a cumulative incidence involve respiratory pathogens from the normal,
of 40% after day 10 [13 ]. Whether neuromuscular
&
community-acquired oropharyngeal microbiota
blockade agents use increases and head of bed (Table 3), whereas late-onset VAP (occurring on
elevation or prone positioning decreases the risk day 5 of mechanical ventilation or later) mostly

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 Infectious diseases

Table 1. Effects of the main preventive measures for ventilator-associated pneumonia prevention in randomized
controlled studies or last meta-analyses
Intervention Year, design References Patients (n) RRR of VAP (%)

Reducing the time at risk

NPPV 2005, meta-analysis (12 studies) [18] 3030 # 25%
Daily SBT 2000, RCT (two ICUs) [19] 385 No effect
2006, RCT (five ICUs) [20] 144 No effect
Daily sedation interruption 2000, RCT (one ICU) [21] 128 No effect
Early tracheotomy 2012, meta-analysis (7 RCTs) [22] 1044 No effect
Preventing endotracheal tube colonization and minimizing contaminated microaspirations
Silver-coated ET 2008, RCT (54 ICUs) [23] 1509 # 36%
Saline instillation before tracheal suctioning 2009, RCT (one ICU) [24] 262 # 54%
ET with SSD 2010, meta-analysis (13 RCTs) [25] 2442 # 48% (four RCTs)
ET with ultrathin membrane and SSD 2007, RCT (one ICU) [26] 280 # 64%
ET with an ultrathin and tapered-shape cuff 2008, RCT (one ICU) [27] 134 # 45%
membrane
Continuous control of tracheal cuff pressure 2007, RCT (two ICUs) [28] 142 No effect
2011, RCT (one ICU) [29] 122 # 63%
Head-of-bed elevation 1999, RCT (two ICUs) [30] 86 # 78%
2006, RCT (four ICUs) [31] 221 No effect
Prone position 2008, meta-analysis (five RCTs) [32] 1372 No effect
Kinetic beds 2006, meta-analysis (15 RCTs) [33] 1169 # 53% (10 RCTs)
Positive end-expiratory pressure 2008, RCT (three ICUs) [34] 131 # 63%
Physiotherapy 1998, RCT (one ICU) [35] 46 No effect
2002,RCT (one ICU) [36] 60 # 79%
2007, RCT (one ICU) [37] 180 No effect
2009, RCT (one ICU) [38] 144 No effect
Modulation of colonization
Oral care with chlorhexidine 2010, meta-analysis (12 RCTs) [39] 2341 # 24%
Probiotics 2010, RCT (one ICU) [40] 146 # 47%
Iseganan 2006, RCT (one ICU) [41] 709 No effect
Closed tracheal suction system 2008, meta-analysis (nine RCTs) [42] 1292 No effect

Data from [17]. ET, endotracheal tube; NPPV, noninvasive positive pressure ventilation; RCT, randomized controlled trial; RRR, relative risk reduction; SBT,
spontaneous breathing trial; SSD, subglottic secretion drainage; VAP, ventilator-associated pneumonia.

&&
involve hospital-acquired and potentially MDR [14 ,50,54]. The recent description of plasmidic
pathogens as a combined result of antibiotic linezolid resistance in MRSA elicits significant
selective pressure, cross-transmission and coloniza- concerns [58,59]. Resistance to third-generation
tion from in-ICU environmental sources [1,53,54]. and fourth-generation cephalosporins in Enterobac-
However, MDR pathogens may be isolated in teriaceae strains mostly depends on the expression
early-onset VAP when risk factors exist prior to of acquired extended-spectrum b-lactamases (ESBLs)
ICU admission, and even when such risk factors and/or AmpC b-lactamases [56–60]. The spread of
are lacking [notably for Pseudomonas aeruginosa carbapenemase-producing strains is even more
and methicillin-resistant Staphylococcus aureus alarming (Table 4) [57]. MDR isolates of P. aerugi-
(MRSA)] [53], enlightening the limits of this classi- nosa are increasingly prevalent, whereas one-half
fication in the current context of bacterial resis- to two-thirds of Acinetobacter baumannii strains
tance. causing VAP are currently carbapenem-resistant
&&
Resistance frequencies differ from one ICU to [14 ,50]. Polymyxins (mainly colistin) are more
another and at the geographic scale, but trends and more seen as a last-line therapeutic option to
converge across international surveys (Table 4) treat MDR Gram-negative bacilli (GNB) [61].

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 Table 2. Current bacterial epidemiology of hospital-acquired pneumonia and ventilator-associated pneumonia (first episodes only): data from recent
clinical trials and surveys
&
Study/reference ACURASYS [13 ] Ferrer et al. [53] Ferrer et al. [53] ANSRPSG [50] SENTRY [54]
Country France Spain Spain Asia Worldwide
Setting 20 ICUs Six ICUs, one hospital Six ICUs, one hospital 73 hospitals Surveillance System
Type of pneumonia VAP in ARDS patients HAP and VAPa HAP and VAPb HAP and VAP HAP and VAP
Patients, n 98 38 (VAP, n ¼ 18) 238 (VAP, n ¼ 128) 2554 (VAP, n ¼ 977) 31 436

Bacterial documentation 100 63 54 67 –

Gram-negative bacteria
Haemophilus influenza 3 5 3 1 3
Enterobacteriaceae 35 22 19 23 26
Escherichia coli 11 8 6 5 7
Klebsiella pneumoniae 4 3 3 14 10
Enterobacter sp. 10 3 5 4 6
Serratia marcescens 3 – 2 <1% 3
Other enterobacteria 7 8 3 – –

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Pseudomonas aeruginosa 34 16 18 19 22
Stenotrophomonas maltophilia 5 – 3 4 3
Acinetobacter baumannii – – 1 22 7
Gram-positive bacteria
Staphylococcus aureus 21 27 16 14 28
Methicillin-susceptible 12 11 8 3 –
Methicillin-resistant 9 16 8 11 –
Streptococcus pneumoniae Other GP: 10 5 2 2 3
Other streptococci – – – –
Enterococcus sp. vancomycin-resistant – – – –

Data presented in the table are percentages. ANSRPSG, Asian Network for Surveillance of Resistant Pathogens Study Group; ARDS, acute respiratory distress syndrome; GP, Gram-positive bacteria; HAP, hospital-
acquired pneumonia; VAP, ventilator-associated pneumonia.
a
No risk factor of multidrug-resistant (MDR) bacteria according to the 2005 Infectious Disease Society of America (IDSA)/American Thoracic Society (ATS) criterion [1].
b
At least one risk factor of MDR bacteria according to the 2005 IDSA/ATS criterion.

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219

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 Infectious diseases

Table 3. Current guidelines for the empirical treatment of hospital-acquired pneumonia, including ventilator-
associated pneumonia
Early-onset HAP/VAP (day 4 of Late-onset HAP/VAP (day 5 of
hospital stay/MV) without risk hospital stay/MV) OR presence of
Reference factors for MDR pathogena  1 risk factor for MDR pathogenb

Most common (i.e. targeted) MSSA MRSA

pathogens Streptococcus pneumonia and other Pseudomonas aeruginosa
streptococci, Haemophilus sp. Drug-resistant Enterobacteriacae
Wild-type Enterobacteriaceae Acinetobacter baumannii
Stenotrophomonas maltophilia
Society which issued the guidelines
(date of publication)
American Thoracic Society/ [1] Ceftriaxone Cefepime or ceftazidime
Infectious Diseases Society or or
of America (2005)
Levofloxacin, moxifloxacin, Imipenem/cilastatin or
or ciprofloxacin meropenem
or or
Ampicillin/sulbactam Piperacillin/tazobactam
or plus
Ertapenem Ciprofloxacin or levofloxacin
or
Amikacin, gentamicin, or tobramycin
European Respiratory Society/ [10] Ampicillin/sulbactam or amoxicillin/ Ceftazidime
European Society of Clinical clavulanate or
Microbiology and Infectious
or Imipenem/cilastatin or meropenem
Diseases/European Society of
Intensive Care Medicine (2009) Cefuroxime, cefotaxime or or
ceftriaxone Piperacillin/tazobactam
or plus
Moxifloxacin or levofloxacin Ciprofloxacin or levofloxacin
(not ciprofloxacin)
British Society of Antimicrobial [8] Aminopenicillin/b-lactamase Early-onset pneumonia with risk
Chemotherapy (2008) inhibitor factor for MDR pathogen:
or Cefotaxime or ceftriaxone
Cefuroxime or
Fluoroquinolone
or
Piperacillin/tazobactam
Late-onset pneumonia:
Depending on local epidemiology
If Pseudomonas aeruginosa is
suspected, treatment options include
ceftazidime, ciprofloxacin, meropenem
and piperacillin/tazobactam
Association of Medical Microbiology [9] Only if severity criteria are Also to be applied for severe early-onset
and Infectious Disease Canada/ lacking: pneumoniad:
Canadian Thoracic Societyc (2008) Cefotaxime or ceftriaxone Ceftazidime or cefepime
or cefepime or
or Piperacillin/tazobactam
Piperacillin-tazobactam or
or Imipenem/cilastatin or merepenem
Imipenem/cilastatin or meropenem plus
or Ciprofloxacin or levofloxacin
Levofloxacin or moxifloxacin or
Gentamicin, tobramycin or amikacin

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 HAP and VAP Barbier et al.

Table 3 (Continued)

Early-onset HAP/VAP (day 4 of Late-onset HAP/VAP (day 5 of

hospital stay/MV) without risk hospital stay/MV) OR presence of
Reference factors for MDR pathogena  1 risk factor for MDR pathogenb

In all guidelines [1,8–10] Add vancomycin or linezolid if MRSA

is suspected

MV, mechanical ventilation; MDR, multidrug-resistant; MRSA, methicillin-resistant Staphylococcus aureus; MSSA, methicillin-susceptible Staphylococcus aureus.
a
Risk factors for MDR pathogen are a current hospitalization of 5 days or more, an antimicrobial therapy within the preceding 90 days, a high frequency of
antibiotic resistance in the specific hospital unit, an immunosuppressive disease and/or therapy, and risk factors for healthcare-associated pneumonia (i.e.
hospitalization for 2 days or more in the preceding 90 days, residence in a nursing home or extended care facility, home infusion therapy including antibiotics,
chronic dialysis within 30 days, home wound care, and known carriage of multidrug-resistant pathogen in family members).
b
The cephalosporins (ceftazidime and cefepime), carbapenems (imipenem/cilastatin and meropenem), b-lactamin/b-lactamase inhibitor combination (piperacillin/
tazobactam), fluoroquinolone (ciprofloxacin and levofloxacin) and aminoglycosides (amikacin, gentamicin, and tobramycin) listed above are all considered as
effective against wild-type Pseudomonas aeruginosa.
c
Only VAP guidelines are shown here (see [9] for nonventilator HAP guidelines).
d
Severity criteria include hypotension, sepsis syndrome, rapid progression of infiltrates and end organ dysfunction.

Unfortunately, colistin resistance is now also on the of mechanical ventilation and ICU stay [71],
rise in ICUs with high prevalence of carbapenems but a direct role of mimivirus in VAP is uncertain
resistance and heavy colistin consumption [72,73].
&&
[62 ,63,64]. The situation of bacterial resistance
appears as critical when HAPs in nonintubated
patients are considered (Table 4). DOES FUNGAL VENTILATOR-ASSOCIATED
PNEUMONIA EXIST IN ICU PATIENTS
WITHOUT MAJOR
THE ROLE OF VIRUS IN VENTILATOR- IMMUNOSUPPRESSION?
ASSOCIATED PNEUMONIA Colonization of the lower respiratory tract by
The Herpesviridae herpes simplex virus (HSV) and Candida spp. affects 18–56% of intubated patients
cytomegalovirus (CMV) can cause viral reactivation and is associated with an increased risk of bacterial
pneumonia in intubated patients without a usual VAP, most notably caused by P. aeruginosa or other
criterion for immune deficiencies [65]. HSV repli- MDR pathogens, and possibly a poorer outcome
cation may be documented in tracheal/bronchial [74–77]. However, available data do not support a
aspirates from 32 to 64% of patients requiring direct role of Candida spp. as a VAP-causative
prolonged mechanical ventilation [66–68], with pathogen [78,79]. Aspergillus spp. (mainly Aspergillus
subsequent histopathological evidence of HSV fumigatus) may be involved in 3% of late-onset
bronchopneumonitis in up to 21% of patients with VAP [53], and invasive pulmonary aspergillosis
worsening respiratory status [68]. Patients with has been proven in 15% of critically ill patients with
ARDS and those receiving steroids may be at higher one or more Aspergillus-positive tracheal aspirate
risk [65]. CMV reactivation is observed in 30%
&
cultures [80 ]. A clinical algorithm was recently
of critically ill patients experiencing multiorgan proposed to assess the clinical relevance of these
failure and prolonged ICU stay [69], most notably cultures and ease the decision to start or not a
&
in survivors of severe bacterial sepsis, and may specific therapy [80 ].
directly involve the lung. The incidence of his-
tologically proven CMV pneumonia may reach
30% in ARDS patients with clinical deterioration RECENT ADVANCES IN THE DIAGNOSIS
suggesting VAC and negative bronchoalveolar OF HOSPITAL-ACQUIRED PNEUMONIA
lavage fluid (BALF) culture [70]. Acyclovir and AND VENTILATOR-ASSOCIATED
gancyclovir are the main therapeutic options for PNEUMONIA
HSV and CMV pneumonia, respectively, but both The diagnosis of HAP/VAP is challenging and con-
remain to be fully evaluated by appropriate ventional strategies have been extensively reviewed
randomized controlled trials (RCTs). A positive in recent guidelines [1,8–10]. However, two current
mimivirus (Acanthamoeba polyphaga) serology has research areas warrant developments. First, several
been documented in 20% of patients with suspected biomarkers have been evaluated as complementary
VAP and was associated with an increased duration diagnostic tools during the past years [81,82].

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 Infectious diseases

Table 4. Prevalence of major antibiotic resistance in Staphylococcus aureus, Klebsiella pneumoniae,

Escherichia coli, Pseudomonas aeruginosa and Acinetobacter baumannii strains causing hospital-acquired
and ventilator-associated pneumonia: recent data (2004) from international multicentric surveillance programs
INICC SENTRY ANSRPSG
Study/reference VAP [14 ] HAP/VAP [54] HAP þ VAP (pooled) [50]
&&

Pathogen, antimicrobial
Staphylococcus aureus
Oxacillin 73 59/51 82
Gentamicin – 13/22 –
Fluoroquinolones – 58/48 78
Klebsiella pneumonia
Fluoroquinolones – 16/24 31
Third-generation/fourth-generation 69 23/32 43
cephalosporinsa
Carbapenemsb 7 <1/<1 2
Escherichia coli
Fluoroquinolones 55 28/26 –
Third-generation/fourth-generation 67 16/22 –
cephalosporinsa
Carbapenemsb 4 0/0 –
Pseudomonas aeruginosa
Fluoroquinolones 46 40/42 30
Aminosides 28 28/34 –
Piperacillin and/or piperacillin–tazobactam 40 24/29 37
Antipseudomonal cephalosporins 37 32/37 35
c
Carbapenems 43 28/34 30
Acinetobacter baumannii
Carbapenemsc 66 42/54 67
Colistin – – 1

Data presented in the table are percentages. ANSRPSG, Asian Network for Surveillance of Resistant Pathogens Study Group; HAP, hospital-acquired pneumonia;
INICC, International Nosocomial Infection Control Consortium; VAP, ventilator-associated pneumonia.
a
Resistance to third-generation and fourth-generation cephalosporins in carbapenem-susceptible strains of Escherichia coli and Klebsiella pneumoniae is almost
exclusively because of the acquisition of plasmidic Ambler class A extended-spectrum b-lactamases (CTX-M, TEM and SHV) or AmpC-like cephalosporinases [56].
b
Carbapenems resistance in Enterobacteriaceae is almost exclusively because of acquired, plasmidic carbapenemases, either of Ambler class A (mainly KPC),
B (mainly VIM and IMP-type metallo-b-lactamases, with the recently described genotype NDM-1 spreading worldwide) or D (oxacillinases, mainly OXA-48) [57]. It
is noteworthy that plasmids harbouring ESBL-encoding and/or carbapenemase-encoding genes often carry other resistance genes (e.g. qnr for fluoroquinolones
resistance, or aminoglycosides modifying enzymes, including the AAC(60 )-1b-cr variant which also confers low level resistance to ciprofloxacin), thus conferring a
multidrug-resistant phenotype as the result of a single plasmid conjugation.
c
Carbapenem resistance in Pseudomonas aeruginosa and Acinetobacter baumannii may involve distinct mechanisms including impermeability (loss of outer
membrane porins), hyperexpression of efflux pomp systems, and carbapenemase production.

Studies on BALF concentrations of the soluble 16 (CC-16), soluble receptor for advanced glyca-
triggered receptor expressed on myeloid cells 1 tion end products (sRAGE) and surfactant protein
(sTREM-1) yielded conflicting results [83–86]. D (SP-D) is unclear [92]. Copeptin [93,94], midre-
C-reactive protein may lack sensitivity in ICU gional atrial natriuretic factor (MR-ANF) [95,96] and
patients [87,88]. The diagnostic values of BALF adrenomedullin [97] were evaluated as prognostic
concentrations of interleukin-1b, interleukin-8, rather than diagnostic biomarkers in pneumonia. To
granulocyte colony-stimulating factor and macro- date, the literature does not support a clinical role
phage inflammatory protein-1a could be discrimi- for these biomarkers, including procalcitonin (PCT),
native but require validation on larger cohorts [89], in predicting VAP. However, using serum PCT
as do BALF levels of plasminogen activation inhibi- concentration to customize antibiotic-treatment
tor 1 (PAI-1) [90]. By contrast, BALF levels of Clara duration in patients with VAP has been evaluated
cell protein 10 yield poor diagnostic accuracy [91]. in five studies, all showing less antibiotic consump-
The usefulness of plasma levels of Clara cell protein tion when a PCT-based algorithm was applied, with

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 HAP and VAP Barbier et al.

no detrimental impact on outcomes. Consequently, regimen (e.g. 25 mg/kg for amikacin). Empirical
in patients treated for a VAP whose serum PCT indications of polymyxins in patients at risk for
concentration is less than 0.5 ng/ml or decreased carbapenem-resistant GNB should be clarified in
by more than 80% (compared with the peak con- updated guidelines [107].
centration), antibiotic discontinuation may be con- Re-assessment is mandatory at day 2–3, both to
&&
sidered at day 3 after initiation [87,88,98,99,100 , correct inadequate regimens when appropriate and
101,102]. to avoid an overconsumption of broad-spectrum
Conventional bacteriological methods imply drugs [1,8–10]. Antimicrobials must be stopped
an incompressible delay of 48–72 h for complete when the diagnosis is not bacteriologically vali-
antimicrobial susceptibility testing of pneumonia- dated, except for particular situations [10]. When
causative pathogens. Therefore, the on-going pneumonia is confirmed, the antimicrobial spec-
development of rapid molecular methods raises trum must be narrowed whenever possible on the
comprehensible hopes for optimizing the choice basis of susceptibility testing. Monotherapy is con-
of initial drugs and avoiding the overprescription ceivable provided that the empirical regimen was
of very broad-spectrum molecules in this situation adequate, the patient’s condition improves and
[103]. Such tools should reliably identify both the the causative pathogens do not exhibit extensive
most common pathogens and their most frequent resistance patterns [10]. Even not validated in HAP/
resistance genotypes within a time ranging from 2 to VAP, retrocession to b-lactam/b-lactamase inhibitor
6 h. Real-time PCR, in-situ DNA hybridization and might be discussed for ESBL-producing enterobac-
mass spectrometry are currently the leading inves- teria with minimal inhibitory concentration (MIC)
tigation methods [104]. Several systems are already below the break-point values [108,109]. A control
commercialized for direct analysis of clinical sample should be obtained to assess bacterial load
samples such as blood cultures and swabs (most kinetics and detect precocious resistant mutants
notably for MRSA screening). However, and despite [10]. The 8-day standard duration of treatment
&&
promising preliminary results [103,104,105 ], no can be safely shortened by monitoring plasma
&&
system has been validated so far for direct appli- PCT levels [100 ]. Longer treatments may be dis-
cation on BALF or tracheal aspirates in suspected cussed in cases of immunosuppression, unfavour-
VAP/HAP. Oversensitivity and quantification of bac- able clinical response or extensively drug-resistant
terial loads may represent important issues. Indeed, pathogens [10].
genetic material from more than 15 distinct patho- Colistin appears as effective as other antimicro-
gens (including bacteria, virus and fungi) can be bial classes for VAP caused by MDR-GNB [110]. The
detected in BALF from ICU patients, most of them optimal dosing regimen of this concentration-
being not reliably considered as causative for the dependent antibiotic is still debated; however,
&
current pneumonia episode [106 ]. an intravenous loading dose of 9 million units
followed by 4.5 million units twice daily (with pro-
tocolized adaptation in case of renal failure) may be
ANTIMICROBIAL TREATMENT OF &&
an adequate scheme [111 ], in accordance with
HOSPITAL-ACQUIRED PNEUMONIA AND previous pharmacokinetic/pharmacodynamic data
VENTILATOR-ASSOCIATED PNEUMONIA [112], the median colistin dose being correlated
Delayed effective therapy increases hospital with clinical and microbiological success rates
mortality in HAP/VAP patients, making the choice [113]. The incidence of colistin-induced nephro-
of empirical drugs a crucial dilemma [1,6]. To toxicity is 18–43%, especially with a high-dosing
improve the likelihood of adequate coverage, regimen or when other nephrotoxic drugs are pre-
&&
current guidelines (Table 3) usually recommend scribed [111 ,113,114]. The nephroprotective effect
an antipseudomonal combination therapy except of ascorbic acid co-administration during colistin
for early-onset pneumonia with no risk factor therapy should be evaluated in clinical practice
for MDR bacteria [1,8–10]. Facing the epidemic of [115]. Experimental data suggest that inhaled coli-
ESBL-producing enterobacteria and other MDR- stin should be used as an adjunctive therapy to reach
GNB, antipseudomonal carbapenems (imipenem/ high lung concentrations [116], but available
cilastatin and meropenem) have become the most clinical evaluations yielded ambiguous results
empirically prescribed b-lactams in European ICU [117–120], and further RCTs are needed to clarify
for HAP/VAP [51]. Despite limited lung diffusion this issue. Other inhaled antimicrobials have been
[10], aminoglycosides should be preferred to fluo- tested in experimental or clinical VAP caused by
&
roquinolones, given the resistance frequencies in MDR-GNB, namely ceftazidime [121,122 ], imipe-
P. aeruginosa and the possibility to achieve bac- nem/cilastatin [123], amikacin [124] and tobramy-
tericidal lung concentrations with a high-dosing cin [118,125]. Nebulized ceftazidime/amikacin

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 Infectious diseases

combination does not improve the course of clinical pneumonia [146–149]. These recent results may be a
P. aeruginosa VAP when compared with intravenous first basis towards further clinical trials, notably for
&
administration [122 ]. difficult-to-treat MDR pathogens. Next, and despite
Both vancomycin and linezolid are recom- an inappropriate bacterial spectrum, macrolides
mended for the therapy of suspected or proven have immunomodulatory and anti-inflammatory
MRSA pneumonia [1,8–10]. In experimental effects that may be of interest in HAP/VAP [150].
models, linezolid is associated with faster bacterial A short course of clarithromycin may ease the cure
clearances and a lower histological severity of pneu- of otherwise adequately treated VAP and modulate
monia [126–128], with better pharmacokinetic/ the risk of death from septic shock or multiorgan
pharmacodynamic profiles [127] and a possible failure [151–152]. Macrolides also inhibit P. aerugi-
immunomodulatory effect [129]. However, previous nosa quorum sensing, but the clinical impact of this
meta-analysis did not demonstrate a superiority of property remains to be confirmed [153]. Finally, in a
linezolid in terms of clinical cure and bacteriological recent RCT, monoclonal antibodies targeting the
&&
eradication [130,131]. In a recent RCT [132 ], lin- type III secretion system, a major pseudomonal
ezolid was associated with a higher clinical success virulence factor in pneumonia [154], reduced the
rate and a lower incidence of renal impairment than incidence of VAP in patients with P. aeruginosa
vancomycin, but all-cause 60-day fatality rates were tracheal colonization [155]. Further evaluation of
similar in both groups. We believe that linezolid immunotherapy in HAP/VAP is warranted.
should be preferred to vancomycin when other risk
factors of acute kidney injury are present and for
HAP/VAP caused by MRSA strains with vancomycin CONCLUSION
MIC higher than 1 mg/l, a cut-off associated with An increasing burden of HAP/VAP may be expected
&
vancomycin therapy failure [133 ,134]. in the coming years, as a result of intensification of
New antibiotics that may complete the thera- care, progressive ageing and a growing prevalence of
peutic arsenal for HAP/VAP are scarce. Lipoglyco- severe underlying diseases in ICU patients. The cur-
peptides (i.e. dalbavancin, oritavancin and rent epidemiology of bacterial resistance is more
telavancin) are bactericidal for MRSA strains with alarming than ever. In this context, the imple-
high vancomycin MIC [135]. Telavancin is not mentation of preventive policies is of major import-
inferior to vancomycin for the treatment of MRSA ance [17]. Both diagnosis and treatment of HAP/VAP
pneumonia, but may be associated with an remain challenging and justify intensive research
increased incidence of acute kidney injury [136]. work for the development and validation of mole-
Ceftaroline [137,138] and ceftobiprole [139], two cular diagnostic tools, new drugs for MDR patho-
new-generation cephalosporins, and iclaprim gens, and nonantibiotic therapeutic options.
[140], a dihydrofolate reductase inhibitor, are also
active against MRSA. None of these drugs are cur- Acknowledgements
rently approved by the US Food and Drug Admin-
None.
istration (FDA) for the treatment of MRSA HAP/VAP.
Novel carbapenem-sparing molecules for the treat-
Conflicts of interest
ment of MDR-GNB include temocillin [141], a
F.B. received lecture fees from Novartis. M.W. received
6-hydroxymethyl-ticarcilline with activity against
fees for lectures and board participation from Gilead,
ESBL-producing and AmpC-producing enterobacte-
ria, and avibactam (formerly NXL104) [142–145], Astellas, Pfizer, Novartis, Roche and Cubist.
which restores the activity of various b-lactams (e.g.
ceftazidime) in isolates producing Ambler class A REFERENCES AND RECOMMENDED
(ESBL and KPC-type carbapenemase) and AmpC b- READING
lactamases (including P. aeruginosa); these two Papers of particular interest, published within the annual period of review, have
been highlighted as:
promising antibiotics remain to be evaluated in & of special interest
HAP/VAP. && of outstanding interest

Additional references related to this topic can also be found in the Current
World Literature section in this issue (pp. 321–322).

NEW THERAPEUTIC APPROACH FOR 1. American Thoracic Society–Infectious Diseases Society of America. Guide-
lines for the management of adults with hospital-acquired, ventilator-asso-
VENTILATOR-ASSOCIATED PNEUMONIA ciated, and healthcare-associated pneumonia. Am J Respir Crit Care Med
2005; 171:388–416.
Bacteriophages are viruses that infect bacteria in a 2. Anand N, Kollef MH. The alphabet soup of pneumonia: CAP, HAP, HCAP,
species-specific way. In animal studies, phage NHAP, and VAP. Semin Respir Crit Care Med 2009; 30:3–9.
3. Agrafiotis M, Siempos II, Ntaidou TK, Falagas ME. Attributable mortality of
therapy can both prevent and cure P. aeruginosa, ventilator-associated pneumonia: a meta-analysis. Int J Tuberc Lung Dis
Klebsiella pneumoniae and Streptococcus pneumoniae 2011; 15:1154–1163.

224 www.co-pulmonarymedicine.com Volume 19
Number 3
May 2013

Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
 HAP and VAP Barbier et al.

4. Melsen WG, Rovers MM, Koeman M, Bonten MJ. Estimating the attributable 27. Poelaert J, Depuydt P, De Wolf A, et al. Polyurethane cuffed endotracheal
mortality of ventilator-associated pneumonia from randomized prevention tubes to prevent early postoperative pneumonia after cardiac surgery: a pilot
studies. Crit Care Med 2011; 39:2736–2742. study. J Thorac Cardiovasc Surg 2008; 135:771–776.
5. Timsit JF, Zahar JR, Chevret S. Attributable mortality of ventilator-associated 28. Valencia M, Ferrer M, Farre R, et al. Automatic control of tracheal tube cuff
& pneumonia. Curr Opin Crit Care 2011; 17:464–471. pressure in ventilated patients in semirecumbent position: a randomized trial.
At the ICU scale, this study estimates that VAP accounts for 1% of all deaths Crit Care Med 2007; 35:1543–1549.
when the overall mortality is 23% at day 30. 29. Nseir S, Zerimech F, Fournier C, et al. Continuous control of tracheal cuff
6. Chastre J, Fagon JY. Ventilator-associated pneumonia. Am J Respir Crit Care pressure and microaspiration of gastric contents in critically ill patients. Am J
Med 2002; 165:867–903. Respir Crit Care Med 2011; 184:1041–1047.
7. Kollef MH, Hamilton CW, Ernst FR. Economic impact of ventilator-associated 30. Drakulovic MB, Torres A, Bauer TT, et al. Supine body position as a risk factor
& pneumonia in a large matched cohort. Infect Control Hosp Epidemiol 2012; for nosocomial pneumonia in mechanically ventilated patients: a randomised
33:250–256. trial. Lancet 1999; 354:1851–1858.
This recent matched case–control study from a large US database confirmed that 31. van Nieuwenhoven CA, Vandenbroucke-Grauls C, van Tiel FH, et al.
patients with VAP (n ¼ 2238; VAP incidence ¼ 1.3 episode per 1000 ventilator- Feasibility and effects of the semirecumbent position to prevent ventilator-
days) had significantly longer durations of mechanical ventilation (21.8 versus associated pneumonia: a randomized study. Crit Care Med 2006; 34:396–
10.3 days), ICU stay (20.5 versus 11.6 days) and hospitalization (32.6 versus 402.
19.5 days) than patients without VAP. 32. Abroug F, Ouanes-Besbes L, Elatrous S, Brochard L. The effect of prone
8. Masterton RG, Galloway A, French G, et al. Guidelines for the management positioning in acute respiratory distress syndrome or acute lung injury: a
of hospital-acquired pneumonia in the UK: report of the working party meta-analysis. Areas of uncertainty and recommendations for research.
on hospital-acquired pneumonia of the British Society for Antimicrobial Intensive Care Med 2008; 34:1002–1011.
Chemotherapy. J Antimicrob Chemother 2008; 62:5–34. 33. Delaney A, Gray H, Laupland KB, Zuege DJ. Kinetic bed therapy to prevent
9. Rotstein C, Evans G, Born A, et al. Clinical practice guidelines for hospital- nosocomial pneumonia in mechanically ventilated patients: a systematic
acquired pneumonia and ventilator-associated pneumonia in adults. Can J review and meta-analysis. Crit Care 2006; 10:R70.
Infect Dis Med Microbiol 2008; 19:19–53. 34. Manzano F, Fernandez-Mondejar E, Colmenero M, et al. Positive-end
10. Torres A, Ewig S, Lode H, Carlet J. Defining, treating and preventing hospital- expiratory pressure reduces incidence of ventilator-associated pneumonia
acquired pneumonia: European perspective. Intensive Care Med 2009; in nonhypoxemic patients. Crit Care Med 2008; 36:2225–2231.
35:9–29. 35. Ntoumenopoulos G, Gild A, Cooper DJ. The effect of manual lung hyperin-
11. Chawla R. Epidemiology, etiology, and diagnosis of hospital-acquired pneu- flation and postural drainage on pulmonary complications in mechanically
monia and ventilator-associated pneumonia in Asian countries. Am J Infect ventilated trauma patients. Anaesth Intensive Care 1998; 26:492–496.
Control 2008; 36:S93–S100. 36. Ntoumenopoulos G, Presneill JJ, McElholum M, Cade JF. Chest physiother-
12. Vincent JL, Rello J, Marshall J, et al. International study of the prevalence and apy for the prevention of ventilator-associated pneumonia. Intensive Care
outcomes of infection in intensive care units. JAMA 2009; 302:2323–2329. Med 2002; 28:850–856.
13. Forel JM, Voillet F, Pulina D, et al. Ventilator-associated pneumonia and ICU 37. Templeton M, Palazzo MG. Chest physiotherapy prolongs duration of venti-
& mortality in severe ARDS patients ventilated according to a lung-protective lation in the critically ill ventilated for more than 48 h. Intensive Care Med
strategy. Crit Care 2012; 16:R65. 2007; 33:1938–1945.
In this recent RCT including 339 patients with severe ARDS, the overall prevalence 38. Patman S, Jenkins S, Stiller K. Physiotherapy does not prevent, or hasten
of VAP was 29%, with a cumulative incidence of 40% after 10 days of recovery from, ventilator-associated pneumonia in patients with acquired
mechanical ventilation. In contrast to older studies, no significant association brain injury. Intensive Care Med 2009; 35:258–265.
between neuromuscular blockades agents use and the risk of VAP was observed 39. Labeau SO, Van de Vyver K, Brusselaers N, et al. Prevention of ventilator-
in this study. associated pneumonia with oral antiseptics: a systematic review and meta-
14. Rosenthal VD, Bijie H, Maki DG, et al. International Nosocomial Infection analysis. Lancet Infect Dis 2011; 11:845–854.
&& Control Consortium (INICC) report, data summary of 36 countries, for 40. Morrow LE, Kollef MH, Casale TB. Probiotic prophylaxis of ventilator-
2004–2009. Am J Infect Control 2012; 40:396–407. associated pneumonia: a blinded, randomized, controlled trial. Am J Respir
In this article, the International Nosocomial Infection Control Consortium (INICC) Crit Care Med 2010; 182:1058–1064.
reports a pooled mean VAP incidence of 15.8 episodes for 1000 ventilator-days in 41. Kollef M, Pittet D, Sanchez Garcia M, et al. A randomized double-blind trial of
386 ICUs of 36 countries on the 2004–2009 period. This incidence was lower iseganan in prevention of ventilator-associated pneumonia. Am J Respir Crit
than the 24 episodes per 1000 ventilator-days incidence reported by the same Care Med 2006; 173:91–97.
network between 2002 and 2005, an evolution that probably reflects the advances 42. Siempos II, Ntaidou TK, Falagas ME. Impact of the administration of probio-
made in prevention policies during the latest period. tics on the incidence of ventilator-associated pneumonia: a meta-analysis of
15. Lee GM, Kleinman K, Soumerai SB, et al. Effect of nonpayment for randomized controlled trials. Crit Care Med 2010; 38:954–962.
preventable infections in U.S. hospitals. N Engl J Med 2012; 367:1428– 43. Mounier R, Adrie C, Francais A, et al. Study of prone positioning to reduce
1437. ventilator-associated pneumonia in hypoxaemic patients. Eur Respir J 2010;
16. Cook DJ, Walter SD, Cook RJ, et al. Incidence of and risk factors for 35:795–804.
ventilator-associated pneumonia in critically ill patients. Ann Intern Med 44. Trouillet JL, Luyt CE, Guiguet M, et al. Early percutaneous tracheotomy
1998; 129:433–440. & versus prolonged intubation of mechanically ventilated patients after cardiac
17. Bouadma L, Wolff M, Lucet JC. Ventilator-associated pneumonia and its surgery: a randomized trial. Ann Intern Med 2011; 154:373–383.
prevention. Curr Opin Infect Dis 2012; 25:395–404. This recent RCT compared immediate versus late (after day 15 from randomiza-
18. Hess DR. Noninvasive positive-pressure ventilation and ventilator-associated tion) tracheostomy in 216 cardiac surgery patients still ventilated 4 days after the
pneumonia. Respir Care 2005; 50:924–929. surgical procedure: the prevalence of VAP was similar in both groups (46 versus
19. Marelich GP, Murin S, Battistella F, et al. Protocol weaning of mechanical 44%, respectively, P ¼ 0.77).
ventilation in medical and surgical patients by respiratory care practitioners 45. Terragni PP, Antonelli M, Fumagalli R, et al. Early vs late tracheotomy for
and nurses: effect on weaning time and incidence of ventilator-associated prevention of pneumonia in mechanically ventilated adult ICU patients: a
pneumonia. Chest 2000; 118:459–467. randomized controlled trial. JAMA 2010; 303:1483–1489.
20. Lellouche F, Mancebo J, Jolliet P, et al. A multicenter randomized trial of 46. Asehnoune K, Mahe PJ, Seguin P, et al. Etomidate increases susceptibility to
computer-driven protocolized weaning from mechanical ventilation. Am J pneumonia in trauma patients. Intensive Care Med 2012; 38:1673–1682.
Respir Crit Care Med 2006; 174:894–900. 47. Faisy C, Candela Llerena M, Savalle M, et al. Early ICU energy deficit is a risk
21. Kress JP, Pohlman AS, O’Connor MF, Hall JB. Daily interruption of sedative factor for Staphylococcus aureus ventilator-associated pneumonia. Chest
infusions in critically ill patients undergoing mechanical ventilation. N Engl J 2011; 140:1254–1260.
Med 2000; 342:1471–1477. 48. Roquilly A, Mahe PJ, Seguin P, et al. Hydrocortisone therapy for patients with
22. Wang F, Wu Y, Bo L, et al. The timing of tracheotomy in critically ill patients multiple trauma: the randomized controlled HYPOLYTE study. JAMA 2011;
undergoing mechanical ventilation: a systematic review and meta-analysis of 305:1201–1209.
randomized controlled trials. Chest 2011; 140:1456–1465. 49. Makris D, Manoulakas E, Komnos A, et al. Effect of pravastatin on the
23. Kollef MH, Afessa B, Anzueto A, et al. Silver-coated endotracheal tubes and frequency of ventilator-associated pneumonia and on intensive care unit
incidence of ventilator-associated pneumonia: the NASCENT randomized mortality: open-label, randomized study. Crit Care Med 2011; 39:2440–
trial. JAMA 2008; 300:805–813. 2446.
24. Caruso P, Denari S, Ruiz SA, et al. Saline instillation before tracheal 50. Chung DR, Song JH, Kim SH, et al. High prevalence of multidrug-resistant
suctioning decreases the incidence of ventilator-associated pneumonia. Crit nonfermenters in hospital-acquired pneumonia in Asia. Am J Respir Crit Care
Care Med 2009; 37:32–38. Med 2011; 184:1409–1417.
25. Muscedere J, Rewa O, McKechnie K, et al. Subglottic secretion drainage for 51. Rello J, Ulldemolins M, Lisboa T, et al. Determinants of prescription and
the prevention of ventilator-associated pneumonia: a systematic review and choice of empirical therapy for hospital-acquired and ventilator-associated
meta-analysis. Crit Care Med 2011; 39:1985–1991. pneumonia. Eur Respir J 2011; 37:1332–1339.
26. Lorente L, Lecuona M, Jimenez A, et al. Influence of an endotracheal tube with 52. Iwashyna TJ, Ely EW, Smith DM, Langa KM. Long-term cognitive impairment
polyurethane cuff and subglottic secretion drainage on pneumonia. Am J and functional disability among survivors of severe sepsis. JAMA 2010;
Respir Crit Care Med 2007; 176:1079–1083. 304:1787–1794.

1070-5287 ß 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins www.co-pulmonarymedicine.com 225

Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
 Infectious diseases

53. Ferrer M, Liapikou A, Valencia M, et al. Validation of the American Thoracic 79. Wood GC, Mueller EW, Croce MA, et al. Candida sp. isolated from
Society–Infectious Diseases Society of America guidelines for hospital- bronchoalveolar lavage: clinical significance in critically ill trauma patients.
acquired pneumonia in the intensive care unit. Clin Infect Dis 2010; 50: Intensive Care Med 2006; 32:599–603.
945–952. 80. Blot SI, Taccone FS, Van den Abeele AM, et al. A clinical algorithm to
54. Jones RN. Microbial etiologies of hospital-acquired bacterial pneumonia & diagnose invasive pulmonary aspergillosis in critically ill patients. Am J Respir
and ventilator-associated bacterial pneumonia. Clin Infect Dis 2010; 51 Crit Care Med 2012; 186:56–64.
(Suppl 1):S81–S87. The authors of this multicentric observational study propose and validate a clinical
55. Hyllienmark P, Martling CR, Struwe J, Petersson J. Pathogens in the lower algorithm to distingusih colonization from invasive pulmonary aspergillosis in
& respiratory tract of intensive care unit patients: impact of duration of hospital mechanically ventilated patients without usual criteria for immune deficiency.
care and mechanical ventilation. Scand J Infect Dis 2012; 44:444–452. 81. Blasi F, Bocchino M, Di Marco F, et al. The role of biomarkers in low
This retrospective, monocentric study reports the distribution of bacterial isolates respiratory tract infections. Eur J Intern Med 2012; 23:429–435.
from tracheal aspirates in 346 mechanically ventilated patients acocording to the 82. Fagon JY. Biological markers and diagnosis of ventilator-associated pneu-
duration of mechanical ventilation. The prevalence of cefotaxime-resistant patho- monia. Crit Care 2011; 15:130.
gen was as high as 23% upon day 1 of mechanical ventilation. 83. Anand NJ, Zuick S, Klesney-Tait J, Kollef MH. Diagnostic implications of
56. Hawkey PM, Jones AM. The changing epidemiology of resistance. J Anti- soluble triggering receptor expressed on myeloid cells-1 in BAL fluid of
microb Chemother 2009; 64 (Suppl 1):i3–i10. patients with pulmonary infiltrates in the ICU. Chest 2009; 135:641–647.
57. Nordmann P, Naas T, Poirel L. Global spread of carbapenemase-producing 84. Gibot S, Cravoisy A, Levy B, et al. Soluble triggering receptor expressed on
Enterobacteriaceae. Emerg Infect Dis 2011; 17:1791–1798. myeloid cells and the diagnosis of pneumonia. N Engl J Med 2004;
58. Morales G, Picazo JJ, Baos E, et al. Resistance to linezolid is mediated by the 350:451–458.
cfr gene in the first report of an outbreak of linezolid-resistant Staphylococcus 85. Oudhuis GJ, Beuving J, Bergmans D, et al. Soluble triggering receptor
aureus. Clin Infect Dis 2010; 50:821–825. expressed on myeloid cells-1 in bronchoalveolar lavage fluid is not predictive
59. Sanchez Garcia M, De la Torre MA, Morales G, et al. Clinical outbreak of for ventilator-associated pneumonia. Intensive Care Med 2009; 35:1265–
linezolid-resistant Staphylococcus aureus in an intensive care unit. JAMA 1270.
2010; 303:2260–2264. 86. Palazzo SJ, Simpson TA, Simmons JM, Schnapp LM. sTREM-1 as a diag-
60. Jacoby GA. AmpC beta-lactamases. Clin Microbiol Rev 2009; 22:161–182. nostic marker of ventilator-associated pneumonia. Respir Care 2012; 57:
61. Livermore DM. Has the era of untreatable infections arrived? J Antimicrob 2052–2058.
Chemother 2009; 64 (Suppl 1):i29–i36. 87. Palazzo SJ, Simpson T, Schnapp L. Biomarkers for ventilator-associated
62. Zagorianou A, Sianou E, Iosifidis E, et al. Microbiological and molecular pneumonia: review of the literature. Heart Lung 2011; 40:293–298.
&& characteristics of carbapenemase-producing Klebsiella pneumoniae 88. Ramirez P, Garcia MA, Ferrer M, et al. Sequential measurements of procal-
endemic in a tertiary Greek hospital during 2004-2010. Euro Surveill citonin levels in diagnosing ventilator-associated pneumonia. Eur Respir J
2012; 17. 2008; 31:356–362.
This recent study conducted in a single Greek ICU reported that colistin resistance 89. Conway Morris A, Kefala K, Wilkinson TS, et al. Diagnostic importance of
increased from 3.5 to 20.8% in carbapenemase-producing (KPC and/or VIM) K. pulmonary interleukin-1beta and interleukin-8 in ventilator-associated pneu-
pneumoniae strains between 2004 and 2010, as a likely result of increasing monia. Thorax 2010; 65:201–207.
colistin consumption. 90. Srinivasan R, Song Y, Wiener-Kronish J, Flori HR. Plasminogen activation
63. Bogdanovich T, Adams-Haduch JM, Tian GB, et al. Colistin-resistant, inhibitor concentrations in bronchoalveolar lavage fluid distinguishes venti-
Klebsiella pneumoniae carbapenemase (KPC)-producing Klebsiella pneu- lator-associated pneumonia from colonization in mechanically ventilated
moniae belonging to the international epidemic clone ST258. Clin Infect Dis pediatric patients. Pediatr Crit Care Med 2011; 12:21–27.
2011; 53:373–376. 91. Vanspauwen MJ, Linssen CF, Bruggeman CA, et al. Clara cell protein in
64. Antoniadou A, Kontopidou F, Poulakou G, et al. Colistin-resistant isolates of bronchoalveolar lavage fluid: a predictor of ventilator-associated pneumo-
Klebsiella pneumoniae emerging in intensive care unit patients: first report of nia? Crit Care 2011; 15:R14.
a multiclonal cluster. J Antimicrob Chemother 2007; 59:786–790. 92. Determann RM, Millo JL, Waddy S, et al. Plasma CC16 levels are associated
65. Lopez-Giraldo A, Sialer S, Esperatti M, Torres A. Viral-reactivated pneumonia with development of ALI/ARDS in patients with ventilator-associated pneu-
during mechanical ventilation: is there need for antiviral treatment? Front monia: a retrospective observational study. BMC Pulm Med 2009; 9:49.
Pharmacol 2011; 2:66. 93. Boeck L, Eggimann P, Smyrnios N, et al. The Sequential Organ Failure
66. De Vos N, Van Hoovels L, Vankeerberghen A, et al. Monitoring of herpes Assessment score and copeptin for predicting survival in ventilator-asso-
simplex virus in the lower respiratory tract of critically ill patients using real- ciated pneumonia. J Crit Care 2012; 27:523e.1–523e.9.
time PCR: a prospective study. Clin Microbiol Infect 2009; 15:358–363. 94. Seligman R, Papassotiriou J, Morgenthaler NG, et al. Copeptin, a novel
67. Linssen CF, Jacobs JA, Stelma FF, et al. Herpes simplex virus load in prognostic biomarker in ventilator-associated pneumonia. Crit Care 2008;
bronchoalveolar lavage fluid is related to poor outcome in critically ill patients. 12:R11.
Intensive Care Med 2008; 34:2202–2209. 95. Boeck L, Eggimann P, Smyrnios N, et al. Midregional pro-atrial natriuretic
68. Luyt CE, Combes A, Deback C, et al. Herpes simplex virus lung infection in peptide and procalcitonin improve survival prediction in VAP. Eur Respir J
patients undergoing prolonged mechanical ventilation. Am J Respir Crit Care 2011; 37:595–603.
Med 2007; 175:935–942. 96. Seligman R, Papassotiriou J, Morgenthaler NG, et al. Prognostic value of
69. Limaye AP, Kirby KA, Rubenfeld GD, et al. Cytomegalovirus reactivation in midregional pro-atrial natriuretic peptide in ventilator-associated pneumonia.
critically ill immunocompetent patients. JAMA 2008; 300:413–422. Intensive Care Med 2008; 34:2084–2091.
70. Papazian L, Doddoli C, Chetaille B, et al. A contributive result of open-lung 97. Bello S, Lasierra AB, Minchole E, et al. Prognostic power of proadrenome-
biopsy improves survival in acute respiratory distress syndrome patients. Crit dullin in community-acquired pneumonia is independent of aetiology. Eur
Care Med 2007; 35:755–762. Respir J 2012; 39:1144–1155.
71. Vincent A, La Scola B, Forel JM, et al. Clinical significance of a positive 98. Bloos F, Marshall JC, Dellinger RP, et al. Multinational, observational study of
serology for mimivirus in patients presenting a suspicion of ventilator-asso- procalcitonin in ICU patients with pneumonia requiring mechanical ventila-
ciated pneumonia. Crit Care Med 2009; 37:111–118. tion: a multicenter observational study. Crit Care 2011; 15:R88.
72. Costa C, Bergallo M, Astegiano S, et al. Detection of mimivirus in bronch- 99. Bouadma L, Luyt CE, Tubach F, et al. Use of procalcitonin to reduce patients’
oalveolar lavage of ventilated and nonventilated patients. Intervirology 2012; exposure to antibiotics in intensive care units (PRORATA trial): a multicentre
55:303–305. randomised controlled trial. Lancet 2010; 375:463–474.
73. Dare RK, Chittaganpitch M, Erdman DD. Screening pneumonia patients for 100. Schuetz P, Briel M, Christ-Crain M, et al. Procalcitonin to guide initiation and
mimivirus. Emerg Infect Dis 2008; 14:465–467. && duration of antibiotic treatment in acute respiratory infections: an individual

74. Azoulay E, Timsit JF, Tafflet M, et al. Candida colonization of the respiratory patient data meta-analysis. Clin Infect Dis 2012; 55:651–662.
tract and subsequent pseudomonas ventilator-associated pneumonia. Chest This meta-analysis pooled 4221 adult patients with respiratory tract infections from
2006; 129:110–117. 14 clinical trials (including 242 patients with VAP and 79 with other HAP) and
75. Delisle MS, Williamson DR, Perreault MM, et al. The clinical significance of confirmed that PCT was a reliable and safe tool for guiding the duration of antibiotic
Candida colonization of respiratory tract secretions in critically ill patients. therapy in patients with confirmed pneumonia. A significant 2.2-day reduction of
J Crit Care 2008; 23:11–17. antibiotic exposure was allowed in VAP patients with PCT-guided therapy, which is
76. Williamson DR, Albert M, Perreault MM, et al. The relationship between of crucial importance in light of the current epidemiology of bacterial resistance.
Candida species cultured from the respiratory tract and systemic inflamma- 101. Stolz D, Smyrnios N, Eggimann P, et al. Procalcitonin for reduced antibiotic
tion in critically ill patients with ventilator-associated pneumonia. Can J exposure in ventilator-associated pneumonia: a randomised study. Eur
Anaesth 2011; 58:275–284. Respir J 2009; 34:1364–1375.
77. Hamet M, Pavon A, Dalle F, et al. Candida spp. airway colonization could 102. Wolff M, Bouadma L. What procalcitonin brings to management of sepsis in
promote antibiotic-resistant bacteria selection in patients with suspected the ICU. Crit Care 2010; 14:1007.
ventilator-associated pneumonia. Intensive Care Med 2012; 38:1272– 103. Endimiani A, Hujer KM, Hujer AM, et al. Are we ready for novel detection
1279. methods to treat respiratory pathogens in hospital-acquired pneumonia? Clin
78. Meersseman W, Lagrou K, Spriet I, et al. Significance of the isolation of Infect Dis 2011; 52 (Suppl 4):S373–S383.
Candida species from airway samples in critically ill patients: a prospective, 104. Lung M, Codina G. Molecular diagnosis in HAP/VAP. Curr Opin Crit Care
autopsy study. Intensive Care Med 2009; 35:1526–1531. 2012; 18:487–494.

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 HAP and VAP Barbier et al.

105. Bogaerts P, Hamels S, de Mendonca R, et al. Analytical validation of a 124. Niederman MS, Chastre J, Corkery K, et al. BAY41-6551 achieves bacter-
&& novel high multiplexing real-time PCR array for the identification of key icidal tracheal aspirate amikacin concentrations in mechanically ventilated
pathogens causative of bacterial ventilator-associated pneumonia and patients with Gram-negative pneumonia. Intensive Care Med 2012; 38:
their associated resistance genes. J Antimicrob Chemother 2012; 68: 263–271.
340–347. 125. Hallal A, Cohn SM, Namias N, et al. Aerosolized tobramycin in the treatment
This novel closed-cartridge kit combining multiplex PCR with real-time microarray of ventilator-associated pneumonia: a pilot study. Surg Infect (Larchmt)
detection has recently shown promising results for the detection of 13 major 2007; 8:73–82.
VAP-causative pathogens and 24 relevant b-lactam resistance genes (including 126. Luna CM, Bruno DA, Garcia-Morato J, et al. Effect of linezolid compared with
ESBL and carbapenemases) on a collection of reference strains and clinical glycopeptides in methicillin-resistant Staphylococcus aureus severe pneu-
isolates. monia in piglets. Chest 2009; 135:1564–1571.
106. Bousbia S, Papazian L, Saux P, et al. Repertoire of intensive care unit 127. Martinez-Olondris P, Rigol M, Soy D, et al. Efficacy of linezolid compared to
& pneumonia microbiota. PLoS One 2012; 7:e32486. vancomycin in an experimental model of pneumonia induced by methicillin-
This recent study combining rDNA sequencing and pathogen-targeted PCRs on resistant Staphylococcus aureus in ventilated pigs. Crit Care Med 2012;
BALF of ICU patients revealed that up to 16 distinct pathogens could be identified 40:162–168.
in a single specimen (including bacteria, virus and fungi), most of them being not 128. Docobo-Perez F, Lopez-Rojas R, Dominguez-Herrera J, et al. Efficacy of
reliably considered as causative for the current pneumonia episode. In this work, linezolid versus a pharmacodynamically optimized vancomycin therapy in an
the number of bacterial species by positive sample was even higher in control experimental pneumonia model caused by methicillin-resistant Staphylococ-
patients (4.61  2.95) than in those with confirmed VAP (3.49  2.87) or non- cus aureus. J Antimicrob Chemother 2012; 67:1961–1967.
ventilator in-ICU HAP (3.43  2.22). 129. Yoshizawa S, Tateda K, Saga T, et al. Virulence-suppressing effects of
107. Falagas ME, Rafailidis PI. When to include polymyxins in the empirical linezolid on methicillin-resistant Staphylococcus aureus: possible contribu-
antibiotic regimen in critically ill patients with fever? A decision analysis tion to early defervescence. Antimicrob Agents Chemother 2012; 56:1744–
approach. Shock 2007; 27:605–609. 1748.
108. Leclercq R, Canton R, Brown DF, et al. EUCAST expert rules in antimicrobial 130. Beibei L, Yun C, Mengli C, et al. Linezolid versus vancomycin for the
susceptibility testing. Clin Microbiol Infect 2013; 19:141–160. treatment of Gram-positive bacterial infections: meta-analysis of randomised
109. Rodriguez-Bano J, Navarro MD, Retamar P, et al. beta-Lactam/beta-lactam controlled trials. Int J Antimicrob Agents 2010; 35:3–12.
inhibitor combinations for the treatment of bacteremia due to extended- 131. Kalil AC, Murthy MH, Hermsen ED, et al. Linezolid versus vancomycin or
spectrum beta-lactamase-producing Escherichia coli: a post hoc analysis of teicoplanin for nosocomial pneumonia: a systematic review and meta-ana-
prospective cohorts. Clin Infect Dis 2012; 54:167–174. lysis. Crit Care Med 2010; 38:1802–1808.
110. Florescu DF, Qiu F, McCartan MA, et al. What is the efficacy and safety of 132. Wunderink RG, Niederman MS, Kollef MH, et al. Linezolid in methicillin-
colistin for the treatment of ventilator-associated pneumonia? A systematic && resistant Staphylococcus aureus nosocomial pneumonia: a randomized,

review and meta-regression. Clin Infect Dis 2012; 54:670–680. controlled study. Clin Infect Dis 2012; 54:621–629.
111. Dalfino L, Puntillo F, Mosca A, et al. High-dose, extended-interval colistin In the ZEPHYR RCT, per-protocol analysis showed that linezolid (n ¼ 172) was
&& administration in critically ill patients: is this the right dosing strategy? associated with a higher clinical success rate than vancomycin (n ¼ 176) in proven
A preliminary study. Clin Infect Dis 2012; 54:1720–1726. MRSA pneumonia at end-of-study evaluation (58 versus 47%, P ¼ 0.042). How-
One of the most exciting recent articles on the use of high-dose colistin regimen in ever, all-cause 60-day fatality rates (16 versus 17%, respectively) and the overall
ICU-acquired infections because of MDR pathogens, including VAP. incidence of adverse effects were similar in both groups, even if renal impairment
112. Plachouras D, Karvanen M, Friberg LE, et al. Population pharmacokinetic was more frequent with vancomycin (8 versus 18%, respectively).
analysis of colistin methanesulfonate and colistin after intravenous adminis- 133. Choi EY, Huh JW, Lim CM, et al. Relationship between the MIC of vanco-
tration in critically ill patients with infections caused by Gram-negative & mycin and clinical outcome in patients with MRSA nosocomial pneumonia.
bacteria. Antimicrob Agents Chemother 2009; 53:3430–3436. Intensive Care Med 2011; 37:639–647.
113. Vicari G, Bauer SR, Neuner EA, Lam SW. Association between colistin dose In this retrospective study including 70 patients with MRSA HAP, about half of the
and microbiologic outcomes in patients with multidrug resistant Gram- MRSA isolates had vancomycin MIC  1.5 mg/l. Patients infected with these
negative bacteremia. Clin Infect Dis 2013; 56:398–404. strains showed slower clinical response and higher relapse rate than patients
114. Pogue JM, Lee J, Marchaim D, et al. Incidence of and risk factors for colistin- infected with low vancomycin MIC isolates.
associated nephrotoxicity in a large academic health system. Clin Infect Dis 134. Haque NZ, Zuniga LC, Peyrani P, et al. Relationship of vancomycin minimum
2011; 53:879–884. inhibitory concentration to mortality in patients with methicillin-resistant
115. Yousef JM, Chen G, Hill PA, et al. Ascorbic acid protects against the Staphylococcus aureus hospital-acquired, ventilator-associated, or health-
nephrotoxicity and apoptosis caused by colistin and affects its pharmaco- care-associated pneumonia. Chest 2010; 138:1356–1362.
kinetics. J Antimicrob Chemother 2012; 67:452–459. 135. Zhanel GG, Calic D, Schweizer F, et al. New lipoglycopeptides: a compara-
116. Lu Q, Girardi C, Zhang M, et al. Nebulized and intravenous colistin in tive review of dalbavancin, oritavancin and telavancin. Drugs 2010; 70:859–
experimental pneumonia caused by Pseudomonas aeruginosa. Intensive 886.
Care Med 2010; 36:1147–1155. 136. Rubinstein E, Lalani T, Corey GR, et al. Telavancin versus vancomycin for
117. Korbila IP, Michalopoulos A, Rafailidis PI, et al. Inhaled colistin as adjunctive hospital-acquired pneumonia due to Gram-positive pathogens. Clin Infect
therapy to intravenous colistin for the treatment of microbiologically docu- Dis 2011; 52:31–40.
mented ventilator-associated pneumonia: a comparative cohort study. Clin 137. Farrell DJ, Castanheira M, Mendes RE, et al. In vitro activity of ceftaroline
Microbiol Infect 2010; 16:1230–1236. against multidrug-resistant Staphylococcus aureus and Streptococcus
118. Arnold HM, Sawyer AM, Kollef MH. Use of adjunctive aerosolized antimi- pneumoniae: a review of published studies and the AWARE Surveillance
crobial therapy in the treatment of Pseudomonas aeruginosa and Acineto- Program (2008–2010). Clin Infect Dis 2012; 55 (Suppl 3):S206–
bacter baumannii ventilator-associated pneumonia. Respir Care 2012; S214.
57:1226–1233. 138. File TM Jr, Wilcox MH, Stein GE. Summary of ceftaroline fosamil clinical trial
119. Rattanaumpawan P, Lorsutthitham J, Ungprasert P, et al. Randomized studies and clinical safety. Clin Infect Dis 2012; 55 (Suppl 3):S173–S180.
controlled trial of nebulized colistimethate sodium as adjunctive therapy of 139. Widmer AF. Ceftobiprole: a new option for treatment of skin and soft-tissue
ventilator-associated pneumonia caused by Gram-negative bacteria. J Anti- infections due to methicillin-resistant Staphylococcus aureus. Clin Infect Dis
microb Chemother 2010; 65:2645–2649. 2008; 46:656–658.
120. Lu Q, Luo R, Bodin L, et al. Efficacy of high-dose nebulized colistin in 140. Krievins D, Brandt R, Hawser S, et al. Multicenter, randomized study of the
ventilator-associated pneumonia caused by multidrug-resistant Pseudomo- efficacy and safety of intravenous iclaprim in complicated skin and skin
nas aeruginosa and Acinetobacter baumannii. Anesthesiology 2012; structure infections. Antimicrob Agents Chemother 2009; 53:2834–
117:1335–1347. 2840.
121. Ferrari F, Lu Q, Girardi C, et al. Nebulized ceftazidime in experimental 141. Balakrishnan I, Awad-El-Kariem FM, Aali A, et al. Temocillin use in England:
pneumonia caused by partially resistant Pseudomonas aeruginosa. Intensive clinical and microbiological efficacies in infections caused by extended-
Care Med 2009; 35:1792–1800. spectrum and/or derepressed AmpC beta-lactamase-producing Enterobac-
122. Lu Q, Yang J, Liu Z, et al. Nebulized ceftazidime and amikacin in ventilator- teriaceae. J Antimicrob Chemother 2011; 66:2628–2631.
& associated pneumonia caused by Pseudomonas aeruginosa. Am J Respir 142. Ehmann DE, Jahic H, Ross PL, et al. Avibactam is a covalent, reversible,
Crit Care Med 2011; 184:106–115. nonbeta-lactam beta-lactamase inhibitor. Proc Natl Acad Sci U S A 2012;
This RCT compared nebulized ceftazidime plus amikacin therapy (n ¼ 20) versus 109:11663–11668.
intravenous administration of these drugs (n ¼ 17) in VAP caused by P. aerugi- 143. Walkty A, DeCorby M, Lagace-Wiens PR, et al. In vitro activity of ceftazidime
nosa: no statistical difference was observed in terms of treatment success combined with NXL104 versus Pseudomonas aeruginosa isolates obtained
(70 versus 55%, respectively), superinfections or antibiotic-induced changes in from patients in Canadian hospitals (CANWARD 2009 study). Antimicrob
lung aeration as measured by computed tomography. However, emergence of Agents Chemother 2011; 55:2992–2994.
resistance under therapy was exclusively observed in patients receiving intra- 144. Castanheira M, Sader HS, Farrell DJ, et al. Activity of ceftaroline-avibactam
venous antibiotics. tested against Gram-negative organism populations, including strains
123. Radhakrishnan M, Jaganath A, Rao GS, Kumari HB. Nebulized imipenem to expressing one or more beta-lactamases and methicillin-resistant Staphylo-
control nosocomial pneumonia caused by Pseudomonas aeruginosa. J Crit coccus aureus carrying various staphylococcal cassette chromosome mec
Care 2008; 23:148–150. types. Antimicrob Agents Chemother 2012; 56:4779–4785.

1070-5287 ß 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins www.co-pulmonarymedicine.com 227

Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
 Infectious diseases

145. Lagace-Wiens PR, Tailor F, Simner P, et al. Activity of NXL104 in combina- 151. Giamarellos-Bourboulis EJ, Pechere JC, Routsi C, et al. Effect of clarithro-
tion with beta-lactams against genetically characterized Escherichia coli and mycin in patients with sepsis and ventilator-associated pneumonia. Clin
Klebsiella pneumoniae isolates producing class A extended-spectrum beta- Infect Dis 2008; 46:1157–1164.
lactamases and class C beta-lactamases. Antimicrob Agents Chemother 152. Spyridaki A, Raftogiannis M, Antonopoulou A, et al. Effect of clarithromycin in
2011; 55:2434–2437. inflammatory markers of patients with ventilator-associated pneumonia and
146. Debarbieux L, Leduc D, Maura D, et al. Bacteriophages can treat and prevent sepsis caused by Gram-negative bacteria: results from a randomized clinical
Pseudomonas aeruginosa lung infections. J Infect Dis 2010; 201:1096– study. Antimicrob Agents Chemother 2012; 56:3819–3825.
1104. 153. van Delden C, Kohler T, Brunner-Ferber F, et al. Azithromycin to prevent
147. Morello E, Saussereau E, Maura D, et al. Pulmonary bacteriophage therapy Pseudomonas aeruginosa ventilator-associated pneumonia by inhibition of
on Pseudomonas aeruginosa cystic fibrosis strains: first steps towards quorum sensing: a randomized controlled trial. Intensive Care Med 2012;
treatment and prevention. PLoS One 2011; 6:e16963. 38:1118–1125.
148. Chhibber S, Kaur S, Kumari S. Therapeutic potential of bacteriophage in 154. Le Berre R, Nguyen S, Nowak E, et al. Relative contribution of three main
treating Klebsiella pneumoniae B5055-mediated lobar pneumonia in mice. virulence factors in Pseudomonas aeruginosa pneumonia. Crit Care Med
J Med Microbiol 2008; 57:1508–1513. 2011; 39:2113–2120.
149. Witzenrath M, Schmeck B, Doehn JM, et al. Systemic use of the endolysin 155. Francois B, Luyt CE, Dugard A, et al. Safety and pharmacokinetics of
Cpl-1 rescues mice with fatal pneumococcal pneumonia. Crit Care Med an anti-PcrV PEGylated monoclonal antibody fragment in mechanically
2009; 37:642–649. ventilated patients colonized with Pseudomonas aeruginosa: a randomi-
150. Mouktaroudi M, Giamarellos-Bourboulis EJ. Macrolides for the therapy of zed,double-blind, placebo-controlled trial. Crit Care Med 2012; 40:
nosocomial infections. Curr Opin Infect Dis 2012; 25:205–210. 2320–2326.

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