Download Hospital-acquired Pneumonia and Ventilator

Hospital-acquired Pneumonia and
Ventilator-associated Pneumonia
Recent Advances in Epidemiology and Management
François Barbier, Antoine Andremont, Michel Wolff, Lila Bouadma
Curr Opin Pulm Med. 2013;19(3):216-228.
Abstract
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.
Introduction
Hospital-acquired pneumonia (HAP) is a pulmonary infection that develops in patients hospitalized
for more than 48 h, either in the ICU or in other wards.[1,2] Ventilator-associated pneumonia (VAP), a
subset of HAP that occurs in mechanically ventilated patients more than 48 h after tracheal
intubation, is the most frequent ventilator-associated complication (VAC).[1,2] HAP/VAP represents a
major cause of deaths, morbidity and resources utilization in hospitalized patients, most notably in
those with severe underlying conditions.[1,3-7] The adequacy of empirical antimicrobial therapy is
strongly predictive of hospital survival,[3] making the definition of patients at risk for
multidrug-resistant (MDR) pathogens a pivotal challenge.[1,8–10] In this short review, we summarize
the recently published data on clinical epidemiology, trends in bacterial resistance, diagnostic
methods and therapeutic strategies in HAP, with a special focus on VAP.
Current Clinical Epidemiology: The Burden of Hospital-acquired
Pneumonia and Ventilator-associated Pneumonia
The incidence of HAP ranges from five to more than 20 cases per 1000 hospital admissions. [1,11]
Outside the ICU, highest rates are observed in the elderly, immunocompromised hosts, surgical
patients and those receiving enteral feeding through 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-acquired infection.[12-14] Recent surveys
from large healthcare networks reported a pooled incidence density of VAP ranging from two to 16
episodes per 1000 ventilator-days.[14,15] The daily incidence of VAP peaks between day 5 and day 9
of mechanical ventilation, whereas the cumulative incidence appears as roughly proportional to
mechanical ventilation duration.[13,16,17] The main other risk factors for VAP and corresponding
preventive measures are exposed in .[17–42] Patients with the acute respiratory distress syndrome
(ARDS) are especially at risk, as a likely result of prolonged mechanical ventilation and heavy
sedation requirement, with a cumulative incidence of ~40% after day 10.[13] Whether neuromuscular
blockade agents use increases and head of bed elevation or prone positioning decreases the risk of
VAP in ARDS patients has not been confirmed by recent studies.[13,31–43] Early tracheostomy (i.e.
within the first 7 days of mechanical ventilation) in patients with predictable weaning difficulties does
not appear as an independent predictor of VAP when compared with late tracheostomy or
prolonged tracheal intubation.[22,44,45] Other potential risk factors have been recently suggested, such
as etomidate use for tracheal intubation or energetic deficit during the early ICU course (at least for
Staphylococcus aureus VAP),[46,47] whereas steroids (for trauma patients) or statin use could be
protective.[48,49]
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
RRR of VAP
(n)
(%)
Reducing the time at risk
NPPV
Daily SBT
Daily sedation interruption
Early tracheotomy
2005, meta-analysis
(12 studies)
[18]
2000, RCT (two ICUs)
[19]
2006, RCT (five ICUs)
[20]
2000, RCT (one ICU)
[21]
2012, meta-analysis (7
RCTs)
[22]
3030 ↓ 25%
385 No
effect
144 No effect
128 No
effect
1044 No effect
Preventing endotracheal tube colonization and minimizing contaminated microaspirations
Silver-coated ET
Saline instillation before tracheal
suctioning
ET with SSD
ET with ultrathin membrane and
2008, RCT (54 ICUs)
[23]
1509 ↓ 36%
2009, RCT (one ICU)
[24]
262 ↓ 54%
2010, meta-analysis
(13 RCTs)
2007, RCT (one ICU)
[25]
[26]
2442
↓ 48% (four
RCTs)
280 ↓ 64%
SSD
ET with an ultrathin and
tapered-shape cuff membrane
Continuous control of tracheal
cuff pressure
Head-of-bed elevation
2008, RCT (one ICU)
[27]
134 ↓ 45%
2007, RCT (two ICUs)
[28]
142 No effect
2011, RCT (one ICU)
[29]
122 ↓ 63%
1999, RCT (two ICUs)
[30]
86 ↓ 78%
2006, RCT (four ICUs) [31]
Prone position
Kinetic beds
Positive end-expiratory pressure
Physiotherapy
2008, meta-analysis
(five RCTs)
2006, meta-analysis
(15 RCTs)
2008, RCT (three
ICUs)
221 No effect
[32]
1372 No effect
[33]
1169
[34]
↓ 53% (10
RCTs)
131 ↓ 63%
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
[42]
1292 No effect
Closed tracheal suction system
2008, meta-analysis
(nine RCTs)
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.
Nonventilator-associated HAPs dramatically increase both the hospital length of stay and the cost
of care, and are associated with an overall mortality of 27–51%,[11,50,51] the poorer prognosis being
reported in the elderly. Subsequent functional disability and accelerated cognitive impairment in
aged patients surviving bacterial sepsis may increase the social burden of this nosocomial event.[52]
The crude mortality of VAP ranges from 22 to 60%.[7,13,14,53] Although the prognostic weight of
underlying conditions prevails in many cases, the occurrence of VAP is associated with a two-fold
increase of the likelihood of in-ICU death, most notably for patients with inadequate empirical
therapy.[3] The directly attributable mortality is 6–9%, but varies from 3 to 17% depending on patient
subgroups.[4,5] In addition, survivors experience poorer outcome than ICU patients who do not
develop VAP, with significantly longer durations of mechanical ventilation, ICU stay and
hospitalization.[7] The absolute increase in hospitalization costs is estimated to be ~40 000 USD per
episode.[7]
The Alarming Situation of Bacterial Resistance
The bacterial epidemiology of VAP ( )[54] depends on a panel of factors including mechanical
ventilation duration, length of hospital and ICU stays, previous exposure to antimicrobials, local
epidemiology and potential epidemic phenomenon in a given ICU.[1] Rapid changes in the
oropharyngeal flora of intubated patients (even in the absence of antibiotic exposure) represent a
key determinant,[55] as microaspirations of pharyngeal secretions constitute the leading
physiopathological mechanism of VAP. Early-onset VAP (within the first 4 days of mechanical
ventilation) usually involve respiratory pathogens from the normal, community-acquired
oropharyngeal microbiota ( ), whereas late-onset VAP (occurring on day 5 of mechanical ventilation
or later) mostly involve hospital-acquired and potentially MDR pathogens as a combined result of
antibiotic selective pressure, cross-transmission and colonization from in-ICU environmental
sources.[1,53,54] However, MDR pathogens may be isolated in early-onset VAP when risk factors exist
prior to ICU admission, and even when such risk factors are lacking [notably for Pseudomonas
aeruginosa and methicillin-resistant Staphylococcus aureus (MRSA)],[53] enlightening the limits of
this classification in the current context of bacterial resistance.
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
Country
Setting
Type of pneumonia
Patients, n
ACURASYS
Ferrer et
Ferrer et
ANSRPSG
[13•]
al. [53]
al. [53]
[50]
France
Spain
Spain
Asia
Six ICUs,
Six ICUs,
one
one
hospital
hospital
20 ICUs
SENTRY [54]
Worldwide
73 hospitals
Surveillance
System
VAP in ARDS HAP and
HAP and
HAP and
HAP and
patients
VAPa
VAPb
VAP
VAP
38 (VAP,
238 (VAP, 2554 (VAP,
n=18)
n=128)
n=977)
98
31 436
100
63
54
67
–
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
Bacterial documentation
Gram-negative bacteria
Enterobacter sp.
10
3
5
4
6
Serratia marcescens
3
–
2
<1%
3
7
8
3
–
–
34
16
18
19
22
5
–
3
4
3
–
–
1
22
7
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 enterobacteria
Pseudomonas aeruginosa
Stenotrophomonas
maltophilia
Acinetobacter baumannii
Gram-positive bacteria
Staphylococcus aureus
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, hospitalacquired pneumonia; VAP, ventilator-associated pneumonia.
No risk factor of multidrug-resistant (MDR) bacteria according to the 2005 Infectious Disease
a
Society of America (IDSA)/American Thoracic Society (ATS) criterion [1].
At least one risk factor of MDR bacteria according to the 2005 IDSA/ATS criterion.
b
Table 3. Current guidelines for the empirical treatment of hospital-acquired pneumonia,
including ventilatorassociated pneumonia
Reference
Early-onset HAP/VAP (≤day 4
Late-onset HAP/VAP (≥day
of hospital stay/MV) without
5 of hospital stay/MV) OR
risk factors for MDR
presence of ≥1 risk factor
pathogen
for MDR pathogenb
a
MSSA
Most common (i.e.
targeted) pathogens
Streptococcus pneumonia and
other streptococci,
Haemophilus sp.
Wild-type Enterobacteriaceae
MRSA
Pseudomonas aeruginosa
Drug-resistant
Enterobacteriacae
Acinetobacter baumannii
Stenotrophomonas
maltophilia
Society which issued the
guidelines (date of
publication)
Cefepime or ceftazidime
or
Ceftriaxone
Imipenem/cilastatin or
American Thoracic
Society/Infectious
Diseases Society of
or
meropenem
Levofloxacin, moxifloxacin, or
or
ciprofloxacin
[1]
Piperacillin/tazobactam
or
America (2005)
plus
Ampicillin/sulbactam
Ciprofloxacin or
or
levofloxacin
Ertapenem
or
Amikacin, gentamicin, or
tobramycin
Ampicillin/sulbactam or
amoxicillin/clavulanate
European Respiratory
Society/European
or
Society of Clinical
Microbiology and
Infectious
[10]
Cefuroxime, cefotaxime or
ceftriaxone
Diseases/European
Society of Intensive Care
or
Medicine (2009)
Moxifloxacin or levofloxacin
(not ciprofloxacin)
British Society of
Antimicrobial
Chemotherapy (2008)
Ceftazidime or
Imipenem/cilastatin or
meropenem
or Piperacillin/tazobactam
plus
Ciprofloxacin or
levofloxacin
Aminopenicillin/b-lactamase
Early-onset pneumonia with
inhibitor
risk factor for MDR
[8]
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
Also to be applied for
severe early-onset
Only if severity criteria are
lacking:
Cefotaxime or ceftriaxone or
cefepime
or
Association of Medical
Microbiology and
Infectious Disease
Canada/Canadian
Thoracic Society (2008)
c
[9]
Piperacillin-tazobactam
or
Imipenem/cilastatin or
meropenem
or
Levofloxacin or moxifloxacin
pneumoniad:
Ceftazidime or cefepime
or
Piperacillin/tazobactam
or
Imipenem/cilastatin or
merepenem
plus
Ciprofloxacin or
levofloxacin
or
Gentamicin, tobramycin or
amikacin
In all guidelines
Add vancomycin or linezolid
[1,8–10]
if MRSA is suspected
MV, mechanical ventilation; MDR, multidrug-resistant; MRSA, methicillin-resistant Staphylococcus
aureus; MSSA, methicillin-susceptible Staphylococcus aureus.
Risk factors for MDR pathogen are a current hospitalization of 5 days or more, an antimicrobial
a
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).
The cephalosporins (ceftazidime and cefepime), carbapenems (imipenem/cilastatin and
b
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).
Severity criteria include hypotension, sepsis syndrome, rapid progression of infiltrates and end
d
organ dysfunction.
Resistance frequencies differ from one ICU to another and at the geographic scale, but trends
converge across international surveys ( ).[14,50,54] The recent description of plasmidic linezolid
resistance in MRSA elicits significant concerns.[58,59] Resistance to third-generation and
fourth-generation cephalosporins in Enterobacteriaceae strains mostly depends on the expression
of acquired extended-spectrum β-lactamases (ESBLs) and/or AmpC β-lactamases.[56–60] The spread
of carbapenemase-producing strains is even more alarming ( ).[57] MDR isolates of P. aeruginosa
are increasingly prevalent, whereas one-half to two-thirds of Acinetobacter baumannii strains
causing VAP are currently carbapenem-resistant.[14,50] Polymyxins (mainly colistin) are more and
more seen as a last-line therapeutic option to treat MDR Gram-negative bacilli (GNB).[61]
Unfortunately, colistin resistance is now also on the rise in ICUs with high prevalence of
carbapenems resistance and heavy colistin consumption.[62-64] The situation of bacterial resistance
appears as critical when HAPs in nonintubated patients are considered ( ).
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
Study/reference
INICC
SENTRY
VAP [14••] HAP/VAP [54]
ANSRPSG HAP +
VAP (pooled) [50]
Pathogen, antimicrobial
Staphylococcus aureus
Oxacillin
73
59/51
82
Gentamicin
–
13/22
–
Fluoroquinolones
–
58/48
78
–
16/24
31
69
23/32
43
7
<1/<1
2
55
28/26
–
67
16/22
–
4
0/0
–
Fluoroquinolones
46
40/42
30
Aminosides
28
28/34
–
40
24/29
37
Antipseudomonal cephalosporins
37
32/37
35
Carbapenemsc
43
28/34
30
Carbapenemsc
66
42/54
67
Colistin
–
–
1
Klebsiella pneumonia
Fluoroquinolones
Third-generation/fourth-generation
cephalosporinsa
Carbapenemsb
Escherichia coli
Fluoroquinolones
Third-generation/fourth-generation
cephalosporinsa
Carbapenemsb
Pseudomonas aeruginosa
Piperacillin and/or
piperacillin–tazobactam
Acinetobacter baumannii
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.
Resistance to third-generation and fourth-generation cephalosporins in carbapenem-susceptible
a
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].
Carbapenems resistance in Enterobacteriaceae is almost exclusively because of acquired,
b
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.
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
Study/reference
INICC
SENTRY
VAP [14••] HAP/VAP [54]
ANSRPSG HAP +
VAP (pooled) [50]
Pathogen, antimicrobial
Staphylococcus aureus
Oxacillin
73
59/51
82
Gentamicin
–
13/22
–
Fluoroquinolones
–
58/48
78
–
16/24
31
69
23/32
43
7
<1/<1
2
55
28/26
–
67
16/22
–
4
0/0
–
Fluoroquinolones
46
40/42
30
Aminosides
28
28/34
–
Piperacillin and/or
40
24/29
37
Klebsiella pneumonia
Fluoroquinolones
Third-generation/fourth-generation
cephalosporinsa
Carbapenemsb
Escherichia coli
Fluoroquinolones
Third-generation/fourth-generation
cephalosporinsa
Carbapenemsb
Pseudomonas aeruginosa
piperacillin–tazobactam
Antipseudomonal cephalosporins
37
32/37
35
Carbapenemsc
43
28/34
30
Carbapenemsc
66
42/54
67
Colistin
–
–
1
Acinetobacter baumannii
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.
Resistance to third-generation and fourth-generation cephalosporins in carbapenem-susceptible
a
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].
Carbapenems resistance in Enterobacteriaceae is almost exclusively because of acquired,
b
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.
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
Study/reference
INICC
SENTRY
VAP [14••] HAP/VAP [54]
ANSRPSG HAP +
VAP (pooled) [50]
Pathogen, antimicrobial
Staphylococcus aureus
Oxacillin
73
59/51
82
Gentamicin
–
13/22
–
Fluoroquinolones
–
58/48
78
Klebsiella pneumonia
–
16/24
31
69
23/32
43
7
<1/<1
2
55
28/26
–
67
16/22
–
4
0/0
–
Fluoroquinolones
46
40/42
30
Aminosides
28
28/34
–
40
24/29
37
Antipseudomonal cephalosporins
37
32/37
35
Carbapenemsc
43
28/34
30
Carbapenemsc
66
42/54
67
Colistin
–
–
1
Fluoroquinolones
Third-generation/fourth-generation
cephalosporinsa
Carbapenemsb
Escherichia coli
Fluoroquinolones
Third-generation/fourth-generation
cephalosporinsa
Carbapenemsb
Pseudomonas aeruginosa
Piperacillin and/or
piperacillin–tazobactam
Acinetobacter baumannii
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.
Resistance to third-generation and fourth-generation cephalosporins in carbapenem-susceptible
a
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].
Carbapenems resistance in Enterobacteriaceae is almost exclusively because of acquired,
b
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.
The Role of Virus in Ventilator-associated Pneumonia
The Herpesviridae herpes simplex virus (HSV) and cytomegalovirus (CMV) can cause viral
reactivation pneumonia in intubated patients without a usual criterion for immune deficiencies.[65]
HSV replication may be documented in tracheal/bronchial aspirates from 32 to 64% of patients
requiring prolonged mechanical ventilation,[66–68] with subsequent histopathological evidence of HSV
bronchopneumonitis in up to 21% of patients with worsening respiratory status.[68] Patients with
ARDS and those receiving steroids may be at higher risk.[65] CMV reactivation is observed in ~30%
of critically ill patients experiencing multiorgan failure and prolonged ICU stay,[69] most notably in
survivors of severe bacterial sepsis, and may directly involve the lung. The incidence of
histologically proven CMV pneumonia may reach 30% in ARDS patients with clinical deterioration
suggesting VAC and negative bronchoalveolar lavage fluid (BALF) culture.[70] Acyclovir and
gancyclovir are the main therapeutic options for HSV and CMV pneumonia, respectively, but both
remain to be fully evaluated by appropriate randomized controlled trials (RCTs). A positive
mimivirus (Acanthamoeba polyphaga) serology has been documented in 20% of patients with
suspected VAP and was associated with an increased duration of mechanical ventilation and ICU
stay,[71] but a direct role of mimivirus in VAP is uncertain.[72,73]
Does Fungal Ventilator-associated Pneumonia Exist in ICU Patients
Without Major Immunosuppression?
Colonization of the lower respiratory tract by Candida spp. affects 18–56% of intubated patients and
is associated with an increased risk of bacterial VAP, most notably caused by P. aeruginosa or
other MDR pathogens, and possibly a poorer outcome.[74–77] However, available data do not support
a direct role of Candida spp. as a VAP-causative pathogen.[78,79] Aspergillus spp. (mainly Aspergillus
fumigatus) may be involved in ~3% of late-onset VAP,[53] and invasive pulmonary aspergillosis has
been proven in 15% of critically ill patients with one or more Aspergillus-positive tracheal aspirate
cultures.[80] A clinical algorithm was recently proposed to assess the clinical relevance of these
cultures and ease the decision to start or not a specific therapy.[80]
Recent Advances in the Diagnosis of Hospital-acquired Pneumonia
and Ventilator-associated Pneumonia
The diagnosis of HAP/VAP is challenging and conventional strategies have been extensively
reviewed in recent guidelines.[1,8–10] However, two current research areas warrant developments.
First, several biomarkers have been evaluated as complementary diagnostic tools during the past
years.[81,82] Studies on BALF concentrations of the soluble triggered receptor expressed on myeloid
cells 1 (sTREM-1) yielded conflicting results.[83–86] C-reactive protein may lack sensitivity in ICU
patients.[87,88] The diagnostic values of BALF concentrations of interleukin-1β, interleukin-8,
granulocyte colony-stimulating factor and macrophage inflammatory protein-1[alpha] could be
discriminative but require validation on larger cohorts,[89] as do BALF levels of plasminogen
activation inhibitor 1 (PAI-1).[90] By contrast, BALF levels of Clara cell protein 10 yield poor
diagnostic accuracy.[91] The usefulness of plasma levels of Clara cell protein 16 (CC-16), soluble
receptor for advanced glycation end products (sRAGE) and surfactant protein D (SP-D) is
unclear.[92] Copeptin,[93,94] midregional atrial natriuretic factor (MR-ANF)[95,96] and adrenomedullin[97]
were evaluated as prognostic rather than diagnostic biomarkers in pneumonia. To date, the
literature does not support a clinical role for these biomarkers, including procalcitonin (PCT), in
predicting VAP. However, using serum PCT concentration to customize antibiotic-treatment
duration in patients with VAP has been evaluated in five studies, all showing less antibiotic
consumption when a PCT-based algorithm was applied, with no detrimental impact on outcomes.
Consequently, in patients treated for a VAP whose serum PCT concentration is less than 0.5 ng/ml
or decreased by more than 80% (compared with the peak concentration), antibiotic discontinuation
may be considered at day 3 after initiation.[87,88,98-102]
Conventional bacteriological methods imply an incompressible delay of 48–72 h for complete
antimicrobial susceptibility testing of pneumonia-causative pathogens. Therefore, the on-going
development of rapid molecular methods raises comprehensible hopes for optimizing the choice of
initial drugs and avoiding the overprescription of very broad-spectrum molecules in this situation.[103]
Such tools should reliably identify both the most common pathogens and their most frequent
resistance genotypes within a time ranging from 2 to 6 h. Real-time PCR, in-situ DNA hybridization
and mass spectrometry are currently the leading investigation methods.[104] Several systems are
already commercialized for direct analysis of clinical samples such as blood cultures and swabs
(most notably for MRSA screening). However, and despite promising preliminary results, [103-105] no
system has been validated so far for direct application on BALF or tracheal aspirates in suspected
VAP/HAP. Oversensitivity and quantification of bacterial loads may represent important issues.
Indeed, genetic material from more than 15 distinct pathogens (including bacteria, virus and fungi)
can be detected in BALF from ICU patients, most of them being not reliably considered as
causative for the current pneumonia episode.[106]
Antimicrobial Treatment of Hospital-acquired Pneumonia and
Ventilator-associated Pneumonia
Delayed effective therapy increases hospital mortality in HAP/VAP patients, making the choice of
empirical drugs a crucial dilemma.[1,6] To improve the likelihood of adequate coverage, current
guidelines ( ) usually recommend an antipseudomonal combination therapy except for early-onset
pneumonia with no risk factor for MDR bacteria.[1,8–10] Facing the epidemic of ESBL-producing
enterobacteria and other MDR-GNB, antipseudomonal carbapenems (imipenem/cilastatin and
meropenem) have become the most empirically prescribed β-lactams in European ICU for
HAP/VAP.[51] Despite limited lung diffusion,[10] aminoglycosides should be preferred to
fluoroquinolones, given the resistance frequencies in P. aeruginosa and the possibility to achieve
bactericidal lung concentrations with a high-dosing regimen (e.g. 25 mg/kg for amikacin). Empirical
indications of polymyxins in patients at risk for carbapenem-resistant GNB should be clarified in
updated guidelines.[107]
Table 3. Current guidelines for the empirical treatment of hospital-acquired pneumonia,
including ventilatorassociated pneumonia
Early-onset HAP/VAP (≤day 4
Reference of hospital stay/MV) without
risk factors for MDR
Late-onset HAP/VAP (≥day
5 of hospital stay/MV) OR
presence of ≥1 risk factor
pathogena
for MDR pathogenb
MRSA
MSSA
Streptococcus pneumonia and
Most common (i.e.
other streptococci,
targeted) pathogens
Haemophilus sp.
Wild-type Enterobacteriaceae
Pseudomonas aeruginosa
Drug-resistant
Enterobacteriacae
Acinetobacter baumannii
Stenotrophomonas
maltophilia
Society which issued the
guidelines (date of
publication)
Cefepime or ceftazidime
or
Ceftriaxone
Imipenem/cilastatin or
American Thoracic
Society/Infectious
Diseases Society of
or
meropenem
Levofloxacin, moxifloxacin, or
or
ciprofloxacin
[1]
Piperacillin/tazobactam
or
America (2005)
plus
Ampicillin/sulbactam
Ciprofloxacin or
or
levofloxacin
Ertapenem
or
Amikacin, gentamicin, or
tobramycin
European Respiratory
Ampicillin/sulbactam or
Society/European
amoxicillin/clavulanate
Society of Clinical
Microbiology and
Ceftazidime or
Imipenem/cilastatin or
or
meropenem
Diseases/European
Cefuroxime, cefotaxime or
or Piperacillin/tazobactam
Society of Intensive Care
ceftriaxone
Infectious
Medicine (2009)
[10]
plus
or
Ciprofloxacin or
Moxifloxacin or levofloxacin
levofloxacin
(not ciprofloxacin)
Early-onset pneumonia with
risk factor for MDR
pathogen:
Cefotaxime or ceftriaxone
or
Fluoroquinolone
Aminopenicillin/b-lactamase
inhibitor
British Society of
Antimicrobial
[8]
Chemotherapy (2008)
or
Cefuroxime
or
Piperacillin/tazobactam
Late-onset pneumonia:
Depending on local
epidemiology
If Pseudomonas
aeruginosa is suspected,
treatment options include
ceftazidime, ciprofloxacin,
meropenem and
piperacillin/tazobactam
Only if severity criteria are
Also to be applied for
lacking:
severe early-onset
pneumoniad:
Cefotaxime or ceftriaxone or
Association of Medical
Microbiology and
Infectious Disease
Canada/Canadian
Thoracic Societyc (2008)
[9]
cefepime
Ceftazidime or cefepime
or
or
Piperacillin-tazobactam
Piperacillin/tazobactam
or
or
Imipenem/cilastatin or
Imipenem/cilastatin or
meropenem
merepenem
or
plus
Levofloxacin or moxifloxacin
Ciprofloxacin or
levofloxacin
or
Gentamicin, tobramycin or
amikacin
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.
Risk factors for MDR pathogen are a current hospitalization of 5 days or more, an antimicrobial
a
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).
The cephalosporins (ceftazidime and cefepime), carbapenems (imipenem/cilastatin and
b
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).
Severity criteria include hypotension, sepsis syndrome, rapid progression of infiltrates and end
d
organ dysfunction.
Re-assessment is mandatory at day 2–3, both to correct inadequate regimens when appropriate
and to avoid an overconsumption of broad-spectrum drugs.[1,8–10] Antimicrobials must be stopped
when the diagnosis is not bacteriologically validated, except for particular situations.[10] When
pneumonia is confirmed, the antimicrobial spectrum must be narrowed whenever possible on the
basis of susceptibility testing. Monotherapy is conceivable provided that the empirical regimen was
adequate, the patient's condition improves and the causative pathogens do not exhibit extensive
resistance patterns.[10] Even not validated in HAP/VAP, retrocession to β-lactam/β-lactamase
inhibitor might be discussed for ESBL-producing enterobacteria with minimal inhibitory
concentration (MIC) below the break-point values.[108,109] A control sample should be obtained to
assess bacterial load kinetics and detect precocious resistant mutants. [10] The 8-day standard
duration of treatment can be safely shortened by monitoring plasma PCT levels.[100] Longer
treatments may be discussed in cases of immunosuppression, unfavourable clinical response or
extensively drug-resistant pathogens.[10]
Colistin appears as effective as other antimicrobial classes for VAP caused by MDR-GNB.[110] The
optimal dosing regimen of this concentration-dependent antibiotic is still debated; however, an
intravenous loading dose of 9 million units followed by 4.5 million units twice daily (with protocolized
adaptation in case of renal failure) may be an adequate scheme,[111] in accordance with previous
pharmacokinetic/pharmacodynamic data,[112] the median colistin dose being correlated with clinical
and microbiological success rates.[113] The incidence of colistin-induced nephrotoxicity is 18–43%,
especially with a high-dosing regimen or when other nephrotoxic drugs are prescribed.[111,113,114] The
nephroprotective effect of ascorbic acid co-administration during colistin therapy should be
evaluated in clinical practice.[115] Experimental data suggest that inhaled colistin should be used as
an adjunctive therapy to reach high lung concentrations,[116] but available clinical evaluations yielded
ambiguous results,[117–120] and further RCTs are needed to clarify this issue. Other inhaled
antimicrobials have been tested in experimental or clinical VAP caused by MDR-GNB, namely
ceftazidime,[121,122] imipenem/cilastatin,[123] amikacin[124] and tobramycin.[118,125] Nebulized
ceftazidime/amikacin combination does not improve the course of clinical P. aeruginosa VAP when
compared with intravenous administration.[122]
Both vancomycin and linezolid are recommended for the therapy of suspected or proven MRSA
pneumonia.[1,8–10] In experimental models, linezolid is associated with faster bacterial clearances and
a lower histological severity of pneumonia,[126–128] with better pharmacokinetic/pharmacodynamic
profiles[127] and a possible immunomodulatory effect.[129] However, previous meta-analysis did not
demonstrate a superiority of linezolid in terms of clinical cure and bacteriological eradication. [130,131]
In a recent RCT,[132] linezolid was associated with a higher clinical success rate and a lower
incidence of renal impairment than vancomycin, but all-cause 60-day fatality rates were similar in
both groups. We believe that linezolid 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 MIC
higher than 1 mg/l, a cut-off associated with vancomycin therapy failure.[133,134]
New antibiotics that may complete the therapeutic arsenal for HAP/VAP are scarce.
Lipoglycopeptides (i.e. dalbavancin, oritavancin and telavancin) are bactericidal for MRSA strains
with high vancomycin MIC.[135] Telavancin is not inferior to vancomycin for the treatment of MRSA
pneumonia, but may be associated with an increased incidence of acute kidney injury. [136]
Ceftaroline[137,138] and ceftobiprole,[139] two new-generation cephalosporins, and iclaprim,[140] a
dihydrofolate reductase inhibitor, are also active against MRSA. None of these drugs are currently
approved by the US Food and Drug Administration (FDA) for the treatment of MRSA HAP/VAP.
Novel carbapenem-sparing molecules for the treatment of MDR-GNB include temocillin,[141] a
6-hydroxymethyl-ticarcilline with activity against ESBL-producing and AmpC-producing
enterobacteria, and avibactam (formerly NXL104),[142–145] which restores the activity of various
β-lactams (e.g. ceftazidime) in isolates producing Ambler class A (ESBL and KPC-type
carbapenemase) and AmpC β-lactamases (including P. aeruginosa); these two promising
antibiotics remain to be evaluated in HAP/VAP.
New Therapeutic Approach for Ventilator-associated Pneumonia
Bacteriophages are viruses that infect bacteria in a species-specific way. In animal studies, phage
therapy can both prevent and cure P. aeruginosa, Klebsiella pneumoniae and Streptococcus
pneumoniae pneumonia.[146–149] These recent results may be a first basis towards further clinical
trials, notably for difficult-to-treat MDR pathogens. Next, and despite an inappropriate bacterial
spectrum, macrolides have immunomodulatory and anti-inflammatory effects that may be of interest
in HAP/VAP.[150] A short course of clarithromycin may ease the cure of otherwise adequately treated
VAP and modulate the risk of death from septic shock or multiorgan failure.[151–152] Macrolides also
inhibit P. aeruginosa quorum sensing, but the clinical impact of this property remains to be
confirmed.[153] Finally, in a recent RCT, monoclonal antibodies targeting the type III secretion system,
a major pseudomonal virulence factor in pneumonia,[154] reduced the incidence of VAP in patients
with P. aeruginosa tracheal colonization.[155] Further evaluation of immunotherapy in HAP/VAP is
warranted.
Conclusion
An increasing burden of HAP/VAP may be expected in the coming years, as a result of
intensification of care, progressive ageing and a growing prevalence of severe underlying diseases
in ICU patients. The current epidemiology of bacterial resistance is more alarming than ever. In this
context, the implementation of preventive policies is of major importance. [17] Both diagnosis and
treatment of HAP/VAP remain challenging and justify intensive research work for the development
and validation of molecular diagnostic tools, new drugs for MDR pathogens, and nonantibiotic
therapeutic options.
Sidebar
Key Points

HAP/VAP are the most common acquired infections in critically ill patients, and are
responsible for high morbidity and mortality in this population.

The main concern on antimicrobial resistance currently relates to GNB, with the worldwide
spread of carbapenemase-producing strains and the emergence of colistin resistance.

Molecular assays directly applicable on respiratory samples are urgently needed, both to
improve the adequacy of empirical therapy and to spare broadspectrum drugs.

A few novel drugs in the pipeline remain to be fully assessed in HAP/VAP caused by MDR
pathogens.

New therapeutic approaches such as phage therapy and immunotherapy warrant clinical
evaluation in this context.
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Papers of particular interest, published within the annual period of review, have been
highlighted as:
* of special interest
** 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).
Acknowledgements
None
Curr Opin Pulm Med. 2013;19(3):216-228. © 2013 Lippincott Williams & Wilkins