(Chest. 2001;119:373S-384S.)
© 2001
American College of Chest Physicians
Hospital-Acquired Pneumonia*
Risk Factors, Microbiology, and Treatment
Joseph P. Lynch, III, MD, FCCP
*
From the Division of Pulmonary and Critical Care Medicine, University of Michigan Medical Center, Ann Arbor, MI.
Correspondence to: Joseph P. Lynch III, MD, FCCP, Professor of Internal Medicine, Division of Pulmonary and Critical Care Medicine, The University of Michigan Medical Center, 3916 Taubman Center, Ann Arbor, MI 48109; e-mail: jlynch{at}umich.edu
 |
Abstract
|
|---|
Pneumonia complicates hospitalization in 0.5 to 2.0% of patients
and is associated with considerable morbidity and mortality. Risk
factors for hospital-acquired pneumonia (HAP) include mechanical
ventilation for > 48 h, residence in an ICU, duration of ICU or
hospital stay, severity of underlying illness, and presence of
comorbidities. Pseudomonas aeruginosa,
Staphylococcus aureus, and Enterobacter are the most
common causes of HAP. Nearly half of HAP cases are polymicrobial. In
patients receiving mechanical ventilation, P aeruginosa,
Acinetobacter, methicillin-resistant S aureus, and other
antibiotic-resistant bacteria assume increasing importance. Optimal
therapy for HAP should take into account severity of illness,
demographics, specific pathogens involved, and risk factors for
antimicrobial resistance. When P aeruginosa is
implicated, monotherapy, even with broad-spectrum antibiotics, is
associated with rapid evolution of resistance and a high rate of
clinical failures. For pseudomonal HAP, we advise combination therapy
with an antipseudomonal ß-lactam plus an aminoglycoside or a
fluoroquinolone (eg, ciprofloxacin).
Key Words: antibiotics • combination therapy • determinants of therapy • nosocomial infections • risk factors
|
Introduction
|
|---|
Hospital
-acquired pneumonia (HAP) accounts for 15% of all nosocomial
infections1
and affects 0.5 to 2.0% of hospitalized
patients.2
3
The mortality rate for HAP exceeds 30%,
although attributable mortality is lower.4
5
6
7
8
9
Prompt use
of appropriate antibiotics is essential to optimize the outcome of
HAP.10
11
12
Antimicrobial strategies that encompass the most likely causative
organisms while preventing emergence of resistance and controlling
costs are needed.13
14
Unfortunately, antimicrobial
resistance has escalated dramatically within the past
decade15
16
17
18
and has created obstacles to effective
antibiotic choices. These trends are most problematic in
ICUs.17
18
19
20
21
22
23
24
Appropriate choice of antibiotics requires an
awareness of the relevant pathogens, antimicrobial resistance patterns,
and the host and demographic factors that may lead to infections and/or
evolution of antibiotic resistance.
|
Microbiology of HAP
|
|---|
The etiologic agents responsible for HAP have been elucidated in
numerous studies.1
7
9
25
26
27
28
29
30
31
32
Gram-negative
bacteria, including Pseudomonas aeruginosa, Enterobacter,
Acinetobacter, and enteric Gram-negative rods, are implicated in 55 to
85% of HAP cases; Gram-positive cocci (particularly
Staphylococcus aureus) account for 20 to 30%; and 40 to
60% of cases are polymicrobial.1
7
9
25
26
27
28
29
Acuity and
severity of illness, duration of hospitalization, and prior antibiotic
exposure are major determinants of likely
pathogens.9
28
30
In critically ill patients requiring
prolonged mechanical ventilation (MV) in ICUs, P aeruginosa
and Acinetobacter (eg, Acinetobacter
calcoaceticus and Acinetobacter
baumannii),30
which are resistant to many
antibiotics, account for 30 to 50% of HAP; these pathogens are
uncommon in non-ICU settings.5
20
27
30
31
32
Over the past 2 decades, antimicrobial resistance has escalated
dramatically in the United States and worldwide. The National
Nosocomial Infections Surveillance System, which incorporates data from
community, university, and municipal hospitals, elucidated the major
pathogens responsible for HAP in the United States since the
1970s.25
29
33
34
During this time, some pathogens
have emerged as important opportunistic pathogens in ICUs
(Acinetobacter, methicillin-resistant S aureus [MRSA],
Enterobacter), whereas the prevalence of other pathogens
(Klebsiella pneumoniae and P aeruginosa) has
remained stable or declined. S aureus was implicated in 13%
of HAP from 1981 to 1986, 16% from 1986 to 1989, and 19% from 1990 to
1996.25
33
34
During these intervals, Enterobacter was
implicated in 7%, 11%, and 11% of cases of HAP, respectively. The
prevalence of K pneumoniae during these time periods was
12%, 7%, and 8%, respectively. The prevalence of P
aeruginosa remained constant, causing 17% of HAP during each of
these time periods. The increasing prevalence of Enterobacter reflects
selection pressure from heavy use of third-generation cephalosporins
(particularly ceftazidime), which facilitates evolution of chromosomal
inducible ß-lactamases.35
36
S aureus has
also increased in frequency as a cause of nosocomial infections,
bacteremias, and pneumonias.25
29
37
An analysis of 112
medical ICUs from 97 National Nosocomial Infections Surveillance System
hospitals from 1992 to 1997 cited S aureus as a cause of
20% of HAPs and 13% of bacteremias.29
Liberal use of
intravascular catheters and nasal carriage of S aureus are
major risk factors for pneumonia caused by this
pathogen.37
38
39
40
Currently, > 30% of nosocomial isolates
of S aureus in the United States are resistant to
methicillin.1
22
Awareness of the relevant pathogens is critical to the successful
design of empiric and pathogen-directed antibiotic therapies for HAP.
Understanding the salient risk factors for HAP and for development of
antimicrobial resistance may facilitate the development of strategies
to decrease mortality and morbidity due to HAP. This will, in turn,
decrease the overall cost and burden on the health-care system.
|
Early-Onset and Late-Onset Pneumonia: Influence of Duration of
Hospitalization on Etiologic Agent
|
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Early-onset HAP (occurring in the first 4 days of hospitalization)
is often caused by community-acquired pathogens such as
Haemophilus influenzae, Streptococcus pneumoniae,
or methicillin-susceptible S aureus (MSSA). In this context,
pathogens with strong intrinsic or acquired antimicrobial resistances
are rarely causative. In contrast, HAP developing 
5 days after
hospitalization ("late onset") is often caused by aerobic
Gram-negative bacilli (eg, P aeruginosa,
Enterobacteriaceae, or Acinetobacter) or MRSA.27
30
32
Late-onset pneumonia is due to P aeruginosa,
Acinetobacter, or MRSA in 30 to 71% of
cases.26
27
30
41
42
P aeruginosa and drug-resistant pathogens are uncommon in
the absence of previous antibiotic therapy or other risk factors. In
two studies of ventilator-associated pneumonia (VAP), P
aeruginosa was never implicated in 35 cases of early-onset VAP but
was the causative agent in 6 of 29 cases (28%)41
and 6 of
21 (29%) cases of late-onset VAP.27
One
study41
of 24 patients with early-onset VAP implicated
S pneumoniae, H influenzae, or S
aureus in 54% of VAP cases. Only 17% had Gram-negative
infections. In a separate study,27
S pneumoniae
and H influenzae were implicated in 25% of early-onset
VAP cases but were never found in late-onset VAP. French
investigators30
evaluated 135 consecutive episodes
of VAP and found that VAP occurring > 6 days after MV was caused by
P aeruginosa, A baumannii,
Stenotrophomonas maltophilia, or MRSA in 93 of 101
episodes (92%). In striking contrast, only 6 of 34 cases (18%) of VAP
occurring within the first 6 days were caused by these four pathogens.
All patients with these resistant organisms had received prior
antibiotics. In a separate study, P aeruginosa,
Acinetobacter, or Xanthomonas maltophilia were implicated in
20 of 87 cases (23%) of VAP occurring > 5 days after
MV.42
Mortality with these "high-risk" pathogens was
65%. In contrast, the mortality rate for other pathogens was 31%.
Other studies6
8
9
28
have confirmed higher mortality
rates when these pathogens are implicated.
Influence of Prior Antibiotics on the Causative Pathogen
Prior antibiotic use, particularly the use of broad-spectrum
antibiotics, is a critical risk factor for colonization or infection
with P aeruginosa, Acinetobacter, MRSA, and other
antibiotic-resistant bacteria. A sentinel study9
of VAP in
a French ICU noted that prior antimicrobial therapy markedly increased
the rate of VAP caused by P aeruginosa or Acinetobacter.
These two pathogens accounted for 65% of VAP cases among patients who
had previously received antibiotics, compared with only 19% of VAP
cases among antibiotic-naive patients.9
In a subsequent
study8
of 48 patients with VAP, these investigators
confirmed a higher mortality rate when VAP was caused by P
aeruginosa or Acinetobacter (71% mortality), as compared with
other pathogens (41% mortality). Spanish investigators28
substantiated the impact of prior antibiotic use on pathogens
responsible for VAP; in their study of 129 consecutive ICU patients
with VAP, P aeruginosa was the causative agent in 40% of
patients who had previously received antibiotics (within the preceding
10 days) but in only 5% of those who had not received antibiotics.
Community-acquired pathogens (eg, Gram-positive cocci or
H influenzae) were responsible for only 19% of VAP cases
among patients who had received prior antibiotics but for 77% of VAP
in antibiotic-naive patients. Consistent with earlier
reports,8
9
mortality was substantially higher when
P aeruginosa was the causative agent.28
Attributable mortality was only 4% among the antibiotic-naive cohort
vs 28% among patients who had previously received
antibiotics.28
No patient with VAP due to Gram-positive
cocci or H influenzae died. This heightened mortality
associated with prior antibiotic use reflects selection for more
virulent, inherently antibiotic-resistant organisms. Additional risk
factors associated with mortality in that study were advanced age, use
of corticosteroids, presence of shock, late-onset VAP, and
concomitant COPD. Others42
have confirmed that
late-onset VAP is often due to potentially antibiotic-resistant
pathogens, which independently influence mortality.
Prior antibiotic use is the most common risk factor for colonization
and infection with MRSA. In a retrospective study43
from
Japan, 31 of 32 patients (97%) with HAP due to MRSA had received prior
antibiotics. Rello and colleagues44
reviewed 49 patients
with VAP due to S aureus. All 11 with MRSA had received
prior antibiotics during that hospitalization. In contrast, only 8 of
38 patients (21%) with MSSA had received prior antibiotics. Other risk
factors for pneumonia due to MRSA include use of corticosteroids,
prolonged (> 6 days) MV, and COPD (Table 1
). Cranioencephalic trauma was more common (58%) among patients with
HAP due to MSSA than among those with MRSA (18%). A recent
study37
of 86 cases of bacteremic pneumonia due to S
aureus cited higher rates of prior antibiotic use (38%) among 32
patients with MRSA than among 54 cases of MSSA (7%). Mortality rates
are higher in patients with pneumonia caused by MRSA than in those with
pneumonia caused by methicillin-susceptible
strains.37
44
45
This heightened mortality likely reflects
more serious comorbidities rather than differences in the virulence of
the organisms.46
French investigators30
evaluated 135 consecutive episodes of VAP in an ICU to identify risk
factors for P aeruginosa, Acinetobacter, MRSA, and S
maltophilia. Independent risk factors for these pathogens included
prior antibiotic use (odds ratio [OR], 13.5), MV lasting > 6 days
(OR, 6.0), and prior use of broad-spectrum antibiotics (OR, 4.1). Of 39
patients with VAP caused by P aeruginosa, 37 patients
(90%) had previously received antibiotics and 35 (90%) had received
MV for > 6 days.
|
MV as a Risk Factor for HAP
|
|---|
The critical risk factors for developing HAP are summarized in
Table 2
. Prolonged (> 48 h) MV is the most important factor associated with
HAP, with pneumonia developing in 9 to 40% of patients who require
> 48 h of MV.4
7
8
9
26
27
47
48
49
However, HAP may occur
within 48 h of intubation.50
Risk factors for VAP
within the first 48 h following intubation as determined by
univariate analysis include large-volume aspiration, sedation,
decreased level of consciousness, Glasgow coma scale rating < 9,
emergency procedure, cardiopulmonary resuscitation, and
respiratory/cardiac arrest as cause of intubation.50
By
multivariate analysis, cardiopulmonary resuscitation (OR, 5.1) and
continuous sedation (OR, 4.4) remained as risk factors for HAP, while
prior antibiotic use was protective (OR, 0.29).
In a prospective study,27
HAP developed in 27 of
223 patients (12.1%) receiving MV but in only 1 of 135 patients
(0.7%) not receiving MV. In this study,27
independent
risk factors for VAP were low serum albumin level on hospital admission
(
2.2 g/dL), high maximum positive end-expiratory pressure ( 7.5
cm H2O), absence of antibiotic therapy,
upper-respiratory-tract colonization by Gram-negative bacilli, smoking,
and duration of MV. In a multicenter prospective study49
of 16 ICUs in Canada, VAP developed in 177 of 1,014 patients (17.5%)
requiring MV for > 48 h. The daily risk for VAP was highest (3.3%)
among patients who were in the ICU for 5 days and decreased to 1.3%
for patients who were in the ICU for 15 days.49
Decreasing
the risk of pneumonia from MV may be difficult, since the greatest risk
lies in the intubation itself. Increasing use of noninvasive
ventilatory methods51
52
in lieu of conventional MV may
ultimately lead to fewer cases of VAP, but this has yet to be
confirmed.
|
Role of Oropharyngeal, Tracheal, and Gastric Colonization
|
|---|
Several studies27
53
54
55
56
indicate that the
dominant mechanism responsible for HAP is colonization of the upper
respiratory tract (ie, oropharynx and trachea) with
pathogenic bacteria, followed by subclinical microaspiration, while
colonization of the GI tract plays a minor role. Oropharyngeal or
tracheal colonization with P aeruginosa or enteric
Gram-negative bacilli (EGNB) is common in ICU patients, increases with
length of hospitalization and severity of illness, and is an important
risk factor for HAP.53
54
55
In a prospective
study27
of VAP, the causative organism was recovered from
tracheal secretions in 29 of 31 patients (93.5%) before the onset of
pneumonia. Other sites were colonized less frequently, including the
oropharynx (42%), the nares (42%), and the stomach (36%). Gastric
colonization preceded tracheal colonization in only four cases.
In one prospective study,56
surveillance cultures of
oropharynx, trachea, and stomach were performed in 141 ICU patients
requiring MV for > 48 h. VAP due to EGNB or P aeruginosa
developed in 26 patients (18%). Prior colonization with the same
species was documented in the oropharynx in 85% and in the trachea in
96% of patients with VAP. Gastric colonization was not a risk factor
for VAP. Talon and colleagues54
prospectively assessed
rates of colonization with P aeruginosa among 190 patients
requiring MV in a surgical ICU. During the ICU stay, P
aeruginosa grew from tracheal aspirates of 44 patients (23%), 13
of whom developed pneumonia. Consistent with other
studies,27
56
the lower respiratory tract (not the
GI tract) was the first site of colonization, and the contribution of
environmental sources was small. Risk factors for tracheal or bronchial
colonization with P aeruginosa included length of
hospitalization of > 10 days, prior use of third-generation
cephalosporins, surgical emergencies, and alcoholism. Multivariate
analysis revealed two risk factors for pseudomonal pneumonia: treatment
with metronidazole (OR, 16) and COPD (OR, 37.9).
A recent prospective study26
of 48 head-injured patients
requiring MV found a strong relationship between upper-airway
colonization and subsequent colonization of the tracheobronchial tree.
During ICU stay, colonization with P aeruginosa or EGNB
increased significantly at all sites (ie, upper airway,
lower airway, stomach).26
Previous use of antibiotics
increased the risk of colonization with EGNB or P
aeruginosa (OR, 6.1) but protected against colonization with
S pneumoniae, H influenzae, or S
aureus (OR, 0.20).26
Factors associated with
late-onset VAP included the following: tracheobronchial colonization
with EGNB or P aeruginosa (OR, 5.4), duration of MV (OR,
7.7), and prolonged antibiotic treatment (OR, 11.1).26
By
multivariate analysis, only the use of antibiotics for > 24 h within
the preceding 15 days was a risk factor for late-onset pneumonia (OR,
9.2).
Although these various studies suggest that gastric colonization is not
a dominant factor, it is undoubtedly involved in some cases of VAP.
Direct microaspiration of gastric contents to lower airways,
particularly in the supine position, may cause VAP in some
patients.32
57
Strategies that alkalinize the GI tract may
promote colonization and infection.57
58
59
The use of
antacids or histamine H2-receptor antagonists
appears to increase the risk of HAP when compared with
sucralfate,57
58
59
60
but the clinical importance of this
finding is disputed.59
60
61
62
|
Other Potential Causes of HAP
|
|---|
Although uncommon, inhalation of contaminated aerosols from
environmental sources such as nebulizers or ventilator tubing has been
implicated in epidemics of infections due to diverse
pathogens.32
54
57
Inadequate hand washing by medical
personnel may facilitate the spread of resistant
bacteria.32
53
Nosocomial sinusitis may also cause VAP. In
three studies63
64
65
of patients requiring MV, the
incidence of VAP ranged from 29 to 67% among patients with sinusitis,
compared with 5 to 43% in patients without sinusitis. The same
microorganism was isolated from lung and sinuses in 38 to 56% of
patients.63
64
65
Sinusitis may be less common in
orotracheally vs nasotracheally intubated patients.65
Aggressive search for and treatment of sinusitis may reduce the
incidence of VAP. Hematogenous spread from extrapulmonary sites of
infection (eg, wounds, soft tissue, or the urinary tract) is
a well-documented but less common cause of HAP.59
|
ARDS
|
|---|
VAP complicates ARDS in 34 to 60% of patients, typically
> 7 days after initiation of MV.7
66
67
Clinical and
radiographic criteria cannot distinguish VAP from progression of the
fibroproliferative phase of ARDS.67
Chastre and
colleagues7
evaluated 243 consecutive patients who
required MV for > 48 h. VAP developed in 31 of 56 patients (55%)
with ARDS but in only 53 of 187 (28%) patients without ARDS. The
actuarial risk of VAP in patients with ARDS was 14% at 10 days and
58% by day 20. Another study66
prospectively examined 30
patients with severe ARDS; 24 episodes of VAP developed in 18 patients
(60%) at a mean of 9.8 days after the onset of ARDS. Antecedent
colonization of the lower respiratory tract was detected in 18 episodes
in 14 patients, 16 of which developed into VAP within 2 to 6 days.
Thus, colonization preceded VAP in 16 of 24 cases (67%). Recurrent
infections were caused by the same infecting organism.
Pathogens that cause VAP-complicating ARDS are often highly resistant,
reflecting selection pressure from prior antibiotic use.7
P aeruginosa is implicated in 20 to 43% of cases, MRSA in
15 to 28%, and Acinetobacter in 6 to 25%.7
66
67
Mortality rates of VAP in patients with ARDS are high
(> 50%).7
66
67
|
Role of Prophylactic Antibiotics
|
|---|
The use of prophylactic antibiotics to prevent HAP is
controversial. Some studies27
50
have documented a
protective effect of antibiotics (ie, reduced risk of HAP)
among high-risk ICU patients. In one randomized controlled
trial,68
two 1.5-g doses of cefuroxime given 12 h apart
reduced the incidence of VAP and shortened ICU stay in a cohort of 100
ICU patients with closed head injuries or stroke who required MV for
> 3 days. VAP developed in 12 of 50 patients (24%) receiving
cefuroxime compared with 25 of 50 patients (50%) in the control group
not receiving prophylactic antibiotics. Brief prophylaxis with a single
antibiotic may have a role for focused indications (eg,
head-injured patients in ICUs), but liberal and prolonged use of
prophylactic antibiotics may contribute to acquisition of P
aeruginosa, Acinetobacter, and other potentially resistant
pathogens.26
28
30
54
69
Aggressive multiagent
prophylactic regimens aimed at reducing the incidence of HAP and
regimens employing nonabsorbable antibiotics, an oral adhesive
antimicrobial paste, and parenteral agents to reduce GI tract
colonization and infection with EGNB failed to influence mortality or
length of hospital stay.69
Such regimens are expensive and
logistically difficult and may actually increase antimicrobial
resistance. Additional studies are required to determine whether
prophylactic antibiotic therapy can reduce morbidity, mortality, or
costs in selected groups of patients. Additional nonantibiotic
preventive strategies to prevent HAP are promising and are reviewed
elsewhere.32
59
|
Empiric Treatment of HAP
|
|---|
Initial inadequate antimicrobial therapy for HAP is an independent
risk factor for increased mortality.11
12
Prompt use of
appropriate antibiotics for HAP is critical to optimization of outcome.
Because of the high mortality associated with HAP, initial therapy
(while awaiting results of cultures) must be empiric and cover a broad
spectrum of possible pathogens. Demographics, host factors
(eg, severity and acuity of illness, comorbidities),
duration of hospitalization, prior antibiotic use, and antimicrobial
resistance patterns within the hospital or ICU need to be taken into
account when selecting antibiotics for empiric treatment. Rates of
resistance are influenced by type and size of hospital, ICU or non-ICU
setting, anatomic site of isolation, and patterns of prior antibiotic
use within individual patients or institutions.17
70
Empiric treatment for HAP occurring within the first 4 days of
hospitalization in patients without severe comorbidities or exposure to
antibiotics need not encompass P aeruginosa or potentially
resistant pathogens. However, broader-spectrum coverage (to include
these pathogens) is advised for HAP in critically ill ICU patients
requiring prolonged MV or those who have received prior antibiotics. In
this context, we combine an antipseudomonal ß-lactam plus an
aminoglycoside (if no contraindications to aminoglycoside use exist).
Alternatively, a fluoroquinolone can be substituted for the
aminoglycoside.
|
Treatment of Pseudomonal HAP
|
|---|
Because of the high mortality rates among patients with
pseudomonal HAP, most investigators use two antibiotics with in
vitro activity against P aeruginosa.6
P aeruginosa is intrinsically resistant to most antibiotics.
The most active agents (> 80% activity) are the carbapenems,
piperacillin, cefepime, ceftazidime, ciprofloxacin, and
aminoglycosides.17
71
72
The optimal agent(s) for
pseudomonal HAP is not clear, as randomized therapeutic trials have not
been done (to my knowledge). Data have been extrapolated from subsets
of patients with pseudomonal pneumonia enrolled in HAP
studies5
73
74
or from retrospective
reviews.75
Efficacy of antibiotic therapy is clouded by
small sample sizes and heterogeneous patient populations. Several
studies5
75
76
have shown that monotherapy for pseudomonal
HAP is associated with a high rate of clinical failures, relapses,
mortality, and development of resistance in 30 to 50% of patients. A
multicenter trial5
randomized 405 patients with severe
pneumonia (78% were nosocomial; 79% required MV) to monotherapy with
either imipenem/cilastatin, 1 g q8h, or ciprofloxacin, 500 mg q8h.
Clinical responses occurred in 59% with imipenem/cilastatin and in
69% with ciprofloxacin. However, when P aeruginosa was
isolated, only 41% responded to imipenem/cilastatin and 33% responded
to ciprofloxacin. Resistance developed in 53% of patients treated with
imipenem/cilastatin and in 33% of patients treated with ciprofloxacin.
Other studies74
77
78
using cephalosporin-based
regimens have noted high failure rates when Pseudomonas was
responsible for HAP. One study77
randomized ICU patients
with pneumonia to treatment with ceftazidime or cefpirome (with or
without a second agent). Of 49 patients with pseudomonal HAP, 18
patients (37%) died. Other randomized trials of HAP using ceftazidime
plus an aminoglycoside cited clinical responses in only 33% of
patients74
to 50% of patients78
when P
aeruginosa was the causative agent.
Theoretically, combining antimicrobial agents that act at different
sites in a bacterial cell may limit resistance. However, the advantage
of adding a second agent has not been proven in clinical trials. A
retrospective review75
of 38 consecutive ICU patients with
VAP due to P aeruginosa found no survival benefit with
combination antibiotic therapy. Overall mortality was 69%
(attributable mortality was at least 38%). Nine of the 10 patients
whose deaths were attributed to P aeruginosa had received
combination therapy with a ß-lactam and an aminoglycoside. Mortality
was lower in patients receiving ciprofloxacin as part of the regimen.
The impact of antibiotic choice could not be ascertained, since other
factors (ie, multiorgan failure, septic shock, and APACHE
[acute physiology and chronic health evaluation] III scores) were
independently associated with mortality.75
Rello and
colleagues6
prospectively studied 30 patients with
pseudomonal VAP. All four patients receiving inappropriate therapy
died. The remaining 26 patients received combination therapy with
amikacin plus either piperacillin, ciprofloxacin, or
imipenem/cilastatin. In this group, overall mortality was 42%,
although attributable mortality was only 14%. Again, the influence of
antibiotic regimen on mortality in this study6
was not
clear, since independent risk factors for mortality included severe
sepsis, severe comorbidities, multiple organ failure, residence in
ICUs, and increasing APACHE II scores. Recurrent infection in patients
with P aeruginosa HAP is common and usually reflects
relapse due to persistent infection rather than a new
infection.79
Persistent or relapsing disease may occur
despite use of a combination of agents to which P
aeruginosa is susceptible in in vitro
testing.6
75
79
|
Combination of Aminoglycoside and ß-Lactam Antibiotics
|
|---|
Aminoglycosides are not adequate as monotherapy for treating HAP,
but the combination of an aminoglycoside plus a ß-lactam may extend
the spectrum of activity, achieve synergy, and (theoretically) reduce
the emergence of resistance. Despite extensive clinical use, the
adjunctive benefit of aminoglycosides in treating HAP is controversial.
Aminoglycosides penetrate poorly into bronchopulmonary secretions and
the lung, are inactivated under conditions of low pH, and have serious
potential toxicities (particularly nephrotoxicity).80
Optimization of aminoglycoside dosing and pharmacodynamics may be
critical to successful treatment of severe HAP caused by Gram-negative
bacteria. In one series81
of 78 patients with HAP,
clinical response to therapy was more rapid when target ratios of
maximal concentration of aminoglycoside in serum to the minimal
inhibitory concentration were achieved.
Data supporting incremental benefit of aminoglycosides for the
treatment of HAP are sparse. One nonrandomized prospective
study82
of 200 patients with P aeruginosa
bacteremias cited lower mortality rates with combination therapy than
with monotherapy (Table 3 ). The most common antibiotic combinations used were
piperacillin/tobramycin (25%) and ticarcillin/tobramycin (24%). Among
the subset of patients with pseudomonal pneumonia, the incremental
benefit of combination therapy was striking (Table 3)
. A
controlled, multicenter, randomized European trial83
of
129 patients with cancer, granulocytopenia, and Gram-negative
bacteremia supported an adjunctive role for an aminoglycoside. In that
study, patients were randomized to one of three treatment arms (Table 4
). Clinical response rates were highest with ceftazidime plus
long-course (9 days) amikacin treatment. The benefit of the
aminoglycoside was more pronounced when P aeruginosa was
implicated. Among patients with pseudomonal bacteremias, only 5 of 13
patients (38%) responded to ceftazidime/short-course amikacin
treatment, whereas 8 of 9 patients (89%) responded to
ceftazidime/long-course amikacin treatment.
View this table:
[in this window]
[in a new window]
|
Table 3.. Survival in Subsets of Patients With P
aeruginosa Bacteremia: Combination Antibiotic Therapy Compared
With Monotherapy*
|
|
In contrast, two retrospective studies84
85
of bacteremias
due to P aeruginosa cited similar mortality rates with
monotherapy or combination therapy. However, few patients had
pneumonia, so these data are not readily applicable to pseudomonal HAP.
Monotherapy may be adequate therapy for HAP due to Enterobacteriaceae
and susceptible organisms but is suboptimal for infections due to
P aeruginosa or Acinetobacter.5
19
20
In a
randomized trial of 405 patients with severe pneumonia, monotherapy
with ciprofloxacin (400 mg q8h) or imipenem (1 g q8h) was equivalent in
overall clinical response rates (69% and 59%, respectively). Response
rates against Enterobacteriaceae were higher (93% with ciprofloxacin;
65% with imipenem) than against P aeruginosa (only 33% and
41%, respectively).5
Furthermore, P aeruginosa
isolates acquired resistance during therapy in 33% of patients treated
with ciprofloxacin and in 53% of patients receiving
imipenem/cilastatin.
|
Carbapenems
|
|---|
The carbapenems (eg, imipenem/cilastatin, meropenem)
have broad-spectrum activity and resist degradation by ß-lactamases
capable of hydrolyzing penicillins or cephalosporins.16
Despite excellent in vitro antimicrobial activity, response
rates in pseudomonal HAP with imipenem/cilastin monotherapy are
suboptimal (40 to 80%); resistance, which may not be prevented by the
addition of an aminoglycoside,86
develops in up to 53% of
patients treated with imipenem/cilastatin.5
73
Liberal use
of imipenem may result in highly resistant strains of P
aeruginosa,72
Acinetobacter,87
and
Burkholderia cepacia.88
89
90
The risk for
emergence of resistance among P aeruginosa is higher with
imipenem/cilastatin than with other antibiotic classes.91
In a recent study91
of 271 patients with infections caused
by P aeruginosa, resistance developed in 10.2% of patients
receiving antibiotic therapy. Hazards ratios for the emergence of
resistance to individual antibiotics were as follows: ceftazidime, 0.8;
piperacillin, 5.2; ciprofloxacin, 5.2; and imipenem, 44. Given the
propensity for evolution of resistance, we reserve imipenem/cilastatin
for treatment of infections in which resistance to other ß-lactam
antibiotics is proven or suspected.
Data evaluating meropenem for HAP are limited. In one multicenter
trial,92
patients with HAP were randomized to treatment
with meropenem (1 g q8h) alone or ceftazidime (2 g q8h) plus
tobramycin. Clinical responses were cited in 56 of 63 patients (89%)
receiving meropenem and in 42 of 58 patients (72%) receiving
ceftazidime/tobramycin. P aeruginosa was eradicated in 12 of
15 pathogens (80%) isolated from patients receiving meropenem.
Additional studies are required to assess the role of meropenem for
pseudomonal HAP.
A clinical advantage associated with the use of carbapenems is the lack
of an inoculum effect. The inoculum effect is a laboratory phenomenon
in which an increase in the minimum inhibitory concentration of a given
antibiotic results from an increase in the number of organisms
inoculated.93
Imipenem and meropenem have been shown to be
unaffected by such an effect at high inocula.94
95
|
Cephalosporins
|
|---|
Numerous studies (as reviewed by Lynch96
) have
cited high cure rates (> 80%) with third-generation cephalosporins
alone for community-acquired pneumonia or HAP. However, monotherapy
with a cephalosporin may not be adequate for severe HAP due to P
aeruginosa, Acinetobacter, or isolates displaying high-grade
resistance to ß-lactam antibiotics. When P aeruginosa is a
cause of HAP, failure rates with cephalosporins (alone or combined with
aminoglycosides) are high (often > 50%).74
77
78
Further, liberal use of third-generation cephalosporins is associated
with emergence of resistance to ß-lactamases among
Enterobacter35
and extended-spectrum ß-lactamases among
Enterobacteriaceae.36
97
These resistance trends may be
curtailed by switching from cephalosporins to ß-lactam/ß-lactamase
inhibitors.36
97
Perhaps of greater use is the fourth-generation cephalosporin
cefepime. Effective against Gram-positive and Gram-negative aerobic
bacteria, cefepime not only has a broader spectrum of antimicrobial
activity than the third-generation cephalosporins, it also has a
reduced affinity for most ß-lactamases.98
99
Cefepime is
thus less susceptible to hydrolysis and degradation by ß-lactamases
compared with other cephalosporins.98
99
|
Combination Therapy With ß-Lactam and Fluoroquinolones
|
|---|
Strategies combining a ß-lactam antibiotic with a
fluoroquinolone with antipseudomonal activity (eg,
ciprofloxacin, levofloxacin) are of interest, but clinical data
employing such combinations are limited. Ciprofloxacin is the most
active fluoroquinolone in vitro against P
aeruginosa (based on minimal inhibitory
concentrations)100
101
; however, the activity of
levofloxacin may be adequate based on concentration-time curve and
pharmacodynamics.102
While extensive clinical experience
has been gained with ciprofloxacin for HAP,5
103
104
data
evaluating levofloxacin for HAP are limited. Ciprofloxacin monotherapy
may be adequate for Enterobacteriaceae and other selected pathogens,
but it is not adequate for infections due to P aeruginosa.
In a study of 47 ICU patients with Gram-negative HAP, 63% responded to
ciprofloxacin (concomitant antibiotics were administered in
42%).104
However, when P aeruginosa was
isolated, the organism persisted in 10 of 13 patients and resistance
developed in all 10 during therapy. Overzealous use of fluoroquinolones
may lead to higher rates of resistance to
fluoroquinolones105
as well as cross-resistance to other
antibiotic classes. The high rates of clinical failures and evolution
of resistance observed with P aeruginosa5
104
are not unique to ciprofloxacin but suggest that monotherapy,
regardless of agent, is not adequate to treat this pathogen.
|
Piperacillin/Tazobactam
|
|---|
Piperacillin/tazobactam, a ureidopenicillin with excellent
activity against P aeruginosa,30
71
may be used
for serious nosocomial infections (including HAP). For empiric therapy
of HAP, this agent should be combined with an aminoglycoside or
fluoroquinolone until P aeruginosa has been excluded as the
causative agent. Three randomized trials73
74
78
evaluated piperacillin/tazobactam (with or without an aminoglycoside)
as therapy for HAP. One study74
from 27 ICUs in France
randomized 127 patients with VAP to treatment with amikacin plus either
piperacillin/tazobactam, 4.5 g qid, or ceftazidime, 1 g qid.
Clinical cure rates were 51% in the piperacillin/tazobactam cohort,
compared with 36% of patients treated with ceftazidime/amikacin (not
significant). Bacteriologic failures were more common in
ceftazidime-treated patients (51%) compared with those treated with
piperacillin/tazobactam (33%). However, 28-day mortality rates were
similar (16% and 20%, respectively). When P aeruginosa was
isolated, success rates were 40% or 39% with piperacillin/tazobactam
or ceftazidime, respectively. Lower-respiratory-tract superinfections
were more common with ceftazidime (21%) than with the
piperacillin/tazobactam plus amikacin combination (9%).
A multicenter trial78
in the United States
randomized 300 patients with HAP to combination therapy with tobramycin
plus either piperacillin/tazobactam, 3.375 g q4h, or ceftazidime,
2 g q8h. The aminoglycoside therapy could be discontinued at the
discretion of the investigator once a pathogen was known. Among
evaluable patients, final clinical responses, overall microbiological
response rates, and P aeruginosa eradication were higher
with piperacillin/tazobactam than with ceftazidime (Table 5
). Mortality was 7.7% in piperacillin/tazobactam-treated patients
compared with 17% with ceftazidime (p = 0.03).
View this table:
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|
Table 5.. Piperacillin/Tazobactam Plus Tobramycin Compared With
Ceftazidime Plus Tobramycin in Lower-Respiratory-Tract
Infections*
|
|
Another trial73
in Switzerland randomized patients with
HAP to monotherapy with piperacillin/tazobactam, 4.5 g qid, or
imipenem/cilastatin, 0.5 g qid. Among 154 evaluable patients,
clinical success rates were similar with piperacillin/tazobactam and
imipenem/cilastatin (Table 6
). However, among 45 patients with pseudomonal HAP, a higher percentage
of patients responded to treatment with piperacillin/tazobactam
compared with imipenem/cilastatin (Table 6) . Antimicrobial resistance
developed in six patients treated with imipenem/cilastatin but in only
one patient treated with piperacillin/tazobactam. Combined, the results
from the studies cited above suggest that piperacillin/tazobactam is at
least as effective (and possibly more effective) than ceftazidime or
imipenem/cilastatin for HAP, particularly when P aeruginosa
is isolated.
|
Conclusion
|
|---|
HAP is a serious problem in the ICU, leading to lengthened
hospital stays, higher health-care costs, and increased rates of
morbidity and mortality. The problem is perpetuated by the expanding
number of opportunistic antibiotic-resistant pathogens that commonly
cause HAP. Prolonged MV is a critical risk factor for HAP. In addition,
prior use of antibiotics and inadequate antimicrobial therapy increases
the risk of acquiring antimicrobial-resistant pathogens. P
aeruginosa is one of the most difficult to treat of those
pathogens responsible for HAP; it may contain both intrinsic and
acquired forms of antibiotic resistance. Empiric treatment of
late-onset HAP should include antipseudomonal agents until P
aeruginosa is excluded as the causative agent.
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Appendix 1
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TOP
Abstract
Introduction
