(Chest. 2001;119:412S-418S.)
© 2001
American College of Chest Physicians
Guidelines and Critical Pathways for Severe Hospital-Acquired Pneumonia*
Stanley Fiel, MD, FCCP
*
From MCP Hahnemann School of Medicine, Philadelphia, PA.
Correspondence to: Stanley Fiel, MD, FCCP, Professor of Medicine, MCP Hahnemann School of Medicine, 3300 Henry Ave, Philadelphia, PA 19129
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Abstract
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Hospital-acquired pneumonia (HAP) is associated with high morbidity
and mortality. Early, appropriate, and adequate empiric therapy can
increase the chance of survival. In 1995, the American Thoracic Society
provided guidelines for the initial treatment of immunocompetent HAP
patients, which is one of the principal HAP management approaches
available to physicians today. However, these guidelines have several
important limitations, including a lack of recommendations for duration
of therapy and no recognition of newer drugs such as cefepime,
trovafloxacin, and meropenem. Furthermore, they fail to distinguish
among similar compounds (ie, ß-lactam/ß-lactamase
inhibitor combinations) or to recommend specific antibiotics. The
clinician using these guidelines needs to address local patterns of
antimicrobial resistance, especially in ICUs. Effective computerized
antibiotic management programs that incorporate information on local
patterns of antimicrobial resistance can assist physicians in empiric
therapy decision making, improve patient quality of care, and reduce
medical costs.
Key Words: American Thoracic Society guidelines • antibiotic resistance • antibiotics • empiric therapy • hospital-acquired pneumonia • nosocomial pneumonia • patient quality of care
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Introduction
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Hospital
-acquired pneumonia (HAP) is the second most common nosocomial infection
in the United States, but it has the highest morbidity and
mortality.1
Between one third and one half of all HAP
patient deaths are directly attributable to the nosocomial infection,
with mortality rates even higher if bacteremia or certain pathogens
(eg, Pseudomonas aeruginosa or Acinetobacter) are
involved.1
Clinical studies have led to a consensus that
empiric antibiotic therapy can reduce the HAP patient mortality rate
and should be the preferred treatment strategy.2
3
4
5
National guidelines for initial empiric treatment of HAP patients, such
as those proposed by the American Thoracic Society (ATS) in 1995, are
available to assist physicians in the management of their
patients.1
The ATS HAP management recommendations have
provided helpful guidance since 1995, but the guidelines need updating.
Furthermore, some gaps need to be addressed. For example, the original
guidelines do not provide a suggested approach for incorporating
information on local patterns of antibiotic resistance into the HAP
management program of a given hospital. They do not address the growing
role of computers as the premiere vehicles for information
dissemination, nor do they recognize how computer-assisted
anti-infectives management programs can effectively assist clinicians
in their decision making for HAP patients.6
7
This article
will review the 1995 ATS guidelines and key supporting clinical data
for the initial empiric treatment of HAP patients, as well as some of
the limitations of the ATS guidelines and the potential use of
computers in patient care.
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Effective Therapy Reduces HAP Mortality
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Early, appropriate, and adequate antibiotic therapy has been found
to reduce HAP patient mortality rates in clinical studies. A patient
with a diagnosis of nosocomial pneumonia who receives appropriate
antibiotic therapy is more than twice as likely to survive (Fig 1
).2
3
4
A more recent study5
not only supports
those data but further identifies the timing and adequacy of therapy as
equally important factors. Patients with ventilator-associated
pneumonia who receive early and adequate antibiotic therapy before
completion of invasive diagnostic testing (bronchoscopy with BAL) have
the lowest mortality rates, whether or not their HAP is subsequently
confirmed by microbiological data (Fig 2
).5
However, altering therapy after microbiological data
become available has no effect on mortality rate. Patients who
initially receive inadequate therapy that is changed in response to
positive diagnostic test results have outcomes similar to those of
patients who start and continue with inadequate therapy (Fig 2)
.5
Since HAP diagnosis remains difficult and
controversial and the timing of antibiotic therapy in relation to
clinical recognition of the pneumonia is a major factor influencing
mortality, initial empiric therapy is the best response to the
challenge.1
5
8
9
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Review of ATS Guidelines
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In 1995, the ATS, following an extensive review of available
information on HAP, published practical guidelines for the initial
empiric treatment of HAP.1
An HAP clinical management
algorithm was developed using information on disease severity, the
presence of risk factors for specific organisms, and time of onset of
HAP (
5 days after hospital admission). All these factors can
influence the spectrum of likely HAP pathogens.1
An
overview of the ATS algorithm for HAP patient classification and
treatment recommendations is presented in Figure 3
.
Patients who have mild-to-moderate HAP who are free of risk factors for
specific pathogens, and patients with a diagnosis of early-onset severe
HAP are presumed to be infected with one or more microorganisms of the
core group (ATS 1 in Fig 3
and Table 1
). This core group of pathogens includes the usual enteric Gram-negative
bacilli suspects, as well as methicillin-sensitive Staphylococcus
aureus (MSSA) and Streptococcus
pneumoniae.1
The ATS-recommended monotherapy for
those HAP patients include second-generation cephalosporins,
nonpseudomonal third-generation cephalosporins (cefotaxime or
ceftriaxone), or a ß-lactam/ß-lactamase inhibitor combination
(ampicillin/sulbactam, ticarcillin/clavulanate, or
piperacillin/tazobactam). In those patients allergic to penicillin, a
fluoroquinolone (such as ciprofloxacin) may be employed if S
pneumoniae has been excluded. Alternatively, aztreonam may be
given as monotherapy or in combination with clindamycin.1
The presence of specific risk factors (Table 2
) in patients with mild-to-moderate HAP may signal the involvement of
additional organisms such as Legionella, P aeruginosa,
S aureus, or anaerobes in addition to the core pathogen(s)
(ATS 2 in Fig 3
and Table 1 ).1
These risk factors include
patient-related conditions, infection control-related problems, and
intervention-related alterations in host defenses or bacterial
exposure.1
The ATS-recommended therapy for this patient
group is a combination of anti-infective agents directed toward the
core group of pathogens and the specific risk factor-dependent
organism.1
However, in some situations, a
ß-lactam/ß-lactamase inhibitor combination may be sufficient to
combat both the risk factor-associated organism as well as the core
pathogen(s).1
Although a core pathogen, S
aureus is of special concern in HAP patients with diabetes, coma,
head injury, renal failure, or recent influenza.1
In those
patients, the ATS guidelines suggest that additional treatment with
vancomycin be considered until methicillin-resistant S
aureus (MRSA) is excluded.1
The definition of severe HAP is essentially the same as that developed
for severe community-acquired pneumonia (Table 3
).1
10
Patients with severe HAP generally require admission
to an ICU.1
Patients in the ICU for mechanical
ventilation, or with severe sepsis or acute renal failure, also have
increased risk of developing severe HAP.1
If the onset of
severe HAP is within 5 days of hospital admission, patients who do not
present with additional pathogen-specific risk factors are likely to be
infected with only the core organism(s) and should be treated
accordingly (ATS 1 in Fig 3
and Table 1
).1
However, if
severe HAP develops 
5 days after hospitalization, several highly
resistant Gram-negative organisms, such as P aeruginosa and
Acinetobacter, are likely to be involved in addition to the core
pathogen(s) (ATS 3 in Fig 3
and Table 1
).1
This group of
additional pathogens should also be suspected in patients with severe
HAP who present with risk factors (Table 2)
, regardless of time of
onset.1
For patients classified under ATS 3, the group strongly recommends the
addition of antimicrobial agent(s) effective against P
aeruginosa and Acinetobacter to a core antibiotic.1
Antibiotics effective against such pathogens include the
antipseudomonal penicillins, either singly or in combination with a
ß-lactamase inhibitor, some third-generation cephalosporins,
aztreonam, imipenem, aminoglycosides, and
fluoroquinolones.1
Despite these guidelines, if resistance
to the quinolones has been a problem in a particular hospital, a
combination of a ß-lactam/ß-lactamase inhibitor with an
aminoglycoside instead of a fluoroquinolone may be preferred, even in
patients with renal failure. Although the guidelines suggest initial
treatment with a combination of anti-infectives, some patients may be
able to complete therapy with only one antimicrobial agent, especially
if P aeruginosa and other resistant pathogens are not
present and the patient is improving clinically.1
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Limitations of the ATS Guidelines
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The ATS guidelines for initial treatment of immunocompetent HAP
patients, although thoroughly considered, have several important
limitations. Controversy persists over the reliability of methods
(eg, clinical examination vs invasive microbiological
techniques) used to diagnose pneumonia and the role of invasive
diagnostic procedures to quantitate microbial load in patients with
clinical HAP.1
Questions regarding who should be tested
and how frequently, the use of specific bacterial counts for defining
pneumonia, the possibility of false-negative results due to previous
antibiotic therapy, and the reliability of results from the technically
demanding invasive diagnostic procedure are still being
debated.1
The importance of invasive diagnostic procedures
in the management of HAP patients is questionable, since clinical
studies demonstrating the value of invasive diagnostic testing in place
of clinical diagnosis are lacking and because of the proven benefit of
initiating empiric therapy before the causative agent(s) are cultured
and identified.1
The optimal length of antibiotic therapy for HAP needs to be addressed
in clinical studies.1
Except for certain situations
(eg, the presence of multilobar involvement, malnutrition,
severe debilitation, cavitation, a necrotizing Gram-negative bacillus
pneumonia, or an MSSA or Haemophilus influenzae
pneumonia), the ATS guidelines provide no recommendation on the
duration of therapy.1
The ATS guidelines of 1995 have several limitations in the discussion
of antibiotics and recommended therapies. Since the guidelines were
published in 1995 without update, they do not include newer therapies
(eg, cefepime, meropenem, and trovafloxacin) that may be
effective and/or associated with less resistance. For those antibiotic
families containing multiple compounds (eg, cephalosporins,
ß-lactam/ß-lactamase inhibitor combinations), the ATS made no
recommendations or attempts to distinguish among the available options,
either within any particular antibiotic group or between groups, unless
supported by clinical study data.1
The ATS guidelines were
also based on the expected antimicrobial spectra of commonly employed
antibiotics, while acknowledging that few clinical trials have
evaluated the efficacy or superiority of their suggested
protocols.1
However, important data from recent studies
should be evaluated and the information incorporated into the
guidelines.
The heavy use of third-generation cephalosporins and aztreonam is
associated with the emergence of extended-spectrum ß-lactamases,
resulting in significant transferable drug-resistance
problems.11
In contrast, drugs like
piperacillin/tazobactam, which may be substituted for a cephalosporin
in the treatment of patients with moderate-to-severe HAP, are not
associated with extended-spectrum ß-lactamase
emergence.11
Piperacillin/tazobactam has emerged as an
important broad-spectrum antibiotic combination that is active against
Gram-positive aerobes, including enterococci, Gram-negative aerobes,
and anaerobes and may offer the convenience of monotherapy in certain
situations. This ß-lactam/ß-lactamase inhibitor combination drug
coupled with tobramycin has been shown in clinical trials to have
greater efficacy and a more favorable bacteriologic response for both
unimicrobial and polymicrobial pneumonias than ceftazidime plus
tobramycin.12
Those favorable responses translated into
significantly less mortality in the piperacillin/tazobactam therapy
group than in the ceftazidime group.
Studies since the 1980s have well documented the increase in antibiotic
resistance and nosocomial outbreaks worldwide.13
14
15
16
In
hospitals in the United States, Canada, and Latin America, the most
common bacterial pathogens associated with bloodstream infection were
S aureus, Escherichia coli, and
coagulase-negative staphylococci; the most frequent Gram-negative
organisms were E coli, Klebsiella species, and P
aeruginosa (Table 4
).16
Of special concern are antibiotic-resistant
microorganisms encountered in the ICU. A recent analysis of antibiotic
susceptibility among aerobic Gram-negative bacilli in European ICUs
indicated significant resistance to multiple compounds and the need for
more effective strategies to control the selection and spread of
resistant organisms.15
These findings highlight the need
for a faster means of incorporating information on local patterns of
resistance and patterns in particular hospital services (eg,
the ICU or burn unit) into the global framework of the guidelines. This
step is vital in order to maintain effective antimicrobial therapies
and is of special concern for HAP and ICU patients because of their
high proportion of mortalities.
View this table:
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[in a new window]
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Table 4. Frequency of Occurrence of Bacterial Pathogens
Associated With Bloodstream Infection in Medical Centers in the United
States, Canada, and Latin America*
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Computer-Assisted Anti-infectives Management Programs
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Many hospitals have established their own surveillance programs to
monitor pathogen distribution and resistance patterns.
Computer-assisted antibiotic management programs can facilitate the
dissemination of such information to physicians for immediate use in
therapy decision making. One community teaching hospital employed a
computer-assisted antibiotic management program with guidelines devised
by local clinicians for a 7-year period and found antibiotic use had
improved while costs were reduced, and adverse drug reactions were
minimized while the emergence of antibiotic-resistant pathogens
stabilized.6
In a follow-up study, in which a 2-year preintervention period was
compared with a 1-year intervention term, the use of a computerized
anti-infectives management program was found to improve the quality of
patient care and reduce costs.7
The study populations for
both periods were similar, with 10% of patients having respiratory
tract infections. Although the distribution of pathogens did not vary
between periods, there were increases in bacteremias and infections by
P aeruginosa and enterococcal species and decreases in
infections caused by S aureus and E coli during
the intervention period.7
Other outcomes showing
significant changes during the intervention period included the
following: percentage of patients receiving anti-infective agents
(increased), number of adverse drug reactions (decreased), number of
susceptibility-mismatch alerts (decreased), number of drug-allergy
alerts (decreased), number of excessive-drug-dosage alerts (decreased),
and average number of days receiving an excessive anti-infective dosage
(decreased).7
During the intervention period, patients
received an average of 4.7 fewer doses of anti-infective agents
(p = 0.042), had an average decrease of $81 in the cost of
anti-infective agents (p = 0.079), and received an excessive dose of
an anti-infective for an average of 2.9 fewer days.7
Implementation of the program also had a significant impact on factors
affecting cost. A comparison of means adjusted for age, sex, computer
severity index score on admission to unit, medical service, and
mortality indicated reductions in the number of doses of anti-infective
agents, the cost of the anti-infective agents, total length of stay,
and total cost of hospitalization.7
Physicians were
permitted to override the management program’s suggestions, and all
those who overrode had valid reasons for doing so. However, when
suggestions were overridden, cost savings were negated, sometimes to
the point to which preintervention-period costs were
less.7
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Summary
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Despite our improved understanding of the pathogenesis, diagnosis,
therapy, and prevention of HAP, it remains the leading cause of
mortality stemming from nosocomial infections. Early, adequate, and
appropriate empiric antibiotic therapy can save the lives of more than
half of all HAP patients. The 1995 ATS guidelines for initial empiric
treatment of HAP are perhaps the best currently available. However,
they are limited in several important ways, most notably in their
failure to address the need to incorporate information on local
patterns of antibiotic resistance. Computer-assisted antibiotic
management programs can effectively aid clinicians in their
decision-making processes, resulting in improved patient quality of
care and reduced medical costs.
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Appendix 1
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Dr. Stanley Fiel:
In a recent JAMA article
written by Hanberger et al,15
antibiotic susceptibility
among aerobic Gram-negative bacilli was looked at in ICUs in five
European countries. Resistance was either relatively high or higher
than I would have expected in this particular group of European
countries. What are some of the reasons for this observation that you
may know about through your surveillance?
Dr. Ronald Jones:
These data come out of the Merck
ICU program, the same as the one in the United States. It is composed
of groups of 10 to 20 to 30 laboratories in individual nations. The
database is actually old; 1993 to 1995 data points are in the article.
Those rates look fairly comparable with what was coming out of national
programs during that same period of time. I think those rates are
relatively accurate, and they were using a reliable surveillance method
that focused only on Gram-negatives during that surveillance. There are
a lot of differences in antibiotic use among those nations. I think it
is more controlled in Sweden.
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Footnotes
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Abbreviations: ATS = American Thoracic
Society; HAP = hospital-acquired pneumonia;
MRSA = methicillin-resistant Staphylococcus aureus;
MSSA = methicillin-sensitive Staphylococcus aureus
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References
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Fagon, J-Y, Chastre, J, Domart, Y, et al (1989) Nosocomial pneumonia in patients receiving continuous mechanical ventilation. Am Rev Respir Dis 139,877-884[ISI][Medline]
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Abstract
Introduction
