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SUPPLEMENT ARTICLE
Health Care–Associated Pneumonia (HCAP):
A Critical Appraisal to Improve Identification,
Management, and Outcomes—Proceedings
of the HCAP Summit
Marin H. Kollef,1 Lee E. Morrow,3 Robert P. Baughman,4 Donald E. Craven,5 John E. McGowan, Jr.,6 Scott T. Micek,2
Michael S. Niederman,7 David Ost,8 David L. Paterson,9 and John Segreti10
1
Increasingly, patients are receiving treatment at facilities other than hospitals, including long-term–health care
facilities, assisted-living environments, rehabilitation facilities, and dialysis centers. As with hospital environments, nonhospital settings present their own unique risks of pneumonia. Traditionally, pneumonia in these
facilities has been categorized as community-acquired pneumonia (CAP). However, the new designation for
pneumonias acquired in these settings is health care–associated pneumonia (HCAP), which covers pneumonias
acquired in health care environments outside of the traditional hospital setting and excludes hospital-acquired
pneumonia (HAP), ventilator-associated pneumonia (VAP), and CAP. Although HCAP is currently treated
with the same protocols as CAP, recent evidence indicates that HCAP differs from CAP with respect to pathogens
and prognosis and, in fact, more closely resembles HAP and VAP. The HCAP Summit convened national
infectious disease opinion leaders for the purpose of analyzing current literature, clinical trial data, diagnostic
considerations, therapeutic options, and treatment guidelines related to HCAP. After an in-depth analysis of
these areas, the infectious disease investigators participating in the summit were surveyed with regard to 10
clinical practice statements. The results were then compared with results of the same survey as completed by
744 Infectious Diseases Society of America members. The similarities and differences between those survey
results are the basis of this publication.
Pneumonia is one of the most common infections requiring hospitalization. Changes in the location and
manner in which health care is currently administered
have resulted in the need to reassess the classification
scheme employed for pneumonia. This is most evident
when dealing with the increasing numbers of ambulatory and nonhospitalized individuals who are in reg-
Reprints or correspondence: Dr. Marin H. Kollef, Div. of Pulmonary and Critical
Care Medicine, Washington University School of Medicine, 660 S. Euclid Ave.,
Campus Box 8052, St. Louis, MO 63110 ([email protected]).
Clinical Infectious Diseases 2008; 46:S296–334
2008 by the Infectious Diseases Society of America. All rights reserved.
1058-4838/2008/4608S4-0002$15.00
DOI: 10.1086/526355
S296 • CID 2008:46 (Suppl 4) • Kollef et al.
ular contact with the health care system [1, 2]. Currently accepted classifications of pneumonia include
community-acquired pneumonia (CAP), hospital-acquired pneumonia (HAP), ventilator-associated pneumonia (VAP), and nursing home–associated pneumonia (NHAP). The designation of health care–associated
pneumonia (HCAP) was recently introduced to include
an already-ill population of nursing-home residents,
patients in long-term care, patients undergoing sameday procedures, patients receiving home- or hospitalbased intravenous therapy, and patients undergoing dialysis [3]. The patient population at risk for HCAP is
large and diverse, probably making up the largest single
category of patients with pneumonia [2, 4, 5]. In gen-
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Washington University School of Medicine and 2Barnes-Jewish Hospital, St. Louis, Missouri; 3Creighton University Medical Center, Omaha,
Nebraska; 4University of Cincinnati Medical Center, Cincinnati, Ohio; 5Tufts University School of Medicine, Boston, Massachusetts; 6Rollins School
of Public Health of Emory University, Atlanta, Georgia; 7State University of New York at Stony Brook, Stony Brook, and 8New York University
School of Medicine, New York, New York; 9University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania; and 10Rush-Presbyterian–St. Luke’s
Medical Center, Chicago, Illinois
Table 1. Health Care–Associated Pneumonia (HCAP) Summit
clinical practice statements.
Workshop 1: Defining HCAP (statements 1–5)
1. The patient in/from a health care–associated, nonhospital
environment who develops a clinical presentation of pneumonia has HCAP. (J.E.M.)
2. The clinical and microbiological features of HCAP are more
similar to HAP and VAP than to CAP. (L.E.M.)
3. The recommended evaluation of HCAP with treatment failures is the same as that for HAP. (Kenneth Leeper)
4. The definitions are the same for HCAP and HAP treatment
failures. (D.O.)
5. Severe CAP is not HCAP. (D.E.C.)
Workshop 2: Therapeutic Intervention (statements 6–10)
6. Initial empirical therapy for HCAP is the same as that for
HAP. (M.S.N.)
7. Patients with HCAP who are at risk for gram-negative bacterial infections should receive dual empirical antibiotic
coverage. (D.L.P.)
8. Patients should receive initial empirical therapy that covers
MRSA at the time of HCAP diagnosis. (S.T.M.)
9. When microbiological data are unavailable, de-escalation in
patients with HCAP should not occur. (R.P.B.)
10. The duration of antibiotic therapy for patients with HCAP
with a clinical response should be 7 days. (J.S.)
NOTE. CAP, community-acquired pneumonia; HAP, hospital-acquired
pneumonia; MRSA, methicillin-resistant Staphylococcus aureus; VAP, ventilator-associated pneumonia.
each statement, the panel members also outlined additional
data required to further refine the statements for future clinical
use. The main intention of this meeting was to provide a framework for future discussion and research in the area of HCAP.
Before the summit meeting, clinical perspectives of practicing
physicians were measured via a Web-based survey. E-mail polling was done to ascertain their level of support for the same
10 statements. The e-mail invitation to participate in the electronic survey was sent to 3200 members of the Infectious Diseases Society of America (IDSA) (all active e-mail addresses).
Of the IDSA members surveyed, 383 (11.9%) responded. The
purpose of the electronic surveys was to provide information
that would allow for the comparison of data-driven responses
from the content “experts” at the summit with those of clinicians practicing in the field. The summit participants and the
surveyed physicians used the same grading scheme to rate the
10 statements (table 2).
Note. Although the American Thoracic Society (ATS)–
IDSA guidelines were intended to apply only to patients with
HCAP seen in the acute-care setting, those recommendations
were extrapolated to nonhospitalized patients with HCAP for
this summit. Accordingly, voting on the grade of evidence for
each clinical practice statement was done 3 times: first, for the
statement in general; second, for the statement as it applied to
hospitalized patients with HCAP; and third, for the statement
HCAP Summit Critical Appraisal • CID 2008:46 (Suppl 4) • S297
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eral, patients who develop HCAP are more similar to hospitalized patients than to true community patients, in that they
have a greater burden of comorbidities, including cancer,
chronic kidney disease, heart disease, chronic obstructive lung
disease, immunosuppression, dementia, and impaired mobility
[2, 6, 7].
An important distinction of HCAP is that the pathogens are
often multidrug-resistant (MDR) bacteria [2]. Therefore, the
initial treatment of HCAP should be similar to that of HAP
and VAP, which also differentiates it from CAP [3]. This is
particularly important for clinicians working in first-response
areas, such as emergency departments (EDs), to recognize, so
that appropriate initial antimicrobial therapy is not delayed.
Several studies have demonstrated that delaying the delivery of
pathogen-appropriate antimicrobial therapy to patients with
CAP and VAP results in excess mortality [8–10]. Thus, it is
essential for physicians working in the ED to distinguish between HCAP and CAP, in order to correctly assess and manage
suspected cases of pneumonia. This approach to HCAP also
applies to other health care–associated infections in which the
pathogens are more similar to hospital-acquired organisms than
to community-acquired ones [6, 11].
This supplement to Clinical Infectious Diseases represents the
proceedings of a panel of investigators whose goal was to assess
the quality of evidence in support of the clinical classification
of HCAP as a distinct entity and the need for specific therapeutic interventions for HCAP. Ten clinical practice statements
were drafted by the chair (M.H.K.) and the 2 workshop leaders
(L.E.M. and R.P.B.) and were subsequently evaluated by the
11-member panel made up of leaders in infectious diseases,
pulmonary and critical care medicine, and pharmacology (table
1). Before the summit was convened, each participant was assigned a statement and instructed to systematically review and
summarize the evidence supporting or refuting that statement.
In the first phase of the live meeting, the simultaneously
conducted workshops “Defining HCAP” and “Therapeutic Intervention” included a leader and 4–5 content experts and
served as a forum for each individual to present the evidence
for his or her statement. When the data were presented, primary
attention was given to the study methodology, the number of
patients enrolled, and the outcome events. After the presentation of data for each statement, workshop members discussed
the evidence, graded the strength of the evidence, and assigned
the statement a consensus numeric grade for the “Nature of
the Evidence” and the “Grade of Recommendation” (table 2).
In the second phase of the live meeting, all summit panelists
reconvened, reviewed the workshop summaries, and discussed
each statement further. After each discussion, all participants
voted on their individual levels of support, using the grading
scheme shown in table 2.
In addition to defining the level of evidence in support of
Table 2. Workshop and Health Care–Associated Pneumonia (HCAP) Summit panel
voting schemes.
Category
Nature of evidence
I
II
Evidence obtained from at least 1 well-designed, randomized, controlled trial
Evidence obtained from well-designed cohort or case-control studies
III
IV
Evidence obtained from case series, case reports, or flawed clinical trials
Opinions of respected authorities based on clinical experience, descriptive
studies, or reports of expert committees
V
Insufficient evidence to form an opinion
Level of workshop support for statement
There is good evidence to support the statement
There is fair evidence to support the statement
C
There is poor evidence to support the statement, but recommendations
may be made on other grounds
D
There is fair evidence to reject the statement
E
There is good evidence to reject the statement
1
2
Accept recommendation completely
Accept recommendation with some reservations
3
4
Accept recommendation with major reservations
Reject recommendation with reservations
5
Reject recommendation completely
Individual level of support (summit panel members)
as it applied to nonhospitalized patients with HCAP. The rationale for including those with community-acquired HCAP
was that some data were available for this group, especially for
those with NHAP. Therefore, the committee felt that there was
sufficient evidence to make recommendations for some of the
issues. However, several areas with insufficient information
were identified.
STATEMENT 1: THE PATIENT IN/FROM A
HEALTH CARE–ASSOCIATED, NONHOSPITAL
ENVIRONMENT WHO DEVELOPS A CLINICAL
PRESENTATION OF PNEUMONIA HAS HCAP
Rationale and Definition of Statement
In defining HCAP as a distinct clinical entity, the most recent
ATS-IDSA nosocomial pneumonia guidelines defined a subset
of patients at risk for harboring resistant organisms despite
their residence in the community [3]. Criteria included hospitalization in an acute-care facility for ⭓2 days within 90 days
before the infection; residence in a nursing home or long-termcare facility; recent receipt of intravenous antibiotic therapy,
chemotherapy, or wound care, within 30 days before the infection; or attending a hospital or hemodialysis clinic [3]. Although the ATS-IDSA guidelines were intended to apply only
to hospitalized patients with HCAP, it is apparent that these
concepts are being extrapolated to nonhospitalized patients
with HCAP as well [12]. By definition, the ATS-IDSA guidelines
apply to patients coming to an acute-care facility from a nonhospital environment, whether the patient is seen in an outS298 • CID 2008:46 (Suppl 4) • Kollef et al.
patient facility or ED or is admitted directly to the hospital.
However, there is a question regarding whether the guidelines
for such patients should also apply to patients who remain in
a nonhospital environment, such as a nursing home or longterm-care facility, or who remain in another setting but who
meet the other ATS-IDSA criteria for having HCAP [3].
Methods
A search of the OVID “1996-present” database to identify studies related to descriptions of HCAP was completed on 1 November 2006. The search of the combined term “health care
associated or healthcare-associated” produced a total of 144
articles. Next, the text word search for the term “HCAP” yielded
66 articles, and the text word search for “healthcare-associated
pneumonia” resulted in 7 articles. At this point, the 2 text word
searches were combined with the first combined-term search,
and the results were limited to the English language. This produced 82 articles. The same search strategy was then used in
the OVID database “in process,” and an additional 10 articles
were identified. By scanning the titles of these 92 articles, 14
relevant articles were noted, and a review of the references for
these 14 articles added 4 articles to the total. Thus, 18 articles
were considered to be relevant to this statement.
Evidence
Definitions of HCAP. Several definitions of HCAP are stated
or implied in the medical literature. One prevalent use of the
term, considered to be irrelevant to this discussion, is the use
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A
B
that “publication of these recommendations has been recognized by the Centers for Medicare and Medicaid Services in
their application of core measures for the treatment of CAP.”
This action has led to the exclusion of patients with HCAP
from studies of adherence to antibiotic therapy recommendations for patients with CAP. Fujitani et al. [17, pp. 627 and
630] considered the classification of HCAP as a separate disease
entity to be “a good idea” but noted “problems with its execution.” They noted that the definitions of HAP, CAP, and
HCAP have varied among different large-scale studies and suggest that “classification schemes are inherently imprecise because patient groups overlap in the HCAP categories.” Wunderink [18, p. 2686] also noted that “a distinction between
HCAP and CAP has never been totally clear.” He concluded,
however, by stating that “despite these issues, defining the
HCAP category has led to more appropriate antibiotic therapy
for the majority of patients and clearly assisted decision making” [18].
Differences in application of the definition by setting.
The previous studies dealt with patients seen in, or admitted
to, acute-care hospitals. However, many patients with pneumonia acquired in a nursing home setting are not transferred
to an acute-care hospital. For example, Loeb et al. [19] conducted a cluster-randomized controlled trial of different regimens for treatment of pneumonia in nursing home residents
in Canada. Only 110 of 661 evaluated patients were
hospitalized.
The degree to which the HCAP definition applies to patients
with pneumonia who remain in nonhospital health care settings, such as nursing homes, is not clear. Mortality rates for
NHAP are higher than those for CAP [20, 21], but controlling
for different factors that affect this risk is difficult. For example,
in a review by El Sohl et al. [22] of 88 patients with cultureconfirmed cases of severe pneumonia, previous use of antibiotics (a component of the ATS-IDSA definition) was found to
be predictive of the presence of drug-resistant bacteria. However, the other predictor of drug resistance in this study was a
lower Activities of Daily Living (ADL) score, a feature not
considered in the ATS-IDSA definition of HCAP. Likewise, at
least 1 study suggests that the risk of MDR bacteria being
present is no higher for NHAP than for CAP [20]. It was
acknowledged that the literature on NHAP is dated and incomplete; this area needs further investigation.
Grading of Evidence
On the basis of a review of the studies cited above, the 5
members of this workshop agreed that the evidence available
to support this statement was category III (a mixture of the 2
following votes) for the statement in general, category IV (primarily from definition) for the statement as it applies to hospitalized patients with HCAP, and category V (insufficient eviHCAP Summit Critical Appraisal • CID 2008:46 (Suppl 4) • S299
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of “health care associated” as a replacement for or synonym of
“nosocomial” or “hospital associated” [13]. A second use of
the term is “hospitalized with community-acquired pneumonia,” which also fails to capture the concept presented in the
ATS-IDSA guidelines [14]. The relevant concept is that pneumonia not acquired in an acute-care hospital (traditionally labeled as “community-acquired infection”) is more likely to have
a spectrum of pathogens that resemble those associated with
HAP or VAP than to have a distribution of microbes traditionally associated with CAP.
HCAP as a distinct entity. Differences in the likely prevalence of drug-resistant pathogens were highlighted in a study
by Friedman et al. [6] of health care–associated bloodstream
infections in adults, which defined patients with health care–
associated bacteremia in a fashion similar to the ATS-IDSA
guidelines. Patients with health care–associated bacteremia were
similar to those with hospital-acquired bloodstream infections,
with regard to frequency of comorbid conditions, pathogens
and their susceptibility, and mortality rates. The authors concluded that “a separate category for [health care–associated]
infections is justified, and this new category will have obvious
implications for choices about empirical therapy and infectioncontrol surveillance” [6, p. 791]. This theme was echoed and
expanded to include pneumonia in a 2004 editorial by Craven,
who stated, “compared with patients with community-acquired
pneumonia (CAP), those with HCAP are often at greater risk
for colonization and infection with a wider spectrum of multidrug-resistant organisms” [4, p. 153]. However, Grossman et
al., in a review of practice guidelines for treatment of lowerrespiratory-tract infections in hospitalized patients, concluded
that HCAP is treated similarly to HAP “and may be considered
with HAP” [15, p. 295].
Kollef et al. [2] reviewed a large database of 4543 patients
with culture-positive pneumonia and identified 20% as having
HCAP. The percentage of patients with a culture positive for
Staphylococcus aureus was similar among those with HCAP
(46.7%) and those with HAP (47.1%), and mean mortality
rates (19.8% and 18.8%, respectively) were similar for these 2
groups of patients as well. The mean length of stay for patients
with HCAP was intermediate between that for patients with
CAP and that for patients with HAP. The authors concluded
that this analysis “justified HCAP as a new category of pneumonia” [2, p. 3854].
Pop-Vicas et al. [16] noted an increasing prevalence of MDR,
gram-negative bacilli recovered at admission to a tertiary-care
hospital. Factors independently associated with the isolation of
resistant organisms (age ⭓65 years, prior antibiotic therapy for
⭓2 weeks, and residence in a long-term-care facility) were similar to those used to define HCAP.
The editorial response to the ATS-IDSA definition of HCAP
has been mixed. Hiramatsu and Niederman [1, p. 3786] note
dence) for the statement as it applies to nonhospitalized
patients with HCAP (table 2).
Level of Support
Discussion
By definition, the ATS-IDSA guidelines apply to patients coming to an acute-care facility from a nonhospital environment,
whether the patient is seen in an outpatient facility or ED or
is admitted directly to the hospital, and the different panels
supported this definition. The concept is presented graphically
in figure 2, which represents CAP, HCAP, and HAP as separate
entities for which, in general, the likelihood of the presence of
MDR organisms increases [23]. Less well documented, but still
likely, is that rates of mortality and morbidity also increase as
one considers the entities on the right side of the figure. There
is, however, overlap between the 3 defined entities; for example,
patients with severe CAP might have higher mean mortality
rates than do those with HCAP. Similarly, the prevalence of
MDR organisms may be high for patients with CAP in some
areas where selective pressure due to antimicrobial use is high.
It is important to appreciate that these 2 features (severity and
Figure 1. Voting comparison for statement 1 (“The patient in/from a
health care–associated, nonhospital environment who develops a clinical
presentation of pneumonia has HCAP”). “Summit members” refers to the
11-member summit panel; “IDSA members” refers to the members of
the Infectious Diseases Society of America who responded to a Webbased survey. HCAP, health care–associated pneumonia.
S300 • CID 2008:46 (Suppl 4) • Kollef et al.
Figure 2. Relationship of health care–associated pneumonia (HCAP)
to community-acquired pneumonia (CAP), hospital-acquired pneumonia
(HAP), and ventilator-associated pneumonia (VAP). Note also the increased
risk for colonization and infection with multidrug-resistant (MDR) pathogens, morbidity, and mortality in these groups. Adapted in part from
[23].
prevalence of MDR) are not necessarily linked—one may be
high while the other is not.
There is, however, insufficient evidence to decide the validity
of the HCAP category as it relates to patients remaining in
nursing homes or other non–acute-care health settings, as is
reflected in the summit participants’ grading of the evidence.
The value of extrapolating the ATS-IDSA definition to these
settings requires further study. Likewise, for other non–acutecare health settings, including those of specific subsets of patients with HCAP (those receiving hemodialysis, home infusion, wound care, chemotherapy, or recent antibiotics or who
have a relative with resistant pathogens), the available data are
very limited.
Future Directions
The paucity of data highlighted in the previous section provides
valuable opportunities to determine the relevance of HCAP for
the special populations noted and to continue to explore the
validity of specific criteria used to define the entity. Of particular
note is the observation by Fujitani et al. [17, p. 630], who
suggested that a more precise classification to minimize such
overlap would allow easier comparison among studies of this
entity “so a rigorous database can be accumulated for future
investigations.”
STATEMENT 2: THE CLINICAL AND
MICROBIOLOGICAL FEATURES OF HCAP ARE
MORE SIMILAR TO HAP AND VAP THAN TO
CAP
Rationale and Definition of Statement
Historically, patients with HCAP have been treated with antibiotic regimens recommended by CAP guidelines. As the prevalence of antimicrobial resistance has increased, particularly in
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When voting on the support for this statement in the group
at large, 55% of the summit participants accepted the statement
with some reservations, 27% accepted the statement with major
reservations, and 9% rejected the statement completely. In comparison, of the 383 IDSA members who participated in the
online survey, 48% accepted the statement completely, 42%
accepted the statement with some reservations, 4% accepted
the statement with major reservations, 4% rejected the statement with reservations, and 2% rejected the statement completely (figure 1). It was thought by the summit participants
that IDSA members were considering the statement primarily
for its intended purpose of applicability to patients with HCAP
seen in the acute-care hospital setting.
patients whose conditions meet HCAP criteria, many clinicians
have questioned whether these antibiotic regimens are appropriate. This is of particular importance, given the association
between inadequate empirical antibiotic therapy and increased
mortality rates.
To address these concerns, the ATS-IDSA guidelines recommended broad empirical antibiotic therapy followed by culture-guided de-escalation for patients with HCAP. Although
these concepts were intuitive and widely embraced by clinicians,
critics expressed concerns regarding the data supporting such
significant changes to the guidelines. Because the guidelines cite
only 7 references relating to HCAP, this section aims to assess
the strength of evidence supporting the assertion that clinical
and microbiological features of HCAP are more similar to those
of HAP than to those of CAP.
HCAP. A PubMed database search to identify studies related
to the clinical and microbiological features of HCAP was completed on 24 October 2006. The search terms “health care associated pneumonia,” “healthcare associated pneumonia,”
“health care-associated pneumonia,” and “healthcare-associated pneumonia” gave a total of 48,465 articles. The search
terms “microbiology” and “pathogen” yielded 551,438 articles.
Combining the HCAP search with the microbiology search by
use of the “AND” function produced 138 articles. After limiting
these to the English language, 129 articles were reviewed. Only
3 were deemed relevant to the statement. Because HCAP includes multiple entities previously referred to by use of other
terminology, several additional searches were conducted.
NHAP. The search terms “pneumonia” and “lower respiratory tract infection” were combined with the “OR” function
to identify 86,173 articles. The search terms “nursing home”
and “long term care” were combined with the “OR” function
to identify 44,206 articles. The nursing home and pneumonia
searches were combined using the “AND” function to give 616
articles. When these were combined with the previous microbiology search and limited to the English language, 112 articles
were reviewed. Only 5 were deemed relevant to the statement.
One article was then added from these articles’ references, and
another recent abstract also was included.
Hemodialysis-associated pneumonia. The search terms
“hemodialysis” and “dialysis” were combined with the “OR”
function to identify 111,259 articles. When these were combined with the prior pneumonia and microbiology searches
and limited to the English language, 54 articles were reviewed.
One article was deemed relevant to the statement.
Home care– and wound care–associated pneumonia.
The search terms “home care” and “wound care” were combined with the “OR” function for a total of 49,986 articles.
These were combined with the prior pneumonia and micro-
Evidence
HCAP. Only 1 study was identified that specifically focused
on the microbiology of HCAP [2]. In this retrospective cohort
analysis of a multi-institutional database, 4543 cases of culturepositive pneumonia were identified by International Classification of Diseases, Ninth Revision codes. Patients were then
stratified as having CAP (49%), HCAP (22%), HAP (18%), or
VAP (11%). The most common pathogens in HCAP were
methicillin-resistant S. aureus (MRSA) and Pseudomonas aeruginosa (26.5% and 25.3%, respectively), similar to HAP (22.9%
and 18.4%; P ! .01 for P. aeruginosa). Conversely, Streptococcus
pneumoniae and Haemophilus species were seen more frequently in CAP (16.6% and 16.6%) than in HCAP (3.1% and
5.8%; P ! .01 for both). The mortality rates among patients
with HCAP and patients with HAP were similar (19.8% and
18.8%, respectively; P 1 .05 ) and were significantly higher than
that among patients with CAP (10.0%; P ! .0001). Limitations
of this study included the use of data only for hospitalized
patients, inclusion of only patients with early-onset pneumonia,
misclassification bias, and exclusion of patients with negative
culture results. Also unresolved are the very high rates of Pseudomonas species (17.1%) and methicillin-susceptible S. aureus
(17.2%) as the causative pathogens in patients with CAP. The
clinical features of HCAP were not assessed in this study.
Two additional studies assessed the risk factors for colonization with resistant organisms in hospitalized patients, many
of whom did not have pneumonia. The first of these studies
assessed variables associated with MDR gram-negative bacillus
carriage [16]. In this prospective, case-control study, it was
found that predictors of MDR gram-negative bacillus colonization included several subsets of patients also included in the
new ATS-IDSA definition of HCAP: residents of long-termcare facilities, patients undergoing hemodialysis, and patients
who have recently received antibiotic therapy. Similarly, a prospective surveillance study of MRSA showed that patients
whose conditions met HCAP criteria (patients who have recently been hospitalized, residents of long-term-care facilities,
patients undergoing dialysis, or patients receiving home nursing
HCAP Summit Critical Appraisal • CID 2008:46 (Suppl 4) • S301
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Methods
biology searches and limited to the English language, yielding
134 articles for review. One article was deemed relevant to the
statement.
Chemotherapy-associated pneumonia. The search term
“cancer chemotherapy” yielded 311,108 articles. These were
combined with the prior pneumonia and microbiology searches
to give 348 articles. After limiting these to the English language,
268 articles were reviewed, and 4 were deemed relevant.
Queries using multiple search terms relating to pneumonia
in patients who have a family member with resistant pathogens
and/or patients who have received prior antibiotic therapy did
not result in any articles being found.
S302 • CID 2008:46 (Suppl 4) • Kollef et al.
A prospective cohort of 104 “very elderly” patients (mean
age SD, 82.3 5.5 years) admitted to the intensive care unit
(ICU) with severe pneumonia requiring mechanical ventilation
identified a pathogen in 55 patients (53%) by use of an aggressive and invasive approach that included bronchoalveolar
lavage (BAL) [27]. Although no formal statistical comparisons
of community residents and long-term-care–facility residents
were performed, patients with NHAP had higher rates of altered
mental status (76% vs. 42%) and fever (65% vs. 44%) but a
lower rate of chest pain (5% vs. 20%) at admission. Compared
with patients with CAP, fewer patients with NHAP had S. pneumoniae isolated (8.5% vs. 14.0%), but more patients with
NHAP had S. aureus isolated (29.7% vs. 7.0%). All Staphylococcus isolates from patients with CAP were methicillin susceptible, whereas 78.6% of Staphylococcus isolates (11 of 14)
from patients with NHAP were methicillin resistant.
In a similar study by the same authors, patients with NHAP
requiring mechanical ventilation underwent BAL in an attempt
to identify those at risk for harboring resistant pathogens [22].
The most common pathogens included S. aureus (23.9%, of
which 61.9% were MRSA) and S. pneumoniae (18.2%). Predictors of infection with resistant pathogens included functional
dependence and prior antibiotic exposure.
Another recent study assessed the risk factors for colonization with MDR organisms in residents of long-term-care
facilities [28]. In a point-prevalence study of 84 individuals,
surveillance nasal and rectal cultures were assessed for organisms resistant to ⭓3 frequently prescribed antibiotics. The
prevalence of colonization with MDR organisms was 51%,
with the most common organisms being Providencia stuartii
(31% of isolates), Proteus mirabilis (21%), Escherichia coli
(19%), and Morganella morganii (19%). Independent predictors of colonization by multivariate regression analysis included fecal incontinence (OR, 3.78; P p .038 ) and prior antibiotic exposure (OR, 2.5; P p .047). PFGE identified high
rates of identical or related strain types, which suggested substantial horizontal transmission.
Dialysis-associated pneumonia. Only 1 study was identified as dealing specifically with pneumonia in patients undergoing long-term hemodialysis [29]. This retrospective cohort
analysis linked the waves 1, 3, and 4 Dialysis Morbidity and
Mortality Study data sets with Medicare claims to identify 3101
hospital admissions for pneumonia in patients undergoing
long-term hemodialysis. Overall, the frequency of microbiological confirmation was very poor (18.2%). In patients with
microbiologically confirmed pneumonia, the most common
pathogens were S. pneumoniae (18.7%), P. aeruginosa (15.4%),
Klebsiella species (8.8%), and H. influenzae (8.2%). Despite
high rates of colonization with MRSA in the dialysis population,
Staphylococcus species were infrequently the causative pathogen
(2.2%).
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care) accounted for 99% of “community-acquired” MRSA cases
[24].
NHAP. Seven studies of the clinical and microbiological
features of NHAP were identified. A prospective case-control
study comparing patients with NHAP and age-matched patients
with CAP showed that the presentation of pneumonia was
strikingly different between groups. Compared with patients
with CAP, patients with NHAP were less likely to have a productive cough (61% vs. 35%; P ! .05), chills (58% vs. 24%;
P ! .05), headache (32% vs. 5%; P ! .05), sore throat (19% vs.
7%; P ! .05), myalgia (33% vs. 7%; P ! .05), or arthralgia (10%
vs. 0%; P ! .05). Although the difference was reported as being
statistically nonsignificant, patients with NHAP were almost
twice as likely to have confusion (70% vs. 37%). Patients with
NHAP were also more likely to die in the hospital (32% vs.
14%; P ! .05) [21].
A retrospective cohort analysis comparing the clinical presentations of NHAP and CAP found that patients with NHAP
were more likely to have altered mental status (55.9% vs. 11.3%;
P ! .001), tachypnea (40.9% vs. 22.8%; P ! .001), and hypotension (7.0% vs. 1.1%; P ! .001) [25]. The presence of subjective variables, such as cough, dyspnea, and pleuritic chest
pain, could not be assessed. Patients with NHAP also had a
significantly higher mortality rate (18.6% vs. 8.0%; P ! .001).
In a prospective cohort of 437 consecutive patients with pneumonia, 40 (9%) of the patients resided in nursing homes [20].
These patients with NHAP were less likely than were those with
other types of pneumonia to have a productive cough (OR,
0.4; P p .02) or pleuritic pain (OR, 0.1; P p .03) but were
more likely to be confused (OR, 2.6; P ! .001). Compared with
age-matched control individuals living in the community, the
patients with NHAP had a significantly higher mortality rate
(53.0% vs. 13.4%; P ! .001).
An article reviewing 18 primary studies published between
1978 and 1994 evaluated the etiology of pneumonia in residents
of long-term-care facilities [26]. In this study, the most common pathogens were gram-negative bacilli (18%), S. pneumoniae (16%), Haemophilus influenzae (11%), and S. aureus
(6%). Mycoplasma, Chlamydia, and Legionella species accounted for !1% of cases, and 29% of cases did not have an
identifiable pathogen. The primary studies showed marked variability in the frequency of causative pathogens: gram-negative
bacilli isolation varied from 0% to 55% across studies; that of
S. pneumoniae ranged from 0% to 39%; that of S. aureus, from
0% to 33%; and that of Legionella species, from 0% to 6%.
The primary studies’ evaluations of the causative pathogens
were widely discrepant: some had no microbiological criteria,
others required a high-quality sputum specimen, and some
allowed positive blood culture results to suffice if sputum results
were negative. None of the studies rigorously pursued the isolation of atypical organisms.
antibiotic exposure as a risk factor for colonization or infection
with resistant pathogens [16, 22, 28].
Grading of Evidence
On the basis of a review of the 15 studies cited above, the 5
members of this workshop agreed that the evidence available
to support this statement was category II for the statement in
general, category II for the statement as it applies to hospitalized
patients with HCAP, and category V for the statement as it
applies to nonhospitalized patients with HCAP (table 2).
Level of Support
When voting on the support for this statement, 9% of the
summit participants voted to accept the statement completely,
64% voted to accept the statement with some reservations, 18%
voted to accept the statement with major reservations, and 9%
voted to reject the statement with reservations. In comparison,
of the 383 IDSA members who participated in the online survey,
40% voted to accept the statement completely, 47% voted to
accept the statement with some reservations, 7% voted to accept
the statement with major reservations, 5% voted to reject the
statement with reservations, and 1% voted to reject the statement completely (figure 3).
Discussion
This statement is of key importance, given that the relevance
of the remaining statements discussed at the summit hinges on
the assertion that HCAP constitutes a distinct clinical entity
with unique microbiological features. At present, there is limited conclusive evidence supporting this statement, as is reflected in the summit participants’ grading of the evidence.
All of the reviewed studies support the assertion that the
clinical features of HCAP are different from those of CAP.
Although patients with HCAP are generally less likely to have
Figure 3. Voting comparison for statement 2 (“The clinical and microbiological features of HCAP are more similar to HAP and VAP than to
CAP”). “Summit members” refers to the 11-member summit panel; “IDSA
members” refers to the members of the Infectious Diseases Society of
America who responded to a Web-based survey. CAP, community-acquired
pneumonia; HAP, hospital-acquired pneumonia; HCAP, health care–associated pneumonia; VAP, ventilator-associated pneumonia.
HCAP Summit Critical Appraisal • CID 2008:46 (Suppl 4) • S303
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Pneumonia in patients receiving home infusion therapy or
wound care. One study was identified that specifically assessed pneumonia in patients receiving home nursing care. In
this prospective case-control study of 175 patients with MRSA
infection, 41 patients had pneumonia [30]. Multivariate regression analysis identified a highly significant association between MRSA infection and prior receipt of home nursing care
(OR, 3.7; P ! .001). Other independent risk factors included
prior hospitalization and transfer from another institution, such
as a nursing home.
Pneumonia in patients undergoing chemotherapy. Three
studies were identified as relating specifically to pneumonia in
patients undergoing chemotherapy. In a prospective observational cohort study of 52 consecutive pneumonia cases among
patients with acute leukemia undergoing chemotherapy, the
presentation was relatively subtle [31]. The signs and symptoms
present in more than half of patients included fever (98%),
dyspnea (79%), rales (77%), chills (73%), cough (65%), and
sputum production (58%). A causative pathogen was found in
71% of cases, but only 52% were identified antemortem. The
most common organisms were fungi (25.0%), Pseudomonas
species (23.1%), and Klebsiella species (13.4%).
In another prospective cohort of 242 consecutive pneumonia
cases among patients with malignancy undergoing antineoplastic chemotherapy, the clinical presentation was similarly
subtle [32]. Clinical presentation in more than half of patients
included fever (90%), a positive radiographic finding (83%),
and rales (65%). Gram-negative bacilli accounted for 90% of
cases, with the most common pathogens being Klebsiella species
(31.8%) and Pseudomonas species (18.6%).
The final study was a prospective surveillance study of neutropenic patients with bacteremic pneumonia [33]. Although
408 cases of pneumonia were identified, clinical and microbiological data were reported only for the 40 patients with
concurrent bacteremia. The only sign of pneumonia present in
more than half of patients was fever (95%). Cough was the
most common symptom of pneumonia and was present in only
47% of patients. The most common pathogens identified were
P. aeruginosa (42.5%), S. pneumoniae (30.0%), and E. coli
(12.5%).
Pneumonia in patients with a relative harboring MDR
pathogens. No studies were identified as specifically assessing
either the clinical presentation or microbiological features of
pneumonia in patients who have a relative with known MDR
pathogens.
Pneumonia in patients who have recently received
antibiotics. No studies were identified as specifically assessing
either the clinical presentation or microbiological features of
pneumonia in patients who have recently received antibiotics.
However, several of the previously cited studies identified prior
Future Directions
Future directions discussed by the summit members reflect
many of the limitations of previously discussed studies. Appropriately designed epidemiologic studies with rigorous microbiological criteria clearly are needed to better delineate the
causative pathogens of CAP, HAP, and HCAP. Although the
S304 • CID 2008:46 (Suppl 4) • Kollef et al.
use of standardized diagnostic and laboratory criteria would
be essential, these criteria do not exist. These large, observational cohorts would need to be followed longitudinally to
assess changes in pathogens and resistance patterns over time.
STATEMENT 3: THE RECOMMENDED
EVALUATION OF HCAP WITH TREATMENT
FAILURES IS THE SAME AS THAT FOR HAP
Rationale and Definition of Statement
Nonresolving pneumonia is variably defined but represents a
clinical syndrome in which focal infiltrates persist with signs
and symptoms of acute pulmonary infection (e.g., fever, expectoration, malaise, or dyspnea). Despite receiving a minimum
of 10 days of antibiotic therapy, patients either do not improve
or worsen clinically, or radiographic opacities fail to resolve
within 12 weeks after the onset of pneumonia [34–36].
Nonresolving pneumonia often represents treatment failure
or a superinfection [37, 38]. In addition to being the result of
initial therapy failure or a noninfectious etiology, nonresolving
pneumonia may also be the result of an overwhelming immune
response to a specific pathogen. It is critical to identify patients
at risk for nonresponding pneumonia, to institute early appropriate therapy. Patients with severe HCAP, underlying comorbidities, and certain etiologic agents (viral, atypical) are at
greater risk for nonresolving pneumonia and may benefit from
alternative supportive approaches (e.g., early tracheostomy) as
well as from immune modulation in specific circumstances
(e.g., progression to acute lung injury or pneumococcal sepsis).
Methods
The original PubMed search was conducted in November 2006
and was augmented with a search performed in April 2007. By
selection of articles published in English on the duration of
nonresolving pneumonia, 50 references focusing on both CAP
and HCAP were identified. These were reviewed along with
their bibliographies for additional references.
Evidence
The use of the clinical pulmonary infection score (CPIS) to
define resolution of nosocomial pneumonia was evaluated by
Luna et al. [39]. These investigators prospectively evaluated 63
patients with microbiologically confirmed VAP. CPISs were followed serially and were noted to improve as early as the third
day of therapy in the group of survivors. Patients who did not
survive did not demonstrate any improvement in their CPIS,
particularly in oxygenation. Patients without treatment response were also significantly more likely to receive inadequate
initial treatment and had a higher mortality rate, compared
with patients with treatment response. This study suggests that
a clinical scoring system may be useful in the early identification
of patients with pneumonia whose conditions are unlikely to
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symptoms, the fever response is preserved, and the likelihood
of altered mental status is increased. This combination of factors may lead to delayed recognition and initiation of therapy,
thereby explaining the increased rates of hypoxemia, systemic
hypotension, and death.
Presently, there is only 1 study of the microbiology of HCAP
as it is specifically defined by the ATS-IDSA guidelines [2].
Although this study has several limitations, it corroborates the
assertion of earlier, less rigorous studies concluding that HCAP
is more likely to be caused by organisms that are particularly
virulent and/or resistant to antibiotic therapy.
Of the individual subsets grouped together under the HCAP
umbrella, NHAP provides the richest data in terms of the published literature. However, these studies were also the most
likely to be confounded by variables such as comorbid illness
or prior antibiotic therapy. These studies routinely had limited
microbiological data that were of very poor quality. Another
concern is the possible obsolescence of older studies, given the
changes in pathogen susceptibilities over time. Although nursing home residents have very high rates of colonization with
MDR pathogens—and these organisms are seen more frequently in patients with NHAP—CAP pathogens are also frequently isolated from these patients.
The present NHAP knowledge base also suffers from a hospitalization bias; the available studies have rigorously evaluated
the causative organisms only in hospitalized patients. This is
problematic, because prior therapy has frequently failed for
these patients at nursing homes, thereby artificially increasing
the frequency of virulent and/or resistant organisms. There is
also an extensive literature base showing the good clinical responses of many patients with NHAP who receive in-facility
CAP therapy. In all, NHAP appears to be a “hybrid” entity,
blending conventional CAP organisms with increased rates of
HAP pathogens.
For the remaining subsets of patients with HCAP (those
receiving hemodialysis, home infusion, wound care, chemotherapy, or recent antibiotics or who have a relative with resistant pathogens), the available data are very limited and likely
suffer from obsolescence. Although it is intuitive to group these
patients together, given their increased contact with the health
system, the data do not clearly justify doing so. The high rate
of fungal infections in patients undergoing chemotherapy reinforces that HCAP subgroups—although clearly distinct from
CAP—are also different from one another.
tients with treatment response, patients with early treatment
failure had significantly higher rates of complications (58% vs.
24%) and overall mortality (27% vs. 4%) (P ! .001 for both).
An etiologic diagnosis was established in 598 patients with
early treatment response (48%) and 55 patients with early treatment failure (68%) (P ! .01). Of patients with an etiologic diagnosis, 316 (53%) with early response and 48 (87%) with early
failure were classified as definitive. The most frequently identified pathogens in the early-response and early-failure groups
were S. pneumoniae (23% and 22%, respectively), Legionella
species (6% and 21%), H. influenzae (6% and 5%), and organisms associated with aspiration pneumonia (6% and 6%).
Legionella pneumophila and gram-negative bacilli were found
more frequently in patients with early failure (P ! .001 and
P p .03, respectively).
Most patients were initially treated with a single antimicrobial
agent, mainly in the early-response group (77% of those with
early responses and 65% of those with early failures). The antibiotics most frequently prescribed were the b-lactams (mainly
ceftriaxone and amoxicillin-clavulanate). Overall, of the 81 patients for whom treatment failed, concordance of therapy could
be determined in 52 patients. In general, patients with early
failure received discordant antimicrobial therapy more frequently (16 [31%] of 52 patients) than did patients with early
response (52 [9%] of 584 patients). Treatment failed in 1 patient
owing to resistance to a recommended regimen; he experienced
breakthrough levofloxacin-resistant S. pneumoniae bacteremia
(MIC of levofloxacin, 64 mg/mL) after 48 h of intravenous
levofloxacin therapy.
Because most studies of resolution have included only patients with CAP, the normal resolution of nosocomial pneumonia is more uncertain. Several investigators, however, have
identified risk factors for poor outcomes, including death. By
inference, the factors promoting a poor outcome may be linked
to delayed resolution. Celis et al. [43] identified prognostic
factors for nosocomial pneumonia. They reported that respiratory failure, the presence of a fatal underlying condition, age
160 years, and the presence of bilateral radiographic involvement were associated with a significantly increased risk of mortality. Additionally, infection with “high-risk” organisms, such
as P. aeruginosa, S. aureus, other gram-negative bacilli, Candida
species, or Aspergillus species, was associated with worse
outcomes.
In addition to observing longer resolution times with gramnegative bacterial infections, Graybill et al. [44] noted the significance of certain host factors, such as cardiovascular disease,
a variety of malignant neoplasms, prior cerebrovascular accident, alcoholism, chronic obstructive pulmonary disease, renal
impairment requiring hemodialysis, and diabetes. In his 1973
study of 82 patients with nosocomial pneumonia, prolonged
resolution was defined as radiographic abnormalities extending
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respond to therapy or who have delayed resolution, in part
related to inadequate initial therapy.
Resolution can also be defined microbiologically. On the
basis of serial quantitative cultures from respiratory secretions,
the eradication or persistence of an organism can be demonstrated. In the prospective series studied by Garrard and
A’Court [40], nonbronchoscopic lung lavage specimens were
obtained from 83 patients with nosocomial pneumonia. The
investigators found that serial culture results correlated well
with the scored clinical responses. Culture counts increased in
the few days before the onset of therapy and decreased dramatically after its initiation. In most cases, the culture counts
had decreased by 24 h, but they decreased no later than 72 h
in all cases of resolving pneumonia. Nonresolving pneumonia
was thus equally well defined by both clinical and microbiological criteria, although clinical nonresponse required more
time to determine.
Mene´ndez et al. [41] identified factors associated with failure
of empirical treatment and determined the incidence of both
early (!72 h) and late treatment failure and related implications
on the outcome. A prospective, multicenter cohort study was
performed involving 1424 hospitalized patients from 15 hospitals. Treatment failure occurred in 215 patients (15.1%): 134
(62.3%) had early failures and 81 (37.7%) had late failures.
The causes were infectious in 86 patients (40%), noninfectious
in 34 patients (15.8%), and undetermined in 95 patients
(44.2%). The independent risk factors associated with treatment failure in a stepwise logistic regression analysis were liver
disease, pneumonia risk class, leukopenia, multilobar CAP,
pleural effusion, and radiologic signs of cavitation. Independent
factors associated with a lower risk of treatment failure were
influenza vaccination, initial treatment with fluoroquinolones,
and chronic obstructive pulmonary disease. Mortality was significantly higher in patients with treatment failure than in those
without treatment failure (25% vs. 2%). Failure of empirical
treatment increased the rate of mortality due to CAP 11-fold
after adjustment for risk class.
Roso´n et al. [42] performed an observational analysis of a
prospective series of 1383 nonimmunosuppressed hospitalized
adults with CAP to identify and categorize causes and factors
associated with early failure. At 48–72 h, 238 patients (18%)
remained febrile, but most of them responded without further
changes in antibiotic therapy, and 81 patients (6%) had early
failure. The main causes of early failure were progressive pneumonia (n p 54), pleural empyema (n p 18 ), lack of response
(n p 13), and uncontrolled sepsis (n p 9 ). Independent factors
associated with early failure were older age (165 years) (OR,
0.35), multilobar pneumonia (OR, 1.81), Pneumonia Severity
Index (PSI) score 190 (OR, 2.75), Legionella pneumonia (OR,
2.71), gram-negative bacillary pneumonia (OR, 4.34), and discordant antimicrobial therapy (OR, 2.51). Compared with pa-
Grading of Evidence
On the basis of a review of the studies cited previously, the 5
members of this workshop agreed that the evidence available
to support this statement was category V for the statement in
general, category IV for the statement as it applies to hospiS306 • CID 2008:46 (Suppl 4) • Kollef et al.
talized patients with HCAP, and category V for the statement
as it applies to nonhospitalized patients with HCAP (table 2).
Level of Support
When voting on the support for this statement, 9% of the
summit participants voted to accept the statement with some
reservations, 82% voted to accept the statement with major
reservations, and 9% voted to reject the statement completely.
In comparison, of the 383 IDSA members who participated in
the online survey, 51% voted to accept the statement completely, 41% voted to accept the statement with some reservations, 4% voted to accept the statement with major reservations, 3% voted to reject the statement with reservations, and
1% voted to reject the statement completely (figure 4).
Discussion
The optimal evaluation of nonresolving pneumonia is not
clearly established. The existing data regarding treatment failure
in HAP are predominately from VAP studies. In these reports,
the identified causes are very diverse, highlighting the need for
a rigorous stepwise approach incorporating repeated microbiological evaluation, evaluation of infectious complications,
and assessment of noninfectious causes. At present, there are
no existing data evaluating treatment failure in HCAP. The
summit participants agreed, on the basis of professional opinion alone, that the evaluation of nonresolving HCAP should
be the same as that for other classes of pneumonia until definitive data specific to HCAP are available.
Future Directions
Summit participants agreed that, given our current lack of
knowledge regarding the evaluation of HCAP treatment failures, retrospective analyses of large data sets are needed to guide
future prospective studies of this complex topic. Data are specifically needed regarding whether the assessment of HCAP
Figure 4. Voting comparison for statement 3 (“The recommended evaluation of HCAP with treatment failures is the same as that for HAP”).
“Summit members” refers to the 11-member summit panel; “IDSA members” refers to the members of the Infectious Diseases Society of America
who responded to a Web-based survey. HAP, hospital-acquired pneumonia;
HCAP, health care–associated pneumonia.
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beyond 4 weeks. Mortality was higher among patients who
developed the pneumonia postoperatively, while undergoing
ventilation, after aspiration, or while receiving antibiotic therapy. Other studies of nosocomial pneumonia have identified
similar risk factors [45, 46].
Montravers was one of the first investigators to compare
microbiological data with clinical outcomes [45]. Serial bronchoscopy and protected specimen brushings were performed
in 76 patients requiring mechanical ventilation. The level of
eradication of a pathogen was shown to correlate with subsequent clinical improvement: high-level growth (1103) found by
follow-up protected specimen brushing at 72 h was more common among patients with persistent symptoms of pneumonia.
Despite sterilization of the lung in 94% of patients, clinical
resolution occurred in only 20% of cases.
To further evaluate the relationship between clinical and microbiological data, Dennesen et al. [47] performed a prospective
study of 27 patients with VAP. Temperature, WBC count, and
oxygenation (as measured by PaO2/FiO2 ratios) were scored
daily. Semiquantitative cultures of endotracheal aspirates were
also obtained at the day of admission and twice weekly thereafter. Unlike in the Montravers et al. [45] study, persistent
bacterial growth was more common with certain pathogens,
including Pseudomonas and Enterobacteriaceae species, despite
significant clinical improvement. These findings suggest that
bacterial eradication is an imperfect marker of clinical response
in VAP.
Chastre et al. [48] evaluated patients with microbiologically
treated VAP randomized to receive 8 days versus 15 days of
appropriate antimicrobial therapy. This study found similar
rates of survival and secondary outcomes between the 2 treatment groups. However, patients with VAP secondary to P. aeruginosa pneumonia who were treated for 8 days were more likely
to require reevaluation and retreatment in some cases. Similar
findings in nosocomial pneumonia due to P. aeruginosa and
other high-risk pathogens have been demonstrated by other
investigators [49, 50].
The ATS-IDSA guidelines have focused attention on patients
with nonresolving pneumonia, particularly patients showing no
response to the initial antimicrobial regimen [3]. Patients without response to initial therapy or who develop a pattern of
nonresolving pneumonia should be carefully evaluated to ensure that antimicrobial treatment is covering the offending
pathogen, that a noninfectious diagnosis has not been missed,
or that some complicating factor has not occurred.
treatment failure should be universal or should vary by subset
(e.g., patients undergoing dialysis, nursing home residents, and
patients with prior hospitalization).
STATEMENT 4: THE DEFINITIONS ARE THE
SAME FOR HCAP AND HAP TREATMENT
FAILURES
Rationale and Definition of Statement
Methods
The literature search, conducted in the PubMed database, was
completed in November 2006. Because the current definition
of HCAP would include some patients previously classified as
having CAP, the search was intentionally broad. The search
term “Pneumonia treatment failure” yielded 344 articles.
“Health care associated pneumonia treatment failure” yielded
7 articles, “Health care associated pneumonia failure” yielded
94 articles, “Hospital Acquired Pneumonia treatment failure”
yielded 94 articles, and “Hospital Acquired Pneumonia failure”
yielded 33 articles. “Pneumonia Prediction Outcome” yielded
54 articles. “Health care associated pneumonia failure” in a
search for guidelines, meta-analysis, or randomized, controlled
Evidence
As part of the assessment process, the populations of interest
were carefully defined on the basis of the most recent guidelines.
Articles were included that reported information on treatment
failures, provided that at least some of the patients studied met
the current definitions for having either HAP or HCAP. Most
studies fell into 1 of 2 categories: for HAP, most studies involved
patients with VAP or pneumonia in the ICU; for HCAP, most
studies involved patients with CAP, in which at least a subset
would have met the ATS-IDSA definition for having HCAP.
An attempt was made to clarify which definitions of treatment failure were being compared. However, the ATS-IDSA
guidelines are not that specific, and a wide range of definitions
have been used in different studies. Given this ambiguity, it
was important to identify what would constitute a “good” clinical definition of treatment failure and then to ask whether
there was a “good” definition applicable to both HCAP and
HAP.
Conceptual framework for assessing definitions of treatment
failure. When trying to assess whether a particular definition
of treatment failure is “good,” it is important to recognize the
clinical context in which the term “treatment failure” will be
used. Often, there is a significant amount of diagnostic uncertainty as to whether a given patient even has pneumonia, because a specific pathogen often cannot be identified. As a result,
when a presumed pneumonia fails to respond to treatment,
one of the first questions is whether the diagnosis of pneumonia
is correct, because many conditions can mimic the disease.
Therefore, it is more precise to use the term “nonresolving
pneumonia syndrome,” because, in many instances, infection
may not be present. Some authors might consider treatment
failure to include only those patients with true pneumonia. For
the purposes of this review, the more clinically relevant idea of
a nonresolving pneumonia syndrome will be used, because physicians in practice may not always be certain whether their
patients have true pneumonia.
Given the context of high diagnostic uncertainty, another
way to formulate the question is to ask whether there is a set
of criteria that effectively discriminates between those patients
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Nonresolving pneumonia is a common clinical problem among
patients with HCAP and patients with HAP. Although quantifying the frequency of this problem is difficult, previous studies reported that ∼15% of pulmonary consultations and 8% of
bronchoscopies were done to evaluate “nonresolving pneumonia” [51]. Treatment failures constitute a subset of all nonresolving pneumonias. For patients with HCAP and HAP, identifying treatment failure is important because the presence of
treatment failure implies that, without some type of intervention, the patient is more likely to have an adverse outcome.
The most recent ATS-IDSA nosocomial pneumonia guidelines identified a subset of patients at risk for harboring resistant
organisms despite their residence in the community [3]. The
new guidelines tried to define HCAP as a distinct clinical entity
on the basis of this recognition.
However, the guidelines provide a limited discussion of the
definition of treatment failure and nonresolving pneumonia.
The guidelines do recommend serial assessment of clinical parameters to define response to initial empirical therapy and
review some of those parameters that might be useful in assessing response: chest x-ray (CXR film) findings, WBC count,
oxygenation, temperature, CPIS, and culture results. However,
there are few specifics and limited discussion as to whether the
definition of treatment failure should be the same for HCAP
and HAP and whether the causes of treatment failure are the
same in these 2 groups. On the basis of this, the present review
aimed to assess the strength of the evidence supporting the
assertion that the definitions are the same for HCAP and HAP
treatment failures.
trials yielded 34 articles, and “Hospital Acquired Pneumonia
failure” in a search for guidelines, meta-analysis, or randomized, controlled trials yielded 104 articles. After elimination of
duplicates, there were 736 articles. After the search was limited
to articles in English and the titles and abstracts were reviewed,
only 65 manuscripts were relevant. These were reviewed, and
12 studies were selected. References from these articles and
review articles identified 1 additional report, for a total of 13
studies that were included. Subsequently, after assessment of
what would constitute a “good” functional definition of treatment failure, 2 of these were eliminated, leaving 11 studies.
S308 • CID 2008:46 (Suppl 4) • Kollef et al.
A prospective, observational, single-center trial of patients
with VAP by Dennessen et al. [47] described the clinical and
microbiological response to treatment, as well as relapses in
patients with microbiologically confirmed VAP. All patients had
adequate initial antibiotic therapy. The investigators measured
time to resolution of colony-forming units, WBC count, temperature, and oxygenation, as measured by the PaO2/FiO2 ratio.
Most patients who showed improvement in their clinical and
microbiological measures did so within the first 6 days. The
mean (median) time to complete resolution of all parameters
was 9 (8) days. When microbiological parameters were excluded, the mean (median) time to complete resolution of clinical and laboratory parameters was 6 (6) days. The only covariate of resolution that reached statistical significance was
oxygenation, as measured by the PaO2/FiO2ratio (P ! .01 ). Six
patients developed a second episode of VAP; 3 had relapses of
illness caused by the original pathogen, whereas the other 3
had superinfection with new pathogens, all 3 of which were
Pseudomonas species. The study was too small to demonstrate
a difference based on pathogens or between survivors and
nonsurvivors.
Another study of 63 patients with microbiologically confirmed VAP evaluated the utility of the CPIS as a predictor of
response [39]. CPIS was evaluated at days ⫺3, 0, 3, 5, and 7.
The mortality rate was 51% (32 of 63 patients). A decrease in
CPIS after initiation of treatment was associated with significantly lower mortality rate (P p .018 for patients with a CPIS
!6 at 3 or 5 days after onset of VAP, vs. those with a CPIS 16).
Of the components of the CPIS, only oxygenation, as measured
by the PaO2/FiO2 ratio, was able to distinguish survivors from
nonsurvivors. This was consistent with the finding that, among
patients subsequently found to have received adequate initial
antibiotic therapy (defined as the identified pathogen being
susceptible to the initial antibiotics prescribed), PaO2 improved
from day 0 to 3, whereas those receiving inadequate initial
antibiotic therapy had worsening oxygenation. Thus, in this
study, serial measures of CPIS and oxygenation were able to
identify patients more likely to have an adverse outcome.
A similar study of 63 patients with VAP evaluated the ability
of the APACHE II, Sepsis-related Organ Failure Assessment
(SOFA), and CPIS to predict mortality [56]. The mean
APACHE II, SOFA, and CPIS scores all were higher at the time
of VAP diagnosis in survivors than in nonsurvivors (P p
.001, .002, and .025, respectively). However, there was no measurement of APACHE II, SOFA, or CPIS subsequent to the
initiation of treatment for VAP. Therefore, although these scores
were good prognostic markers, they were not considered to
provide clinically useful definitions of treatment failure.
A prospective, multicenter, observational study of ICU-acquired pneumonia evaluated the causes of nonresponse to treatment in 71 patients [52]. Pneumonia was defined as the pres-
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who are likely to do well with their current treatment regimen
and those who are likely to have adverse outcomes. These criteria would need to identify patients with a significant variance
from the normal pattern of resolution for both patients with
HCAP and patients with HAP, to help guide treatment and
management decisions.
Note that, because the definition involves treatment failure,
for any definition to be clinically useful, it must use at least 1
intermediate outcome measure assessed after treatment is
started. Baseline predictors of outcome that are measured only
before initiation of treatment, such as the CPIS, CURB (confusion, urea 17 mmol/L, respiratory rate of ⭓30 breaths/min,
and blood pressure !90 mm Hg systolic or ⭐60 mm Hg diastolic), or Acute Physiology and Chronic Health Evaluation
(APACHE) scores at admission, would not qualify, because they
cannot show whether the treatment is actually working. These
would be prognostic measures but would not, by themselves,
constitute markers of treatment failure. Note that results of
serial testing with these same instruments, such as the development of a worsening CPIS, would constitute a potential definition of treatment failure because it measures how well the
patient responds to treatment. Therefore, a “good” definition
of treatment failure would need to integrate at least some intermediate outcome data obtained after initiation of treatment.
This idea of intermediate outcomes is also relevant when
looking at mortality. Death is frequently used as a definition
of treatment failure. Note that death, while being the ultimate
epidemiologic measure of treatment failure, does not constitute
a clinically useful definition of treatment failure, because it
precludes any corrective action being taken. Indeed, clinical
definitions of treatment failure are really aimed at predicting
the likelihood of death or permanent disability, because the
hidden premise in constructing “good” clinical definitions of
treatment failure is that they must allow clinicians the opportunity to intervene to potentially alter the course of disease.
Therefore, clinically useful definitions of treatment failure will
require measures that occur after the initiation of treatment
but before death, so that intervention is possible. Finally, good
definitions would ideally need to be readily available in everyday
clinical practice, affordable, and highly reproducible between
centers.
Studies of HAP. Given this conceptual framework, studies
were categorized on the basis of sample size, patient population,
the definition of pneumonia used for entry, the definition of
treatment failure used, the treatment failure rate reported, and
the causes of treatment failure reported (table 3). Most studies
could not meet all of the criteria of a good definition of treatment failure, but any study that provided insight into any of
these categories was eligible. The definitions of treatment failure
were analyzed, and only definitions that might have at least 1
intermediate outcome were included.
401
400
Combes et al. 2007 [54]
Wolff 1998 [55]
ICU pneumonia
VAP
ICU pneumonia
VAP
VAP
VAP
Population
73 (18)
27 (7)
110 (27)
44 (62)
28 (27)
NR
6 (22)
Treatment failures or
recurrences, no. (%)
Predictors of death: CPIS and PaO2/FiO2 on day 3
Oxygenation (PaO2/FiO2) associated with relapse risk; recurrent
pneumonias: superinfection, n p 3; relapse, n p 3
Comments
Recurrent pneumonia as defined by Recurrent pneumonia: superinfection, n p 77 (19%); relapse,
CXR film, purulent secretions,
n p 56 (14%)
and BAL findings
Only intermediate outcome associated with mortality was day
8 organ failure score
Persistence pneumonia
3.8% with noninfectious etiology of pneumonia; no clear reSuperinfection
porting on mortality linkage for treatment failure definitions
Oxygenation, fever, CXR film, shock Mortality rate 50%, vs. 7% for treatment failures
Recurrent pneumonia defined by
Recurrent pneumonias: superinfections, n p 17; relapse, n p
CXR film, purulent secretions,
11
and BAL
CPIS and PaO2/FiO2
Microbiological evidence of relapse
Definition of treatment failure or
recurrence
NOTE. CAP, community-acquired pneumonia; CPIS, clinical pulmonary infection score; CXR, chest x-ray; HCAP, health care–associated pneumonia; ICU, intensive care unit; NR, not reported; VAP, ventilatorassociated pneumonia.
71
103
63
Luna et al. 2003 [39]
Ioanas et al. 2004 [52]
Combes et al. 2003 [53]
27
Patients, no.
Studies of pneumonia treatment failure that included patients meeting the definition of having hospital-acquired pneumonia (HAP).
Dennesen et al. 2001 [47]
Study
Table 3.
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S310 • CID 2008:46 (Suppl 4) • Kollef et al.
likely to have an adverse outcome was the organ failure score
on day 8.
A prospective, randomized, controlled trial comparing 2 different drug regimens for empirical treatment of pneumonia in
400 patients in the ICU [55] provided data on treatment failures
as well. Clinical failures in this trial were defined as either
persistence or progression of symptoms leading to a change of
antibiotics, a worsening CXR film finding leading to a change
of antibiotics, superinfection, or death. A nonbacterial origin
of the pneumonia was identified in 3.8% of the patients. In
the clinical efficacy analysis, 73 patients (18%) had persistent
pneumonia. Superinfection occurred in 27 patients, resulting
in the death of 6 patients. There were 277 patients evaluable
for bacteriologic efficacy analysis; of these, 223 had HAP. Death
occurred in 113 (28%) of 399 patients receiving the study drug.
There was no clear linkage between any intermediate outcome
and mortality reported.
Studies of populations that included patients with HCAP.
By use of the same conceptual framework, studies were categorized that included at least a significant proportion of patients
with HCAP on the basis of the same criteria of sample size,
patient population studied, definition of pneumonia used for
entry, definition of treatment failure used, treatment failure rate
reported, and causes of treatment failure reported (table 4).
Most studies could not meet all of the criteria for a good
definition of treatment failure, and many studies were primarily
of CAP. However, any study that provided insight into any of
these categories was eligible. The definitions of treatment failure
were analyzed, and only definitions that might have at least 1
intermediate outcome were included.
A prospective observational study of patients hospitalized for
CAP included a significant number of patients with neoplasia
and immunosuppression and, therefore, was included [57].
CAP was defined as an acute illness with a new or progressive
infiltrate on chest radiograph associated with ⭓1 of the following respiratory signs or symptoms: fever (temperature,
138C), a new cough, purulent sputum production, new dyspnea and/or tachypnea (120 breaths/min), pleuritic pain and
leukocytosis (110 ⫻ 10 9 cells/L) or leukopenia (!4 ⫻ 10 9 cells/
L), or 110% band forms if the leukocyte count was between
4 ⫻ 10 9 cells/L and 10 ⫻ 10 9 cells/L. A total of 224 of 228 patients were evaluable and completed follow-up. Eight patients
developed antibiotic adverse effects, but these were not considered to be treatment failures; 54 patients (24%) had treatment failure. The study defined treatment failure as at least 1
of the following: fever for 13 days (or for 16 days if bacteremic),
clinical deterioration necessitating a change in antibiotics, or
death after at least 48 h of antibiotic therapy. Fourteen patients
(26%) died. The most common causes of treatment failure were
host factors in 34 patients (63%), unusual pathogens in 10
patients (19%), superinfection in 4 patients (7%), incorrect
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ence of a new or progressive infiltrate with at least 2 of the
following 3 criteria: leukocytosis, fever, and purulent sputum.
Not all cases of pneumonia were microbiologically confirmed.
Nonresponse was defined as ⭓1 of the following occurring 72
h after treatment: (1) failure to improve oxygenation or intubation 24 h after initiation of antibiotic therapy plus purulent
respiratory secretions; (2) persistent fever or hypothermia; (3)
worsening radiographic infiltrates; or (4) occurrence of septic
shock or multiple organ system failure not present on day 1.
Nonresponse occurred in 44 (62%) of patients. This definition
of nonresponse was associated with a significantly increased
risk of hospital mortality (50% vs. 7%; P ! .001). Possible causes
of nonresponse could be identified in 28 of the 44 patients
without response, with 8 of these 28 patients having 11 cause.
Causes of nonresponse included noninfectious causes (7), superinfection (6), inadequate initial treatment (10), and concomitant foci of infection (13).
A prospective observational study of VAP evaluated factors
associated with the recurrence of VAP among 103 patients who
survived VAP for 8 days [53]. VAP and recurrent VAP were
defined by CXR film findings, purulent secretions, and BAL
findings. Predictors of recurrence were measured at the time
of the initial bronchoscopy and on day 8 of VAP. Recurrence
was identified in 28 patients (27%) at a mean of 21 days after
the initial episode of VAP. Causes of recurrent VAP included
relapse (same organism) in 11 patients and superinfections in
17 patients. Multivariable analysis identified a day 1 radiology
score 17, a day 8 temperature 138C, and acute respiratory
distress syndrome (ARDS) on day 8 as risk factors for subsequent recurrence of VAP. However, no data were available to
determine whether the presence of these factors on day 8 differentiated survivors from nonsurvivors; this was not considered to be evidence that these markers could be used clinically
as definitions of treatment failure.
A prospective, randomized, controlled trial [48] comparing
8 versus 15 days of therapy for VAP provided the data necessary
for a nested observational cohort trial evaluating predictors of
infection recurrence and death in patients with VAP [54]. Of
401 patients with microbiologically confirmed VAP in the study,
110 (27%) developed recurrent infections, some of which were
polymicrobial. Relapse with the same pathogen occurred in 56
patients (14%), and superinfection occurred in 77 patients
(19%). Predictors of VAP recurrence measured on day 8 after
VAP onset included SAPS II admission score; radiology score;
temperature; gram-negative, nonfermenting pathogens; or
MRSA. VAP recurrence was not associated with 28-day mortality (17% mortality rate for those with recurrence, vs. 18%
for those without recurrence; P p .88 ). Only sex, age, day 8
SOFA score, and gram-negative nonfermenting pathogens were
predictive of 28-day mortality. Therefore, in this study, the only
intermediate outcome measure able to identify those more
3048
Genne et al. 2003 [59]
CAP
CAP and NHAP
CAP
CAP
CAP
Population
11
NR
6
11
24
Treatment failure
or recurrence
rate, %
Definition
Causes and comments
Fever, clinical deterioration, antibiotic change, resistant pathogen
None used
Early fever, hemodynamics, respiratory, CXR film
Causes of failure: unknown, 82%; resistant, 8%; superinfection, 2%
The only intermediate outcome correlated with mortality was 24-h urine output
Progressive pneumonia, 67%; empyema, 22%; failure associated with
increased mortality
One or more: fever for 13 days (or
Cause of treatment failure: host factors, 34 (63%); unusual pathogens, 10
16 days if bacteremic), clinical
(19%); superinfection, 4 (7%); incorrect drug dosing, 3 (6%); not pneumonia,
deterioration necessitating antibi3 (6%)
otic change, or death after 48 h
of antibiotic therapy
Fever, clinical deterioration, CXR film Nonresponding, 61%; progressive, 39%; only HAP related to mortality, persistent infections due to resistance
NOTE. CAP, community-acquired pneumonia; CXR, chest x-ray; HAP, hospital-acquired pneumonia; NHAP, nursing home–associated pneumonia; NR, not reported.
104
1383
444
Arancibia et al. 2000 [58]
El-Solh et al. 2001 [27]
Roso´n et al. 2004 [42]
224
Patients,
no.
Studies of pneumonia treatment failure that included some patients meeting the definition of having health care–associated pneumonia (HCAP).
Genne et al. 2006 [57]
Study
Table 4.
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S312 • CID 2008:46 (Suppl 4) • Kollef et al.
common. Early failure was associated with higher complication
rates (P ! .001), increased hospital length of stay, and increased
mortality (27% vs. 4%; P ! .001).
A meta-analysis of 16 studies evaluating the causes of treatment failure in clinical trials of CAP was included [59]. There
was no stratification with regard to the patient populations
involved, although analysis of the individual studies demonstrated that some patients with HCAP would have been included on the basis of prior antibiotic therapy and comorbidities. In this meta-analysis, 6 different definitions of treatment
failure were used, one of which was death; another was discontinuation for personal reasons. Persistent fever 172 h after
antibiotic therapy, clinical deterioration requiring admission to
an ICU or requiring vasopressors, change of antibiotic therapy
for any cause, and resistant pathogens with worsening symptoms constituted the other 4 definitions of treatment failure
used. There was significant heterogeneity in terms of failure
rates reported (range, 0%–34%; P p .008 ). When adverse effects of medications were excluded, treatment failures occurred
in 333 patients (16%). In the majority of cases (82%), no cause
could be identified. Resistant pathogens were the most common
identified cause (n p 28; 8%). Superinfection occurred in only
7 patients (2%). There was no stratification based on HCAP
risk factors, and no evaluation of the relationship between treatment failure and mortality risk could be made.
Grading of Evidence
On the basis of a review of these 11 studies, the 5 members of
this workshop agreed that the evidence available to support
this statement was category IV for the statement in general,
category V for the statement as it applies to hospitalized patients
with HCAP, and category V for the statement as it applies to
nonhospitalized patients with HCAP (table 2).
Level of Support
When voting on the support for this statement, 9% of the
summit participants voted to accept the statement completely,
36% voted to accept the statement with some reservations, 46%
voted to accept the statement with major reservations, and 9%
voted to reject the statement with reservations. In comparison,
of the 383 IDSA members who participated in the online survey,
47% voted to accept the statement completely, 42% voted to
accept the statement with some reservations, 7% voted to accept
the statement with major reservations, 3% voted to reject the
statement with reservations, and 1% rejected the statement
completely (figure 5).
Discussion
At present, there is limited conclusive evidence supporting this
statement, as is reflected in the summit participants’ grading
of the evidence. Because the recognition and classification of
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drug dosing or compliance in 3 patients (6%), and incorrect
diagnosis of pneumonia in 3 patients (6%).
A prospective, observational, single-center study of treatment
failure in CAP was included because of a high percentage of
cases with malignancy, renal disease, or prior outpatient antibiotic therapy [58]. Treatment failures were defined as either
nonresponding pneumonias (defined as persistent fever with a
temperature 138C and/or clinical symptoms [malaise, cough,
expectoration, dyspnea] after at least 72 h of antimicrobial
treatment) or progressive pneumonias (defined as clinical deterioration in terms of the development of acute respiratory
failure requiring ventilatory support and/or septic shock after
at least 72 h of antimicrobial therapy). During the study, there
were 444 patients with CAP, of whom 49 were identified as
experiencing treatment failure (11%). Of these 49 patients, 30
(61%) were patients without treatment response, and 19 (39%)
had progressive pneumonia. A definite etiology of treatment
failure could be established in 32 (65%) of the 49 patients.
Etiologies comprised primary infections (n p 8 ), definite persistent infection (n p 4), nosocomial infection (n p 8), noninfectious causes (n p 8), and combinations of the above
(n p 4). Those classified as having nonresponding pneumonia
were more likely to have persistent infections (14 of 30) than
nosocomial infections (2 of 30). Those classified as having progressive pneumonia were less likely to have persistent infections
(4 of 19) and more likely to have nosocomial infections (6 of
19). Among those with treatment failure, only nosocomial
pneumonia was associated with mortality in multivariate analysis. However, there was no comparison reported between those
who developed treatment failures and those who did not, in
terms of their mortality risk.
A prospective observational study of severe pneumonia in
very elderly individuals was included because 47 of the 104
patients enrolled were nursing home residents [27]. The primary objective was to evaluate the prevalence of pathogens in
this population and its impact on morbidity and functional
status. No specific definition of treatment failure was used. In
multivariate analysis, only 4 variables were predictive of mortality: multilobar involvement, septic shock at presentation, inadequate antimicrobial therapy, and 24-h urine output.
A prospective, single-center, observational study of early
treatment failures in patients hospitalized for CAP had a small
percentage of patients with either malignancy, renal failure, or
nursing home residence [42]. Early failures were defined as lack
of response or worsening of clinical or radiographic status at
48–72 h, requiring changes in antibiotic therapy or invasive
procedures. Early failure occurred in 81 (6%) of 1383 patients.
The most common causes were progression of pneumonia
(67%) and empyema (22%). Superinfection occurred in only
3 cases (4%). Among patients with an identified pathogen,
initial antibiotics that did not cover the pathogen were more
•
•
•
•
•
•
Figure 5. Voting comparison for statement 4 (“The definitions are the
same for HCAP and HAP treatment failures”). “Summit members” refers
to the 11-member summit panel; “IDSA members” refers to the members
of the Infectious Diseases Society of America who responded to a Webbased survey. HAP, hospital-acquired pneumonia; HCAP, health care–associated pneumonia.
Future Directions
Future directions discussed by the summit members focused
on the limitations of the previously discussed studies. Appropriately designed epidemiologic studies are clearly needed to
better delineate the causes of treatment failure in CAP, HAP,
and HCAP. Careful consideration and construction of clinically
useful definitions of treatment failure should be done before
these studies are performed, so that clinically useful recommendations can be made. Once standardized definitions can
be validated, trends in treatment failure can be followed longitudinally to assess changes in treatment failure rates and
causes over time.
STATEMENT 5: SEVERE CAP IS NOT HCAP
Rationale and Definition of Statement
Over the past decade, there has been an increase in infections
due to MDR pathogens in individuals referred to acute-care
hospitals who have been previously hospitalized, have received
broad-spectrum antibiotics, or reside in nursing homes or other
long-term-care facilities [2, 3, 13, 16, 23, 60]. These individuals
may need different empirical antibiotics for pneumonia, to
avoid delays in receiving appropriate antibiotic therapy. Such
delays have been shown to result in poorer outcomes from
serious infections [2, 3, 61–63].
HCAP, as defined in the 2005 ATS-IDSA guidelines, includes
pneumonia in patients referred to hospitals for evaluation and
treatment who were more likely to be colonized or infected
with MDR pathogens [3]. Risk factors for different MDR pathogens are variable and complex; these factors may include previous hospitalization, prior antibiotic therapy, chemotherapy,
hemodialysis, wound therapy, and residence in nursing homes
and long-term-care facilities, either alone or in combination.
Fewer data are available on these patients managed in non–
acute-care settings where presentations, clinical data, and therapy are more limited [64, 65].
Principles for the treatment of patients with HCAP referred
HCAP Summit Critical Appraisal • CID 2008:46 (Suppl 4) • S313
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HCAP is new, none of the studies cited specifically evaluated
patients with HCAP exclusively. Additionally, the lack of a standardized definition of treatment failure makes conclusive statements regarding treatment failure problematic. Furthermore,
the existing literature did not report stratified analyses for the
HCAP and HAP populations; therefore, any conclusions should
be viewed as preliminary.
Given these limitations, this systematic assessment of treatment failure definitions and their relationship to mortality in
HAP and HCAP raises interesting questions and preliminary
observations. First, because of differences in study design, inclusion criteria, populations studied, and definitions used, there
is significant heterogeneity in terms of treatment failure rates
both within and between groups. Although it appears that treatment failure rates are higher among patients with HAP than
among patients with HCAP, because of the lack of a stratified
analysis, this is not necessarily the case. HCAP may fall somewhere between HAP and CAP in terms of treatment failure
rates. However, a properly stratified analysis needs to be performed before more-specific conclusions can be drawn, and
clinically useful definitions need to be standardized.
One consistent finding was that superinfection appeared to
be more of a problem in patients with HAP than in the CAP/
HCAP population reviewed. Unusual or resistant pathogens
were more of a problem in the latter group. This is probably
a result of differences in infection control and exposure, antibiotic use, and host factors. However, this finding should be
viewed with caution when HAP and HCAP are compared, owing to the lack of properly stratified data analysis.
Finally, this review demonstrates the importance of constructing sound and clinically useful definitions before approaching complex problems. Whether the same or different
definitions of treatment failure are used for HAP and HCAP
does not matter if the definitions are not valid and clinically
useful. At a minimum, a “good” definition of treatment failure
should do the following:
•
Provide good discriminatory power and capture variance
from the norm
Utilize information that is intermediate in time, prior to
the outcome of interest
Identify a group/subset in whom an intervention is needed
Be widely available
Be highly reproducible
Encompass the clinical scenario of treatment failure as a
syndrome of unknown etiology (not necessarily infectious),
rather than being limited to those patients in whom a primary infection is certain, because in clinical practice this is
often not the case
Include proof that definitions of treatment failure are predictive of future adverse outcomes of interest
Methods
Severe CAP. A search of PubMed was performed for severe
CAP on 14 November 2006. The search term “community
acquired infections” (4552) was combined with the search term
“pneumonia” (54,650) and then was combined with the “AND”
function for a total of 2562 articles. A search for articles with
the text words “severe CAP” or “SCAP” yielded 248 articles.
A search for articles with the text words “severe community
acquired pneumonia” yielded 225 articles, and that combined
with the “OR” function yielded a total of 420 articles. The 2
searches above combined with the “AND” function yielded 194
articles. A search for articles with the text words “severe community acquired pneumonia” yielded 200 articles, and, combined with the “OR” function, the above result yielded 194
articles, for a total of 250 articles. No abstracts were included.
HCAP. A literature search of PubMed was performed on
14 November 2006. The search term “cross infection” yielded
31,350 articles. The term “pneumonia” generated 54,650 articles. When the term “pneumonia” was combined with the
“AND” function, there were 24,096 articles noted. The text
words “healthcare associated” or “health care associated”
yielded 331 articles. The search term “pneumonia” yielded
54,650 articles and, when combined with the term “HCAP,”
yielded 23 articles. The text words “healthcare associated pneuS314 • CID 2008:46 (Suppl 4) • Kollef et al.
monia” or “health care associated pneumonia” or “healthcare”
yielded 24 articles. When the 3 searches above were combined
with the “OR” function, there were a total of 2509 articles.
Fewer articles were identified using English as the only language. Eighteen articles were deemed pertinent to this review.
Evidence: What is Severe CAP?
CAP, like HCAP, has varying degrees of severity and may be
caused by a wide spectrum of bacterial, atypical, or viral pathogens [70]. Patients with severe CAP are often evaluated in
EDs before hospital admission, and patients with severe CAP
often require admission to the ICU as a result of shock, ARDS,
or multiple-organ failure requiring mechanical ventilation.
These patients represent a subset of patients with higher morbidity, mortality, and length of stay in the hospital and ICU.
Microbiology of severe CAP. Severe CAP may be caused
by several pathogens, including S. pneumoniae, H. influenzae,
and anaerobic bacteria that typically are not MDR strains [70].
Even in CAP caused by S. aureus or gram-negative bacteria,
such as K. pneumoniae, the pathogen is usually not MDR if
the patient has not had prior antibiotic therapy or close contact
with the health care system. Atypical pathogens, such as Chlamydophila pneumoniae, Mycoplasma pneumoniae, and L.
pneumophila, are common in the United States. Coinfection
with these bacteria occurs, and, in contrast to HCAP, the pathogens are not MDR or necessarily associated with prior antibiotic use or contact with the health care system. In addition,
although CAP is more likely to be caused by bacteria, influenza
viruses, respiratory syncytial viruses, and adenoviruses are also
important. Patient risk factors for CAP include underlying
medical diseases, such as chronic lung disease; exposure to
animals; risk of aspiration; exposure to other infected persons;
or seasonal epidemics.
In a review of severe CAP by Ewig and Torres [71], microbial
patterns in Barcelona, Spain; Lille, France; and South Africa
were examined. Rates of isolation of S. pneumoniae were 15%,
27%, and 29%, respectively; those of K. pneumoniae were 2%,
2%, and 19%, respectively; and those of S. aureus were 0%,
19%, and 3%, respectively. A review of etiologic agents identified in 16 studies of severe CAP found that rates of S. pneumoniae ranged from 12% to 38%, rates of H. influenzae from
0% to 13%, rates of enteric gram-negative bacilli from 0% to
34%, rates of S. aureus and other Staphylococcus species from
0% to 15%, rates of P. aeruginosa from 0% to 5%, and rates
of L. pneumophila from 0% to 30%. Unfortunately, these differences represent the diversity of patient populations studied
and different time periods but do not address MDR pathogens.
The study includes some patients who would now be classified
as having HCAP because of their risk for infection with MDR
pathogens. A later study by Rello et al. [72] in Barcelona, Spain,
compared the microbiological assessments of 106 patients with
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to acute-care hospitals and clinics share more similarities in
etiology and management with those for HAP and VAP than
with those for CAP (figure 2) [3, 23]. Thus, broader-spectrum,
empirical antibiotic therapy has been suggested to be aimed at
MDR pathogens, such as P. aeruginosa, Klebsiella pneumoniae
producing extended-spectrum b-lactamases (ESBLs), or MRSA.
The principles of the 2005 ATS-IDSA guidelines were aimed at
appropriate, initial antibiotic therapy regardless of disease severity. In addition, de-escalation of antibiotics was recommended for patients with treatment response, on the basis of
the availability of microbiological cultures, clinical response,
and reducing duration of antibiotic therapy to 7–8 days.
There are many definitions of severe CAP, and several scoring
systems have been used for assessing CAP severity and the need
for hospital admission or intensive care [66–69]. Patients with
severe CAP or severe HCAP may need intensive care or mechanical ventilation or may have pneumonia complicated by
sepsis, shock, bacteremia, or multiple-organ failure. These assessments, often performed in the ED or clinic for patients with
CAP, should also apply to patients with HCAP.
This section examines the hypothesis that “severe CAP is not
HCAP” in the acute-care setting. Clearly, definitions are key,
and applications to all types of patients are difficult. For example, HCAP management in the acute-care setting is better
defined than management in nursing homes and other types
of long-term-care facilities.
tients evaluated in the ED who had CAP as well as HCAP, and,
thus, these assessments should also apply to those with HCAP.
The PSI is widely used as a benchmark for assessing the need
for hospital admission and risk of mortality. Because the PSI
requires 20 variables, it is labor intensive, difficult for clinical
assessment in the ED, not a good predictor for ICU admission,
and heavily weighted by age. Therefore, it may underestimate
severe CAP in younger patients and is limited for identifying
patients eligible for activated protein C therapy. As a result,
other scoring systems have been evaluated.
A more recent approach using a modified PSI score was
suggested by Espana et al. [73], who evaluated 1057 patients
for CAP in an ED; 11.5% of patients were admitted to the
hospital, 3% were admitted to the ICU, 2.3% had shock, and
1.5% underwent mechanical ventilation. Overall mortality was
9.1%. Severe CAP was defined as a score of 110 points for 2
major criteria, pH !7.3 (13 points) and systolic blood pressure
!90 mm Hg (11 points), and for 6 minor criteria: respiratory
rate 130 breaths/min (9 points), blood urea nitrogen (BUN)
level 130 mg/dL (5 points), change in mental status (5 points),
PaO2/FiO2 (5 points), age 180 years (5 points), and multiple
bilateral infiltrates (5 points). Of note, the scores 120 points
were better predictors of severe CAP.
Another scoring system for stratifying the severity of CAP is
the CURB-65, which awards 1 point each for confusion, urea
concentration 17 nmol/L, respiratory rate ⭓30 breaths/min,
low blood pressure, and age ⭓65 years [74]. Those with 3 points
have been found to have a mortality rate of 21%, those with
4 points a mortality rate of 42%, and those with 5 points a
mortality rate of 60% [74]. This scoring system also correlated
with the need for mechanical ventilation, length of stay, and
PSI score. Because the blood urea concentration is often not
readily available, it was omitted, and the CRB-65 was suggested;
it was easier to apply in the ED. Mortality rates for the CRB65 correlated well with those for the CURB-65 and were 19%
for patients with 2 points, 44% for those with 3 points, and
55% for those with 4 points. Advantages of these methods of
scoring include simplified calculation, clear admission criteria
for those with ⭓2 points, good correlation with both mortality
and the need for ICU admission for those with ⭓2 points, a
good predictor of CAP mortality due to bacteremia, and a good
predictor of those in need of activated protein C therapy [67].
Data on the use of these scoring systems (PSI-V; PSI-IV,V;
CURB-65 ⭓3; and the mATS score for assessing ICU admission
and mortality) are shown in table 5 [66]. Note that, for assessing
ICU admission, sensitivity ranged from 48% to 92%, specificity
ranged from 45% to 87%, the positive predictive value ranged
from 10% to 33%, and the negative predictive value ranged
from 95% to 99%. Better results were identified for assessing
mortality.
There is great heterogeneity of patient populations, definiHCAP Summit Critical Appraisal • CID 2008:46 (Suppl 4) • S315
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severe CAP requiring mechanical ventilation with 98 patients
with CAP who were not receiving ventilation. A microbiological
diagnosis was made in 57.3% of patients, and the most common
bacterial pathogens were S. pneumoniae, L. pneumophila, and
H. influenzae. P. aeruginosa (6.6% vs. 1.0%; P ! .05) and L.
pneumoniae (15.1% vs. 7.1%; P ! .05) infections were more
common in intubated patients than in nonintubated patients.
Overall mortality was 44.3% in intubated patients, versus 23.5%
overall. Of note, bacteriologic investigation led to changes in
antibiotic therapy in 41.6% of patients, including 11 patients
(5%) in whom initial treatment was ineffective.
Definitions of severe CAP. Several methods have been designed to assess CAP severity to determine the need for hospital
admission or triage to intensive care and to identify those with
a higher risk of death [67–69, 73, 74]. Severe CAP is independent of the source of the pathogen or risk for infection with
an MDR pathogen and may occur in patients with CAP or
HCAP.
Because severe CAP has many definitions, a universally accepted one does not exist. Several investigations have suggested
methods of identifying patients with severe CAP who should
be admitted to the hospital or ICU, those at risk for respiratory
or multiple-organ failure, and those with a greater risk of mortality [68–70]. Ewig et al. [68] defined severe CAP as CAP
requiring admission to the ICU. Of the 64 (16%) admitted
patients with severe CAP who were followed prospectively, the
mortality rate was 30%, versus 5% for those not admitted. The
10 criteria for severe CAP, initially defined by the ATS, include
respiratory rate 130 breaths/min, PaO2/FiO2 !250, bilateral involvement on chest radiograph, multilobar involvement, systolic blood pressure !90 mm Hg, diastolic blood pressure !60
mm Hg, mechanical ventilation, progressive infiltrates, septic
shock, and renal failure. Although the ATS criteria demonstrated good sensitivity (98%) but low specificity (32%), the
positive predictive value was low (24%). Therefore, a modified
ATS score (mATS) was suggested, in which 2 or 3 “minor”
baseline criteria (systolic blood pressure !90 mm Hg, multilobar involvement, and PaO2/FiO2 !250) and 2 “major” criteria
(mechanical ventilation and presence of septic shock) demonstrated a sensitivity of 78%, a specificity of 94%, a positive
predictive value of 75%, and a negative predictive value for
mortality of 95% [68].
Fine et al. [69] developed the PSI derived from a large database that used points assigned for age, underlying disease,
physical findings, and laboratory data to identify patients who
required admission to the hospital and those at risk for death.
Of the risk groups (I–V), patients with the highest PSI scores
(190) in risk groups IV and V were considered to have “severe
CAP” and had the highest mortality (8% and 29%, respectively). It is important to note that these studies included pa-
Table 5. Outcomes of severe community-acquired pneumonia in
terms of mortality and intensive care unit (ICU) admission.
Outcome, severity
scoring system
Positive
Negative
predictive predictive
Sensitivity Specificity
value
value
Death
PSI-V
PSI-IV,V
CURB-65⭓ 3
mATS Score
68
97
81
41
82
48
68
85
28
16
21
22
96
99
97
93
PSI-V
PSI IV,V
48
84
79
45
14
10
96
98
CURB-65⭓ 3
mATS Score
58
92
65
87
10
33
96
99
ICU care
tions, etiologic agents, and clinical assessments for severe CAP.
Is severe CAP best defined as admission to the ICU, the need
for mechanical ventilation, or a poor score as defined by PSI,
CURB-65, CRB-65, or modified PSI? Admission to the ICU
varies between hospitals, as does the need for mechanical ventilation, methods of diagnosis, and etiologic agents. In addition,
there is no assessment for MDR pathogens in patients with
severe CAP similar to HCAP, and there is no assessment for
patients in nursing homes or patients receiving long-term care
or who have the use of prior antibiotics as a risk factor.
Many studies defining severe CAP lack validation and have
small study populations and variable study definitions, as well
as variable populations and risks for infection and mortality.
In addition, data for severe CAP may be confounded by the
presence of sepsis.
Evidence: What is HCAP?
According to the ATS-IDSA guidelines, patients with HCAP
are a subset of patients who present to the hospital with pneumonia and are at greater risk of colonization and infection with
MDR pathogens (figure 2) [3]. Previously, many of these patients who presented to acute-care facilities for evaluation of
lower-respiratory-tract infections were considered to have CAP.
Risk factors for infection with MDR pathogens identified in
the ATS-IDSA guidelines are summarized in table 6. MDR and
non-MDR pathogens of concern include MRSA, P. aeruginosa,
Acinetobacter baumannii, and ESBL-producing gram-negative
bacilli, such as E. coli, K. pneumoniae, and Enterobacter species
(table 7). Patients with HCAP managed in nursing homes or
residential facilities, which may have limited resources for evaluation and treatment of pneumonia, may need a referral to
another facility. These nonhospital settings also could employ
S316 • CID 2008:46 (Suppl 4) • Kollef et al.
Table 6. Risk factors for infection with multidrug-resistant
(MDR) pathogens.
Antimicrobial therapy in preceding 90 days
Current hospitalization of at least 5 days
High frequency of antibiotic resistance in the community or in
the specific hospital unit
Presence of risk factors for health care–associated pneumonia:
Hospitalization for at least 2 days in the preceding 90 days
Residence in a nursing home or extended-care facility
Home infusion therapy (including antibiotics)
Long-term dialysis within 30 days
Home wound care
Family member with infection involving MDR pathogen
Immunosuppressive disease and/or therapy
NOTE. Adapted from [3], with permission from the American Thoracic
Society, and from [13].
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NOTE. Data are percentages and are from [66]. PSI, pneumonia severity
index; CURB-65, confusion, urea 17 mmol/L, respiratory rate of ⭓30 breaths/
min, blood pressure !90 mm Hg systolic or ⭐60 mm Hg diastolic, and age
⭓65 years; mATS, modified American Thoracic Society.
an approach that includes assessment, empirical antibiotic therapy based on a clinical suspicion of HCAP, and subsequent
monitoring of response to therapy [64, 65, 75].
The reason for identifying patients with HCAP versus CAP
was based on increasing rates of exposure to and colonization
with MDR pathogens in patients with a greater risk of underlying disease and prior exposure to antibiotics that could increase the risk of receiving inappropriate empirical antibiotic
therapy and having poorer outcomes (table 7) [3]. The use of
broader initial antibiotic coverage for MDR pathogens was coupled with an emphasis on de-escalating and reducing the duration of antibiotic therapy for HCAP, HAP, and VAP (figure
6). If, indeed, broader initial empirical antibiotic therapy was
appropriate for MDR pathogens, then de-escalation of the initial therapy was based on the response of the patients and the
availability of microbiological data within 24–48 h.
If there were no risk factors for infection with MDR pathogens, patients with HCAP would be managed like patients
with CAP, which would cover the usual CAP pathogens, versus
the broader, empirical coverage recommended for MDR
pathogens.
No recommendations were made in the ATS-IDSA guidelines
for altering empirical antibiotic coverage for HCAP on the basis
of disease severity [3]. Furthermore, the focus of these recommendations was on patients referred to acute-care hospitals
for evaluation. The resources for the evaluation and management of severe CAP may be limited in some nursing homes
or long-term-care facilities. Thus, the question arises as to
whether and how the ATS/IDSA guidelines for HCAP apply to
management in nursing homes and long-term-care facilities.
Options for management would include collecting data for documenting the presence of HCAP, initiating empirical antibiotic
therapy, and assessing the clinical response to therapy on site
or making a referral if HCAP becomes severe. If there is no
clinical improvement or progression while receiving the initial
Table 7. Initial antibiotic therapy for patients at risk of infection with multidrug-resistant (MDR) health care–associated pneumonia
(HCAP) pathogens versus those without risk factors for infection with MDR pathogens, as outlined in the American Thoracic Society–
Infectious Diseases Society of America guidelines.
Pathogen type
Empirical antibiotic therapy
Non-MDR
Streptococcus pneumoniae
Haemophilus influenzae
Anaerobes
Non–ESBL+ gram-negative rods
MDR
Pseudomonas aeruginosa
Acinetobacter speciesa
ESBL+ gram-negative rodsa (Klebsiella pneumoniae, Escherichia coli,
or Enterobacter species)
MRSA
Legionella pneumophilac
Ceftriaxone plus azithromycin
or
a
levofloxacin, moxifloxacin, gatifloxacin, gemifloxacin
NOTE. Data are from [3]. ESBL+, extended-spectrum b-lactamase producing; MRSA, methicillin-resistant Staphylococcus aureus.
a
If Acinetobacter species or an ESBL+ isolate is suspected, a carbapenem is recommended, pending susceptibility results.
If MRSA is suspected or there is a high incidence locally.
c
If L. pneumophila is suspected, the combination antibiotic regimen should include a macrolide (e.g., azithromycin), or a fluoroquinolone (e.g., ciprofloxacin
or levofloxacin) should be used rather than the aminoglycoside.
b
antibiotic regimen in the long-term-care setting, the patient
would then be eligible for referral to an acute-care hospital or
clinic for evaluation (figure 7).
Community-acquired MRSA was first seen in the 1990s in
children and more recently has occurred in adults [76]. This
strain is distinct from the hospital MRSA associated with HAP,
VAP, and HCAP, because it has a mec IV gene and the PantonValentine leukocidin gene, which may account, in part, for its
increased virulence and predisposition to abscess formation and
severe pneumonia. Outbreaks have occurred in nursing homes
and long-term-care facilities and have now been identified in
hospitals. In comparison with hospital-acquired MRSA, community-acquired MRSA is more sensitive to antibiotics such as
ciprofloxacin and clindamycin.
HCAP questions of concern. Several questions need attention. Can and should severe HCAP be managed in nursing
homes or long-term-care facilities? Do the HCAP time lines
for prior antibiotic use and prior hospitalization apply to management, or do they need to be altered? Are the HCAP definitions accurate? Should the severity of disease alter initial antibiotic management for patients with HCAP? How does the
rapid evolution of community-acquired MRSA in nursing
homes, long-term-care facilities, and hospitals alter the HCAP
recommendations?
Grading of Evidence
On the basis of a review of the studies cited above, the 5
members of this workshop agreed that the evidence available
to support this statement was category III for the statement in
general, category III for the statement as it applies to hospitalized patients with HCAP, and category V for the statement
as it applies to nonhospitalized patients with HCAP (table 2).
Level of Support
When voting on the support for this statement, 91% of the
summit members and 83% of the IDSA members who responded to the survey accepted it completely; it was accepted
with some reservations by 9% of the summit members and
13% of the IDSA members. One percent of IDSA members
accepted the statement with major reservations, 2% rejected
the statement with reservations, and 1% rejected it completely
(figure 8).
Discussion
The management of pneumonia is dynamic, and the evolution
of MDR pathogens in community and health care settings will
require frequent refining and careful monitoring. The statement
that severe CAP is not HCAP is based on multiple factors,
including the lack of a consensus on the definitions of severe
CAP, the clinical heterogeneity of patients, the pathogens, and
the lack of validation of scoring systems. Other factors include
the lack of assessment for MDR pathogens, patient residence
in nursing homes, prior antibiotic therapy, outcomes related
to appropriate antibiotic therapy, and confounding by other
conditions, such as sepsis syndrome.
HCAP Summit Critical Appraisal • CID 2008:46 (Suppl 4) • S317
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Antipseudomonal cephalosporin (cefepime, ceftazidime)
or
Antipseudomonal carbapenem (imipenem or
meropenem)
or
Antipseudomonal penicillin (piperacillin-tazobactam)
plus
Antipseudomonal fluoroquinolone (ciprofloxacin or
levofloxacin)
or
Aminoglycoside (gentamicin, tobramycin, amikacin)
plus
linezolid or vancomycinb
The definitions and data presented support the concept that
severe CAP is not HCAP. Although the approaches to diagnosis
and the management principles are similar, the definition of
HCAP is focused on the risk factors for infection with MDR
pathogens that may alter initial therapy for pneumonia; the
definition of severe CAP is based on severity of disease that
may be caused by a wide variety of non-MDR pathogens. Several scoring systems have been used to identify patients who
may need more clinical attention or intensive care and have a
greater risk of mortality. Some patients with severe pneumonia
who present to a clinic or hospital ED may have originally
received diagnoses of CAP but, with new definitions, are categorized as having HCAP because of their risk for infection
with MDR pathogens. HCAP may share similar management
principles with CAP, including antibiotic de-escalation and duration of therapy. However, the spectrum of HCAP outside of
the ATS-IDSA guidelines and the rapid evolution of community-acquired MRSA in the community may have had an impact on the spread of MDR isolates in the community outside
of the current concepts of HCAP.
Future Directions
Future directions discussed by the summit members reflected
many needs, including better-designed epidemiologic studies,
more-rigorous definition of terms, improved epidemiologic and
microbiological criteria, and better-standardized diagnostic and
laboratory criteria. Better data for HCAP are also needed in
the acute-care setting versus various long-term-care settings in
terms of epidemiology, diagnosis, management, and short- and
S318 • CID 2008:46 (Suppl 4) • Kollef et al.
long-term outcomes. There is a great deal to learn, and work
is needed to improve our databases and the current guidelines
for both prevention and therapy for specific at-risk patient
populations. Ideally, observational, multicenter cohort studies
using clear definitions and optimal data collection and analysis
are needed. Also, patients should be followed longitudinally to
assess changes in colonization with MDR pathogens over time.
STATEMENT 6: INITIAL EMPIRICAL THERAPY
FOR HCAP IS THE SAME AS THAT FOR HAP
Rationale and Definition of Statement
Many issues in addition to antibiotic choice enter into the
decision making regarding initial empirical therapy for HCAP.
The current definition of HCAP includes a heterogeneous
group of patients, with variability in features such as site of
care (hospital or nonhospital), route of therapy (oral or intravenous), and risk factors for infection with MDR pathogens.
Some patients are also at risk for infection with other organisms, such as Legionella and viruses, which can be seen in CAP
more than in HAP. These organisms can be epidemic in certain
nursing homes. Because of these varying patient characteristics,
the initial empirical therapy needs to account for differences
in treatment approaches to HCAP and HAP, allowing for the
possibility that some subpopulations should be managed like
patients with HAP, some like patients with CAP, and some with
a hybrid approach. HCAP includes many patient populations,
some of which have been extensively studied, such as those
with NHAP; other populations, such as those undergoing he-
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Figure 6. Antibiotic options for patients with suspected health care–associated pneumonia (HCAP) who are referred to the emergency department
or a clinic. MDR, multidrug resistant. Adapted from the American Thoracic Society/Infectious Diseases Society of America guidelines [3], with permission
from the American Thoracic Society.
Methods
combined with the term “antibiotic therapy” (201,780 articles)
by use of the “AND” function, a total of 19 articles remained.
The term “nursing home pneumonia” (452 articles) combined
with “antibiotic therapy” yielded 47 articles. These searches
were limited to adults, clinical trials, reviews, meta-analyses, or
practice guidelines.
To broaden the search, the term “hemodialysis” (35,454 articles) was combined with the term “pneumonia” to yield 107
articles. Finally, the term “prior hospitalization” (5084 articles)
was combined with the term “pneumonia” to yield 205 articles.
Fourteen articles were deemed relevant to the statement. This
database of articles was reviewed and cross-referenced to evaluate original studies of therapy for patient populations included
within the definition of HCAP.
Studies of therapy were evaluated by searching PubMed. When
the term “healthcare associated pneumonia” (399 articles) was
Evidence
Figure 8. Voting comparison for statement 5 (“Severe CAP is not
HCAP”). “Summit members” refers to the 11-member summit panel; “IDSA
members” refers to the members of the Infectious Diseases Society of
America who responded to a Web-based survey. CAP, community-acquired
pneumonia; HCAP, health care–associated pneumonia.
Differences in the approach to therapy between HCAP and
HAP. There are a number of differences between HCAP and
HAP, making it likely that the initial empirical therapy for both
illnesses will not always be the same. By definition, HAP occurs
in the hospital and is treated in the hospital. However, HCAP
can arise outside of the hospital or in patients from health care
environments after they are admitted to the hospital, and it
can be treated both out of and in the hospital. If patients are
managed out of the hospital, therapy can be oral, as in the case
of the quinolones, which have been highly effective as therapy
for patients with NHAP managed both in the nursing home
and in the hospital [19, 77, 78].
HCAP arising in patients in nursing homes has been effectively treated with oral quinolone therapy, and, in many instances, this approach has averted hospital admission. In one
modialysis and those recently hospitalized, are less well
described.
When the ATS-IDSA guidelines suggested that HCAP be
treated like HAP, with a focus on MDR pathogens, it was implied that the patients evaluated were those in the hospital who
were treated with intravenous antibiotics. However, as discussed
in this review, HCAP also includes patients who are not ill
enough to require hospital admission, those who are not at risk
for infection with MDR pathogens but are at risk for infection
with CAP-associated pathogens, those who are treated orally,
and those who prefer to be treated at home or in a nursing
home, regardless of illness severity.
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Figure 7. Management strategies for health care–associated pneumonia (HCAP) for residents in nursing homes or other long-term-care facilities.
Possible management options include “on-site” management versus referral to acute-care hospitals for evaluation. IV, intravenous; PO, by mouth.
S320 • CID 2008:46 (Suppl 4) • Kollef et al.
infection with these organisms is only present in some individuals. In one study of severe NHAP, only 17 of 88 patients
had drug-resistant pathogens, and they were individuals who,
in addition to severe illness, had a history of antibiotic therapy
in the past 6 months, a poor functional status (defined by ADL
scores), or both [22].
Perhaps the best data to address initial empirical therapy for
HCAP are the findings from previous studies showing that
therapies not recommended for HAP and MDR pathogens have
been highly effective in patients with HCAP [27, 84]. Some
data are older, but, even in current studies, not all patients with
HCAP have required multiple antibiotics directed at MDR
gram-negative bacteria and MRSA to achieve high rates of clinical success. In one study of 40 patients with mild-moderate
NHAP treated in the nursing home, both oral ciprofloxacin
and intramuscular cefamandole were effective and were associated with low mortality rates (6.5%), even though some patients had gram-negative bacteria in sputum samples [77]. In
another study of 45 hospitalized patients, many with NHAP,
intravenous ciprofloxacin was more effective than intravenous
ceftazidime [78]. The experience with oral levofloxacin for therapy within the nursing home (nonsevere illness) was mentioned
above [19].
In a prospective, double-blind, randomized study of 51 patients with HCAP, 23 received intravenous monotherapy with
ertapenem, while 28 received intravenous therapy with cefepime; however, patients at risk for pseudomonal infection or
severe illness were excluded. Even though nearly 80% of patients with HCAP had gram-negative bacteria, the favorable
responses with both therapies were high (90% with cefepime
and 75% with ertapenem) [84]. In a retrospective study of 104
patients with severe pneumonia, including 47 from nursing
homes and the rest with CAP, the mortality rate was 57% for
NHAP and 55% for CAP [27]. Although mortality was higher
for inadequate therapy (OR, 2.6; P p .03), 47% of patients
received monotherapy; the mortality was the same as with combination therapy. Common therapies included second- and
third-generation cephalosporins, b-lactam/b-lactamase inhibitor combinations, and quinolones.
One study evaluated 63 patients with CAP who were hospitalized after outpatient antibiotic therapy failed. This group
of patients might be categorized as having HCAP and might
be suspected to be infected with MDR pathogens [85]. Patients
were randomized to receive monotherapy with moxifloxacin
or standard therapy, and both clinical failure rates (6% vs. 30%)
and 28-day failure rates (6% vs. 21%) were lower for the quinolone monotherapy than for standard therapy. These positive
results occurred even though some patients were infected with
S. aureus (5 patients) and enteric gram-negative bacteria (3
patients).
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cluster-randomized trial of 680 patients 165 years of age with
radiographically diagnosed pneumonia at 20 nursing homes,
patients were randomized to receive either usual care or a clinical pathway [19]. The pathway allowed for oral therapy with
500 mg of levofloxacin daily in the nursing home as long as
the patient was able to eat and drink, had an oxygen saturation
of ⭓92%, and had vital signs with a pulse of ⭐100 beats/min,
a respiratory rate of !30 breaths/min, and a systolic blood
pressure of ⭓90 mm Hg. When this pathway was used, only
10% of patients were hospitalized, compared with 22% who
received usual care (P p .001), and there were fewer total hospital days and a cost savings of at least $1000 per patient.
Mortality and functional status were similar in both groups.
Out-of-hospital care is also used for some patients with
HCAP, because of individual preferences for avoiding admission
to the hospital. Thus, the “hospital at home” can include intravenous medications and oxygen [79]. Many patients prefer
to remain in the nursing home, receiving oral therapy for acute
illness [80]. Patients undergoing hemodialysis can receive intravenous antibiotics at each dialysis appointment.
Other factors to consider in the approach to therapy are the
associated mortality rates and related pathogens implicated in
pneumonia. In a retrospective cohort study of a large US database of 59 acute-care hospitals involving 4543 patients, ∼22%
(998) of patients received diagnoses of HCAP. The mean mortality rates were comparable for patients with diagnoses of
HCAP (19.8%) and HAP (18.8%) (P 1 .05) and were statistically significantly higher than those among patients with diagnoses of CAP (P ! .0001). The distribution pattern of pathogens varied among the 4 pneumonia subtypes; however, S.
aureus was the primary organism identified. The incidence of
MRSA infections (56.8%) was significantly higher among patients with diagnoses of HCAP compared with all other pneumonia subcategories, including patients with diagnoses of HAP
(48.6%; P ! .05). S. aureus was the only pathogen associated
with significantly higher mortality rates (P ! .0001).
Should empirical antibiotic choices be the same as for HAP
for all patients with HCAP? The recommendation that empirical antibiotic choice be the same for HCAP as for HAP is
based on the idea that both patient populations are at risk for
infection with the same MDR pathogens. However, many studies of patients with NHAP have shown a high frequency of S.
pneumoniae, atypical pathogens, and Legionella species, as well
as viruses mandating a different approach to therapy than is
common in HAP [81–83]. In some nursing-home epidemics,
colonization of the drinking water has led to Legionella infection, whereas, in other nursing homes, viruses such as rhinovirus have affected up to 40% of hospitalized patients with
pneumonia [81, 83]. In addition, although enteric gram-negative bacteria can be found in patients with NHAP, the risk of
ervations, 18% accepted it with major reservations, and 9%
rejected it with reservations (figure 10).
Discussion
Figure 9. Voting comparison for statement 6 (“Initial empirical therapy
for HCAP is the same as that for HAP”). “Summit members” refers to
the 11-member summit panel; “IDSA members” refers to the members
of the Infectious Diseases Society of America who responded to a Webbased survey. HAP, hospital-acquired pneumonia; HCAP, health care–associated pneumonia.
Grading of Evidence
In evaluating the nature of evidence to support the statement
for all patients, the panel of 6 graded the evidence as category
III. In evaluating the nature of the evidence for patients admitted to the hospital, the panel graded it as category III. In
applying the statement to patients never admitted to the hospital, the panel graded the nature of the evidence as category
I (2 votes), category III (1 vote), category IV (2 votes), and
category V (1 vote) (table 2).
Level of Support
When all members of the summit voted on the initial statement,
9% accepted it with some reservations, 46% accepted it with
major reservations, 36% rejected it with reservations, and 9%
rejected it completely. Of the 383 IDSA members who responded to the survey, 29% voted to accept it completely, 52%
accepted it with some reservations, 7% accepted it with major
reservations, 9% rejected it with reservations, and 3% rejected
it completely (figure 9).
After presentation of the evidence, the members of the summit panel developed a new statement (“statement 6.5”): empirical MDR antibiotics should be given to patients with HCAP
who have at least 2 of the 3 mentioned risk factors (severe
illness [requiring mechanical ventilation or ICU care], prior
antibiotic therapy [for 13 days in the preceding 6 months],
and poor functional status [ADL score, 112.5]). Among the
summit members, 73% accepted this statement with some res-
Figure 10. Voting comparison for statement 6.5 (“Empirical MDR antibiotics should be given to patients with HCAP who have at least 2 of
the 3 mentioned risk factors”). “Summit members” refers to the 11member summit panel. HCAP, health care–associated pneumonia; MDR,
multidrug resistant.
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Thus, in many studies, therapy for patients with HCAP has
been heterogeneous, but therapies not recommended for HAP
due to MDR pathogens, including monotherapy with quinolones, ertapenem, and cephalosporins, have been highly
effective.
The evidence presented highlights the complexity of HCAP and
its empirical therapy. For a number of reasons, HCAP should
not always be treated the same as HAP. If similar therapy were
routinely administered, it could needlessly overtreat some patients with an unnecessarily broad spectrum of antibiotics.
Many of the studies demonstrated the efficacy of monotherapy
regimens that would not be recommended for patients with
HAP at risk for infection with MDR pathogens (ciprofloxacin,
levofloxacin, cefepime, and ertapenem), and some studies
showed efficacy of therapies that did not cover the presumed
MDR pathogens in complex patients with HAP (efficacy was
present in all studies without specific MRSA coverage). In addition, HAP therapy would not adequately treat some patients
with HCAP who might be infected with community pathogens,
such as Legionella species. Finally, the inclusion of outpatients
in the HCAP definition requires that some patients receive oral
therapy instead of intravenous therapy, unlike those already in
the hospital with HAP. The members of the summit panel
recognized these issues when only 50% of members accepted
the initial statement with major reservations and 50% rejected
it.
Although not all members of the panel could accept the
original statement, there are certainly patients with HCAP who
are likely to be infected with MDR pathogens and, thus, who
would require therapy identical to therapy for HAP. These are
patients who generally have multiple risk factors, such as severe
pneumonia, prior antibiotic therapy, and poor functional status
[22]. Thus, the panel voted on a second statement, that empirical therapy for MDR pathogens should be administered to
patients with HCAP who have at least 2 of the 3 risk factors
(severe illness, prior antibiotic therapy, and poor functional
Future Directions
These therapy recommendations are based on the best available
data, which are, unfortunately, quite limited. Future validation
of this approach is required. In addition, more data are needed
for populations of patients with HCAP other than those with
NHAP. As new therapeutic options become available, they
should be tested in patients with HCAP specifically, so that
data from patients with HAP do not need to be extrapolated
to this population.
STATEMENT 7: PATIENTS WITH HCAP WHO
ARE AT RISK FOR GRAM-NEGATIVE
INFECTIONS SHOULD RECEIVE DUAL
EMPIRICAL ANTIBIOTIC COVERAGE
Rationale and Definition of Statement
The issue of monotherapy versus combination antibiotic therapy for serious infections is not new [86, 87]. Many clinicians
S322 • CID 2008:46 (Suppl 4) • Kollef et al.
utilize antibiotic combinations when serious gram-negative
bacterial infections are suspected, whereas others criticize such
an approach as lacking sound evidence [86, 87]. A number of
issues need to be considered if empirical combination antibiotic
therapy is considered. First, what are the consequences of inadequate empirical antibiotic therapy for the bacillary infection?
If data exist showing that mortality or morbidity is seriously
compromised by inadequate empirical therapy, it behooves clinicians to consider how they may improve empirical antibiotic
regimens. For example, inadequate antibiotic therapy may have
few consequences in a patient with an uncomplicated urinary
tract infection but substantial consequences in a critically ill
patient in an ICU who develops a bloodstream infection [88].
Second, is the adequacy of an empirical antibiotic regimen
more likely to be improved by the use of a combination regimen
than by the use of an improved single agent? Incorporated into
this consideration are issues of synergy, development of resistance, and toxicity. Potentially, an advantage may arise when
synergy is observed in vitro between 2 antimicrobial agents
(although, for most infections, this has not been borne out in
clinical studies). For some organisms (e.g., Mycobacterium tuberculosis or HIV), resistance may be less likely to develop when
combinations of antimicrobials are used. Although there are
some in vitro data suggesting that this may also occur with
respect to treatment of gram-negative bacilli, there are also
conflicting data showing no benefit to this approach. Finally,
there is the potential that the use of 2 drugs (e.g., addition of
an aminoglycoside to a b-lactam) may increase the risk of
toxicity and, therefore, detract from the benefit of using combination therapy.
In this review, these issues are addressed with respect to
HCAP. This is first approached from a review of randomized
trials of therapy for patients with HCAP. Second, a review of
epidemiologic studies was performed to determine whether patients with HCAP may be at increased risk for infection with
MDR gram-negative bacilli, thereby necessitating the use of
empirical combination therapy.
Methods
A search of PubMed was performed in November 2006, crosslinking articles with the key words “randomized trial” and
“healthcare-associated pneumonia,” “nursing home pneumonia,” or “hospital-acquired pneumonia.” A second search was
performed with the key words “microbiology” or “pathogen”
and “healthcare-associated pneumonia,” “nursing home pneumonia,” or “hospital-acquired pneumonia.” The references of
articles discovered in this search were reviewed for further articles pertinent to the topic. With regard to studies of patients
with HAP, those with 150% patients receiving ventilation were
excluded (unless there was a subgroup analysis of patients not
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status); 70% of the summit panel accepted the statement with
some reservations, and 20% accepted it with major reservations.
On the basis of the discussion of the panel and the available
evidence, HCAP therapy should probably be divided into 2
categories: limited-spectrum therapy and broad-spectrum therapy. This categorization is dictated by whether the patient with
HCAP has 2 of the 3 identified risk factors for MDR pathogens
in this population. Limited-spectrum therapy can be given to
patients in or out of the hospital who do not have 2 of these
3 risk factors. Therapy can be a respiratory quinolone alone
(moxifloxacin or levofloxacin) or, alternatively, combined with
a selected b-lactam (ceftriaxone, cefepime, piperacillin-tazobactam, or ertapenem) with good activity against drug-resistant
S. pneumoniae, with consideration of adding a macrolide (especially if Legionella, Chlamydophila, or Mycoplasma species
have been present in patients from the same environment).
Patients who receive limited-spectrum therapy can be treated
in the nursing home with oral therapy if a quinolone is used.
Broad-spectrum therapy should be given to patients in or out
of the hospital who do have 2 of the 3 identified risk factors,
and these patients should receive therapy active against drugresistant S. pneumoniae, P. aeruginosa (ideally with 2 agents),
and MRSA, as well as consideration of Legionella in appropriate
settings. This could be achieved with a b-lactam (cefepime,
imipenem, meropenem, or piperacillin/tazobactam) combined
with an antipseudomonal quinolone (ciprofloxacin or highdose levofloxacin), with either linezolid or vancomycin. If a
quinolone cannot be used, because of allergy, intolerance, or
recent therapy in the past 3 months, an aminoglycoside should
be added in its place while considering the addition of a macrolide to the b-lactam and the MRSA therapy. The antimicrobials used for broad-spectrum therapy are primarily available
for parenteral and not oral administration.
receiving ventilation). Eleven articles were reviewed for this
statement.
Evidence
Grading of Evidence
On the basis of a review of the studies cited above, the 5
members of this workshop agreed that the evidence available
to support this statement was category V for the statement in
general, a tie between categories III and IV for the statement
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Randomized trials. There are no randomized trials evaluating
empirical monotherapy versus combination therapy for HCAP.
However, there are several randomized trials evaluating 2 different monotherapy regimens or evaluating 1 combination
therapy regimen versus another combination therapy regimen.
Randomized trials evaluating 2 different monotherapy regimens
have included those of ciprofloxacin versus ceftriaxone, ciprofloxacin versus ceftazidime, and ertapenem versus cefepime.
The trial evaluating combination therapy was of tobramycin
plus piperacillin/tazobactam versus tobramycin plus ceftazidime [89].
Ciprofloxacin monotherapy has been compared with ceftriaxone monotherapy in a small randomized trial of nursing
home–acquired lower-respiratory-tract infection requiring hospitalization [90]. Fifty patients were enrolled, all of whom were
⭓60 years of age. A successful outcome was defined as resolution or marked improvement in clinical signs and symptoms
of lower-respiratory-tract infection and was achieved in 50%
(12/24) of patients treated with ciprofloxacin and 54% (14/26)
of patients treated with ceftriaxone. In a second small study
evaluating ciprofloxacin monotherapy, 44 hospitalized patients
with HAP or NHAP were randomized to receive ciprofloxacin
or ceftazidime [78]. All (23/23) ciprofloxacin-treated patients
had a favorable response, compared with only 71% (15/21) of
the ceftazidime-treated patients.
The largest study of monotherapy was a 303-patient, prospective, double-blind, randomized, international, multicenter
study of ertapenem versus cefepime [84]. Patients enrolled in
the study had pneumonia acquired in a hospital or a skilledcare facility, such as a nursing home. Patients with conditions
believed to increase the risk of P. aeruginosa or Acinetobacter
infection were excluded. These conditions include pneumonia
acquired in an ICU or while receiving mechanical ventilation,
an immunocompromising illness or therapy, and cystic fibrosis.
Fifty-four percent of the population had a pathogen isolated—
this comprised Enterobacteriaceae, such as Klebsiella species or
E. coli (in 20% of enrolled patients); S. pneumoniae (in 13%);
S. aureus (in 12%); and P. aeruginosa (in 4%). A successful
clinical response was observed in 92% of patients treated with
ertapenem and 88% of patients treated with cefepime. A successful microbiological response was observed in 84% of patients treated with ertapenem and in 83% of patients treated
with cefepime.
The trial evaluating combination therapy was a 300-patient,
open-label, randomized, comparative, multicenter study of tobramycin plus piperacillin/tazobactam versus tobramycin plus
ceftazidime [89]. The majority of patients had pneumonia, but
21% had bronchitis. Thirteen percent of patients had nursing
home acquisition of their lower-respiratory-tract infection, with
the remainder having hospital-acquired infections. The most
commonly isolated pathogens in evaluable patients were H.
influenzae (32 patients), S. aureus (31 patients), P. aeruginosa
(22 patients), S. pneumoniae (21 patients), E. coli (16 patients),
and K. pneumoniae (14 patients). Clinical success was observed
in 74.2% of patients treated with piperacillin/tazobactam plus
tobramycin, versus 57.9% of patients treated with ceftazidime
plus tobramycin. Bacteriologic response was observed in 65%
of patients treated with the piperacillin/tazobactam plus tobramycin regimen, versus 38% of patients treated with the
ceftazidime plus tobramycin regimen (P p .03).
Observational studies of the microbiology of HCAP.
A number of studies have evaluated the etiology of HCAP and,
in some circumstances, compared the etiology with that of CAP.
An 18-month prospective cohort study from the United Kingdom compared the etiology of NHAP and CAP [20]. S. pneumoniae was the predominant pathogen identified as being responsible for 55% of NHAP cases and 43% of CAP cases.
Gram-negative bacilli were rarely isolated, and, in general, the
etiologies of NHAP and CAP were similar. In contrast to these
results, a database of 4543 patients with HCAP and a concomitant positive respiratory bacterial culture showed that S. aureus
was responsible for 47% of cases, P. aeruginosa for 25%, Klebsiella species for 8%, and S. pneumoniae for 6% [2]. Etiologies
of HCAP were more similar to those of HAP or even VAP than
to those of CAP.
In a large review of 10,635 hemodialysis recipients with 3101
episodes of pneumonia, no organism was identified in 81.8%
of patients [29]. Gram-positive organisms (predominantly S.
pneumoniae) were found in 4.8% of patients, and gram-negative
bacilli were found in 11.1% of patients. Almost 3% of the
patients had P. aeruginosa.
Similarly, a study of NHAP requiring ICU admission showed
that S. pneumoniae was a common pathogen [22]. However,
MRSA and gram-negative bacilli were isolated quite frequently
in this particular study. Enterobacteriaceae (E. coli; 9/135 patients), K. pneumoniae (6/135 patients), Serratia marcescens (5/
135 patients), Enterobacter cloacae (5/135 patients), and Proteus
mirabilis (3/135 patients) were found in 21% of patients, and
P. aeruginosa was found in 7% of patients. Patients were excluded from this study if they were immunocompromised or
if they had been hospitalized for 148 h in the 6 months before
ICU admission.
as it applies to hospitalized patients with HCAP, and category
V for the statement as it applies to nonhospitalized patients
with HCAP (table 2).
Level of Support
When voting on the support for this statement in the group
at large, 9% of the summit participants voted to accept it completely, 9% accepted the statement with some reservations, 64%
accepted the statement with major reservations, and 18% rejected the statement with reservations. In comparison, of the
383 IDSA members who participated in the online survey, 25%
accepted the statement completely, 33% accepted the statement
with some reservations, 13% accepted the statement with major
reservations, 23% rejected the statement with reservations, and
5% rejected the statement completely (figure 11).
The question raised in this review is whether patients with
HCAP should receive dual empirical antibiotic coverage aimed
against gram-negative pathogens. There are no randomized trials that provide a simple answer to this question. Several studies
of monotherapy antibiotic regimens have been performed.
Monotherapy regimens (comprising ciprofloxacin, ceftriaxone,
ceftazidime, cefepime, or ertapenem) were generally successful,
both clinically and microbiologically. However, inclusion criteria, exclusion criteria, and outcome measures were variable.
In some circumstances, success rates were only 50%, but it is
unclear whether this was a marker of particularly stringent
outcome definitions in these small studies or truly represented
a deficiency in the monotherapy regimen. The optimal study
design to answer the question of superiority of an empirical
dual antibiotic regimen would be a randomized trial of monotherapy versus combination therapy (with the agent used in
the monotherapy arm plus an additional agent). No such study
exists or is currently under way.
The second way to approach this question is to review
whether patients with HCAP are at high risk for infection with
MDR gram-negative bacilli. Organisms such as P. aeruginosa
or A. baumannii are often MDR; in some scenarios (e.g., in
ICUs), no single antibiotic will cover 180%–85% of strains.
Therefore, empirical use of combination therapy may be important to ensure that empirical therapy is likely to be microbiologically adequate. Studies of pneumonia in nursing homes
in the United Kingdom and among hemodialysis recipients in
the United States have not revealed a high frequency of organisms such as P. aeruginosa or A. baumannii as etiologic
agents. The frequency of gram-negative bacilli, including MDR
strains, appears to be higher among patients in nursing homes
who require ICU admission. The study by Kollef et al. [2]
suggests that patients with HCAP have etiologic agents (such
as P. aeruginosa) more like those in hospitalized patients. What
S324 • CID 2008:46 (Suppl 4) • Kollef et al.
is not clear, however, is whether P. aeruginosa and other gramnegative isolates from patients with HCAP have resistance profiles of a magnitude similar to those in patients in the ICU.
It is likely that HCAP is actually quite a heterogeneous condition. Clearly, patients in nursing homes differ in their functional status, and this may, in turn, influence their likelihood
of being colonized (and subsequently infected) with MDR
gram-negative bacilli. Patients with recent hospitalization may
also vary in the likelihood that they are colonized with antibiotic-resistant gram-negative bacilli. In turn, hemodialysis recipients may be at different risk, compared with patients in
nursing homes or previously hospitalized patients.
Future Directions
Like other forms of pneumonia, HCAP varies in severity. The
consequences of inadequate antibiotic therapy for patients with
severe HCAP requiring ICU admission are likely to be greater
than those for patients admitted to a general ward or even
managed in a nursing home or some other setting outside of
the hospital. It is unlikely that a randomized trial will directly
answer the question of whether empirical combination therapy
is optimal for patients with HCAP. Attention is needed to determine which patients are at risk for infection with MDR
gram-negative bacilli, and whether inadequate empirical therapy influences outcomes for all, or subsets of, patients with
HCAP. Only then will the question of optimization of gramnegative coverage for patients with HCAP be answerable.
STATEMENT 8: PATIENTS SHOULD RECEIVE
INITIAL EMPIRICAL THERAPY THAT COVERS
MRSA AT THE TIME OF HCAP DIAGNOSIS
Rationale and Definition of Statement
MRSA infections, a common problem encountered by clinicians, result in significant morbidity, mortality, and economic
consequences. The annual incidence of MRSA has profoundly
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Discussion
Figure 11. Voting comparison for statement 7 (“Patients with HCAP
who are at risk for gram-negative infections should receive dual empirical
antibiotic coverage”). “Summit members” refers to the 11-member summit
panel; “IDSA members” refers to the members of the Infectious Diseases
Society of America who responded to a Web-based survey. HCAP, health
care–associated pneumonia.
Methods
A PubMed database search to identify microbiological features
and clinical outcomes in patients with HCAP was conducted.
The search terms “methicillin-resistant Staphylococcus aureus”
and “health care associated” were combined, using the “AND”
function, to yield 141 articles. This search was combined with
the term “pneumonia” by use of the “AND” function, producing 123 articles that were reviewed and selected. Eleven
articles were deemed relevant to the statement.
Evidence
The microbiological etiology of HCAP in the era of increasing
MRSA incidence has been an understudied subject and has
generally been relegated to the subgroup of patients who require
hospital admission. A retrospective analysis of the Cardinal
Health-Atlas Research Database characterized the microbiology
and outcomes of 4534 cases of pneumonia identified by International Classification of Diseases, Ninth Revision codes. HCAP
was distinguished in this study as a positive respiratory culture
result within 48 h after hospital admission in patients who were
transferred from another health care facility, were receiving
long-term hemodialysis, or had been hospitalized in the previous 30 days and did not require mechanical ventilation [2].
Although this definition is imprecise and likely does not capture
the true HCAP population, 21.7% (n p 988) of the sample
population was designated with this classification of pneumonia. Within this stratum, the pathogen most frequently iso-
lated was MRSA (26.5%), followed by P. aeruginosa (25.3%)
and MSSA (21.1%). Interestingly, S. aureus isolation in all pneumonias was associated with increased in-hospital mortality
(OR, 1.58; 95% CI, 1.32–1.89; P ! .0001). The authors hypothesized that this finding might reflect clinicians’ lack of
precision in differentiating HCAP from CAP, resulting in omitted coverage for MRSA and inappropriate empirical coverage.
A prospective, randomized, multicenter comparative trial of 2
antibiotics lacking activity against MRSA sought to determine
the microbiological etiologies in patients not receiving ventilation who were admitted to the hospital with HCAP or HAP
[84]. In this heterogeneous sample, only 12% of all isolates
were positive for S. aureus, 40% of which were MRSA.
NHAP includes a select group of patients who fall under the
umbrella of HCAP. The isolation of MRSA in this patient population, compared with patients with CAP, has been variable.
A prospective study comparing the clinical and microbiological
characteristics of NHAP with those of CAP requiring hospitalization in the United Kingdom from 1998–1999 revealed only
1 case of pneumonia caused by S. aureus (not differentiated
between MRSA and MSSA) [20]. A prospective study comparing patients with NHAP and patients with CAP at a single
center in the United States from 1996 to 1999 found that patients with NHAP were more likely to be infected with S. aureus
than were patients with CAP (29% vs. 7%). However, the number of patients with MRSA was small (3 vs. 0 cases, respectively)
[27]. In contrast, results of BAL cultures in a group of patients
with severe NHAP who were admitted to the ICU at a single
US hospital between 1998 and 2003 showed S. aureus to be the
most common pathogen identified (23.9%), of which 61.9%
were MRSA [22]. Clearly, microbiological data from patients
with NHAP are limited by the period during which they were
obtained. In fact, it could be argued that differences exist in
the frequency of MRSA isolation in these studies compared
with today. However, outside of the single retrospective study
mentioned above, evidence is lacking.
Given the inconsistencies in the frequency with which MRSA
is thought to cause HCAP, attention must be focused on identifying patients at risk for MRSA infection at admission to the
hospital or in the nursing home. A detailed history of the
patient’s recent contact with health care systems is the most
important component in the categorization of MRSA infection
risk. A prospective surveillance study of MRSA infections found
that, of 123 positive culture samples obtained within the first
48 h of hospitalization, only 1 was from a patient who did not
have recent health care contact, including hospitalization, transfer from another health care facility, residence in a long-termcare facility, dialysis, home nursing care, or day surgery [24].
Similarly, a case-control study comparing patients with blood
cultures positive for MRSA and patients with positive blood
cultures without MRSA in the first 24 h of hospitalization found
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increased throughout ICUs in the United States, rising 3% on
average since 1992 to an estimated 65% of all S. aureus infections in 2004 [91]. Unfortunately, the dissemination of MRSA
is not limited to the ICU. Data reported by the National Nosocomial Infections Surveillance Systems indicate that, on average, 31% of outpatient and 46% of non-ICU inpatient isolates
of S. aureus are MRSA [92]. As a pulmonary pathogen, S. aureus
accounts for 20%–30% of HAPs and VAPs, with MRSA accounting for 150% of these infections, especially in patients
with a high severity of illness and those with prior antibiotic
exposure [93]. MRSA pneumonia has been associated with
longer hospital stays and higher costs, compared with methicillin-susceptible S. aureus (MSSA) pneumonia, regardless of
severity of illness [94–96]. The issue of attributable mortality
due to MRSA pneumonia compared with MSSA pneumonia is
difficult to resolve, because of the high rates of inappropriate
initial antimicrobial therapy in many cases of MRSA pneumonia. However, MRSA doubles the attributable mortality
compared with MSSA in patients with bacteremia [97]. Given
the extraordinary burden of illness caused by MRSA pneumonia
in hospitalized patients, this section reviews the level of evidence
supporting empirical coverage of MRSA in patients with diagnoses of HCAP.
fair evidence to support the statement for hospitalized patients;
there was a range of votes from poor evidence to support to
good evidence to reject the statement for nonhospitalized patients (table 2).
Level of Support
Overall, 9% of the summit participants voted to accept the
statement with some reservations, 55% voted to accept the
statement with major reservations, and 36% voted to reject the
statement with reservations. In comparison, of the 383 IDSA
members who participated in the online survey, 25% accepted
the statement completely, 37% accepted the statement with
some reservations, 13% accepted the statement with major reservations, 2% rejected the statement with reservations, and 5%
rejected the statement completely (figure 12).
Discussion
This statement is of great significance, given the increasing
incidence of MRSA in hospitals and the community. Currently,
the microbiological evidence supporting MRSA as a major
pathogen in HCAP is limited. Similarly, outcome data supporting this statement are nonexistent. Evidence to the contrary
has been published related to NHAP, such that omitting MRSA
coverage in the therapeutic regimen did not appear to have
adverse consequences. One study evaluating patients with
health care–associated MRSA sterile-site infection in comparison with patients with hospital-acquired MRSA infection
found the former group to be significantly less likely to have
MRSA coverage initiated in the first 24 h, which was subsequently associated with increased odds of in-hospital mortality.
Future Directions
Until prospective controlled trials are published that specifically
study microbiology and outcomes in patients with HCAP
Grading of Evidence
On the basis of this literature review, 6 members of the HCAP
Therapeutic Intervention workshop voted that the nature of
the evidence for the statement ranged from category II to V
for all patients, from category II to IV for patients admitted to
the hospital, and from category II to V for patients never admitted to the hospital. Therefore, the workshop voted that there
was poor evidence to support the statement for all patients and
S326 • CID 2008:46 (Suppl 4) • Kollef et al.
Figure 12. Voting comparison for statement 8 (“Patients should receive
initial empirical therapy that covers MRSA at the time of HCAP diagnosis”). “Summit members” refers to the 11-member summit panel; “IDSA
members” refers to the members of the Infectious Diseases Society of
America who responded to a Web-based survey. HCAP, health care–
associated pneumonia; MRSA, methicillin-resistant Staphylococcus
aureus.
Downloaded from http://cid.oxfordjournals.org/ by guest on September 9, 2014
that all patients with MRSA had recent health care exposure
[98]. Risk factors for community-acquired infection with health
care–associated MRSA were elucidated in a prospective, case
(MRSA)–control (MSSA) study conducted at a French teaching
hospital [30]. Among patients with respiratory tract (27.3%),
urinary tract (17.2%), primary bloodstream (9.8%), and skin/
soft tissue (38.5%) infection, risk factors associated with MRSA
infection at hospital admission included home nursing care
(adjusted OR [AOR], 3.7; 95% CI, 2.0–6.7), prior hospitalization (AOR, 3.8; 95% CI, 1.8–7.9), transfer from another hospital or nursing home (AOR, 2.3; 95% CI, 1.2–74.3), age ⭓65
years (AOR, 1.8; 95% CI, 1.1–2.5), and home nursing care or
inpatient surgery in the past 3 years (AOR, 3.1; 95% CI, 1.2–
8.0). Additionally, previous use of antibiotics has been linked
to infection with drug-resistant bacteria, including MRSA in
patients with severe NHAP [22]. These findings suggest that
patients presenting from the community with pneumonia who
have recent health care exposure or antibiotic use should be
considered at risk for MRSA HCAP.
The ATS-IDSA guidelines for the empirical treatment of
HCAP indicate that coverage for MRSA with either vancomycin
or linezolid should be instituted [3]. However, the impact of
this recommendation on clinical outcomes, including mortality,
is limited. In general, omission of antibiotic coverage with
MRSA activity has not been associated with poor outcomes in
patients with NHAP [19, 84, 85]. This finding may be a result
of the low incidence of MRSA in these specific study populations. A retrospective study of MRSA sterile-site infections at
a single institution found that appropriate empirical therapy
was significantly more likely to be prescribed to patients who
had MRSA isolated ⭓48 h after admission (hospital acquired,
39%), versus those with MRSA isolated within the first 48 h
after admission (health care associated, 22%) (P ! .001) [99].
This was despite the finding that 86% of the patients with
positive culture results within 48 h of hospitalization had recent
health care exposure. Subsequent multivariate regression analysis found inappropriate initial empirical therapy (omission of
MRSA coverage) to be an independent predictor of hospital
mortality in this cohort (AOR, 1.92; 95% CI, 1.48–2.50). This
suggests that a thorough assessment of health care exposure
was not undertaken in this population and may have had an
impact on patient outcomes.
treated with and without antibiotics that have MRSA activity,
support of this statement is based on opinion.
STATEMENT 9: WHEN MICROBIOLOGICAL
DATA ARE UNAVAILABLE, DE-ESCALATION IN
PATIENTS WITH HCAP SHOULD NOT OCCUR
Rationale and Definition of Statement
Methods
A PubMed search was performed in November 2006. By looking at “duration of antibiotic therapy pneumonia” and limiting
the search to clinical trials published in English, 180 references
were identified. By looking specifically at “health care associated
pneumonia duration of therapy,” 14 references were identified;
all were regarding VAP. Searching with the term “nursing home
pneumonia duration of therapy” identified 23 references.
References from the last 2 categories were reviewed. The
majority of references simply provided the duration of therapy
and made no attempt to analyze why one duration was used
versus another. There were some exceptions, and 13 studies
were reviewed.
Evidence
The most direct evidence regarding duration of antibiotic therapy has been for cases of VAP. Although this is a subset of
nosocomial pneumonia, the information was believed to be
relevant for several reasons. First, it provides a worst-case scenario, since the rate of mortality due to VAP is higher than
that reported for HCAP. However, the mortality rate for HCAP
is closer to that for VAP and HAP than to that for CAP [2].
In addition, the microbiology information from invasive procedures done for VAP were felt to be more revealing than those
done for most cases of HCAP. In particular, semiquantitative
cultures from bronchoscopic and nonbronchoscopic BAL samples were often used in VAP studies. Current opinion is that
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“De-escalation” can mean discontinuation of therapy with
some antibiotics, changing from a broad-spectrum to a narrowspectrum antibiotic, or discontinuation of all antibiotic therapy.
The concept of de-escalation arose from the treatment of patients with HAP, especially those with VAP, and was proposed
as a method to minimize exposure to broad-spectrum antibiotics [61, 100, 101]. Shorter courses of antibiotic therapy are
associated with lower rates of superinfection with resistant bacteria [48, 101]. However, some pathogens seem to require
longer treatment to avoid clinical relapse [102]. Because of this
discrepancy, the decision to de-escalate may require microbiological data. This concept is included in the ATS-IDSA guidelines for treating HAP [3].
Clinicians often de-escalate treatment only on the basis of
clinical response to therapy. The safety and relapse rates associated with this approach are not known.
such semiquantitative information is more accurate than information from nonquantitated samples, such as sputum [103].
One study directly compared 2 treatment durations in patients with VAP. All patients had undergone diagnostic BAL
and had received initial, appropriate, adequate antibiotics to
remain in the study. In a randomized trial of 8 versus 15 days
of therapy for VAP, those patients who had nonfermenting
gram-negative rods (e.g., P. aeruginosa) were more likely to
relapse if treated for only 8 days [48]. Although the rate of
relapse was not statistically significantly different, the 60%
higher relapse rate has led some physicians to require microbiological data before stopping antibiotic therapy at 1 week.
In another study examining the clinical outcome of S. aureus
versus other pathogens in serial nonbronchoscopic BAL studies
of VAP, it was determined that patients with S. aureus and drugresistant gram-negative rods were likely to have persistent bacteria in the BAL sample 2–5 days into therapy [102]. The authors found that patients with 11000 cfu of bacteria/mL of BAL
sample in the follow-up BAL had a significantly higher 28-day
mortality rates than did those who cleared the bacteria [102].
There is no similar microbiological information for HCAP.
Guidelines have been established for treating patients in nursing
homes who have suspected pneumonia [104], and these led to
a reduction in the number of hospitalizations and overuse of
antibiotics but did not change mortality rates [105].
A cluster-randomized controlled trial of 680 nursing-home
residents was performed over a 16-month period in 22 nursing
homes in Canada. Patients who met a predefined criterion of
pneumonia based on clinical grounds were treated with either
standard care or a clinical pathway, which included use of oral
antimicrobials, portable chest radiographs, and oxygen-saturation monitoring. Although 76 (22%) of 353 residents receiving standard care for their pneumonia required hospitalization, only 34 (10%) of 327 of those in the clinical pathway
were hospitalized. There also was a reduction in the number
of hospital days for those in the clinical pathway group who
were admitted, compared with the standard care group. Overall,
health care costs were significantly reduced, with no difference
in mortality [19]. The clinical pathway did not have a specific
de-escalation procedure.
Another study used the clinical status of the patient to separate 170 episodes of pneumonia in nursing home patients into
4 broad categories: pneumonia, aspiration pneumonitis with
infiltrates that resolve within 24 h, aspiration pneumonitis with
infiltrates that persist for 124 h, and aspiration without pneumonitis [106]. Patients were categorized prospectively on the
basis of their initial presentation and follow-up evaluation at
day 3–5. The results are summarized in table 8. The authors
found that patients believed to have aspiration pneumonitis
who did not have infiltrates after day 3 were treated for a shorter
time and were less likely to receive antibiotics at discharge [106].
Grading of Evidence
On the basis of a review of the studies cited above, the 6
members of this workshop agreed that the evidence available
to support this statement was category V for the statement in
general, category V for the statement as it applies to hospitalized
patients with HCAP, and category IV for the statement as it
applies to nonhospitalized patients with HCAP (table 2).
Level of Support
As shown in figure 13, 9% of the summit members accepted
the statement with major reservations, 82% rejected it with
reservations, and 9% rejected it completely. In contrast, 54%
of the 383 IDSA members who completed the online survey
believed there was some degree of support for the statement.
However, this may have been based on the assumption that
what was true for VAP would apply to HCAP. Thirty-five per-
Table 8.
Figure 13. Voting comparison for statement 9 (“When microbiological
data are unavailable, de-escalation in patients with HCAP should not
occur”). “Summit members” refers to the 11-member summit panel; “IDSA
members” refers to the members of the Infectious Diseases Society of
America who responded to a Web-based survey. HCAP, health care–
associated pneumonia.
cent rejected the statement with reservations, and 1% rejected
it completely.
Discussion
The summit panel recommended that broad-spectrum antibiotic therapy for possible MDR pathogens could be modified
or even discontinued at days 3–7 on the basis of clinical criteria
alone. This is especially true when a CXR film shows improvement. Although this recommendation was not supported by
strong evidence, the current information would support this
conclusion.
The major limitation of this analysis was the infrequency
with which an adequate lower respiratory culture was obtained
from patients with HCAP. Because of this, the clinician was
left with the dilemma of making a decision on the basis of the
clinical presentation of the patient. Although this appears to
be common practice, there is little scientific evidence to support
it.
The studies to date do suggest that de-escalation can be done
in HCAP when the patient meets certain clinical criteria, such
as a clear CXR film and return to baseline respiratory status.
Comparison of pneumonia and aspiration pneumonitis.
Aspiration pneumonitis
Aspiration event
with no infiltrate
(n p 60)
P
14 (23)
35 (67)
.19
.04
⭐24 h (n p 47)
124 h (n p 21)
Pneumonia
(n p 42)
Antibiotic prescribed in nursing home
Antibiotic prescribed in ED
16 (34)
36 (77)
6 (29)
18 (86)
6 (14)
28 (67)
Antibiotic prescribed after admission
No antibiotic prescribed, 1 dose of antibiotic, or
!24 h of antibiotic therapy
Duration of antibiotic therapy, mean days SD
(sample size)
Antibiotic prescribed at time of discharge
42 (89)
20 (95)
41 (97)
45 (75)
.004
6 (13)
2 (10)
1 (2)
17 (28)
.003
5.2 2.0 (n p 36)
6.4 2.5 (n p 15)
5.5 3.1 (n p 34)
4.7 3.0 (n p 40)
.19
25 (66)
11 (69)
28 (82)
18 (45)
.01
Therapy
NOTE. Data are no. (%) unless otherwise indicated. ED, emergency department. Adapted from [106], with permission from Blackwell Publishing.
S328 • CID 2008:46 (Suppl 4) • Kollef et al.
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A major problem with this study was that treatment was not
directed by any protocol. Many of the patients without evidence
of pneumonia were still treated with antibiotics in this study.
The ATS-IDSA HAP guidelines have focused attention on
the reevaluation of the patient at day 3. In addition to the
microbiological data, clinical criteria are useful. These include
variations of the CPIS. Patients whose conditions respond to
therapy for VAP will have a decrease in their CPIS by day 3,
whereas those who die have no change or have an increase in
the score [39]. The major reason for the decrease in the CPIS
was improvement in the PaO2/FiO2 ratio [39]. Other physicians
have discontinued antibiotic therapy as soon as day 3 if the
CPIS has remained stable or has decreased [101].
These observations have led to the suggestion that the use
of broad-spectrum antibiotics for possible MDR pathogens can
be modified or even discontinued at days 3–7 on the basis of
clinical criteria alone. This is especially true when a CXR film
shows resolution of the infiltrate and the clinical status of the
patient is improving by day 3.
“antibiotic” produced 410,820 articles. Combining the above
searches gave a total of 157 articles. When these searches were
combined with the term “duration,” 23 articles remained.
When the search was limited to English, 20 articles were reviewed, of which 5 were deemed relevant.
Future Directions
Evidence
There is a need for specific studies of de-escalation in HCAP
cases. It would be useful to obtain microbiological data in these
cases. However, studies without microbiological information
could still be informative if the reasons for de-escalation were
clearly defined before the study. Outcomes could then be tested
against those obtained with standard therapy.
Identifying risk factors for truly resistant bacteria, which may
require longer antibiotic therapy, is also an issue. These bacteria
could include MRSA and P. aeruginosa. Clearly, not all cases
of HCAP are the same, and the approach for de-escalation may
need differ among groups.
Although no study was identified that specifically focused on
the optimal duration of therapy for HCAP, these 5 studies
provided insight into the optimal duration of therapy for hospitalized adult patients with VAP.
Dennison et al. [47] performed a prospective cohort study
of 27 adult patients with VAP receiving appropriate antibiotic
therapy. The primary objective was to define the time to resolution of VAP symptoms after initiation of antibiotics. They
observed that response to antimicrobial therapy for VAP occurs
within the first 6 days of therapy. However, colonization with
resistant pathogens occurs after 6 days, and colonization with
resistant gram-negative bacteria will persist in many patients.
Singh et al. [101] conducted a prospective and randomized
but unblinded study of 81 patients with VAP. The goal was to
devise an operational approach for patients with possible nosocomial pneumonia. Only patients with a CPIS of ⭓6 were
included in the study and were randomized to receive standard
therapy, as determined by the clinician, or a 3-day course of
ciprofloxacin. Mortality, extrapulmonary infections, and the
number of patients who developed a CPIS of 16 at 3 days did
not differ. However, antimicrobial resistance and/or superinfections were encountered significantly less frequently in the
patients treated for 3 days.
Ibrahim et al. [108] investigated the impact of a guideline
that incorporated de-escalation, by use of a cohort design including 50 patients treated before implementation of the guideline and 52 patients treated after implementation. The guideline
called for a respiratory culture, followed by empirical therapy
using the combination of vancomycin, imipenem, and ciprofloxacin, and reassessment after 24–48 h. Patients treated under
the guideline had significantly better rates of adequate therapy,
a shorter duration of therapy, and a lower probability of secondary infections. Length of stay and mortality were numerically but not significantly lower.
Micek et al. [100] also investigated the value of short-course
therapy in a randomized trial involving 290 patients. Of these
patients, 140 received conventional therapy at the discretion of
the treating physician. For the other 150 patients, the investigators followed the patients and made recommendations to the
treating physician. Discontinuation was recommended if the
patient had a noninfectious etiology or if the patient’s signs
and symptoms resolved. Treating physicians usually discontinued antibiotic therapy within 48 h after the recommendation.
Recommendations for discontinuation produced a significant
STATEMENT 10: THE DURATION OF
ANTIBIOTIC THERAPY FOR PATIENTS WITH
HCAP WITH A CLINICAL RESPONSE SHOULD
BE 7 DAYS
Rationale and Definition of Statement
It is widely accepted that appropriate antimicrobial stewardship
includes optimal selection, dose, and duration of treatment, as
well as control of antibiotic use. It is anticipated that appropriate antimicrobial stewardship will prevent or slow the emergence of resistance among microorganisms [107]. However, it
is distressing that there are few data on the optimal duration
of antibiotic therapy for many infectious diseases, including
HCAP.
The recent ATS-IDSA nosocomial pneumonia guidelines define HCAP as a distinct clinical entity occurring in a subset of
patients at risk for harboring resistant organisms despite their
residence in the community [3]. These patients have historically
been treated with antibiotic regimens recommended in CAP
guidelines. As the prevalence of antimicrobial resistance has
increased in patients meeting HCAP criteria, many clinicians
questioned whether these antibiotic regimens were appropriate.
The present review aims to ascertain whether evidence exists
and to assess the strength of that evidence supporting the assertion that the duration of antibiotic therapy for patients with
HCAP who have a clinical response should be 7 days.
Methods
A PubMed database search to identify studies related to the
duration of treatment of HCAP was completed on 31 October
2006. The search terms “pneumonia” and “health-care associated” resulted in 79,547 and 46,168 articles, respectively.
Combining the 2 terms yielded 632 articles. The text word
HCAP Summit Critical Appraisal • CID 2008:46 (Suppl 4) • S329
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One caveat is that most of this information was based on
patients with probable susceptible microbacteria. The VAP data
would suggest that de-escalation may not be possible in cases
caused by MDR bacteria. This would be especially true if the
patient does not receive adequate initial antibiotic therapy.
Figure 14. Voting comparison for statement 10 (“The duration of antibiotic therapy for patients with HCAP with a clinical response should
be 7 days”). “Summit members” refers to the 11-member summit panel;
“IDSA members” refers to the members of the Infectious Diseases Society
of America who responded to a Web-based survey. HCAP, health care–
associated pneumonia.
are collected, it seems prudent to recommend that the duration
of antibiotic therapy for patients with HCAP with a clinical
response should be 7 days.
Future Directions
Grading of Evidence
On the basis of a review of the 5 studies cited above, the
members of the workshop agreed that the evidence available
to support this statement was category V for the statement in
general, category IV for the statement as it applies to hospitalized patients with HCAP, and category IV for the statement
as it applies to nonhospitalized patients with HCAP (table 2).
Level of Support
When voting on the support for this statement, 9% of the
summit participants voted to accept the statement completely,
64% voted to accept the statement with some reservations, and
27% voted to accept the statement with major reservations. In
comparison, of the 383 IDSA members who participated in the
online survey, 13% voted to accept the statement completely,
55% voted to accept the statement with some reservations, 15%
voted to accept the statement with major reservations, 14%
voted to reject the statement with reservations, and 3% rejected
the statement completely (figure 14).
Discussion
There are currently no data on whether the duration of antibiotic therapy for patients with HCAP with a clinical response
should be 7 days. However, hospitalized patient data demonstrate that patients with VAP can have a shorter therapy duration, and data on nonhospitalized patients with CAP indicate
that we can treat with shorter duration [109]. The benefits of
a shorter course of antibiotic therapy include lower cost, fewer
potential adverse drug events, and, most importantly, a lower
likelihood of selecting resistant bacteria. Until adequate data
S330 • CID 2008:46 (Suppl 4) • Kollef et al.
Appropriately designed epidemiologic studies with rigorous microbiological criteria are clearly needed to better delineate the
optimal duration of therapy for HCAP.
CONCLUSIONS
The recent definition of HCAP as a distinct subset of pneumonia was intended to identify those patients with an increased
risk of infection caused by MDR pathogens. Identification of
patients at risk for infection with MDR pathogens increases the
likelihood of adequate empirical therapy while minimizing
overuse of broad-spectrum antibiotics. Because initially inappropriate antibiotic therapy is associated with increased mortality and overuse of antibiotics leads to increased antibiotic
resistance, this strategy is intended to improve short-term outcomes for individual patients and long-term outcomes for the
general population.
The goal of the HCAP Summit was to critically appraise the
existing literature to assess the relative strengths and limitations
of our current knowledge in this area. The review was particularly challenging, given the historic use of the term “HCAP”
to describe many diverse entities, including HAP, VAP, and
NHAP. Overall, it is very clear that much is still unknown
regarding every aspect of HCAP examined during the summit.
A recurring theme, regardless of which practice statement
was being discussed, was the paucity of HCAP-specific data
and the frequent extrapolation of data from other nosocomial
infections. In the Defining HCAP workshop, the constraints of
the current definition of HCAP were frequently identified as
problematic. Because this is a relatively new definition, there
is room for debate regarding which patient subsets should be
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reduction in the duration of therapy, with no significant differences in mortality, length of stay, or occurrence of secondary
VAP.
Finally, Chastre et al. [48] completed a prospective, randomized, double-blind study of 401 patients with VAP diagnosed
by use of BAL and quantitative cultures. Only patients receiving
effective antibiotic therapy, as determined by their respiratory
culture findings, were enrolled in the study. The objective was
to determine whether 8 days is as effective as 15 days of antibiotic therapy. Patients who received a short course had neither excess mortality nor excess pulmonary infection recurrence. There were no significant differences regarding the
number of days alive without mechanical ventilation or without
organ failure, new antibiotic therapy received during the study
period, the duration of ICU stay, or the mortality rate at day
60. Patients infected with nonfermenting gram-negative rods
had a trend toward a higher chance of relapse when treated for
8 days. Resistant pathogens emerged more frequently in patients
with recurrent pulmonary infection who had received antibiotics for 15 days.
ter our summit was held, a new guideline by the IDSA and the
Society for Healthcare Epidemiology of America addressing the
issue of antimicrobial stewardship was published [110]. We
include this reference for completeness, recognizing that this
document was not used in the summit discussions.
Acknowledgments
Supplement sponsorship. This article was published as part of a supplement entitled “Health Care–Associated Pneumonia (HCAP): A Critical
Appraisal to Improve Identification, Management, and Outcomes—Proceedings of the HCAP Summit,” sponsored by Medical Education Resources and Consensus Medical Communications and supported by an
unrestricted educational grant from Ortho-McNeil administered by OrthoMcNeil Janssen Scientific Affairs, LLC.
Potential conflicts of interest. M.H.K. has received grants/research
support from Merck, Pfizer, Elan, Bard, Wyeth, and Johnson & Johnson.
L.E.M. has been a speakers’ bureau participant for Pfizer, Ortho-McNeil,
and Schering Plough. D.E.C. has received grants/research support from
Bard and Nomir; has been a speakers’ bureau participant for Merck, Elan,
Pfizer, Wyeth, and Sanofi Pasteur; and has received financial support from
the Data and Safety Monitoring Board of Johnson & Johnson. J.E.M. has
received grants/research support from AstraZeneca, Elan, Johnson & Johnson, PRD, Pfizer, and 3M, and has been a consultant for Merck, Elan,
Replidyne, and Wyeth. S.T.M. has received grants/research support from
Johnson & Johnson. M.S.N. has been a consultant, shareholder, and speakers’ bureau participant for Pfizer, Schering Plough, Ortho-McNeil, Aventis,
Merck, Elan, AstraZeneca, and Wyeth. D.L.P. has received grants/research
support from AstraZeneca, Elan, and Pfizer; has been a consultant for
Merck, Cubist Pharmaceuticals, Elan, Genzyne, KeyBay, Acureon, Wyeth,
and Johnson & Johnson; and has been a speakers’ bureau participant for
Merck, Elan, and Cubist Pharmaceuticals. All other authors: no conflicts.
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