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SUPPLEMENT ARTICLE

Health Care–Associated Pneumonia (HCAP):


A Critical Appraisal to Improve Identification,
Management, and Outcomes—Proceedings

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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
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

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 environ-
ments, 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 re- ular contact with the health care system [1, 2]. Cur-
quiring hospitalization. Changes in the location and rently accepted classifications of pneumonia include
manner in which health care is currently administered community-acquired pneumonia (CAP), hospital-ac-
have resulted in the need to reassess the classification quired pneumonia (HAP), ventilator-associated pneu-
scheme employed for pneumonia. This is most evident monia (VAP), and nursing home–associated pneumo-
when dealing with the increasing numbers of ambu- nia (NHAP). The designation of health care–associated
latory and nonhospitalized individuals who are in reg- pneumonia (HCAP) was recently introduced to include
an already-ill population of nursing-home residents,
patients in long-term care, patients undergoing same-
Reprints or correspondence: Dr. Marin H. Kollef, Div. of Pulmonary and Critical day procedures, patients receiving home- or hospital-
Care Medicine, Washington University School of Medicine, 660 S. Euclid Ave.,
Campus Box 8052, St. Louis, MO 63110 (mkollef@imwustl.edu). based intravenous therapy, and patients undergoing di-
Clinical Infectious Diseases 2008; 46:S296–334 alysis [3]. The patient population at risk for HCAP is
 2008 by the Infectious Diseases Society of America. All rights reserved.
large and diverse, probably making up the largest single
1058-4838/2008/4608S4-0002$15.00
DOI: 10.1086/526355 category of patients with pneumonia [2, 4, 5]. In gen-

S296 • CID 2008:46 (Suppl 4) • Kollef et al.


eral, patients who develop HCAP are more similar to hospi- Table 1. Health Care–Associated Pneumonia (HCAP) Summit
talized patients than to true community patients, in that they clinical practice statements.
have a greater burden of comorbidities, including cancer,
Workshop 1: Defining HCAP (statements 1–5)
chronic kidney disease, heart disease, chronic obstructive lung
1. The patient in/from a health care–associated, nonhospital
disease, immunosuppression, dementia, and impaired mobility environment who develops a clinical presentation of pneu-
[2, 6, 7]. monia has HCAP. (J.E.M.)
An important distinction of HCAP is that the pathogens are 2. The clinical and microbiological features of HCAP are more
often multidrug-resistant (MDR) bacteria [2]. Therefore, the similar to HAP and VAP than to CAP. (L.E.M.)
3. The recommended evaluation of HCAP with treatment fail-
initial treatment of HCAP should be similar to that of HAP
ures is the same as that for HAP. (Kenneth Leeper)

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and VAP, which also differentiates it from CAP [3]. This is 4. The definitions are the same for HCAP and HAP treatment
particularly important for clinicians working in first-response failures. (D.O.)
areas, such as emergency departments (EDs), to recognize, so 5. Severe CAP is not HCAP. (D.E.C.)
that appropriate initial antimicrobial therapy is not delayed. Workshop 2: Therapeutic Intervention (statements 6–10)
Several studies have demonstrated that delaying the delivery of 6. Initial empirical therapy for HCAP is the same as that for
HAP. (M.S.N.)
pathogen-appropriate antimicrobial therapy to patients with
7. Patients with HCAP who are at risk for gram-negative bac-
CAP and VAP results in excess mortality [8–10]. Thus, it is terial infections should receive dual empirical antibiotic
essential for physicians working in the ED to distinguish be- coverage. (D.L.P.)
tween HCAP and CAP, in order to correctly assess and manage 8. Patients should receive initial empirical therapy that covers
MRSA at the time of HCAP diagnosis. (S.T.M.)
suspected cases of pneumonia. This approach to HCAP also
9. When microbiological data are unavailable, de-escalation in
applies to other health care–associated infections in which the patients with HCAP should not occur. (R.P.B.)
pathogens are more similar to hospital-acquired organisms than 10. The duration of antibiotic therapy for patients with HCAP
to community-acquired ones [6, 11]. with a clinical response should be 7 days. (J.S.)
This supplement to Clinical Infectious Diseases represents the NOTE. CAP, community-acquired pneumonia; HAP, hospital-acquired
proceedings of a panel of investigators whose goal was to assess pneumonia; MRSA, methicillin-resistant Staphylococcus aureus; VAP, ven-
tilator-associated pneumonia.
the quality of evidence in support of the clinical classification
of HCAP as a distinct entity and the need for specific thera-
peutic interventions for HCAP. Ten clinical practice statements each statement, the panel members also outlined additional
were drafted by the chair (M.H.K.) and the 2 workshop leaders data required to further refine the statements for future clinical
(L.E.M. and R.P.B.) and were subsequently evaluated by the use. The main intention of this meeting was to provide a frame-
11-member panel made up of leaders in infectious diseases, work for future discussion and research in the area of HCAP.
pulmonary and critical care medicine, and pharmacology (table Before the summit meeting, clinical perspectives of practicing
1). Before the summit was convened, each participant was as- physicians were measured via a Web-based survey. E-mail poll-
signed a statement and instructed to systematically review and ing was done to ascertain their level of support for the same
summarize the evidence supporting or refuting that statement. 10 statements. The e-mail invitation to participate in the elec-
In the first phase of the live meeting, the simultaneously tronic survey was sent to 3200 members of the Infectious Dis-
conducted workshops “Defining HCAP” and “Therapeutic In- eases Society of America (IDSA) (all active e-mail addresses).
tervention” included a leader and 4–5 content experts and Of the IDSA members surveyed, 383 (11.9%) responded. The
served as a forum for each individual to present the evidence purpose of the electronic surveys was to provide information
for his or her statement. When the data were presented, primary that would allow for the comparison of data-driven responses
attention was given to the study methodology, the number of from the content “experts” at the summit with those of cli-
patients enrolled, and the outcome events. After the presen- nicians practicing in the field. The summit participants and the
tation of data for each statement, workshop members discussed surveyed physicians used the same grading scheme to rate the
the evidence, graded the strength of the evidence, and assigned 10 statements (table 2).
the statement a consensus numeric grade for the “Nature of Note. Although the American Thoracic Society (ATS)–
the Evidence” and the “Grade of Recommendation” (table 2). IDSA guidelines were intended to apply only to patients with
In the second phase of the live meeting, all summit panelists HCAP seen in the acute-care setting, those recommendations
reconvened, reviewed the workshop summaries, and discussed were extrapolated to nonhospitalized patients with HCAP for
each statement further. After each discussion, all participants this summit. Accordingly, voting on the grade of evidence for
voted on their individual levels of support, using the grading each clinical practice statement was done 3 times: first, for the
scheme shown in table 2. statement in general; second, for the statement as it applied to
In addition to defining the level of evidence in support of hospitalized patients with HCAP; and third, for the statement

HCAP Summit Critical Appraisal • CID 2008:46 (Suppl 4) • S297


Table 2. Workshop and Health Care–Associated Pneumonia (HCAP) Summit panel
voting schemes.

Category Nature of evidence


I Evidence obtained from at least 1 well-designed, randomized, controlled trial
II Evidence obtained from well-designed cohort or case-control studies
III Evidence obtained from case series, case reports, or flawed clinical trials
IV Opinions of respected authorities based on clinical experience, descriptive
studies, or reports of expert committees
V Insufficient evidence to form an opinion

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Level of workshop support for statement
A There is good evidence to support the statement
B 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
Individual level of support (summit panel members)
1 Accept recommendation completely
2 Accept recommendation with some reservations
3 Accept recommendation with major reservations
4 Reject recommendation with reservations
5 Reject recommendation completely

as it applied to nonhospitalized patients with HCAP. The ra- patient facility or ED or is admitted directly to the hospital.
tionale for including those with community-acquired HCAP However, there is a question regarding whether the guidelines
was that some data were available for this group, especially for for such patients should also apply to patients who remain in
those with NHAP. Therefore, the committee felt that there was a nonhospital environment, such as a nursing home or long-
sufficient evidence to make recommendations for some of the term-care facility, or who remain in another setting but who
issues. However, several areas with insufficient information meet the other ATS-IDSA criteria for having HCAP [3].
were identified.
Methods
STATEMENT 1: THE PATIENT IN/FROM A
A search of the OVID “1996-present” database to identify stud-
HEALTH CARE–ASSOCIATED, NONHOSPITAL
ies related to descriptions of HCAP was completed on 1 No-
ENVIRONMENT WHO DEVELOPS A CLINICAL
vember 2006. The search of the combined term “health care
PRESENTATION OF PNEUMONIA HAS HCAP
associated or healthcare-associated” produced a total of 144
Rationale and Definition of Statement articles. Next, the text word search for the term “HCAP” yielded
In defining HCAP as a distinct clinical entity, the most recent 66 articles, and the text word search for “healthcare-associated
ATS-IDSA nosocomial pneumonia guidelines defined a subset pneumonia” resulted in 7 articles. At this point, the 2 text word
of patients at risk for harboring resistant organisms despite searches were combined with the first combined-term search,
their residence in the community [3]. Criteria included hos- and the results were limited to the English language. This pro-
pitalization in an acute-care facility for ⭓2 days within 90 days duced 82 articles. The same search strategy was then used in
before the infection; residence in a nursing home or long-term- the OVID database “in process,” and an additional 10 articles
care facility; recent receipt of intravenous antibiotic therapy, were identified. By scanning the titles of these 92 articles, 14
chemotherapy, or wound care, within 30 days before the in- relevant articles were noted, and a review of the references for
fection; or attending a hospital or hemodialysis clinic [3]. Al- these 14 articles added 4 articles to the total. Thus, 18 articles
though the ATS-IDSA guidelines were intended to apply only were considered to be relevant to this statement.
to hospitalized patients with HCAP, it is apparent that these
concepts are being extrapolated to nonhospitalized patients Evidence
with HCAP as well [12]. By definition, the ATS-IDSA guidelines Definitions of HCAP. Several definitions of HCAP are stated
apply to patients coming to an acute-care facility from a non- or implied in the medical literature. One prevalent use of the
hospital environment, whether the patient is seen in an out- term, considered to be irrelevant to this discussion, is the use

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of “health care associated” as a replacement for or synonym of that “publication of these recommendations has been recog-
“nosocomial” or “hospital associated” [13]. A second use of nized by the Centers for Medicare and Medicaid Services in
the term is “hospitalized with community-acquired pneumo- their application of core measures for the treatment of CAP.”
nia,” which also fails to capture the concept presented in the This action has led to the exclusion of patients with HCAP
ATS-IDSA guidelines [14]. The relevant concept is that pneu- from studies of adherence to antibiotic therapy recommen-
monia not acquired in an acute-care hospital (traditionally la- dations for patients with CAP. Fujitani et al. [17, pp. 627 and
beled as “community-acquired infection”) is more likely to have 630] considered the classification of HCAP as a separate disease
a spectrum of pathogens that resemble those associated with entity to be “a good idea” but noted “problems with its exe-
HAP or VAP than to have a distribution of microbes tradi- cution.” They noted that the definitions of HAP, CAP, and
HCAP have varied among different large-scale studies and sug-

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tionally associated with CAP.
HCAP as a distinct entity. Differences in the likely prev- gest that “classification schemes are inherently imprecise be-
alence of drug-resistant pathogens were highlighted in a study cause patient groups overlap in the HCAP categories.” Wun-
by Friedman et al. [6] of health care–associated bloodstream derink [18, p. 2686] also noted that “a distinction between
infections in adults, which defined patients with health care– HCAP and CAP has never been totally clear.” He concluded,
associated bacteremia in a fashion similar to the ATS-IDSA however, by stating that “despite these issues, defining the
guidelines. Patients with health care–associated bacteremia were HCAP category has led to more appropriate antibiotic therapy
similar to those with hospital-acquired bloodstream infections, for the majority of patients and clearly assisted decision mak-
with regard to frequency of comorbid conditions, pathogens ing” [18].
and their susceptibility, and mortality rates. The authors con- Differences in application of the definition by setting.
cluded that “a separate category for [health care–associated] The previous studies dealt with patients seen in, or admitted
infections is justified, and this new category will have obvious to, acute-care hospitals. However, many patients with pneu-
implications for choices about empirical therapy and infection- monia acquired in a nursing home setting are not transferred
control surveillance” [6, p. 791]. This theme was echoed and to an acute-care hospital. For example, Loeb et al. [19] con-
expanded to include pneumonia in a 2004 editorial by Craven, ducted a cluster-randomized controlled trial of different reg-
who stated, “compared with patients with community-acquired imens for treatment of pneumonia in nursing home residents
pneumonia (CAP), those with HCAP are often at greater risk in Canada. Only 110 of 661 evaluated patients were
for colonization and infection with a wider spectrum of mul- hospitalized.
tidrug-resistant organisms” [4, p. 153]. However, Grossman et The degree to which the HCAP definition applies to patients
al., in a review of practice guidelines for treatment of lower- with pneumonia who remain in nonhospital health care set-
respiratory-tract infections in hospitalized patients, concluded tings, such as nursing homes, is not clear. Mortality rates for
that HCAP is treated similarly to HAP “and may be considered NHAP are higher than those for CAP [20, 21], but controlling
with HAP” [15, p. 295]. for different factors that affect this risk is difficult. For example,
Kollef et al. [2] reviewed a large database of 4543 patients in a review by El Sohl et al. [22] of 88 patients with culture-
with culture-positive pneumonia and identified 20% as having confirmed cases of severe pneumonia, previous use of antibi-
HCAP. The percentage of patients with a culture positive for otics (a component of the ATS-IDSA definition) was found to
Staphylococcus aureus was similar among those with HCAP be predictive of the presence of drug-resistant bacteria. How-
(46.7%) and those with HAP (47.1%), and mean mortality ever, the other predictor of drug resistance in this study was a
rates (19.8% and 18.8%, respectively) were similar for these 2 lower Activities of Daily Living (ADL) score, a feature not
groups of patients as well. The mean length of stay for patients considered in the ATS-IDSA definition of HCAP. Likewise, at
with HCAP was intermediate between that for patients with least 1 study suggests that the risk of MDR bacteria being
CAP and that for patients with HAP. The authors concluded present is no higher for NHAP than for CAP [20]. It was
that this analysis “justified HCAP as a new category of pneu- acknowledged that the literature on NHAP is dated and in-
monia” [2, p. 3854]. complete; this area needs further investigation.
Pop-Vicas et al. [16] noted an increasing prevalence of MDR,
gram-negative bacilli recovered at admission to a tertiary-care Grading of Evidence
hospital. Factors independently associated with the isolation of On the basis of a review of the studies cited above, the 5
resistant organisms (age ⭓65 years, prior antibiotic therapy for members of this workshop agreed that the evidence available
⭓2 weeks, and residence in a long-term-care facility) were sim- to support this statement was category III (a mixture of the 2
ilar to those used to define HCAP. following votes) for the statement in general, category IV (pri-
The editorial response to the ATS-IDSA definition of HCAP marily from definition) for the statement as it applies to hos-
has been mixed. Hiramatsu and Niederman [1, p. 3786] note pitalized patients with HCAP, and category V (insufficient evi-

HCAP Summit Critical Appraisal • CID 2008:46 (Suppl 4) • S299


dence) 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, 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 com-
parison, of the 383 IDSA members who participated in the

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online survey, 48% accepted the statement completely, 42%
accepted the statement with some reservations, 4% accepted
the statement with major reservations, 4% rejected the state-
Figure 2. Relationship of health care–associated pneumonia (HCAP)
ment with reservations, and 2% rejected the statement com-
to community-acquired pneumonia (CAP), hospital-acquired pneumonia
pletely (figure 1). It was thought by the summit participants (HAP), and ventilator-associated pneumonia (VAP). Note also the increased
that IDSA members were considering the statement primarily risk for colonization and infection with multidrug-resistant (MDR) path-
for its intended purpose of applicability to patients with HCAP ogens, morbidity, and mortality in these groups. Adapted in part from
seen in the acute-care hospital setting. [23].

Discussion prevalence of MDR) are not necessarily linked—one may be


By definition, the ATS-IDSA guidelines apply to patients com- high while the other is not.
ing to an acute-care facility from a nonhospital environment, There is, however, insufficient evidence to decide the validity
whether the patient is seen in an outpatient facility or ED or of the HCAP category as it relates to patients remaining in
is admitted directly to the hospital, and the different panels nursing homes or other non–acute-care health settings, as is
supported this definition. The concept is presented graphically reflected in the summit participants’ grading of the evidence.
in figure 2, which represents CAP, HCAP, and HAP as separate The value of extrapolating the ATS-IDSA definition to these
entities for which, in general, the likelihood of the presence of settings requires further study. Likewise, for other non–acute-
MDR organisms increases [23]. Less well documented, but still care health settings, including those of specific subsets of pa-
likely, is that rates of mortality and morbidity also increase as tients with HCAP (those receiving hemodialysis, home infu-
one considers the entities on the right side of the figure. There sion, wound care, chemotherapy, or recent antibiotics or who
is, however, overlap between the 3 defined entities; for example, have a relative with resistant pathogens), the available data are
patients with severe CAP might have higher mean mortality very limited.
rates than do those with HCAP. Similarly, the prevalence of
MDR organisms may be high for patients with CAP in some Future Directions
areas where selective pressure due to antimicrobial use is high. The paucity of data highlighted in the previous section provides
It is important to appreciate that these 2 features (severity and 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
Figure 1. Voting comparison for statement 1 (“The patient in/from a
health care–associated, nonhospital environment who develops a clinical Rationale and Definition of Statement
presentation of pneumonia has HCAP”). “Summit members” refers to the
11-member summit panel; “IDSA members” refers to the members of Historically, patients with HCAP have been treated with anti-
the Infectious Diseases Society of America who responded to a Web- biotic regimens recommended by CAP guidelines. As the prev-
based survey. HCAP, health care–associated pneumonia. alence of antimicrobial resistance has increased, particularly in

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patients whose conditions meet HCAP criteria, many clinicians biology searches and limited to the English language, yielding
have questioned whether these antibiotic regimens are appro- 134 articles for review. One article was deemed relevant to the
priate. This is of particular importance, given the association statement.
between inadequate empirical antibiotic therapy and increased Chemotherapy-associated pneumonia. The search term
mortality rates. “cancer chemotherapy” yielded 311,108 articles. These were
To address these concerns, the ATS-IDSA guidelines rec- combined with the prior pneumonia and microbiology searches
ommended broad empirical antibiotic therapy followed by cul- to give 348 articles. After limiting these to the English language,
ture-guided de-escalation for patients with HCAP. Although 268 articles were reviewed, and 4 were deemed relevant.
these concepts were intuitive and widely embraced by clinicians, Queries using multiple search terms relating to pneumonia

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critics expressed concerns regarding the data supporting such in patients who have a family member with resistant pathogens
significant changes to the guidelines. Because the guidelines cite and/or patients who have received prior antibiotic therapy did
only 7 references relating to HCAP, this section aims to assess not result in any articles being found.
the strength of evidence supporting the assertion that clinical
and microbiological features of HCAP are more similar to those Evidence
of HAP than to those of CAP. HCAP. Only 1 study was identified that specifically focused
on the microbiology of HCAP [2]. In this retrospective cohort
Methods analysis of a multi-institutional database, 4543 cases of culture-
HCAP. A PubMed database search to identify studies related positive pneumonia were identified by International Classifi-
to the clinical and microbiological features of HCAP was com- cation of Diseases, Ninth Revision codes. Patients were then
pleted on 24 October 2006. The search terms “health care as- stratified as having CAP (49%), HCAP (22%), HAP (18%), or
sociated pneumonia,” “healthcare associated pneumonia,” VAP (11%). The most common pathogens in HCAP were
“health care-associated pneumonia,” and “healthcare-associ- methicillin-resistant S. aureus (MRSA) and Pseudomonas aeru-
ated pneumonia” gave a total of 48,465 articles. The search ginosa (26.5% and 25.3%, respectively), similar to HAP (22.9%
terms “microbiology” and “pathogen” yielded 551,438 articles. and 18.4%; P ! .01 for P. aeruginosa). Conversely, Streptococcus
Combining the HCAP search with the microbiology search by pneumoniae and Haemophilus species were seen more fre-
use of the “AND” function produced 138 articles. After limiting quently in CAP (16.6% and 16.6%) than in HCAP (3.1% and
these to the English language, 129 articles were reviewed. Only 5.8%; P ! .01 for both). The mortality rates among patients
3 were deemed relevant to the statement. Because HCAP in- with HCAP and patients with HAP were similar (19.8% and
cludes multiple entities previously referred to by use of other 18.8%, respectively; P 1 .05 ) and were significantly higher than
terminology, several additional searches were conducted. that among patients with CAP (10.0%; P ! .0001). Limitations
NHAP. The search terms “pneumonia” and “lower respi- of this study included the use of data only for hospitalized
ratory tract infection” were combined with the “OR” function patients, inclusion of only patients with early-onset pneumonia,
to identify 86,173 articles. The search terms “nursing home” misclassification bias, and exclusion of patients with negative
and “long term care” were combined with the “OR” function culture results. Also unresolved are the very high rates of Pseu-
to identify 44,206 articles. The nursing home and pneumonia domonas species (17.1%) and methicillin-susceptible S. aureus
searches were combined using the “AND” function to give 616 (17.2%) as the causative pathogens in patients with CAP. The
articles. When these were combined with the previous micro- clinical features of HCAP were not assessed in this study.
biology search and limited to the English language, 112 articles Two additional studies assessed the risk factors for coloni-
were reviewed. Only 5 were deemed relevant to the statement. zation with resistant organisms in hospitalized patients, many
One article was then added from these articles’ references, and of whom did not have pneumonia. The first of these studies
another recent abstract also was included. assessed variables associated with MDR gram-negative bacillus
Hemodialysis-associated pneumonia. The search terms carriage [16]. In this prospective, case-control study, it was
“hemodialysis” and “dialysis” were combined with the “OR” found that predictors of MDR gram-negative bacillus coloni-
function to identify 111,259 articles. When these were com- zation included several subsets of patients also included in the
bined with the prior pneumonia and microbiology searches new ATS-IDSA definition of HCAP: residents of long-term-
and limited to the English language, 54 articles were reviewed. care facilities, patients undergoing hemodialysis, and patients
One article was deemed relevant to the statement. who have recently received antibiotic therapy. Similarly, a pro-
Home care– and wound care–associated pneumonia. spective surveillance study of MRSA showed that patients
The search terms “home care” and “wound care” were com- whose conditions met HCAP criteria (patients who have re-
bined with the “OR” function for a total of 49,986 articles. cently been hospitalized, residents of long-term-care facilities,
These were combined with the prior pneumonia and micro- patients undergoing dialysis, or patients receiving home nursing

HCAP Summit Critical Appraisal • CID 2008:46 (Suppl 4) • S301


care) accounted for 99% of “community-acquired” MRSA cases A prospective cohort of 104 “very elderly” patients (mean
[24]. age  SD, 82.3  5.5 years) admitted to the intensive care unit
NHAP. Seven studies of the clinical and microbiological (ICU) with severe pneumonia requiring mechanical ventilation
features of NHAP were identified. A prospective case-control identified a pathogen in 55 patients (53%) by use of an ag-
study comparing patients with NHAP and age-matched patients gressive and invasive approach that included bronchoalveolar
with CAP showed that the presentation of pneumonia was lavage (BAL) [27]. Although no formal statistical comparisons
strikingly different between groups. Compared with patients of community residents and long-term-care–facility residents
with CAP, patients with NHAP were less likely to have a pro- were performed, patients with NHAP had higher rates of altered
ductive cough (61% vs. 35%; P ! .05), chills (58% vs. 24%; mental status (76% vs. 42%) and fever (65% vs. 44%) but a

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P ! .05), headache (32% vs. 5%; P ! .05), sore throat (19% vs. lower rate of chest pain (5% vs. 20%) at admission. Compared
7%; P ! .05), myalgia (33% vs. 7%; P ! .05), or arthralgia (10% with patients with CAP, fewer patients with NHAP had S. pneu-
vs. 0%; P ! .05). Although the difference was reported as being moniae isolated (8.5% vs. 14.0%), but more patients with
statistically nonsignificant, patients with NHAP were almost NHAP had S. aureus isolated (29.7% vs. 7.0%). All Staphylo-
twice as likely to have confusion (70% vs. 37%). Patients with coccus isolates from patients with CAP were methicillin sus-
NHAP were also more likely to die in the hospital (32% vs. ceptible, whereas 78.6% of Staphylococcus isolates (11 of 14)
14%; P ! .05) [21]. from patients with NHAP were methicillin resistant.
A retrospective cohort analysis comparing the clinical pre- In a similar study by the same authors, patients with NHAP
sentations of NHAP and CAP found that patients with NHAP requiring mechanical ventilation underwent BAL in an attempt
were more likely to have altered mental status (55.9% vs. 11.3%; to identify those at risk for harboring resistant pathogens [22].
P ! .001), tachypnea (40.9% vs. 22.8%; P ! .001), and hypo- The most common pathogens included S. aureus (23.9%, of
tension (7.0% vs. 1.1%; P ! .001) [25]. The presence of sub- which 61.9% were MRSA) and S. pneumoniae (18.2%). Pre-
jective variables, such as cough, dyspnea, and pleuritic chest dictors of infection with resistant pathogens included functional
pain, could not be assessed. Patients with NHAP also had a dependence and prior antibiotic exposure.
significantly higher mortality rate (18.6% vs. 8.0%; P ! .001). Another recent study assessed the risk factors for coloni-
In a prospective cohort of 437 consecutive patients with pneu- zation with MDR organisms in residents of long-term-care
monia, 40 (9%) of the patients resided in nursing homes [20]. facilities [28]. In a point-prevalence study of 84 individuals,
These patients with NHAP were less likely than were those with surveillance nasal and rectal cultures were assessed for or-
other types of pneumonia to have a productive cough (OR, ganisms resistant to ⭓3 frequently prescribed antibiotics. The
0.4; P p .02) or pleuritic pain (OR, 0.1; P p .03) but were prevalence of colonization with MDR organisms was 51%,
more likely to be confused (OR, 2.6; P ! .001). Compared with with the most common organisms being Providencia stuartii
age-matched control individuals living in the community, the (31% of isolates), Proteus mirabilis (21%), Escherichia coli
patients with NHAP had a significantly higher mortality rate (19%), and Morganella morganii (19%). Independent predic-
(53.0% vs. 13.4%; P ! .001). tors of colonization by multivariate regression analysis in-
An article reviewing 18 primary studies published between cluded fecal incontinence (OR, 3.78; P p .038 ) and prior an-
1978 and 1994 evaluated the etiology of pneumonia in residents tibiotic exposure (OR, 2.5; P p .047). PFGE identified high
of long-term-care facilities [26]. In this study, the most com- rates of identical or related strain types, which suggested sub-
mon pathogens were gram-negative bacilli (18%), S. pneu- stantial horizontal transmission.
moniae (16%), Haemophilus influenzae (11%), and S. aureus Dialysis-associated pneumonia. Only 1 study was identi-
(6%). Mycoplasma, Chlamydia, and Legionella species ac- fied as dealing specifically with pneumonia in patients under-
counted for !1% of cases, and 29% of cases did not have an going long-term hemodialysis [29]. This retrospective cohort
identifiable pathogen. The primary studies showed marked var- analysis linked the waves 1, 3, and 4 Dialysis Morbidity and
iability in the frequency of causative pathogens: gram-negative Mortality Study data sets with Medicare claims to identify 3101
bacilli isolation varied from 0% to 55% across studies; that of hospital admissions for pneumonia in patients undergoing
S. pneumoniae ranged from 0% to 39%; that of S. aureus, from long-term hemodialysis. Overall, the frequency of microbio-
0% to 33%; and that of Legionella species, from 0% to 6%. logical confirmation was very poor (18.2%). In patients with
The primary studies’ evaluations of the causative pathogens microbiologically confirmed pneumonia, the most common
were widely discrepant: some had no microbiological criteria, pathogens were S. pneumoniae (18.7%), P. aeruginosa (15.4%),
others required a high-quality sputum specimen, and some Klebsiella species (8.8%), and H. influenzae (8.2%). Despite
allowed positive blood culture results to suffice if sputum results high rates of colonization with MRSA in the dialysis population,
were negative. None of the studies rigorously pursued the iso- Staphylococcus species were infrequently the causative pathogen
lation of atypical organisms. (2.2%).

S302 • CID 2008:46 (Suppl 4) • Kollef et al.


Pneumonia in patients receiving home infusion therapy or antibiotic exposure as a risk factor for colonization or infection
wound care. One study was identified that specifically as- with resistant pathogens [16, 22, 28].
sessed pneumonia in patients receiving home nursing care. In
this prospective case-control study of 175 patients with MRSA Grading of Evidence
infection, 41 patients had pneumonia [30]. Multivariate re- On the basis of a review of the 15 studies cited above, the 5
gression analysis identified a highly significant association be- members of this workshop agreed that the evidence available
tween MRSA infection and prior receipt of home nursing care to support this statement was category II for the statement in
(OR, 3.7; P ! .001). Other independent risk factors included general, category II for the statement as it applies to hospitalized
prior hospitalization and transfer from another institution, such patients with HCAP, and category V for the statement as it

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as a nursing home. applies to nonhospitalized patients with HCAP (table 2).
Pneumonia in patients undergoing chemotherapy. Three
studies were identified as relating specifically to pneumonia in Level of Support
patients undergoing chemotherapy. In a prospective observa- When voting on the support for this statement, 9% of the
tional cohort study of 52 consecutive pneumonia cases among summit participants voted to accept the statement completely,
patients with acute leukemia undergoing chemotherapy, the 64% voted to accept the statement with some reservations, 18%
presentation was relatively subtle [31]. The signs and symptoms voted to accept the statement with major reservations, and 9%
present in more than half of patients included fever (98%), voted to reject the statement with reservations. In comparison,
dyspnea (79%), rales (77%), chills (73%), cough (65%), and of the 383 IDSA members who participated in the online survey,
sputum production (58%). A causative pathogen was found in 40% voted to accept the statement completely, 47% voted to
accept the statement with some reservations, 7% voted to accept
71% of cases, but only 52% were identified antemortem. The
the statement with major reservations, 5% voted to reject the
most common organisms were fungi (25.0%), Pseudomonas
statement with reservations, and 1% voted to reject the state-
species (23.1%), and Klebsiella species (13.4%).
ment completely (figure 3).
In another prospective cohort of 242 consecutive pneumonia
cases among patients with malignancy undergoing antineo-
Discussion
plastic chemotherapy, the clinical presentation was similarly
This statement is of key importance, given that the relevance
subtle [32]. Clinical presentation in more than half of patients
of the remaining statements discussed at the summit hinges on
included fever (90%), a positive radiographic finding (83%),
the assertion that HCAP constitutes a distinct clinical entity
and rales (65%). Gram-negative bacilli accounted for 90% of
with unique microbiological features. At present, there is lim-
cases, with the most common pathogens being Klebsiella species
ited conclusive evidence supporting this statement, as is re-
(31.8%) and Pseudomonas species (18.6%).
flected in the summit participants’ grading of the evidence.
The final study was a prospective surveillance study of neu- All of the reviewed studies support the assertion that the
tropenic patients with bacteremic pneumonia [33]. Although clinical features of HCAP are different from those of CAP.
408 cases of pneumonia were identified, clinical and micro- Although patients with HCAP are generally less likely to have
biological 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. Figure 3. Voting comparison for statement 2 (“The clinical and micro-
Pneumonia in patients who have recently received biological features of HCAP are more similar to HAP and VAP than to
antibiotics. No studies were identified as specifically assessing CAP”). “Summit members” refers to the 11-member summit panel; “IDSA
members” refers to the members of the Infectious Diseases Society of
either the clinical presentation or microbiological features of America who responded to a Web-based survey. CAP, community-acquired
pneumonia in patients who have recently received antibiotics. pneumonia; HAP, hospital-acquired pneumonia; HCAP, health care–asso-
However, several of the previously cited studies identified prior ciated pneumonia; VAP, ventilator-associated pneumonia.

HCAP Summit Critical Appraisal • CID 2008:46 (Suppl 4) • S303


symptoms, the fever response is preserved, and the likelihood use of standardized diagnostic and laboratory criteria would
of altered mental status is increased. This combination of fac- be essential, these criteria do not exist. These large, observa-
tors may lead to delayed recognition and initiation of therapy, tional cohorts would need to be followed longitudinally to
thereby explaining the increased rates of hypoxemia, systemic assess changes in pathogens and resistance patterns over time.
hypotension, and death.
Presently, there is only 1 study of the microbiology of HCAP STATEMENT 3: THE RECOMMENDED
as it is specifically defined by the ATS-IDSA guidelines [2]. EVALUATION OF HCAP WITH TREATMENT
Although this study has several limitations, it corroborates the FAILURES IS THE SAME AS THAT FOR HAP
assertion of earlier, less rigorous studies concluding that HCAP Rationale and Definition of Statement

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is more likely to be caused by organisms that are particularly
Nonresolving pneumonia is variably defined but represents a
virulent and/or resistant to antibiotic therapy.
clinical syndrome in which focal infiltrates persist with signs
Of the individual subsets grouped together under the HCAP
and symptoms of acute pulmonary infection (e.g., fever, ex-
umbrella, NHAP provides the richest data in terms of the pub-
pectoration, malaise, or dyspnea). Despite receiving a minimum
lished literature. However, these studies were also the most of 10 days of antibiotic therapy, patients either do not improve
likely to be confounded by variables such as comorbid illness or worsen clinically, or radiographic opacities fail to resolve
or prior antibiotic therapy. These studies routinely had limited within 12 weeks after the onset of pneumonia [34–36].
microbiological data that were of very poor quality. Another Nonresolving pneumonia often represents treatment failure
concern is the possible obsolescence of older studies, given the or a superinfection [37, 38]. In addition to being the result of
changes in pathogen susceptibilities over time. Although nurs- initial therapy failure or a noninfectious etiology, nonresolving
ing home residents have very high rates of colonization with pneumonia may also be the result of an overwhelming immune
MDR pathogens—and these organisms are seen more fre- response to a specific pathogen. It is critical to identify patients
quently in patients with NHAP—CAP pathogens are also fre- at risk for nonresponding pneumonia, to institute early ap-
quently isolated from these patients. propriate therapy. Patients with severe HCAP, underlying co-
The present NHAP knowledge base also suffers from a hos- morbidities, and certain etiologic agents (viral, atypical) are at
pitalization bias; the available studies have rigorously evaluated greater risk for nonresolving pneumonia and may benefit from
the causative organisms only in hospitalized patients. This is alternative supportive approaches (e.g., early tracheostomy) as
problematic, because prior therapy has frequently failed for well as from immune modulation in specific circumstances
these patients at nursing homes, thereby artificially increasing (e.g., progression to acute lung injury or pneumococcal sepsis).
the frequency of virulent and/or resistant organisms. There is
also an extensive literature base showing the good clinical re- Methods
sponses of many patients with NHAP who receive in-facility The original PubMed search was conducted in November 2006
CAP therapy. In all, NHAP appears to be a “hybrid” entity, and was augmented with a search performed in April 2007. By
blending conventional CAP organisms with increased rates of selection of articles published in English on the duration of
HAP pathogens. nonresolving pneumonia, 50 references focusing on both CAP
For the remaining subsets of patients with HCAP (those and HCAP were identified. These were reviewed along with
receiving hemodialysis, home infusion, wound care, chemo- their bibliographies for additional references.
therapy, or recent antibiotics or who have a relative with re-
sistant pathogens), the available data are very limited and likely Evidence
suffer from obsolescence. Although it is intuitive to group these
The use of the clinical pulmonary infection score (CPIS) to
patients together, given their increased contact with the health
define resolution of nosocomial pneumonia was evaluated by
system, the data do not clearly justify doing so. The high rate
Luna et al. [39]. These investigators prospectively evaluated 63
of fungal infections in patients undergoing chemotherapy re- patients with microbiologically confirmed VAP. CPISs were fol-
inforces that HCAP subgroups—although clearly distinct from lowed serially and were noted to improve as early as the third
CAP—are also different from one another. day of therapy in the group of survivors. Patients who did not
survive did not demonstrate any improvement in their CPIS,
Future Directions particularly in oxygenation. Patients without treatment re-
Future directions discussed by the summit members reflect sponse were also significantly more likely to receive inadequate
many of the limitations of previously discussed studies. Ap- initial treatment and had a higher mortality rate, compared
propriately designed epidemiologic studies with rigorous mi- with patients with treatment response. This study suggests that
crobiological criteria clearly are needed to better delineate the a clinical scoring system may be useful in the early identification
causative pathogens of CAP, HAP, and HCAP. Although the of patients with pneumonia whose conditions are unlikely to

S304 • CID 2008:46 (Suppl 4) • Kollef et al.


respond to therapy or who have delayed resolution, in part tients with treatment response, patients with early treatment
related to inadequate initial therapy. failure had significantly higher rates of complications (58% vs.
Resolution can also be defined microbiologically. On the 24%) and overall mortality (27% vs. 4%) (P ! .001 for both).
basis of serial quantitative cultures from respiratory secretions, An etiologic diagnosis was established in 598 patients with
the eradication or persistence of an organism can be demon- early treatment response (48%) and 55 patients with early treat-
strated. In the prospective series studied by Garrard and ment failure (68%) (P ! .01). Of patients with an etiologic di-
A’Court [40], nonbronchoscopic lung lavage specimens were agnosis, 316 (53%) with early response and 48 (87%) with early
obtained from 83 patients with nosocomial pneumonia. The failure were classified as definitive. The most frequently iden-
investigators found that serial culture results correlated well tified pathogens in the early-response and early-failure groups

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with the scored clinical responses. Culture counts increased in were S. pneumoniae (23% and 22%, respectively), Legionella
the few days before the onset of therapy and decreased dra- species (6% and 21%), H. influenzae (6% and 5%), and or-
matically after its initiation. In most cases, the culture counts ganisms associated with aspiration pneumonia (6% and 6%).
had decreased by 24 h, but they decreased no later than 72 h Legionella pneumophila and gram-negative bacilli were found
in all cases of resolving pneumonia. Nonresolving pneumonia more frequently in patients with early failure (P ! .001 and
was thus equally well defined by both clinical and microbio- P p .03, respectively).
logical criteria, although clinical nonresponse required more Most patients were initially treated with a single antimicrobial
time to determine. agent, mainly in the early-response group (77% of those with
Menéndez et al. [41] identified factors associated with failure early responses and 65% of those with early failures). The an-
of empirical treatment and determined the incidence of both tibiotics most frequently prescribed were the b-lactams (mainly
early (!72 h) and late treatment failure and related implications ceftriaxone and amoxicillin-clavulanate). Overall, of the 81 pa-
on the outcome. A prospective, multicenter cohort study was tients for whom treatment failed, concordance of therapy could
performed involving 1424 hospitalized patients from 15 hos- be determined in 52 patients. In general, patients with early
pitals. Treatment failure occurred in 215 patients (15.1%): 134 failure received discordant antimicrobial therapy more fre-
(62.3%) had early failures and 81 (37.7%) had late failures. quently (16 [31%] of 52 patients) than did patients with early
The causes were infectious in 86 patients (40%), noninfectious response (52 [9%] of 584 patients). Treatment failed in 1 patient
in 34 patients (15.8%), and undetermined in 95 patients owing to resistance to a recommended regimen; he experienced
(44.2%). The independent risk factors associated with treat- breakthrough levofloxacin-resistant S. pneumoniae bacteremia
ment failure in a stepwise logistic regression analysis were liver (MIC of levofloxacin, 64 mg/mL) after 48 h of intravenous
disease, pneumonia risk class, leukopenia, multilobar CAP, levofloxacin therapy.
pleural effusion, and radiologic signs of cavitation. Independent Because most studies of resolution have included only pa-
factors associated with a lower risk of treatment failure were tients with CAP, the normal resolution of nosocomial pneu-
influenza vaccination, initial treatment with fluoroquinolones, monia is more uncertain. Several investigators, however, have
and chronic obstructive pulmonary disease. Mortality was sig- identified risk factors for poor outcomes, including death. By
nificantly higher in patients with treatment failure than in those inference, the factors promoting a poor outcome may be linked
without treatment failure (25% vs. 2%). Failure of empirical to delayed resolution. Celis et al. [43] identified prognostic
treatment increased the rate of mortality due to CAP 11-fold factors for nosocomial pneumonia. They reported that respi-
after adjustment for risk class. ratory failure, the presence of a fatal underlying condition, age
Rosón et al. [42] performed an observational analysis of a 160 years, and the presence of bilateral radiographic involve-
prospective series of 1383 nonimmunosuppressed hospitalized ment were associated with a significantly increased risk of mor-
adults with CAP to identify and categorize causes and factors tality. Additionally, infection with “high-risk” organisms, such
associated with early failure. At 48–72 h, 238 patients (18%) as P. aeruginosa, S. aureus, other gram-negative bacilli, Candida
remained febrile, but most of them responded without further species, or Aspergillus species, was associated with worse
changes in antibiotic therapy, and 81 patients (6%) had early outcomes.
failure. The main causes of early failure were progressive pneu- In addition to observing longer resolution times with gram-
monia (n p 54), pleural empyema (n p 18 ), lack of response negative bacterial infections, Graybill et al. [44] noted the sig-
(n p 13), and uncontrolled sepsis (n p 9 ). Independent factors nificance of certain host factors, such as cardiovascular disease,
associated with early failure were older age (165 years) (OR, a variety of malignant neoplasms, prior cerebrovascular acci-
0.35), multilobar pneumonia (OR, 1.81), Pneumonia Severity dent, alcoholism, chronic obstructive pulmonary disease, renal
Index (PSI) score 190 (OR, 2.75), Legionella pneumonia (OR, impairment requiring hemodialysis, and diabetes. In his 1973
2.71), gram-negative bacillary pneumonia (OR, 4.34), and dis- study of 82 patients with nosocomial pneumonia, prolonged
cordant antimicrobial therapy (OR, 2.51). Compared with pa- resolution was defined as radiographic abnormalities extending

HCAP Summit Critical Appraisal • CID 2008:46 (Suppl 4) • S305


beyond 4 weeks. Mortality was higher among patients who talized patients with HCAP, and category V for the statement
developed the pneumonia postoperatively, while undergoing as it applies to nonhospitalized patients with HCAP (table 2).
ventilation, after aspiration, or while receiving antibiotic ther-
apy. Other studies of nosocomial pneumonia have identified Level of Support
similar risk factors [45, 46]. When voting on the support for this statement, 9% of the
Montravers was one of the first investigators to compare summit participants voted to accept the statement with some
microbiological data with clinical outcomes [45]. Serial bron- reservations, 82% voted to accept the statement with major
choscopy and protected specimen brushings were performed reservations, and 9% voted to reject the statement completely.
in 76 patients requiring mechanical ventilation. The level of In comparison, of the 383 IDSA members who participated in

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eradication of a pathogen was shown to correlate with subse- the online survey, 51% voted to accept the statement com-
quent clinical improvement: high-level growth (1103) found by pletely, 41% voted to accept the statement with some reser-
follow-up protected specimen brushing at 72 h was more com- vations, 4% voted to accept the statement with major reser-
mon among patients with persistent symptoms of pneumonia. vations, 3% voted to reject the statement with reservations, and
Despite sterilization of the lung in 94% of patients, clinical 1% voted to reject the statement completely (figure 4).
resolution occurred in only 20% of cases.
To further evaluate the relationship between clinical and mi- Discussion
crobiological data, Dennesen et al. [47] performed a prospective The optimal evaluation of nonresolving pneumonia is not
study of 27 patients with VAP. Temperature, WBC count, and clearly established. The existing data regarding treatment failure
oxygenation (as measured by PaO2/FiO2 ratios) were scored in HAP are predominately from VAP studies. In these reports,
daily. Semiquantitative cultures of endotracheal aspirates were the identified causes are very diverse, highlighting the need for
also obtained at the day of admission and twice weekly there- a rigorous stepwise approach incorporating repeated micro-
after. Unlike in the Montravers et al. [45] study, persistent biological evaluation, evaluation of infectious complications,
bacterial growth was more common with certain pathogens, and assessment of noninfectious causes. At present, there are
including Pseudomonas and Enterobacteriaceae species, despite no existing data evaluating treatment failure in HCAP. The
significant clinical improvement. These findings suggest that summit participants agreed, on the basis of professional opin-
bacterial eradication is an imperfect marker of clinical response ion alone, that the evaluation of nonresolving HCAP should
in VAP. be the same as that for other classes of pneumonia until de-
Chastre et al. [48] evaluated patients with microbiologically finitive data specific to HCAP are available.
treated VAP randomized to receive 8 days versus 15 days of
appropriate antimicrobial therapy. This study found similar Future Directions
rates of survival and secondary outcomes between the 2 treat- Summit participants agreed that, given our current lack of
ment groups. However, patients with VAP secondary to P. aeru- knowledge regarding the evaluation of HCAP treatment fail-
ginosa pneumonia who were treated for 8 days were more likely ures, retrospective analyses of large data sets are needed to guide
to require reevaluation and retreatment in some cases. Similar future prospective studies of this complex topic. Data are spe-
findings in nosocomial pneumonia due to P. aeruginosa and cifically needed regarding whether the assessment of HCAP
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 with-
out response to initial therapy or who develop a pattern of
nonresolving pneumonia should be carefully evaluated to en-
sure that antimicrobial treatment is covering the offending
pathogen, that a noninfectious diagnosis has not been missed,
or that some complicating factor has not occurred.

Grading of Evidence Figure 4. Voting comparison for statement 3 (“The recommended eval-
On the basis of a review of the studies cited previously, the 5 uation of HCAP with treatment failures is the same as that for HAP”).
“Summit members” refers to the 11-member summit panel; “IDSA mem-
members of this workshop agreed that the evidence available bers” refers to the members of the Infectious Diseases Society of America
to support this statement was category V for the statement in who responded to a Web-based survey. HAP, hospital-acquired pneumonia;
general, category IV for the statement as it applies to hospi- HCAP, health care–associated pneumonia.

S306 • CID 2008:46 (Suppl 4) • Kollef et al.


treatment failure should be universal or should vary by subset trials yielded 34 articles, and “Hospital Acquired Pneumonia
(e.g., patients undergoing dialysis, nursing home residents, and failure” in a search for guidelines, meta-analysis, or random-
patients with prior hospitalization). ized, controlled trials yielded 104 articles. After elimination of
duplicates, there were 736 articles. After the search was limited
STATEMENT 4: THE DEFINITIONS ARE THE to articles in English and the titles and abstracts were reviewed,
SAME FOR HCAP AND HAP TREATMENT only 65 manuscripts were relevant. These were reviewed, and
FAILURES 12 studies were selected. References from these articles and
review articles identified 1 additional report, for a total of 13
Rationale and Definition of Statement
studies that were included. Subsequently, after assessment of
Nonresolving pneumonia is a common clinical problem among
what would constitute a “good” functional definition of treat-

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patients with HCAP and patients with HAP. Although quan-
ment failure, 2 of these were eliminated, leaving 11 studies.
tifying the frequency of this problem is difficult, previous stud-
ies reported that ∼15% of pulmonary consultations and 8% of
bronchoscopies were done to evaluate “nonresolving pneu- Evidence
monia” [51]. Treatment failures constitute a subset of all non- As part of the assessment process, the populations of interest
resolving pneumonias. For patients with HCAP and HAP, iden- were carefully defined on the basis of the most recent guidelines.
tifying treatment failure is important because the presence of Articles were included that reported information on treatment
treatment failure implies that, without some type of interven- failures, provided that at least some of the patients studied met
tion, the patient is more likely to have an adverse outcome. the current definitions for having either HAP or HCAP. Most
The most recent ATS-IDSA nosocomial pneumonia guide- studies fell into 1 of 2 categories: for HAP, most studies involved
lines identified a subset of patients at risk for harboring resistant patients with VAP or pneumonia in the ICU; for HCAP, most
organisms despite their residence in the community [3]. The studies involved patients with CAP, in which at least a subset
new guidelines tried to define HCAP as a distinct clinical entity would have met the ATS-IDSA definition for having HCAP.
on the basis of this recognition. An attempt was made to clarify which definitions of treat-
However, the guidelines provide a limited discussion of the ment failure were being compared. However, the ATS-IDSA
definition of treatment failure and nonresolving pneumonia. guidelines are not that specific, and a wide range of definitions
The guidelines do recommend serial assessment of clinical pa- have been used in different studies. Given this ambiguity, it
rameters to define response to initial empirical therapy and was important to identify what would constitute a “good” clin-
review some of those parameters that might be useful in as- ical definition of treatment failure and then to ask whether
sessing response: chest x-ray (CXR film) findings, WBC count, there was a “good” definition applicable to both HCAP and
oxygenation, temperature, CPIS, and culture results. However, HAP.
there are few specifics and limited discussion as to whether the Conceptual framework for assessing definitions of treatment
definition of treatment failure should be the same for HCAP failure. When trying to assess whether a particular definition
and HAP and whether the causes of treatment failure are the of treatment failure is “good,” it is important to recognize the
same in these 2 groups. On the basis of this, the present review clinical context in which the term “treatment failure” will be
aimed to assess the strength of the evidence supporting the used. Often, there is a significant amount of diagnostic uncer-
assertion that the definitions are the same for HCAP and HAP tainty as to whether a given patient even has pneumonia, be-
treatment failures. cause a specific pathogen often cannot be identified. As a result,
when a presumed pneumonia fails to respond to treatment,
Methods one of the first questions is whether the diagnosis of pneumonia
The literature search, conducted in the PubMed database, was is correct, because many conditions can mimic the disease.
completed in November 2006. Because the current definition Therefore, it is more precise to use the term “nonresolving
of HCAP would include some patients previously classified as pneumonia syndrome,” because, in many instances, infection
having CAP, the search was intentionally broad. The search may not be present. Some authors might consider treatment
term “Pneumonia treatment failure” yielded 344 articles. failure to include only those patients with true pneumonia. For
“Health care associated pneumonia treatment failure” yielded the purposes of this review, the more clinically relevant idea of
7 articles, “Health care associated pneumonia failure” yielded a nonresolving pneumonia syndrome will be used, because phy-
94 articles, “Hospital Acquired Pneumonia treatment failure” sicians in practice may not always be certain whether their
yielded 94 articles, and “Hospital Acquired Pneumonia failure” patients have true pneumonia.
yielded 33 articles. “Pneumonia Prediction Outcome” yielded Given the context of high diagnostic uncertainty, another
54 articles. “Health care associated pneumonia failure” in a way to formulate the question is to ask whether there is a set
search for guidelines, meta-analysis, or randomized, controlled of criteria that effectively discriminates between those patients

HCAP Summit Critical Appraisal • CID 2008:46 (Suppl 4) • S307


who are likely to do well with their current treatment regimen A prospective, observational, single-center trial of patients
and those who are likely to have adverse outcomes. These cri- with VAP by Dennessen et al. [47] described the clinical and
teria would need to identify patients with a significant variance microbiological response to treatment, as well as relapses in
from the normal pattern of resolution for both patients with patients with microbiologically confirmed VAP. All patients had
HCAP and patients with HAP, to help guide treatment and adequate initial antibiotic therapy. The investigators measured
management decisions. time to resolution of colony-forming units, WBC count, tem-
Note that, because the definition involves treatment failure, perature, and oxygenation, as measured by the PaO2/FiO2 ratio.
for any definition to be clinically useful, it must use at least 1 Most patients who showed improvement in their clinical and
intermediate outcome measure assessed after treatment is microbiological measures did so within the first 6 days. The

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started. Baseline predictors of outcome that are measured only mean (median) time to complete resolution of all parameters
before initiation of treatment, such as the CPIS, CURB (con- was 9 (8) days. When microbiological parameters were ex-
fusion, urea 17 mmol/L, respiratory rate of ⭓30 breaths/min, cluded, the mean (median) time to complete resolution of clin-
and blood pressure !90 mm Hg systolic or ⭐60 mm Hg di- ical and laboratory parameters was 6 (6) days. The only co-
astolic), or Acute Physiology and Chronic Health Evaluation variate of resolution that reached statistical significance was
(APACHE) scores at admission, would not qualify, because they oxygenation, as measured by the PaO2/FiO2ratio (P ! .01 ). Six
cannot show whether the treatment is actually working. These patients developed a second episode of VAP; 3 had relapses of
would be prognostic measures but would not, by themselves, illness caused by the original pathogen, whereas the other 3
constitute markers of treatment failure. Note that results of had superinfection with new pathogens, all 3 of which were
serial testing with these same instruments, such as the devel- Pseudomonas species. The study was too small to demonstrate
opment of a worsening CPIS, would constitute a potential def- a difference based on pathogens or between survivors and
inition of treatment failure because it measures how well the nonsurvivors.
patient responds to treatment. Therefore, a “good” definition Another study of 63 patients with microbiologically con-
of treatment failure would need to integrate at least some in- firmed VAP evaluated the utility of the CPIS as a predictor of
termediate outcome data obtained after initiation of treatment. response [39]. CPIS was evaluated at days ⫺3, 0, 3, 5, and 7.
This idea of intermediate outcomes is also relevant when The mortality rate was 51% (32 of 63 patients). A decrease in
looking at mortality. Death is frequently used as a definition CPIS after initiation of treatment was associated with signifi-
of treatment failure. Note that death, while being the ultimate cantly lower mortality rate (P p .018 for patients with a CPIS
epidemiologic measure of treatment failure, does not constitute !6 at 3 or 5 days after onset of VAP, vs. those with a CPIS 16).
a clinically useful definition of treatment failure, because it Of the components of the CPIS, only oxygenation, as measured
precludes any corrective action being taken. Indeed, clinical by the PaO2/FiO2 ratio, was able to distinguish survivors from
definitions of treatment failure are really aimed at predicting nonsurvivors. This was consistent with the finding that, among
the likelihood of death or permanent disability, because the patients subsequently found to have received adequate initial
hidden premise in constructing “good” clinical definitions of antibiotic therapy (defined as the identified pathogen being
treatment failure is that they must allow clinicians the oppor- susceptible to the initial antibiotics prescribed), PaO2 improved
tunity to intervene to potentially alter the course of disease. from day 0 to 3, whereas those receiving inadequate initial
Therefore, clinically useful definitions of treatment failure will antibiotic therapy had worsening oxygenation. Thus, in this
require measures that occur after the initiation of treatment study, serial measures of CPIS and oxygenation were able to
but before death, so that intervention is possible. Finally, good identify patients more likely to have an adverse outcome.
definitions would ideally need to be readily available in everyday A similar study of 63 patients with VAP evaluated the ability
clinical practice, affordable, and highly reproducible between of the APACHE II, Sepsis-related Organ Failure Assessment
centers. (SOFA), and CPIS to predict mortality [56]. The mean
Studies of HAP. Given this conceptual framework, studies APACHE II, SOFA, and CPIS scores all were higher at the time
were categorized on the basis of sample size, patient population, of VAP diagnosis in survivors than in nonsurvivors (P p
the definition of pneumonia used for entry, the definition of .001, .002, and .025, respectively). However, there was no mea-
treatment failure used, the treatment failure rate reported, and surement of APACHE II, SOFA, or CPIS subsequent to the
the causes of treatment failure reported (table 3). Most studies initiation of treatment for VAP. Therefore, although these scores
could not meet all of the criteria of a good definition of treat- were good prognostic markers, they were not considered to
ment failure, but any study that provided insight into any of provide clinically useful definitions of treatment failure.
these categories was eligible. The definitions of treatment failure A prospective, multicenter, observational study of ICU-ac-
were analyzed, and only definitions that might have at least 1 quired pneumonia evaluated the causes of nonresponse to treat-
intermediate outcome were included. ment in 71 patients [52]. Pneumonia was defined as the pres-

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Table 3. Studies of pneumonia treatment failure that included patients meeting the definition of having hospital-acquired pneumonia (HAP).

Treatment failures or Definition of treatment failure or


Study Patients, no. Population recurrences, no. (%) recurrence Comments
Dennesen et al. 2001 [47] 27 VAP 6 (22) Microbiological evidence of relapse Oxygenation (PaO2/FiO2) associated with relapse risk; recurrent
pneumonias: superinfection, n p 3; relapse, n p 3
Luna et al. 2003 [39] 63 VAP NR CPIS and PaO2/FiO2 Predictors of death: CPIS and PaO2/FiO2 on day 3
Ioanas et al. 2004 [52] 71 ICU pneumonia 44 (62) Oxygenation, fever, CXR film, shock Mortality rate 50%, vs. 7% for treatment failures
Combes et al. 2003 [53] 103 VAP 28 (27) Recurrent pneumonia defined by Recurrent pneumonias: superinfections, n p 17; relapse, n p
CXR film, purulent secretions, 11
and BAL
Combes et al. 2007 [54] 401 VAP 110 (27) 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
Wolff 1998 [55] 400 ICU pneumonia 73 (18) Persistence pneumonia 3.8% with noninfectious etiology of pneumonia; no clear re-
27 (7) Superinfection porting on mortality linkage for treatment failure definitions

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, ventilator-
associated pneumonia.

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ence of a new or progressive infiltrate with at least 2 of the likely to have an adverse outcome was the organ failure score
following 3 criteria: leukocytosis, fever, and purulent sputum. on day 8.
Not all cases of pneumonia were microbiologically confirmed. A prospective, randomized, controlled trial comparing 2 dif-
Nonresponse was defined as ⭓1 of the following occurring 72 ferent drug regimens for empirical treatment of pneumonia in
h after treatment: (1) failure to improve oxygenation or in- 400 patients in the ICU [55] provided data on treatment failures
tubation 24 h after initiation of antibiotic therapy plus purulent as well. Clinical failures in this trial were defined as either
respiratory secretions; (2) persistent fever or hypothermia; (3) persistence or progression of symptoms leading to a change of
worsening radiographic infiltrates; or (4) occurrence of septic antibiotics, a worsening CXR film finding leading to a change
shock or multiple organ system failure not present on day 1. of antibiotics, superinfection, or death. A nonbacterial origin
of the pneumonia was identified in 3.8% of the patients. In

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Nonresponse occurred in 44 (62%) of patients. This definition
of nonresponse was associated with a significantly increased the clinical efficacy analysis, 73 patients (18%) had persistent
risk of hospital mortality (50% vs. 7%; P ! .001). Possible causes pneumonia. Superinfection occurred in 27 patients, resulting
of nonresponse could be identified in 28 of the 44 patients in the death of 6 patients. There were 277 patients evaluable
without response, with 8 of these 28 patients having 11 cause. for bacteriologic efficacy analysis; of these, 223 had HAP. Death
Causes of nonresponse included noninfectious causes (7), su- occurred in 113 (28%) of 399 patients receiving the study drug.
perinfection (6), inadequate initial treatment (10), and con- There was no clear linkage between any intermediate outcome
comitant foci of infection (13). and mortality reported.
A prospective observational study of VAP evaluated factors Studies of populations that included patients with HCAP.
associated with the recurrence of VAP among 103 patients who By use of the same conceptual framework, studies were cate-
survived VAP for 8 days [53]. VAP and recurrent VAP were gorized that included at least a significant proportion of patients
defined by CXR film findings, purulent secretions, and BAL with HCAP on the basis of the same criteria of sample size,
findings. Predictors of recurrence were measured at the time patient population studied, definition of pneumonia used for
of the initial bronchoscopy and on day 8 of VAP. Recurrence entry, definition of treatment failure used, treatment failure rate
was identified in 28 patients (27%) at a mean of 21 days after reported, and causes of treatment failure reported (table 4).
the initial episode of VAP. Causes of recurrent VAP included Most studies could not meet all of the criteria for a good
relapse (same organism) in 11 patients and superinfections in definition of treatment failure, and many studies were primarily
17 patients. Multivariable analysis identified a day 1 radiology of CAP. However, any study that provided insight into any of
score 17, a day 8 temperature 138C, and acute respiratory these categories was eligible. The definitions of treatment failure
distress syndrome (ARDS) on day 8 as risk factors for subse- were analyzed, and only definitions that might have at least 1
quent recurrence of VAP. However, no data were available to intermediate outcome were included.
determine whether the presence of these factors on day 8 dif- A prospective observational study of patients hospitalized for
ferentiated survivors from nonsurvivors; this was not consid- CAP included a significant number of patients with neoplasia
ered to be evidence that these markers could be used clinically and immunosuppression and, therefore, was included [57].
as definitions of treatment failure. CAP was defined as an acute illness with a new or progressive
A prospective, randomized, controlled trial [48] comparing infiltrate on chest radiograph associated with ⭓1 of the fol-
8 versus 15 days of therapy for VAP provided the data necessary lowing respiratory signs or symptoms: fever (temperature,
for a nested observational cohort trial evaluating predictors of 138C), a new cough, purulent sputum production, new dysp-
infection recurrence and death in patients with VAP [54]. Of nea and/or tachypnea (120 breaths/min), pleuritic pain and
401 patients with microbiologically confirmed VAP in the study, leukocytosis (110 ⫻ 10 9 cells/L) or leukopenia (!4 ⫻ 10 9 cells/
110 (27%) developed recurrent infections, some of which were L), or 110% band forms if the leukocyte count was between
polymicrobial. Relapse with the same pathogen occurred in 56 4 ⫻ 10 9 cells/L and 10 ⫻ 10 9 cells/L. A total of 224 of 228 pa-
patients (14%), and superinfection occurred in 77 patients tients were evaluable and completed follow-up. Eight patients
(19%). Predictors of VAP recurrence measured on day 8 after developed antibiotic adverse effects, but these were not con-
VAP onset included SAPS II admission score; radiology score; sidered to be treatment failures; 54 patients (24%) had treat-
temperature; gram-negative, nonfermenting pathogens; or ment failure. The study defined treatment failure as at least 1
MRSA. VAP recurrence was not associated with 28-day mor- of the following: fever for 13 days (or for 16 days if bacteremic),
tality (17% mortality rate for those with recurrence, vs. 18% clinical deterioration necessitating a change in antibiotics, or
for those without recurrence; P p .88 ). Only sex, age, day 8 death after at least 48 h of antibiotic therapy. Fourteen patients
SOFA score, and gram-negative nonfermenting pathogens were (26%) died. The most common causes of treatment failure were
predictive of 28-day mortality. Therefore, in this study, the only host factors in 34 patients (63%), unusual pathogens in 10
intermediate outcome measure able to identify those more patients (19%), superinfection in 4 patients (7%), incorrect

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Table 4. Studies of pneumonia treatment failure that included some patients meeting the definition of having health care–associated pneumonia (HCAP).

Treatment failure
Patients, or recurrence
Study no. Population rate, % Definition Causes and comments
Genne et al. 2006 [57] 224 CAP 24 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 antibi- 3 (6%)
otic change, or death after 48 h
of antibiotic therapy
Arancibia et al. 2000 [58] 444 CAP 11 Fever, clinical deterioration, CXR film Nonresponding, 61%; progressive, 39%; only HAP related to mortality, persis-
tent infections due to resistance
El-Solh et al. 2001 [27] 104 CAP and NHAP NR None used The only intermediate outcome correlated with mortality was 24-h urine output
Rosón et al. 2004 [42] 1383 CAP 6 Early fever, hemodynamics, respira- Progressive pneumonia, 67%; empyema, 22%; failure associated with
tory, CXR film increased mortality
Genne et al. 2003 [59] 3048 CAP 11 Fever, clinical deterioration, antibi- Causes of failure: unknown, 82%; resistant, 8%; superinfection, 2%
otic change, resistant pathogen

NOTE. CAP, community-acquired pneumonia; CXR, chest x-ray; HAP, hospital-acquired pneumonia; NHAP, nursing home–associated pneumonia; NR, not reported.

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drug dosing or compliance in 3 patients (6%), and incorrect common. Early failure was associated with higher complication
diagnosis of pneumonia in 3 patients (6%). rates (P ! .001), increased hospital length of stay, and increased
A prospective, observational, single-center study of treatment mortality (27% vs. 4%; P ! .001).
failure in CAP was included because of a high percentage of A meta-analysis of 16 studies evaluating the causes of treat-
cases with malignancy, renal disease, or prior outpatient anti- ment failure in clinical trials of CAP was included [59]. There
biotic therapy [58]. Treatment failures were defined as either was no stratification with regard to the patient populations
nonresponding pneumonias (defined as persistent fever with a involved, although analysis of the individual studies demon-
temperature 138C and/or clinical symptoms [malaise, cough, strated that some patients with HCAP would have been in-
expectoration, dyspnea] after at least 72 h of antimicrobial cluded on the basis of prior antibiotic therapy and comorbid-
ities. In this meta-analysis, 6 different definitions of treatment

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treatment) or progressive pneumonias (defined as clinical de-
terioration in terms of the development of acute respiratory failure were used, one of which was death; another was dis-
failure requiring ventilatory support and/or septic shock after continuation for personal reasons. Persistent fever 172 h after
at least 72 h of antimicrobial therapy). During the study, there antibiotic therapy, clinical deterioration requiring admission to
were 444 patients with CAP, of whom 49 were identified as an ICU or requiring vasopressors, change of antibiotic therapy
experiencing treatment failure (11%). Of these 49 patients, 30 for any cause, and resistant pathogens with worsening symp-
(61%) were patients without treatment response, and 19 (39%) toms constituted the other 4 definitions of treatment failure
had progressive pneumonia. A definite etiology of treatment used. There was significant heterogeneity in terms of failure
failure could be established in 32 (65%) of the 49 patients. rates reported (range, 0%–34%; P p .008 ). When adverse ef-
Etiologies comprised primary infections (n p 8 ), definite per- fects of medications were excluded, treatment failures occurred
sistent infection (n p 4), nosocomial infection (n p 8), non- in 333 patients (16%). In the majority of cases (82%), no cause
infectious causes (n p 8), and combinations of the above could be identified. Resistant pathogens were the most common
(n p 4). Those classified as having nonresponding pneumonia identified cause (n p 28; 8%). Superinfection occurred in only
were more likely to have persistent infections (14 of 30) than 7 patients (2%). There was no stratification based on HCAP
nosocomial infections (2 of 30). Those classified as having pro- risk factors, and no evaluation of the relationship between treat-
gressive pneumonia were less likely to have persistent infections ment failure and mortality risk could be made.
(4 of 19) and more likely to have nosocomial infections (6 of
19). Among those with treatment failure, only nosocomial Grading of Evidence
pneumonia was associated with mortality in multivariate anal- On the basis of a review of these 11 studies, the 5 members of
ysis. However, there was no comparison reported between those this workshop agreed that the evidence available to support
who developed treatment failures and those who did not, in this statement was category IV for the statement in general,
terms of their mortality risk. category V for the statement as it applies to hospitalized patients
A prospective observational study of severe pneumonia in with HCAP, and category V for the statement as it applies to
very elderly individuals was included because 47 of the 104 nonhospitalized patients with HCAP (table 2).
patients enrolled were nursing home residents [27]. The pri-
mary objective was to evaluate the prevalence of pathogens in Level of Support
this population and its impact on morbidity and functional When voting on the support for this statement, 9% of the
status. No specific definition of treatment failure was used. In summit participants voted to accept the statement completely,
multivariate analysis, only 4 variables were predictive of mor- 36% voted to accept the statement with some reservations, 46%
tality: multilobar involvement, septic shock at presentation, in- voted to accept the statement with major reservations, and 9%
adequate antimicrobial therapy, and 24-h urine output. voted to reject the statement with reservations. In comparison,
A prospective, single-center, observational study of early of the 383 IDSA members who participated in the online survey,
treatment failures in patients hospitalized for CAP had a small 47% voted to accept the statement completely, 42% voted to
percentage of patients with either malignancy, renal failure, or accept the statement with some reservations, 7% voted to accept
nursing home residence [42]. Early failures were defined as lack the statement with major reservations, 3% voted to reject the
of response or worsening of clinical or radiographic status at statement with reservations, and 1% rejected the statement
48–72 h, requiring changes in antibiotic therapy or invasive completely (figure 5).
procedures. Early failure occurred in 81 (6%) of 1383 patients.
The most common causes were progression of pneumonia Discussion
(67%) and empyema (22%). Superinfection occurred in only At present, there is limited conclusive evidence supporting this
3 cases (4%). Among patients with an identified pathogen, statement, as is reflected in the summit participants’ grading
initial antibiotics that did not cover the pathogen were more of the evidence. Because the recognition and classification of

S312 • CID 2008:46 (Suppl 4) • Kollef et al.


• 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 pri-

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Figure 5. Voting comparison for statement 4 (“The definitions are the
same for HCAP and HAP treatment failures”). “Summit members” refers mary infection is certain, because in clinical practice this is
to the 11-member summit panel; “IDSA members” refers to the members often not the case
of the Infectious Diseases Society of America who responded to a Web- • Include proof that definitions of treatment failure are pre-
based survey. HAP, hospital-acquired pneumonia; HCAP, health care–as- dictive of future adverse outcomes of interest
sociated pneumonia.

Future Directions
HCAP is new, none of the studies cited specifically evaluated
Future directions discussed by the summit members focused
patients with HCAP exclusively. Additionally, the lack of a stan-
on the limitations of the previously discussed studies. Appro-
dardized definition of treatment failure makes conclusive state-
priately designed epidemiologic studies are clearly needed to
ments regarding treatment failure problematic. Furthermore,
better delineate the causes of treatment failure in CAP, HAP,
the existing literature did not report stratified analyses for the
and HCAP. Careful consideration and construction of clinically
HCAP and HAP populations; therefore, any conclusions should
useful definitions of treatment failure should be done before
be viewed as preliminary.
these studies are performed, so that clinically useful recom-
Given these limitations, this systematic assessment of treat-
mendations can be made. Once standardized definitions can
ment failure definitions and their relationship to mortality in
be validated, trends in treatment failure can be followed lon-
HAP and HCAP raises interesting questions and preliminary
gitudinally to assess changes in treatment failure rates and
observations. First, because of differences in study design, in-
causes over time.
clusion criteria, populations studied, and definitions used, there
is significant heterogeneity in terms of treatment failure rates
STATEMENT 5: SEVERE CAP IS NOT HCAP
both within and between groups. Although it appears that treat-
ment failure rates are higher among patients with HAP than Rationale and Definition of Statement
among patients with HCAP, because of the lack of a stratified Over the past decade, there has been an increase in infections
analysis, this is not necessarily the case. HCAP may fall some- due to MDR pathogens in individuals referred to acute-care
where between HAP and CAP in terms of treatment failure hospitals who have been previously hospitalized, have received
rates. However, a properly stratified analysis needs to be per- broad-spectrum antibiotics, or reside in nursing homes or other
formed before more-specific conclusions can be drawn, and long-term-care facilities [2, 3, 13, 16, 23, 60]. These individuals
clinically useful definitions need to be standardized. may need different empirical antibiotics for pneumonia, to
One consistent finding was that superinfection appeared to avoid delays in receiving appropriate antibiotic therapy. Such
be more of a problem in patients with HAP than in the CAP/ delays have been shown to result in poorer outcomes from
HCAP population reviewed. Unusual or resistant pathogens serious infections [2, 3, 61–63].
were more of a problem in the latter group. This is probably HCAP, as defined in the 2005 ATS-IDSA guidelines, includes
a result of differences in infection control and exposure, an- pneumonia in patients referred to hospitals for evaluation and
tibiotic use, and host factors. However, this finding should be treatment who were more likely to be colonized or infected
viewed with caution when HAP and HCAP are compared, ow- with MDR pathogens [3]. Risk factors for different MDR path-
ing to the lack of properly stratified data analysis. ogens are variable and complex; these factors may include pre-
Finally, this review demonstrates the importance of con- vious hospitalization, prior antibiotic therapy, chemotherapy,
structing sound and clinically useful definitions before ap- hemodialysis, wound therapy, and residence in nursing homes
proaching complex problems. Whether the same or different and long-term-care facilities, either alone or in combination.
definitions of treatment failure are used for HAP and HCAP Fewer data are available on these patients managed in non–
does not matter if the definitions are not valid and clinically acute-care settings where presentations, clinical data, and ther-
useful. At a minimum, a “good” definition of treatment failure apy are more limited [64, 65].
should do the following: Principles for the treatment of patients with HCAP referred

HCAP Summit Critical Appraisal • CID 2008:46 (Suppl 4) • S313


to acute-care hospitals and clinics share more similarities in monia” or “health care associated pneumonia” or “healthcare”
etiology and management with those for HAP and VAP than yielded 24 articles. When the 3 searches above were combined
with those for CAP (figure 2) [3, 23]. Thus, broader-spectrum, with the “OR” function, there were a total of 2509 articles.
empirical antibiotic therapy has been suggested to be aimed at Fewer articles were identified using English as the only lan-
MDR pathogens, such as P. aeruginosa, Klebsiella pneumoniae guage. Eighteen articles were deemed pertinent to this review.
producing extended-spectrum b-lactamases (ESBLs), or MRSA.
The principles of the 2005 ATS-IDSA guidelines were aimed at Evidence: What is Severe CAP?
appropriate, initial antibiotic therapy regardless of disease se- CAP, like HCAP, has varying degrees of severity and may be
verity. In addition, de-escalation of antibiotics was recom- caused by a wide spectrum of bacterial, atypical, or viral path-

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mended for patients with treatment response, on the basis of ogens [70]. Patients with severe CAP are often evaluated in
the availability of microbiological cultures, clinical response, EDs before hospital admission, and patients with severe CAP
and reducing duration of antibiotic therapy to 7–8 days. often require admission to the ICU as a result of shock, ARDS,
There are many definitions of severe CAP, and several scoring or multiple-organ failure requiring mechanical ventilation.
systems have been used for assessing CAP severity and the need These patients represent a subset of patients with higher mor-
for hospital admission or intensive care [66–69]. Patients with bidity, mortality, and length of stay in the hospital and ICU.
severe CAP or severe HCAP may need intensive care or me- Microbiology of severe CAP. Severe CAP may be caused
chanical ventilation or may have pneumonia complicated by by several pathogens, including S. pneumoniae, H. influenzae,
sepsis, shock, bacteremia, or multiple-organ failure. These as- and anaerobic bacteria that typically are not MDR strains [70].
sessments, often performed in the ED or clinic for patients with Even in CAP caused by S. aureus or gram-negative bacteria,
CAP, should also apply to patients with HCAP. such as K. pneumoniae, the pathogen is usually not MDR if
This section examines the hypothesis that “severe CAP is not the patient has not had prior antibiotic therapy or close contact
HCAP” in the acute-care setting. Clearly, definitions are key, with the health care system. Atypical pathogens, such as Chla-
and applications to all types of patients are difficult. For ex- mydophila pneumoniae, Mycoplasma pneumoniae, and L.
ample, HCAP management in the acute-care setting is better pneumophila, are common in the United States. Coinfection
defined than management in nursing homes and other types with these bacteria occurs, and, in contrast to HCAP, the path-
of long-term-care facilities. ogens are not MDR or necessarily associated with prior anti-
biotic use or contact with the health care system. In addition,
Methods although CAP is more likely to be caused by bacteria, influenza
Severe CAP. A search of PubMed was performed for severe viruses, respiratory syncytial viruses, and adenoviruses are also
CAP on 14 November 2006. The search term “community important. Patient risk factors for CAP include underlying
acquired infections” (4552) was combined with the search term medical diseases, such as chronic lung disease; exposure to
“pneumonia” (54,650) and then was combined with the “AND” animals; risk of aspiration; exposure to other infected persons;
function for a total of 2562 articles. A search for articles with or seasonal epidemics.
the text words “severe CAP” or “SCAP” yielded 248 articles. In a review of severe CAP by Ewig and Torres [71], microbial
A search for articles with the text words “severe community patterns in Barcelona, Spain; Lille, France; and South Africa
acquired pneumonia” yielded 225 articles, and that combined were examined. Rates of isolation of S. pneumoniae were 15%,
with the “OR” function yielded a total of 420 articles. The 2 27%, and 29%, respectively; those of K. pneumoniae were 2%,
searches above combined with the “AND” function yielded 194 2%, and 19%, respectively; and those of S. aureus were 0%,
articles. A search for articles with the text words “severe com- 19%, and 3%, respectively. A review of etiologic agents iden-
munity acquired pneumonia” yielded 200 articles, and, com- tified in 16 studies of severe CAP found that rates of S. pneu-
bined with the “OR” function, the above result yielded 194 moniae ranged from 12% to 38%, rates of H. influenzae from
articles, for a total of 250 articles. No abstracts were included. 0% to 13%, rates of enteric gram-negative bacilli from 0% to
HCAP. A literature search of PubMed was performed on 34%, rates of S. aureus and other Staphylococcus species from
14 November 2006. The search term “cross infection” yielded 0% to 15%, rates of P. aeruginosa from 0% to 5%, and rates
31,350 articles. The term “pneumonia” generated 54,650 ar- of L. pneumophila from 0% to 30%. Unfortunately, these dif-
ticles. When the term “pneumonia” was combined with the ferences represent the diversity of patient populations studied
“AND” function, there were 24,096 articles noted. The text and different time periods but do not address MDR pathogens.
words “healthcare associated” or “health care associated” The study includes some patients who would now be classified
yielded 331 articles. The search term “pneumonia” yielded as having HCAP because of their risk for infection with MDR
54,650 articles and, when combined with the term “HCAP,” pathogens. A later study by Rello et al. [72] in Barcelona, Spain,
yielded 23 articles. The text words “healthcare associated pneu- compared the microbiological assessments of 106 patients with

S314 • CID 2008:46 (Suppl 4) • Kollef et al.


severe CAP requiring mechanical ventilation with 98 patients tients evaluated in the ED who had CAP as well as HCAP, and,
with CAP who were not receiving ventilation. A microbiological thus, these assessments should also apply to those with HCAP.
diagnosis was made in 57.3% of patients, and the most common The PSI is widely used as a benchmark for assessing the need
bacterial pathogens were S. pneumoniae, L. pneumophila, and for hospital admission and risk of mortality. Because the PSI
H. influenzae. P. aeruginosa (6.6% vs. 1.0%; P ! .05) and L. requires 20 variables, it is labor intensive, difficult for clinical
pneumoniae (15.1% vs. 7.1%; P ! .05) infections were more assessment in the ED, not a good predictor for ICU admission,
common in intubated patients than in nonintubated patients. and heavily weighted by age. Therefore, it may underestimate
Overall mortality was 44.3% in intubated patients, versus 23.5% severe CAP in younger patients and is limited for identifying
overall. Of note, bacteriologic investigation led to changes in patients eligible for activated protein C therapy. As a result,

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antibiotic therapy in 41.6% of patients, including 11 patients other scoring systems have been evaluated.
(5%) in whom initial treatment was ineffective. A more recent approach using a modified PSI score was
Definitions of severe CAP. Several methods have been de- suggested by Espana et al. [73], who evaluated 1057 patients
signed to assess CAP severity to determine the need for hospital for CAP in an ED; 11.5% of patients were admitted to the
admission or triage to intensive care and to identify those with hospital, 3% were admitted to the ICU, 2.3% had shock, and
a higher risk of death [67–69, 73, 74]. Severe CAP is indepen- 1.5% underwent mechanical ventilation. Overall mortality was
9.1%. Severe CAP was defined as a score of 110 points for 2
dent of the source of the pathogen or risk for infection with
major criteria, pH !7.3 (13 points) and systolic blood pressure
an MDR pathogen and may occur in patients with CAP or
!90 mm Hg (11 points), and for 6 minor criteria: respiratory
HCAP.
rate 130 breaths/min (9 points), blood urea nitrogen (BUN)
Because severe CAP has many definitions, a universally ac-
level 130 mg/dL (5 points), change in mental status (5 points),
cepted one does not exist. Several investigations have suggested
PaO2/FiO2 (5 points), age 180 years (5 points), and multiple
methods of identifying patients with severe CAP who should
bilateral infiltrates (5 points). Of note, the scores 120 points
be admitted to the hospital or ICU, those at risk for respiratory
were better predictors of severe CAP.
or multiple-organ failure, and those with a greater risk of mor-
Another scoring system for stratifying the severity of CAP is
tality [68–70]. Ewig et al. [68] defined severe CAP as CAP
the CURB-65, which awards 1 point each for confusion, urea
requiring admission to the ICU. Of the 64 (16%) admitted
concentration 17 nmol/L, respiratory rate ⭓30 breaths/min,
patients with severe CAP who were followed prospectively, the
low blood pressure, and age ⭓65 years [74]. Those with 3 points
mortality rate was 30%, versus 5% for those not admitted. The
have been found to have a mortality rate of 21%, those with
10 criteria for severe CAP, initially defined by the ATS, include
4 points a mortality rate of 42%, and those with 5 points a
respiratory rate 130 breaths/min, PaO2/FiO2 !250, bilateral in-
mortality rate of 60% [74]. This scoring system also correlated
volvement on chest radiograph, multilobar involvement, sys-
with the need for mechanical ventilation, length of stay, and
tolic blood pressure !90 mm Hg, diastolic blood pressure !60 PSI score. Because the blood urea concentration is often not
mm Hg, mechanical ventilation, progressive infiltrates, septic readily available, it was omitted, and the CRB-65 was suggested;
shock, and renal failure. Although the ATS criteria demon- it was easier to apply in the ED. Mortality rates for the CRB-
strated good sensitivity (98%) but low specificity (32%), the 65 correlated well with those for the CURB-65 and were 19%
positive predictive value was low (24%). Therefore, a modified for patients with 2 points, 44% for those with 3 points, and
ATS score (mATS) was suggested, in which 2 or 3 “minor” 55% for those with 4 points. Advantages of these methods of
baseline criteria (systolic blood pressure !90 mm Hg, multi- scoring include simplified calculation, clear admission criteria
lobar involvement, and PaO2/FiO2 !250) and 2 “major” criteria for those with ⭓2 points, good correlation with both mortality
(mechanical ventilation and presence of septic shock) dem- and the need for ICU admission for those with ⭓2 points, a
onstrated a sensitivity of 78%, a specificity of 94%, a positive good predictor of CAP mortality due to bacteremia, and a good
predictive value of 75%, and a negative predictive value for predictor of those in need of activated protein C therapy [67].
mortality of 95% [68]. Data on the use of these scoring systems (PSI-V; PSI-IV,V;
Fine et al. [69] developed the PSI derived from a large da- CURB-65 ⭓3; and the mATS score for assessing ICU admission
tabase that used points assigned for age, underlying disease, and mortality) are shown in table 5 [66]. Note that, for assessing
physical findings, and laboratory data to identify patients who ICU admission, sensitivity ranged from 48% to 92%, specificity
required admission to the hospital and those at risk for death. ranged from 45% to 87%, the positive predictive value ranged
Of the risk groups (I–V), patients with the highest PSI scores from 10% to 33%, and the negative predictive value ranged
(190) in risk groups IV and V were considered to have “severe from 95% to 99%. Better results were identified for assessing
CAP” and had the highest mortality (8% and 29%, respec- mortality.
tively). It is important to note that these studies included pa- There is great heterogeneity of patient populations, defini-

HCAP Summit Critical Appraisal • CID 2008:46 (Suppl 4) • S315


Table 5. Outcomes of severe community-acquired pneumonia in an approach that includes assessment, empirical antibiotic ther-
terms of mortality and intensive care unit (ICU) admission. apy based on a clinical suspicion of HCAP, and subsequent
monitoring of response to therapy [64, 65, 75].
Positive Negative
The reason for identifying patients with HCAP versus CAP
Outcome, severity predictive predictive
scoring system Sensitivity Specificity value value was based on increasing rates of exposure to and colonization
Death
with MDR pathogens in patients with a greater risk of under-
PSI-V 68 82 28 96 lying disease and prior exposure to antibiotics that could in-
PSI-IV,V 97 48 16 99 crease the risk of receiving inappropriate empirical antibiotic
CURB-65⭓ 3 81 68 21 97 therapy and having poorer outcomes (table 7) [3]. The use of
broader initial antibiotic coverage for MDR pathogens was cou-

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mATS Score 41 85 22 93
ICU care pled with an emphasis on de-escalating and reducing the du-
PSI-V 48 79 14 96 ration of antibiotic therapy for HCAP, HAP, and VAP (figure
PSI IV,V 84 45 10 98 6). If, indeed, broader initial empirical antibiotic therapy was
CURB-65⭓ 3 58 65 10 96 appropriate for MDR pathogens, then de-escalation of the ini-
mATS Score 92 87 33 99
tial therapy was based on the response of the patients and the
NOTE. Data are percentages and are from [66]. PSI, pneumonia severity availability of microbiological data within 24–48 h.
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
If there were no risk factors for infection with MDR path-
⭓65 years; mATS, modified American Thoracic Society. ogens, 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
tions, etiologic agents, and clinical assessments for severe CAP.
pathogens.
Is severe CAP best defined as admission to the ICU, the need
No recommendations were made in the ATS-IDSA guidelines
for mechanical ventilation, or a poor score as defined by PSI,
for altering empirical antibiotic coverage for HCAP on the basis
CURB-65, CRB-65, or modified PSI? Admission to the ICU
of disease severity [3]. Furthermore, the focus of these rec-
varies between hospitals, as does the need for mechanical ven-
ommendations was on patients referred to acute-care hospitals
tilation, methods of diagnosis, and etiologic agents. In addition,
for evaluation. The resources for the evaluation and manage-
there is no assessment for MDR pathogens in patients with
ment of severe CAP may be limited in some nursing homes
severe CAP similar to HCAP, and there is no assessment for
or long-term-care facilities. Thus, the question arises as to
patients in nursing homes or patients receiving long-term care
whether and how the ATS/IDSA guidelines for HCAP apply to
or who have the use of prior antibiotics as a risk factor.
management in nursing homes and long-term-care facilities.
Many studies defining severe CAP lack validation and have
Options for management would include collecting data for doc-
small study populations and variable study definitions, as well
umenting the presence of HCAP, initiating empirical antibiotic
as variable populations and risks for infection and mortality.
therapy, and assessing the clinical response to therapy on site
In addition, data for severe CAP may be confounded by the
or making a referral if HCAP becomes severe. If there is no
presence of sepsis.
clinical improvement or progression while receiving the initial

Evidence: What is HCAP?


Table 6. Risk factors for infection with multidrug-resistant
According to the ATS-IDSA guidelines, patients with HCAP (MDR) pathogens.
are a subset of patients who present to the hospital with pneu-
monia and are at greater risk of colonization and infection with Antimicrobial therapy in preceding 90 days
MDR pathogens (figure 2) [3]. Previously, many of these pa- Current hospitalization of at least 5 days
tients who presented to acute-care facilities for evaluation of High frequency of antibiotic resistance in the community or in
the specific hospital unit
lower-respiratory-tract infections were considered to have CAP.
Presence of risk factors for health care–associated pneumonia:
Risk factors for infection with MDR pathogens identified in
Hospitalization for at least 2 days in the preceding 90 days
the ATS-IDSA guidelines are summarized in table 6. MDR and
Residence in a nursing home or extended-care facility
non-MDR pathogens of concern include MRSA, P. aeruginosa, Home infusion therapy (including antibiotics)
Acinetobacter baumannii, and ESBL-producing gram-negative Long-term dialysis within 30 days
bacilli, such as E. coli, K. pneumoniae, and Enterobacter species Home wound care
(table 7). Patients with HCAP managed in nursing homes or Family member with infection involving MDR pathogen
residential facilities, which may have limited resources for eval- Immunosuppressive disease and/or therapy
uation and treatment of pneumonia, may need a referral to NOTE. Adapted from [3], with permission from the American Thoracic
another facility. These nonhospital settings also could employ Society, and from [13].

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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 Ceftriaxone plus azithromycin
Streptococcus pneumoniae or
a
Haemophilus influenzae levofloxacin, moxifloxacin, gatifloxacin, gemifloxacin
Anaerobes
Non–ESBL+ gram-negative rods
MDR Antipseudomonal cephalosporin (cefepime, ceftazidime)

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Pseudomonas aeruginosa or
Acinetobacter speciesa Antipseudomonal carbapenem (imipenem or
ESBL+ gram-negative rodsa (Klebsiella pneumoniae, Escherichia coli, meropenem)
or Enterobacter species) or
MRSA Antipseudomonal penicillin (piperacillin-tazobactam)
Legionella pneumophilac plus
Antipseudomonal fluoroquinolone (ciprofloxacin or
levofloxacin)
or
Aminoglycoside (gentamicin, tobramycin, amikacin)
plus
linezolid or vancomycinb

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.
b
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.

antibiotic regimen in the long-term-care setting, the patient to support this statement was category III for the statement in
would then be eligible for referral to an acute-care hospital or general, category III for the statement as it applies to hospi-
clinic for evaluation (figure 7). talized patients with HCAP, and category V for the statement
Community-acquired MRSA was first seen in the 1990s in as it applies to nonhospitalized patients with HCAP (table 2).
children and more recently has occurred in adults [76]. This
strain is distinct from the hospital MRSA associated with HAP, Level of Support
VAP, and HCAP, because it has a mec IV gene and the Panton- When voting on the support for this statement, 91% of the
Valentine leukocidin gene, which may account, in part, for its
summit members and 83% of the IDSA members who re-
increased virulence and predisposition to abscess formation and
sponded to the survey accepted it completely; it was accepted
severe pneumonia. Outbreaks have occurred in nursing homes
with some reservations by 9% of the summit members and
and long-term-care facilities and have now been identified in
13% of the IDSA members. One percent of IDSA members
hospitals. In comparison with hospital-acquired MRSA, com-
accepted the statement with major reservations, 2% rejected
munity-acquired MRSA is more sensitive to antibiotics such as
the statement with reservations, and 1% rejected it completely
ciprofloxacin and clindamycin.
(figure 8).
HCAP questions of concern. Several questions need atten-
tion. Can and should severe HCAP be managed in nursing
homes or long-term-care facilities? Do the HCAP time lines Discussion
for prior antibiotic use and prior hospitalization apply to man- The management of pneumonia is dynamic, and the evolution
agement, or do they need to be altered? Are the HCAP defi- of MDR pathogens in community and health care settings will
nitions accurate? Should the severity of disease alter initial an- require frequent refining and careful monitoring. The statement
tibiotic management for patients with HCAP? How does the that severe CAP is not HCAP is based on multiple factors,
rapid evolution of community-acquired MRSA in nursing including the lack of a consensus on the definitions of severe
homes, long-term-care facilities, and hospitals alter the HCAP CAP, the clinical heterogeneity of patients, the pathogens, and
recommendations? the lack of validation of scoring systems. Other factors include
the lack of assessment for MDR pathogens, patient residence
Grading of Evidence in nursing homes, prior antibiotic therapy, outcomes related
On the basis of a review of the studies cited above, the 5 to appropriate antibiotic therapy, and confounding by other
members of this workshop agreed that the evidence available conditions, such as sepsis syndrome.

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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.

The definitions and data presented support the concept that long-term outcomes. There is a great deal to learn, and work
severe CAP is not HCAP. Although the approaches to diagnosis is needed to improve our databases and the current guidelines
and the management principles are similar, the definition of for both prevention and therapy for specific at-risk patient
HCAP is focused on the risk factors for infection with MDR populations. Ideally, observational, multicenter cohort studies
pathogens that may alter initial therapy for pneumonia; the using clear definitions and optimal data collection and analysis
definition of severe CAP is based on severity of disease that are needed. Also, patients should be followed longitudinally to
may be caused by a wide variety of non-MDR pathogens. Sev- assess changes in colonization with MDR pathogens over time.
eral scoring systems have been used to identify patients who
may need more clinical attention or intensive care and have a STATEMENT 6: INITIAL EMPIRICAL THERAPY
greater risk of mortality. Some patients with severe pneumonia FOR HCAP IS THE SAME AS THAT FOR HAP
who present to a clinic or hospital ED may have originally
received diagnoses of CAP but, with new definitions, are cat- Rationale and Definition of Statement
egorized as having HCAP because of their risk for infection Many issues in addition to antibiotic choice enter into the
with MDR pathogens. HCAP may share similar management decision making regarding initial empirical therapy for HCAP.
principles with CAP, including antibiotic de-escalation and du- The current definition of HCAP includes a heterogeneous
ration of therapy. However, the spectrum of HCAP outside of group of patients, with variability in features such as site of
the ATS-IDSA guidelines and the rapid evolution of commu- care (hospital or nonhospital), route of therapy (oral or intra-
nity-acquired MRSA in the community may have had an im- venous), and risk factors for infection with MDR pathogens.
pact on the spread of MDR isolates in the community outside Some patients are also at risk for infection with other organ-
of the current concepts of HCAP. isms, such as Legionella and viruses, which can be seen in CAP
more than in HAP. These organisms can be epidemic in certain
Future Directions nursing homes. Because of these varying patient characteristics,
Future directions discussed by the summit members reflected the initial empirical therapy needs to account for differences
many needs, including better-designed epidemiologic studies, in treatment approaches to HCAP and HAP, allowing for the
more-rigorous definition of terms, improved epidemiologic and possibility that some subpopulations should be managed like
microbiological criteria, and better-standardized diagnostic and patients with HAP, some like patients with CAP, and some with
laboratory criteria. Better data for HCAP are also needed in a hybrid approach. HCAP includes many patient populations,
the acute-care setting versus various long-term-care settings in some of which have been extensively studied, such as those
terms of epidemiology, diagnosis, management, and short- and with NHAP; other populations, such as those undergoing he-

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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.

modialysis and those recently hospitalized, are less well combined with the term “antibiotic therapy” (201,780 articles)
described. by use of the “AND” function, a total of 19 articles remained.
When the ATS-IDSA guidelines suggested that HCAP be The term “nursing home pneumonia” (452 articles) combined
treated like HAP, with a focus on MDR pathogens, it was im- with “antibiotic therapy” yielded 47 articles. These searches
plied that the patients evaluated were those in the hospital who were limited to adults, clinical trials, reviews, meta-analyses, or
were treated with intravenous antibiotics. However, as discussed practice guidelines.
in this review, HCAP also includes patients who are not ill To broaden the search, the term “hemodialysis” (35,454 ar-
enough to require hospital admission, those who are not at risk ticles) was combined with the term “pneumonia” to yield 107
for infection with MDR pathogens but are at risk for infection articles. Finally, the term “prior hospitalization” (5084 articles)
with CAP-associated pathogens, those who are treated orally, was combined with the term “pneumonia” to yield 205 articles.
and those who prefer to be treated at home or in a nursing Fourteen articles were deemed relevant to the statement. This
home, regardless of illness severity. database of articles was reviewed and cross-referenced to eval-
uate original studies of therapy for patient populations included
Methods within the definition of HCAP.
Studies of therapy were evaluated by searching PubMed. When
the term “healthcare associated pneumonia” (399 articles) was Evidence
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
Figure 8. Voting comparison for statement 5 (“Severe CAP is not
and in the hospital [19, 77, 78].
HCAP”). “Summit members” refers to the 11-member summit panel; “IDSA
members” refers to the members of the Infectious Diseases Society of HCAP arising in patients in nursing homes has been effec-
America who responded to a Web-based survey. CAP, community-acquired tively treated with oral quinolone therapy, and, in many in-
pneumonia; HCAP, health care–associated pneumonia. stances, this approach has averted hospital admission. In one

HCAP Summit Critical Appraisal • CID 2008:46 (Suppl 4) • S319


cluster-randomized trial of 680 patients 165 years of age with infection with these organisms is only present in some indi-
radiographically diagnosed pneumonia at 20 nursing homes, viduals. In one study of severe NHAP, only 17 of 88 patients
patients were randomized to receive either usual care or a clin- had drug-resistant pathogens, and they were individuals who,
ical pathway [19]. The pathway allowed for oral therapy with in addition to severe illness, had a history of antibiotic therapy
500 mg of levofloxacin daily in the nursing home as long as in the past 6 months, a poor functional status (defined by ADL
the patient was able to eat and drink, had an oxygen saturation scores), or both [22].
of ⭓92%, and had vital signs with a pulse of ⭐100 beats/min, Perhaps the best data to address initial empirical therapy for
a respiratory rate of !30 breaths/min, and a systolic blood HCAP are the findings from previous studies showing that
pressure of ⭓90 mm Hg. When this pathway was used, only therapies not recommended for HAP and MDR pathogens have

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10% of patients were hospitalized, compared with 22% who been highly effective in patients with HCAP [27, 84]. Some
received usual care (P p .001), and there were fewer total hos- data are older, but, even in current studies, not all patients with
pital days and a cost savings of at least $1000 per patient. HCAP have required multiple antibiotics directed at MDR
Mortality and functional status were similar in both groups. gram-negative bacteria and MRSA to achieve high rates of clin-
Out-of-hospital care is also used for some patients with ical success. In one study of 40 patients with mild-moderate
HCAP, because of individual preferences for avoiding admission NHAP treated in the nursing home, both oral ciprofloxacin
to the hospital. Thus, the “hospital at home” can include in- and intramuscular cefamandole were effective and were asso-
travenous medications and oxygen [79]. Many patients prefer ciated with low mortality rates (6.5%), even though some pa-
to remain in the nursing home, receiving oral therapy for acute tients had gram-negative bacteria in sputum samples [77]. In
illness [80]. Patients undergoing hemodialysis can receive in- another study of 45 hospitalized patients, many with NHAP,
travenous antibiotics at each dialysis appointment. intravenous ciprofloxacin was more effective than intravenous
Other factors to consider in the approach to therapy are the ceftazidime [78]. The experience with oral levofloxacin for ther-
associated mortality rates and related pathogens implicated in apy within the nursing home (nonsevere illness) was mentioned
pneumonia. In a retrospective cohort study of a large US da- above [19].
tabase of 59 acute-care hospitals involving 4543 patients, ∼22% In a prospective, double-blind, randomized study of 51 pa-
(998) of patients received diagnoses of HCAP. The mean mor- tients with HCAP, 23 received intravenous monotherapy with
tality rates were comparable for patients with diagnoses of ertapenem, while 28 received intravenous therapy with cefe-
HCAP (19.8%) and HAP (18.8%) (P 1 .05) and were statisti- pime; however, patients at risk for pseudomonal infection or
cally significantly higher than those among patients with di- severe illness were excluded. Even though nearly 80% of pa-
agnoses of CAP (P ! .0001). The distribution pattern of path- tients with HCAP had gram-negative bacteria, the favorable
ogens varied among the 4 pneumonia subtypes; however, S. responses with both therapies were high (90% with cefepime
aureus was the primary organism identified. The incidence of and 75% with ertapenem) [84]. In a retrospective study of 104
MRSA infections (56.8%) was significantly higher among pa- patients with severe pneumonia, including 47 from nursing
tients with diagnoses of HCAP compared with all other pneu- homes and the rest with CAP, the mortality rate was 57% for
monia subcategories, including patients with diagnoses of HAP NHAP and 55% for CAP [27]. Although mortality was higher
(48.6%; P ! .05). S. aureus was the only pathogen associated for inadequate therapy (OR, 2.6; P p .03), 47% of patients
with significantly higher mortality rates (P ! .0001). received monotherapy; the mortality was the same as with com-
Should empirical antibiotic choices be the same as for HAP bination therapy. Common therapies included second- and
for all patients with HCAP? The recommendation that em- third-generation cephalosporins, b-lactam/b-lactamase inhibi-
pirical antibiotic choice be the same for HCAP as for HAP is tor combinations, and quinolones.
based on the idea that both patient populations are at risk for One study evaluated 63 patients with CAP who were hos-
infection with the same MDR pathogens. However, many stud- pitalized after outpatient antibiotic therapy failed. This group
ies of patients with NHAP have shown a high frequency of S. of patients might be categorized as having HCAP and might
pneumoniae, atypical pathogens, and Legionella species, as well be suspected to be infected with MDR pathogens [85]. Patients
as viruses mandating a different approach to therapy than is were randomized to receive monotherapy with moxifloxacin
common in HAP [81–83]. In some nursing-home epidemics, or standard therapy, and both clinical failure rates (6% vs. 30%)
colonization of the drinking water has led to Legionella infec- and 28-day failure rates (6% vs. 21%) were lower for the quin-
tion, whereas, in other nursing homes, viruses such as rhino- olone monotherapy than for standard therapy. These positive
virus have affected up to 40% of hospitalized patients with results occurred even though some patients were infected with
pneumonia [81, 83]. In addition, although enteric gram-neg- S. aureus (5 patients) and enteric gram-negative bacteria (3
ative bacteria can be found in patients with NHAP, the risk of patients).

S320 • CID 2008:46 (Suppl 4) • Kollef et al.


ervations, 18% accepted it with major reservations, and 9%
rejected it with reservations (figure 10).

Discussion
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 pa-
tients with an unnecessarily broad spectrum of antibiotics.

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Many of the studies demonstrated the efficacy of monotherapy
Figure 9. Voting comparison for statement 6 (“Initial empirical therapy
for HCAP is the same as that for HAP”). “Summit members” refers to regimens that would not be recommended for patients with
the 11-member summit panel; “IDSA members” refers to the members HAP at risk for infection with MDR pathogens (ciprofloxacin,
of the Infectious Diseases Society of America who responded to a Web- levofloxacin, cefepime, and ertapenem), and some studies
based survey. HAP, hospital-acquired pneumonia; HCAP, health care–as- showed efficacy of therapies that did not cover the presumed
sociated pneumonia. MDR pathogens in complex patients with HAP (efficacy was
present in all studies without specific MRSA coverage). In ad-
dition, HAP therapy would not adequately treat some patients
Thus, in many studies, therapy for patients with HCAP has
with HCAP who might be infected with community pathogens,
been heterogeneous, but therapies not recommended for HAP
such as Legionella species. Finally, the inclusion of outpatients
due to MDR pathogens, including monotherapy with quino-
in the HCAP definition requires that some patients receive oral
lones, ertapenem, and cephalosporins, have been highly
therapy instead of intravenous therapy, unlike those already in
effective.
the hospital with HAP. The members of the summit panel
recognized these issues when only 50% of members accepted
Grading of Evidence the initial statement with major reservations and 50% rejected
In evaluating the nature of evidence to support the statement it.
for all patients, the panel of 6 graded the evidence as category Although not all members of the panel could accept the
III. In evaluating the nature of the evidence for patients ad- original statement, there are certainly patients with HCAP who
mitted to the hospital, the panel graded it as category III. In are likely to be infected with MDR pathogens and, thus, who
applying the statement to patients never admitted to the hos- would require therapy identical to therapy for HAP. These are
pital, the panel graded the nature of the evidence as category patients who generally have multiple risk factors, such as severe
I (2 votes), category III (1 vote), category IV (2 votes), and pneumonia, prior antibiotic therapy, and poor functional status
category V (1 vote) (table 2). [22]. Thus, the panel voted on a second statement, that em-
pirical therapy for MDR pathogens should be administered to
Level of Support patients with HCAP who have at least 2 of the 3 risk factors
When all members of the summit voted on the initial statement, (severe illness, prior antibiotic therapy, and poor functional
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 re-
sponded 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 sum-
mit panel developed a new statement (“statement 6.5”): em-
pirical 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 Figure 10. Voting comparison for statement 6.5 (“Empirical MDR an-
tibiotics should be given to patients with HCAP who have at least 2 of
antibiotic therapy [for 13 days in the preceding 6 months], the 3 mentioned risk factors”). “Summit members” refers to the 11-
and poor functional status [ADL score, 112.5]). Among the member summit panel. HCAP, health care–associated pneumonia; MDR,
summit members, 73% accepted this statement with some res- multidrug resistant.

HCAP Summit Critical Appraisal • CID 2008:46 (Suppl 4) • S321


status); 70% of the summit panel accepted the statement with utilize antibiotic combinations when serious gram-negative
some reservations, and 20% accepted it with major reservations. bacterial infections are suspected, whereas others criticize such
On the basis of the discussion of the panel and the available an approach as lacking sound evidence [86, 87]. A number of
evidence, HCAP therapy should probably be divided into 2 issues need to be considered if empirical combination antibiotic
categories: limited-spectrum therapy and broad-spectrum ther- therapy is considered. First, what are the consequences of in-
apy. This categorization is dictated by whether the patient with adequate empirical antibiotic therapy for the bacillary infection?
HCAP has 2 of the 3 identified risk factors for MDR pathogens If data exist showing that mortality or morbidity is seriously
in this population. Limited-spectrum therapy can be given to compromised by inadequate empirical therapy, it behooves cli-
patients in or out of the hospital who do not have 2 of these nicians to consider how they may improve empirical antibiotic
3 risk factors. Therapy can be a respiratory quinolone alone

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regimens. For example, inadequate antibiotic therapy may have
(moxifloxacin or levofloxacin) or, alternatively, combined with few consequences in a patient with an uncomplicated urinary
a selected b-lactam (ceftriaxone, cefepime, piperacillin-tazo- tract infection but substantial consequences in a critically ill
bactam, or ertapenem) with good activity against drug-resistant patient in an ICU who develops a bloodstream infection [88].
S. pneumoniae, with consideration of adding a macrolide (es-
Second, is the adequacy of an empirical antibiotic regimen
pecially if Legionella, Chlamydophila, or Mycoplasma species
more likely to be improved by the use of a combination regimen
have been present in patients from the same environment).
than by the use of an improved single agent? Incorporated into
Patients who receive limited-spectrum therapy can be treated
this consideration are issues of synergy, development of resis-
in the nursing home with oral therapy if a quinolone is used.
tance, and toxicity. Potentially, an advantage may arise when
Broad-spectrum therapy should be given to patients in or out
synergy is observed in vitro between 2 antimicrobial agents
of the hospital who do have 2 of the 3 identified risk factors,
(although, for most infections, this has not been borne out in
and these patients should receive therapy active against drug-
clinical studies). For some organisms (e.g., Mycobacterium tu-
resistant S. pneumoniae, P. aeruginosa (ideally with 2 agents),
and MRSA, as well as consideration of Legionella in appropriate berculosis or HIV), resistance may be less likely to develop when
settings. This could be achieved with a b-lactam (cefepime, combinations of antimicrobials are used. Although there are
imipenem, meropenem, or piperacillin/tazobactam) combined some in vitro data suggesting that this may also occur with
with an antipseudomonal quinolone (ciprofloxacin or high- respect to treatment of gram-negative bacilli, there are also
dose levofloxacin), with either linezolid or vancomycin. If a conflicting data showing no benefit to this approach. Finally,
quinolone cannot be used, because of allergy, intolerance, or there is the potential that the use of 2 drugs (e.g., addition of
recent therapy in the past 3 months, an aminoglycoside should an aminoglycoside to a b-lactam) may increase the risk of
be added in its place while considering the addition of a mac- toxicity and, therefore, detract from the benefit of using com-
rolide to the b-lactam and the MRSA therapy. The antimicro- bination therapy.
bials used for broad-spectrum therapy are primarily available In this review, these issues are addressed with respect to
for parenteral and not oral administration. HCAP. This is first approached from a review of randomized
trials of therapy for patients with HCAP. Second, a review of
Future Directions epidemiologic studies was performed to determine whether pa-
These therapy recommendations are based on the best available tients with HCAP may be at increased risk for infection with
data, which are, unfortunately, quite limited. Future validation MDR gram-negative bacilli, thereby necessitating the use of
of this approach is required. In addition, more data are needed empirical combination therapy.
for populations of patients with HCAP other than those with
NHAP. As new therapeutic options become available, they Methods
should be tested in patients with HCAP specifically, so that A search of PubMed was performed in November 2006, cross-
data from patients with HAP do not need to be extrapolated linking articles with the key words “randomized trial” and
to this population. “healthcare-associated pneumonia,” “nursing home pneumo-
nia,” or “hospital-acquired pneumonia.” A second search was
STATEMENT 7: PATIENTS WITH HCAP WHO
performed with the key words “microbiology” or “pathogen”
ARE AT RISK FOR GRAM-NEGATIVE
and “healthcare-associated pneumonia,” “nursing home pneu-
INFECTIONS SHOULD RECEIVE DUAL
monia,” or “hospital-acquired pneumonia.” The references of
EMPIRICAL ANTIBIOTIC COVERAGE
articles discovered in this search were reviewed for further ar-
Rationale and Definition of Statement ticles pertinent to the topic. With regard to studies of patients
The issue of monotherapy versus combination antibiotic ther- with HAP, those with 150% patients receiving ventilation were
apy for serious infections is not new [86, 87]. Many clinicians excluded (unless there was a subgroup analysis of patients not

S322 • CID 2008:46 (Suppl 4) • Kollef et al.


receiving ventilation). Eleven articles were reviewed for this 21% had bronchitis. Thirteen percent of patients had nursing
statement. home acquisition of their lower-respiratory-tract infection, with
the remainder having hospital-acquired infections. The most
Evidence commonly isolated pathogens in evaluable patients were H.
Randomized trials. There are no randomized trials evaluating influenzae (32 patients), S. aureus (31 patients), P. aeruginosa
empirical monotherapy versus combination therapy for HCAP. (22 patients), S. pneumoniae (21 patients), E. coli (16 patients),
However, there are several randomized trials evaluating 2 dif- and K. pneumoniae (14 patients). Clinical success was observed
ferent monotherapy regimens or evaluating 1 combination in 74.2% of patients treated with piperacillin/tazobactam plus
therapy regimen versus another combination therapy regimen. tobramycin, versus 57.9% of patients treated with ceftazidime

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Randomized trials evaluating 2 different monotherapy regimens plus tobramycin. Bacteriologic response was observed in 65%
have included those of ciprofloxacin versus ceftriaxone, cip- of patients treated with the piperacillin/tazobactam plus to-
rofloxacin versus ceftazidime, and ertapenem versus cefepime. bramycin regimen, versus 38% of patients treated with the
The trial evaluating combination therapy was of tobramycin ceftazidime plus tobramycin regimen (P p .03).
plus piperacillin/tazobactam versus tobramycin plus ceftazi- Observational studies of the microbiology of HCAP.
dime [89]. A number of studies have evaluated the etiology of HCAP and,
Ciprofloxacin monotherapy has been compared with cef- in some circumstances, compared the etiology with that of CAP.
triaxone monotherapy in a small randomized trial of nursing An 18-month prospective cohort study from the United King-
home–acquired lower-respiratory-tract infection requiring hos- dom compared the etiology of NHAP and CAP [20]. S. pneu-
pitalization [90]. Fifty patients were enrolled, all of whom were moniae was the predominant pathogen identified as being re-
⭓60 years of age. A successful outcome was defined as reso- sponsible for 55% of NHAP cases and 43% of CAP cases.
lution or marked improvement in clinical signs and symptoms Gram-negative bacilli were rarely isolated, and, in general, the
of lower-respiratory-tract infection and was achieved in 50% etiologies of NHAP and CAP were similar. In contrast to these
(12/24) of patients treated with ciprofloxacin and 54% (14/26) results, a database of 4543 patients with HCAP and a concom-
of patients treated with ceftriaxone. In a second small study itant positive respiratory bacterial culture showed that S. aureus
evaluating ciprofloxacin monotherapy, 44 hospitalized patients was responsible for 47% of cases, P. aeruginosa for 25%, Kleb-
with HAP or NHAP were randomized to receive ciprofloxacin siella species for 8%, and S. pneumoniae for 6% [2]. Etiologies
or ceftazidime [78]. All (23/23) ciprofloxacin-treated patients of HCAP were more similar to those of HAP or even VAP than
had a favorable response, compared with only 71% (15/21) of to those of CAP.
the ceftazidime-treated patients. In a large review of 10,635 hemodialysis recipients with 3101
The largest study of monotherapy was a 303-patient, pro- episodes of pneumonia, no organism was identified in 81.8%
spective, double-blind, randomized, international, multicenter of patients [29]. Gram-positive organisms (predominantly S.
study of ertapenem versus cefepime [84]. Patients enrolled in pneumoniae) were found in 4.8% of patients, and gram-negative
the study had pneumonia acquired in a hospital or a skilled- bacilli were found in 11.1% of patients. Almost 3% of the
care facility, such as a nursing home. Patients with conditions patients had P. aeruginosa.
believed to increase the risk of P. aeruginosa or Acinetobacter Similarly, a study of NHAP requiring ICU admission showed
infection were excluded. These conditions include pneumonia that S. pneumoniae was a common pathogen [22]. However,
acquired in an ICU or while receiving mechanical ventilation, MRSA and gram-negative bacilli were isolated quite frequently
an immunocompromising illness or therapy, and cystic fibrosis. in this particular study. Enterobacteriaceae (E. coli; 9/135 pa-
Fifty-four percent of the population had a pathogen isolated— tients), K. pneumoniae (6/135 patients), Serratia marcescens (5/
this comprised Enterobacteriaceae, such as Klebsiella species or 135 patients), Enterobacter cloacae (5/135 patients), and Proteus
E. coli (in 20% of enrolled patients); S. pneumoniae (in 13%); mirabilis (3/135 patients) were found in 21% of patients, and
S. aureus (in 12%); and P. aeruginosa (in 4%). A successful P. aeruginosa was found in 7% of patients. Patients were ex-
clinical response was observed in 92% of patients treated with cluded from this study if they were immunocompromised or
ertapenem and 88% of patients treated with cefepime. A suc- if they had been hospitalized for 148 h in the 6 months before
cessful microbiological response was observed in 84% of pa- ICU admission.
tients treated with ertapenem and in 83% of patients treated
with cefepime. Grading of Evidence
The trial evaluating combination therapy was a 300-patient, On the basis of a review of the studies cited above, the 5
open-label, randomized, comparative, multicenter study of to- members of this workshop agreed that the evidence available
bramycin plus piperacillin/tazobactam versus tobramycin plus to support this statement was category V for the statement in
ceftazidime [89]. The majority of patients had pneumonia, but general, a tie between categories III and IV for the statement

HCAP Summit Critical Appraisal • CID 2008:46 (Suppl 4) • S323


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 com-
pletely, 9% accepted the statement with some reservations, 64%
accepted the statement with major reservations, and 18% re-

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jected the statement with reservations. In comparison, of the Figure 11. Voting comparison for statement 7 (“Patients with HCAP
383 IDSA members who participated in the online survey, 25% who are at risk for gram-negative infections should receive dual empirical
accepted the statement completely, 33% accepted the statement antibiotic coverage”). “Summit members” refers to the 11-member summit
with some reservations, 13% accepted the statement with major panel; “IDSA members” refers to the members of the Infectious Diseases
Society of America who responded to a Web-based survey. HCAP, health
reservations, 23% rejected the statement with reservations, and
care–associated pneumonia.
5% rejected the statement completely (figure 11).

Discussion is not clear, however, is whether P. aeruginosa and other gram-


The question raised in this review is whether patients with negative isolates from patients with HCAP have resistance pro-
HCAP should receive dual empirical antibiotic coverage aimed files of a magnitude similar to those in patients in the ICU.
against gram-negative pathogens. There are no randomized tri- It is likely that HCAP is actually quite a heterogeneous con-
als that provide a simple answer to this question. Several studies dition. Clearly, patients in nursing homes differ in their func-
of monotherapy antibiotic regimens have been performed. tional status, and this may, in turn, influence their likelihood
Monotherapy regimens (comprising ciprofloxacin, ceftriaxone, of being colonized (and subsequently infected) with MDR
gram-negative bacilli. Patients with recent hospitalization may
ceftazidime, cefepime, or ertapenem) were generally successful,
also vary in the likelihood that they are colonized with anti-
both clinically and microbiologically. However, inclusion cri-
biotic-resistant gram-negative bacilli. In turn, hemodialysis re-
teria, exclusion criteria, and outcome measures were variable.
cipients may be at different risk, compared with patients in
In some circumstances, success rates were only 50%, but it is
nursing homes or previously hospitalized patients.
unclear whether this was a marker of particularly stringent
outcome definitions in these small studies or truly represented
Future Directions
a deficiency in the monotherapy regimen. The optimal study
design to answer the question of superiority of an empirical Like other forms of pneumonia, HCAP varies in severity. The
dual antibiotic regimen would be a randomized trial of mono- consequences of inadequate antibiotic therapy for patients with
therapy versus combination therapy (with the agent used in severe HCAP requiring ICU admission are likely to be greater
the monotherapy arm plus an additional agent). No such study than those for patients admitted to a general ward or even
exists or is currently under way. managed in a nursing home or some other setting outside of
The second way to approach this question is to review the hospital. It is unlikely that a randomized trial will directly
whether patients with HCAP are at high risk for infection with answer the question of whether empirical combination therapy
MDR gram-negative bacilli. Organisms such as P. aeruginosa is optimal for patients with HCAP. Attention is needed to de-
termine which patients are at risk for infection with MDR
or A. baumannii are often MDR; in some scenarios (e.g., in
gram-negative bacilli, and whether inadequate empirical ther-
ICUs), no single antibiotic will cover 180%–85% of strains.
apy influences outcomes for all, or subsets of, patients with
Therefore, empirical use of combination therapy may be im-
HCAP. Only then will the question of optimization of gram-
portant to ensure that empirical therapy is likely to be micro-
negative coverage for patients with HCAP be answerable.
biologically adequate. Studies of pneumonia in nursing homes
in the United Kingdom and among hemodialysis recipients in
STATEMENT 8: PATIENTS SHOULD RECEIVE
the United States have not revealed a high frequency of or-
INITIAL EMPIRICAL THERAPY THAT COVERS
ganisms such as P. aeruginosa or A. baumannii as etiologic
MRSA AT THE TIME OF HCAP DIAGNOSIS
agents. The frequency of gram-negative bacilli, including MDR
strains, appears to be higher among patients in nursing homes Rationale and Definition of Statement
who require ICU admission. The study by Kollef et al. [2] MRSA infections, a common problem encountered by clini-
suggests that patients with HCAP have etiologic agents (such cians, result in significant morbidity, mortality, and economic
as P. aeruginosa) more like those in hospitalized patients. What consequences. The annual incidence of MRSA has profoundly

S324 • CID 2008:46 (Suppl 4) • Kollef et al.


increased throughout ICUs in the United States, rising 3% on lated was MRSA (26.5%), followed by P. aeruginosa (25.3%)
average since 1992 to an estimated 65% of all S. aureus infec- and MSSA (21.1%). Interestingly, S. aureus isolation in all pneu-
tions in 2004 [91]. Unfortunately, the dissemination of MRSA monias was associated with increased in-hospital mortality
is not limited to the ICU. Data reported by the National Nos- (OR, 1.58; 95% CI, 1.32–1.89; P ! .0001). The authors hy-
ocomial Infections Surveillance Systems indicate that, on av- pothesized that this finding might reflect clinicians’ lack of
erage, 31% of outpatient and 46% of non-ICU inpatient isolates precision in differentiating HCAP from CAP, resulting in omit-
of S. aureus are MRSA [92]. As a pulmonary pathogen, S. aureus ted coverage for MRSA and inappropriate empirical coverage.
accounts for 20%–30% of HAPs and VAPs, with MRSA ac- A prospective, randomized, multicenter comparative trial of 2
counting for 150% of these infections, especially in patients antibiotics lacking activity against MRSA sought to determine
with a high severity of illness and those with prior antibiotic

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the microbiological etiologies in patients not receiving venti-
exposure [93]. MRSA pneumonia has been associated with lation who were admitted to the hospital with HCAP or HAP
longer hospital stays and higher costs, compared with methi- [84]. In this heterogeneous sample, only 12% of all isolates
cillin-susceptible S. aureus (MSSA) pneumonia, regardless of were positive for S. aureus, 40% of which were MRSA.
severity of illness [94–96]. The issue of attributable mortality NHAP includes a select group of patients who fall under the
due to MRSA pneumonia compared with MSSA pneumonia is umbrella of HCAP. The isolation of MRSA in this patient pop-
difficult to resolve, because of the high rates of inappropriate ulation, compared with patients with CAP, has been variable.
initial antimicrobial therapy in many cases of MRSA pneu- A prospective study comparing the clinical and microbiological
monia. However, MRSA doubles the attributable mortality characteristics of NHAP with those of CAP requiring hospi-
compared with MSSA in patients with bacteremia [97]. Given talization in the United Kingdom from 1998–1999 revealed only
the extraordinary burden of illness caused by MRSA pneumonia 1 case of pneumonia caused by S. aureus (not differentiated
in hospitalized patients, this section reviews the level of evidence between MRSA and MSSA) [20]. A prospective study com-
supporting empirical coverage of MRSA in patients with di- paring patients with NHAP and patients with CAP at a single
agnoses of HCAP. center in the United States from 1996 to 1999 found that pa-
tients with NHAP were more likely to be infected with S. aureus
Methods than were patients with CAP (29% vs. 7%). However, the num-
A PubMed database search to identify microbiological features ber of patients with MRSA was small (3 vs. 0 cases, respectively)
and clinical outcomes in patients with HCAP was conducted. [27]. In contrast, results of BAL cultures in a group of patients
The search terms “methicillin-resistant Staphylococcus aureus” with severe NHAP who were admitted to the ICU at a single
and “health care associated” were combined, using the “AND” US hospital between 1998 and 2003 showed S. aureus to be the
function, to yield 141 articles. This search was combined with most common pathogen identified (23.9%), of which 61.9%
the term “pneumonia” by use of the “AND” function, pro- were MRSA [22]. Clearly, microbiological data from patients
ducing 123 articles that were reviewed and selected. Eleven with NHAP are limited by the period during which they were
articles were deemed relevant to the statement. obtained. In fact, it could be argued that differences exist in
the frequency of MRSA isolation in these studies compared
Evidence with today. However, outside of the single retrospective study
The microbiological etiology of HCAP in the era of increasing mentioned above, evidence is lacking.
MRSA incidence has been an understudied subject and has Given the inconsistencies in the frequency with which MRSA
generally been relegated to the subgroup of patients who require is thought to cause HCAP, attention must be focused on iden-
hospital admission. A retrospective analysis of the Cardinal tifying patients at risk for MRSA infection at admission to the
Health-Atlas Research Database characterized the microbiology hospital or in the nursing home. A detailed history of the
and outcomes of 4534 cases of pneumonia identified by Inter- patient’s recent contact with health care systems is the most
national Classification of Diseases, Ninth Revision codes. HCAP important component in the categorization of MRSA infection
was distinguished in this study as a positive respiratory culture risk. A prospective surveillance study of MRSA infections found
result within 48 h after hospital admission in patients who were that, of 123 positive culture samples obtained within the first
transferred from another health care facility, were receiving 48 h of hospitalization, only 1 was from a patient who did not
long-term hemodialysis, or had been hospitalized in the pre- have recent health care contact, including hospitalization, trans-
vious 30 days and did not require mechanical ventilation [2]. fer from another health care facility, residence in a long-term-
Although this definition is imprecise and likely does not capture care facility, dialysis, home nursing care, or day surgery [24].
the true HCAP population, 21.7% (n p 988) of the sample Similarly, a case-control study comparing patients with blood
population was designated with this classification of pneu- cultures positive for MRSA and patients with positive blood
monia. Within this stratum, the pathogen most frequently iso- cultures without MRSA in the first 24 h of hospitalization found

HCAP Summit Critical Appraisal • CID 2008:46 (Suppl 4) • S325


that all patients with MRSA had recent health care exposure fair evidence to support the statement for hospitalized patients;
[98]. Risk factors for community-acquired infection with health there was a range of votes from poor evidence to support to
care–associated MRSA were elucidated in a prospective, case good evidence to reject the statement for nonhospitalized pa-
(MRSA)–control (MSSA) study conducted at a French teaching tients (table 2).
hospital [30]. Among patients with respiratory tract (27.3%),
urinary tract (17.2%), primary bloodstream (9.8%), and skin/ Level of Support
soft tissue (38.5%) infection, risk factors associated with MRSA Overall, 9% of the summit participants voted to accept the
infection at hospital admission included home nursing care statement with some reservations, 55% voted to accept the
(adjusted OR [AOR], 3.7; 95% CI, 2.0–6.7), prior hospitali- statement with major reservations, and 36% voted to reject the

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zation (AOR, 3.8; 95% CI, 1.8–7.9), transfer from another hos- statement with reservations. In comparison, of the 383 IDSA
pital or nursing home (AOR, 2.3; 95% CI, 1.2–74.3), age ⭓65 members who participated in the online survey, 25% accepted
years (AOR, 1.8; 95% CI, 1.1–2.5), and home nursing care or the statement completely, 37% accepted the statement with
inpatient surgery in the past 3 years (AOR, 3.1; 95% CI, 1.2– some reservations, 13% accepted the statement with major res-
8.0). Additionally, previous use of antibiotics has been linked ervations, 2% rejected the statement with reservations, and 5%
to infection with drug-resistant bacteria, including MRSA in rejected the statement completely (figure 12).
patients with severe NHAP [22]. These findings suggest that
patients presenting from the community with pneumonia who Discussion
have recent health care exposure or antibiotic use should be This statement is of great significance, given the increasing
considered at risk for MRSA HCAP. incidence of MRSA in hospitals and the community. Currently,
The ATS-IDSA guidelines for the empirical treatment of the microbiological evidence supporting MRSA as a major
HCAP indicate that coverage for MRSA with either vancomycin pathogen in HCAP is limited. Similarly, outcome data sup-
or linezolid should be instituted [3]. However, the impact of porting this statement are nonexistent. Evidence to the contrary
this recommendation on clinical outcomes, including mortality, has been published related to NHAP, such that omitting MRSA
is limited. In general, omission of antibiotic coverage with coverage in the therapeutic regimen did not appear to have
MRSA activity has not been associated with poor outcomes in adverse consequences. One study evaluating patients with
patients with NHAP [19, 84, 85]. This finding may be a result health care–associated MRSA sterile-site infection in compar-
of the low incidence of MRSA in these specific study popu- ison with patients with hospital-acquired MRSA infection
lations. A retrospective study of MRSA sterile-site infections at found the former group to be significantly less likely to have
a single institution found that appropriate empirical therapy MRSA coverage initiated in the first 24 h, which was subse-
was significantly more likely to be prescribed to patients who quently associated with increased odds of in-hospital mortality.
had MRSA isolated ⭓48 h after admission (hospital acquired,
39%), versus those with MRSA isolated within the first 48 h Future Directions
after admission (health care associated, 22%) (P ! .001) [99]. Until prospective controlled trials are published that specifically
This was despite the finding that 86% of the patients with study microbiology and outcomes in patients with HCAP
positive culture results within 48 h of hospitalization had recent
health care exposure. Subsequent multivariate regression anal-
ysis 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.

Grading of Evidence
On the basis of this literature review, 6 members of the HCAP
Therapeutic Intervention workshop voted that the nature of Figure 12. Voting comparison for statement 8 (“Patients should receive
the evidence for the statement ranged from category II to V initial empirical therapy that covers MRSA at the time of HCAP diag-
nosis”). “Summit members” refers to the 11-member summit panel; “IDSA
for all patients, from category II to IV for patients admitted to
members” refers to the members of the Infectious Diseases Society of
the hospital, and from category II to V for patients never ad- America who responded to a Web-based survey. HCAP, health care–
mitted to the hospital. Therefore, the workshop voted that there associated pneumonia; MRSA, methicillin-resistant Staphylococcus
was poor evidence to support the statement for all patients and aureus.

S326 • CID 2008:46 (Suppl 4) • Kollef et al.


treated with and without antibiotics that have MRSA activity, such semiquantitative information is more accurate than in-
support of this statement is based on opinion. formation from nonquantitated samples, such as sputum [103].
One study directly compared 2 treatment durations in pa-
STATEMENT 9: WHEN MICROBIOLOGICAL tients with VAP. All patients had undergone diagnostic BAL
DATA ARE UNAVAILABLE, DE-ESCALATION IN and had received initial, appropriate, adequate antibiotics to
PATIENTS WITH HCAP SHOULD NOT OCCUR remain in the study. In a randomized trial of 8 versus 15 days
Rationale and Definition of Statement of therapy for VAP, those patients who had nonfermenting
gram-negative rods (e.g., P. aeruginosa) were more likely to
“De-escalation” can mean discontinuation of therapy with
relapse if treated for only 8 days [48]. Although the rate of
some antibiotics, changing from a broad-spectrum to a narrow-
relapse was not statistically significantly different, the 60%

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spectrum antibiotic, or discontinuation of all antibiotic therapy.
higher relapse rate has led some physicians to require micro-
The concept of de-escalation arose from the treatment of pa-
biological data before stopping antibiotic therapy at 1 week.
tients with HAP, especially those with VAP, and was proposed
as a method to minimize exposure to broad-spectrum antibi- In another study examining the clinical outcome of S. aureus
otics [61, 100, 101]. Shorter courses of antibiotic therapy are versus other pathogens in serial nonbronchoscopic BAL studies
associated with lower rates of superinfection with resistant bac- of VAP, it was determined that patients with S. aureus and drug-
teria [48, 101]. However, some pathogens seem to require resistant gram-negative rods were likely to have persistent bac-
longer treatment to avoid clinical relapse [102]. Because of this teria in the BAL sample 2–5 days into therapy [102]. The au-
discrepancy, the decision to de-escalate may require microbi- thors found that patients with 11000 cfu of bacteria/mL of BAL
ological data. This concept is included in the ATS-IDSA guide- sample in the follow-up BAL had a significantly higher 28-day
lines for treating HAP [3]. mortality rates than did those who cleared the bacteria [102].
Clinicians often de-escalate treatment only on the basis of There is no similar microbiological information for HCAP.
clinical response to therapy. The safety and relapse rates as- Guidelines have been established for treating patients in nursing
sociated with this approach are not known. homes who have suspected pneumonia [104], and these led to
a reduction in the number of hospitalizations and overuse of
Methods antibiotics but did not change mortality rates [105].
A PubMed search was performed in November 2006. By look- A cluster-randomized controlled trial of 680 nursing-home
ing at “duration of antibiotic therapy pneumonia” and limiting residents was performed over a 16-month period in 22 nursing
the search to clinical trials published in English, 180 references homes in Canada. Patients who met a predefined criterion of
were identified. By looking specifically at “health care associated pneumonia based on clinical grounds were treated with either
pneumonia duration of therapy,” 14 references were identified; standard care or a clinical pathway, which included use of oral
all were regarding VAP. Searching with the term “nursing home antimicrobials, portable chest radiographs, and oxygen-satu-
pneumonia duration of therapy” identified 23 references. ration monitoring. Although 76 (22%) of 353 residents re-
References from the last 2 categories were reviewed. The ceiving standard care for their pneumonia required hospitali-
majority of references simply provided the duration of therapy zation, only 34 (10%) of 327 of those in the clinical pathway
and made no attempt to analyze why one duration was used were hospitalized. There also was a reduction in the number
versus another. There were some exceptions, and 13 studies of hospital days for those in the clinical pathway group who
were reviewed. were admitted, compared with the standard care group. Overall,
health care costs were significantly reduced, with no difference
Evidence in mortality [19]. The clinical pathway did not have a specific
The most direct evidence regarding duration of antibiotic ther- de-escalation procedure.
apy has been for cases of VAP. Although this is a subset of Another study used the clinical status of the patient to sep-
nosocomial pneumonia, the information was believed to be arate 170 episodes of pneumonia in nursing home patients into
relevant for several reasons. First, it provides a worst-case sce- 4 broad categories: pneumonia, aspiration pneumonitis with
nario, since the rate of mortality due to VAP is higher than infiltrates that resolve within 24 h, aspiration pneumonitis with
that reported for HCAP. However, the mortality rate for HCAP infiltrates that persist for 124 h, and aspiration without pneu-
is closer to that for VAP and HAP than to that for CAP [2]. monitis [106]. Patients were categorized prospectively on the
In addition, the microbiology information from invasive pro- basis of their initial presentation and follow-up evaluation at
cedures done for VAP were felt to be more revealing than those day 3–5. The results are summarized in table 8. The authors
done for most cases of HCAP. In particular, semiquantitative found that patients believed to have aspiration pneumonitis
cultures from bronchoscopic and nonbronchoscopic BAL sam- who did not have infiltrates after day 3 were treated for a shorter
ples were often used in VAP studies. Current opinion is that time and were less likely to receive antibiotics at discharge [106].

HCAP Summit Critical Appraisal • CID 2008:46 (Suppl 4) • S327


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

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the score [39]. The major reason for the decrease in the CPIS
Figure 13. Voting comparison for statement 9 (“When microbiological
was improvement in the PaO2/FiO2 ratio [39]. Other physicians
data are unavailable, de-escalation in patients with HCAP should not
have discontinued antibiotic therapy as soon as day 3 if the occur”). “Summit members” refers to the 11-member summit panel; “IDSA
CPIS has remained stable or has decreased [101]. members” refers to the members of the Infectious Diseases Society of
These observations have led to the suggestion that the use America who responded to a Web-based survey. HCAP, health care–
of broad-spectrum antibiotics for possible MDR pathogens can associated pneumonia.
be modified or even discontinued at days 3–7 on the basis of
cent rejected the statement with reservations, and 1% rejected
clinical criteria alone. This is especially true when a CXR film
it completely.
shows resolution of the infiltrate and the clinical status of the
patient is improving by day 3.
Discussion
The summit panel recommended that broad-spectrum anti-
Grading of Evidence
biotic therapy for possible MDR pathogens could be modified
On the basis of a review of the studies cited above, the 6
or even discontinued at days 3–7 on the basis of clinical criteria
members of this workshop agreed that the evidence available
alone. This is especially true when a CXR film shows improve-
to support this statement was category V for the statement in
ment. Although this recommendation was not supported by
general, category V for the statement as it applies to hospitalized
strong evidence, the current information would support this
patients with HCAP, and category IV for the statement as it
conclusion.
applies to nonhospitalized patients with HCAP (table 2). The major limitation of this analysis was the infrequency
with which an adequate lower respiratory culture was obtained
Level of Support from patients with HCAP. Because of this, the clinician was
As shown in figure 13, 9% of the summit members accepted left with the dilemma of making a decision on the basis of the
the statement with major reservations, 82% rejected it with clinical presentation of the patient. Although this appears to
reservations, and 9% rejected it completely. In contrast, 54% be common practice, there is little scientific evidence to support
of the 383 IDSA members who completed the online survey it.
believed there was some degree of support for the statement. The studies to date do suggest that de-escalation can be done
However, this may have been based on the assumption that in HCAP when the patient meets certain clinical criteria, such
what was true for VAP would apply to HCAP. Thirty-five per- as a clear CXR film and return to baseline respiratory status.

Table 8. Comparison of pneumonia and aspiration pneumonitis.

Aspiration event
Aspiration pneumonitis
Pneumonia with no infiltrate
Therapy ⭐24 h (n p 47) 124 h (n p 21) (n p 42) (n p 60) P
Antibiotic prescribed in nursing home 16 (34) 6 (29) 6 (14) 14 (23) .19
Antibiotic prescribed in ED 36 (77) 18 (86) 28 (67) 35 (67) .04
Antibiotic prescribed after admission 42 (89) 20 (95) 41 (97) 45 (75) .004
No antibiotic prescribed, 1 dose of antibiotic, or 6 (13) 2 (10) 1 (2) 17 (28) .003
!24 h of antibiotic therapy
Duration of antibiotic therapy, mean days  SD 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
(sample size)
Antibiotic prescribed at time of discharge 25 (66) 11 (69) 28 (82) 18 (45) .01

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.


One caveat is that most of this information was based on “antibiotic” produced 410,820 articles. Combining the above
patients with probable susceptible microbacteria. The VAP data searches gave a total of 157 articles. When these searches were
would suggest that de-escalation may not be possible in cases combined with the term “duration,” 23 articles remained.
caused by MDR bacteria. This would be especially true if the When the search was limited to English, 20 articles were re-
patient does not receive adequate initial antibiotic therapy. viewed, of which 5 were deemed relevant.

Future Directions Evidence


There is a need for specific studies of de-escalation in HCAP Although no study was identified that specifically focused on
cases. It would be useful to obtain microbiological data in these the optimal duration of therapy for HCAP, these 5 studies

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cases. However, studies without microbiological information provided insight into the optimal duration of therapy for hos-
could still be informative if the reasons for de-escalation were pitalized adult patients with VAP.
clearly defined before the study. Outcomes could then be tested Dennison et al. [47] performed a prospective cohort study
against those obtained with standard therapy. of 27 adult patients with VAP receiving appropriate antibiotic
Identifying risk factors for truly resistant bacteria, which may therapy. The primary objective was to define the time to res-
require longer antibiotic therapy, is also an issue. These bacteria olution of VAP symptoms after initiation of antibiotics. They
could include MRSA and P. aeruginosa. Clearly, not all cases observed that response to antimicrobial therapy for VAP occurs
of HCAP are the same, and the approach for de-escalation may within the first 6 days of therapy. However, colonization with
need differ among groups. resistant pathogens occurs after 6 days, and colonization with
resistant gram-negative bacteria will persist in many patients.
STATEMENT 10: THE DURATION OF
Singh et al. [101] conducted a prospective and randomized
ANTIBIOTIC THERAPY FOR PATIENTS WITH
but unblinded study of 81 patients with VAP. The goal was to
HCAP WITH A CLINICAL RESPONSE SHOULD
devise an operational approach for patients with possible nos-
BE 7 DAYS
ocomial pneumonia. Only patients with a CPIS of ⭓6 were
Rationale and Definition of Statement included in the study and were randomized to receive standard
It is widely accepted that appropriate antimicrobial stewardship therapy, as determined by the clinician, or a 3-day course of
includes optimal selection, dose, and duration of treatment, as ciprofloxacin. Mortality, extrapulmonary infections, and the
well as control of antibiotic use. It is anticipated that appro- number of patients who developed a CPIS of 16 at 3 days did
priate antimicrobial stewardship will prevent or slow the emer- not differ. However, antimicrobial resistance and/or superin-
gence of resistance among microorganisms [107]. However, it fections were encountered significantly less frequently in the
is distressing that there are few data on the optimal duration patients treated for 3 days.
of antibiotic therapy for many infectious diseases, including Ibrahim et al. [108] investigated the impact of a guideline
HCAP. that incorporated de-escalation, by use of a cohort design in-
The recent ATS-IDSA nosocomial pneumonia guidelines de- cluding 50 patients treated before implementation of the guide-
fine HCAP as a distinct clinical entity occurring in a subset of line and 52 patients treated after implementation. The guideline
patients at risk for harboring resistant organisms despite their called for a respiratory culture, followed by empirical therapy
residence in the community [3]. These patients have historically using the combination of vancomycin, imipenem, and cipro-
been treated with antibiotic regimens recommended in CAP floxacin, and reassessment after 24–48 h. Patients treated under
guidelines. As the prevalence of antimicrobial resistance has the guideline had significantly better rates of adequate therapy,
increased in patients meeting HCAP criteria, many clinicians a shorter duration of therapy, and a lower probability of sec-
questioned whether these antibiotic regimens were appropriate. ondary infections. Length of stay and mortality were numeri-
The present review aims to ascertain whether evidence exists cally but not significantly lower.
and to assess the strength of that evidence supporting the as- Micek et al. [100] also investigated the value of short-course
sertion that the duration of antibiotic therapy for patients with therapy in a randomized trial involving 290 patients. Of these
HCAP who have a clinical response should be 7 days. patients, 140 received conventional therapy at the discretion of
the treating physician. For the other 150 patients, the investi-
Methods gators followed the patients and made recommendations to the
A PubMed database search to identify studies related to the treating physician. Discontinuation was recommended if the
duration of treatment of HCAP was completed on 31 October patient had a noninfectious etiology or if the patient’s signs
2006. The search terms “pneumonia” and “health-care asso- and symptoms resolved. Treating physicians usually discontin-
ciated” resulted in 79,547 and 46,168 articles, respectively. ued antibiotic therapy within 48 h after the recommendation.
Combining the 2 terms yielded 632 articles. The text word Recommendations for discontinuation produced a significant

HCAP Summit Critical Appraisal • CID 2008:46 (Suppl 4) • S329


reduction in the duration of therapy, with no significant dif-
ferences in mortality, length of stay, or occurrence of secondary
VAP.
Finally, Chastre et al. [48] completed a prospective, random-
ized, 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 an-
tibiotic therapy. Patients who received a short course had nei-

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Figure 14. Voting comparison for statement 10 (“The duration of an-
ther excess mortality nor excess pulmonary infection recur-
tibiotic therapy for patients with HCAP with a clinical response should
rence. There were no significant differences regarding the be 7 days”). “Summit members” refers to the 11-member summit panel;
number of days alive without mechanical ventilation or without “IDSA members” refers to the members of the Infectious Diseases Society
organ failure, new antibiotic therapy received during the study of America who responded to a Web-based survey. HCAP, health care–
period, the duration of ICU stay, or the mortality rate at day associated pneumonia.
60. Patients infected with nonfermenting gram-negative rods
had a trend toward a higher chance of relapse when treated for are collected, it seems prudent to recommend that the duration
8 days. Resistant pathogens emerged more frequently in patients of antibiotic therapy for patients with HCAP with a clinical
with recurrent pulmonary infection who had received antibi- response should be 7 days.
otics for 15 days.
Future Directions
Grading of Evidence Appropriately designed epidemiologic studies with rigorous mi-
On the basis of a review of the 5 studies cited above, the crobiological criteria are clearly needed to better delineate the
members of the workshop agreed that the evidence available optimal duration of therapy for HCAP.
to support this statement was category V for the statement in
general, category IV for the statement as it applies to hospi- CONCLUSIONS
talized patients with HCAP, and category IV for the statement
The recent definition of HCAP as a distinct subset of pneu-
as it applies to nonhospitalized patients with HCAP (table 2).
monia was intended to identify those patients with an increased
risk of infection caused by MDR pathogens. Identification of
Level of Support patients at risk for infection with MDR pathogens increases the
When voting on the support for this statement, 9% of the likelihood of adequate empirical therapy while minimizing
summit participants voted to accept the statement completely, overuse of broad-spectrum antibiotics. Because initially inap-
64% voted to accept the statement with some reservations, and propriate antibiotic therapy is associated with increased mor-
27% voted to accept the statement with major reservations. In tality and overuse of antibiotics leads to increased antibiotic
comparison, of the 383 IDSA members who participated in the resistance, this strategy is intended to improve short-term out-
online survey, 13% voted to accept the statement completely, comes for individual patients and long-term outcomes for the
55% voted to accept the statement with some reservations, 15% general population.
voted to accept the statement with major reservations, 14% The goal of the HCAP Summit was to critically appraise the
voted to reject the statement with reservations, and 3% rejected existing literature to assess the relative strengths and limitations
the statement completely (figure 14). of our current knowledge in this area. The review was partic-
ularly challenging, given the historic use of the term “HCAP”
Discussion to describe many diverse entities, including HAP, VAP, and
There are currently no data on whether the duration of anti- NHAP. Overall, it is very clear that much is still unknown
biotic therapy for patients with HCAP with a clinical response regarding every aspect of HCAP examined during the summit.
should be 7 days. However, hospitalized patient data demon- A recurring theme, regardless of which practice statement
strate that patients with VAP can have a shorter therapy du- was being discussed, was the paucity of HCAP-specific data
ration, and data on nonhospitalized patients with CAP indicate and the frequent extrapolation of data from other nosocomial
that we can treat with shorter duration [109]. The benefits of infections. In the Defining HCAP workshop, the constraints of
a shorter course of antibiotic therapy include lower cost, fewer the current definition of HCAP were frequently identified as
potential adverse drug events, and, most importantly, a lower problematic. Because this is a relatively new definition, there
likelihood of selecting resistant bacteria. Until adequate data is room for debate regarding which patient subsets should be

S330 • CID 2008:46 (Suppl 4) • Kollef et al.


included, the prevalence of various MDR pathogens in these ter our summit was held, a new guideline by the IDSA and the
patients, the lack of distinction between hospitalized patients Society for Healthcare Epidemiology of America addressing the
and those treated in non–acute-care settings, overlap of the issue of antimicrobial stewardship was published [110]. We
outcomes of HCAP with both CAP and HAP, and the lack of include this reference for completeness, recognizing that this
consideration regarding severity of illness. However, there was document was not used in the summit discussions.
nearly unanimous agreement that severe CAP and HCAP con-
stitute distinct entities. Although the treatment of these entities Acknowledgments
shares similar principles, they are distinguished by the risk for Supplement sponsorship. This article was published as part of a sup-
infection with MDR pathogens, with the former also being plement entitled “Health Care–Associated Pneumonia (HCAP): A Critical
Appraisal to Improve Identification, Management, and Outcomes—Pro-

Downloaded from https://academic.oup.com/cid/article-abstract/46/Supplement_4/S296/273562 by guest on 04 October 2018


defined by severity-of-illness measures.
ceedings of the HCAP Summit,” sponsored by Medical Education Re-
In the Therapeutic Intervention workshop, these complex sources and Consensus Medical Communications and supported by an
theoretical concerns translated into discrepant opinions re- unrestricted educational grant from Ortho-McNeil administered by Ortho-
garding empirical therapy, de-escalation of antibiotic therapy, McNeil Janssen Scientific Affairs, LLC.
Potential conflicts of interest. M.H.K. has received grants/research
and the duration of treatment. These discussions focused on
support from Merck, Pfizer, Elan, Bard, Wyeth, and Johnson & Johnson.
the need to balance empirically covered MDR pathogens L.E.M. has been a speakers’ bureau participant for Pfizer, Ortho-McNeil,
through the use of broad-spectrum therapy while minimizing and Schering Plough. D.E.C. has received grants/research support from
Bard and Nomir; has been a speakers’ bureau participant for Merck, Elan,
the generation of more resistance through unnecessary anti-
Pfizer, Wyeth, and Sanofi Pasteur; and has received financial support from
biotic use. Highlighting the importance—and lack of consen- the Data and Safety Monitoring Board of Johnson & Johnson. J.E.M. has
sus—regarding this issue, summit participants felt compelled received grants/research support from AstraZeneca, Elan, Johnson & John-
son, PRD, Pfizer, and 3M, and has been a consultant for Merck, Elan,
to revise one of the statements to specify that the choice of
Replidyne, and Wyeth. S.T.M. has received grants/research support from
empirical HCAP therapy must consider treatment location, se- Johnson & Johnson. M.S.N. has been a consultant, shareholder, and speak-
verity of illness, prior antibiotic therapy, and functional status. ers’ bureau participant for Pfizer, Schering Plough, Ortho-McNeil, Aventis,
Although this revised statement was more widely accepted, it Merck, Elan, AstraZeneca, and Wyeth. D.L.P. has received grants/research
support from AstraZeneca, Elan, and Pfizer; has been a consultant for
was explicitly stated that this strategy was based more on in- Merck, Cubist Pharmaceuticals, Elan, Genzyne, KeyBay, Acureon, Wyeth,
tuition and opinion than on clinical data. and Johnson & Johnson; and has been a speakers’ bureau participant for
An examination of the disparities between summit partici- Merck, Elan, and Cubist Pharmaceuticals. All other authors: no conflicts.

pants’ opinions regarding the clinical practice statements and


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