Health Care Associated Pneumonia (HCAP): A Critical Appraisal to Improve Identification, Management, and Outcomes Proceedings of the HCAP Summit

SUPPLEMENT ARTICLE Health Care Associated Pneumonia (HCAP): A Critical Appraisal to Improve Identification, Management, and Outcomes Proceedings of the HCAP Summit Marin H. Kollef, 1 Lee E. Morrow, 3 Robert P. Baughman, 4 Donald E. Craven, 5 John E. McGowan, Jr., 6 Scott T. Micek, 2 Michael S. Niederman, 7 David Ost, 8 David L. Paterson, 9 and John Segreti 10 1 Washington University School of Medicine and 2 Barnes-Jewish Hospital, St. Louis, Missouri; 3 Creighton University Medical Center, Omaha, Nebraska; 4 University of Cincinnati Medical Center, Cincinnati, Ohio; 5 Tufts University School of Medicine, Boston, Massachusetts; 6 Rollins School of Public Health of Emory University, Atlanta, Georgia; 7 State University of New York at Stony Brook, Stony Brook, and 8 New York University School of Medicine, New York, New York; 9 University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania; and 10 Rush-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 environments, nonhospital settings present their own unique risks of pneumonia. Traditionally, pneumonia in these facilities has been categorized as community-acquired pneumonia (CAP). However, the new designation for pneumonias acquired in these settings is health care associated pneumonia (HCAP), which covers pneumonias acquired in health care environments outside of the traditional hospital setting and excludes hospital-acquired pneumonia (HAP), ventilator-associated pneumonia (VAP), and CAP. Although HCAP is currently treated with the same protocols as CAP, recent evidence indicates that HCAP differs from CAP with respect to pathogens and prognosis and, in fact, more closely resembles HAP and VAP. The HCAP Summit convened national infectious disease opinion leaders for the purpose of analyzing current literature, clinical trial data, diagnostic considerations, therapeutic options, and treatment guidelines related to HCAP. After an in-depth analysis of these areas, the infectious disease investigators participating in the summit were surveyed with regard to 10 clinical practice statements. The results were then compared with results of the same survey as completed by 744 Infectious Diseases Society of America members. The similarities and differences between those survey results are the basis of this publication. Pneumonia is one of the most common infections requiring hospitalization. Changes in the location and manner in which health care is currently administered have resulted in the need to reassess the classification scheme employed for pneumonia. This is most evident when dealing with the increasing numbers of ambulatory and nonhospitalized individuals who are in reg- Reprints or correspondence: Dr. Marin H. Kollef, Div. of Pulmonary and Critical Care Medicine, Washington University School of Medicine, 660 S. Euclid Ave., Campus Box 8052, St. Louis, MO 63110 (mkollef@imwustl.edu). Clinical Infectious Diseases 2008; 46:S296 334 2008 by the Infectious Diseases Society of America. All rights reserved. 1058-4838/2008/4608S4-0002$15.00 DOI: 10.1086/526355 ular contact with the health care system [1, 2]. Currently accepted classifications of pneumonia include community-acquired pneumonia (CAP), hospital-acquired pneumonia (HAP), ventilator-associated pneumonia (VAP), and nursing home associated pneumonia (NHAP). The designation of health care associated pneumonia (HCAP) was recently introduced to include an already-ill population of nursing-home residents, patients in long-term care, patients undergoing sameday procedures, patients receiving home- or hospitalbased intravenous therapy, and patients undergoing dialysis [3]. The patient population at risk for HCAP is large and diverse, probably making up the largest single category of patients with pneumonia [2, 4, 5]. In gen- S296 CID 2008:46 (Suppl 4) Kollef et al.

eral, patients who develop HCAP are more similar to hospitalized patients than to true community patients, in that they have a greater burden of comorbidities, including cancer, chronic kidney disease, heart disease, chronic obstructive lung disease, immunosuppression, dementia, and impaired mobility [2, 6, 7]. An important distinction of HCAP is that the pathogens are often multidrug-resistant (MDR) bacteria [2]. Therefore, the initial treatment of HCAP should be similar to that of HAP and VAP, which also differentiates it from CAP [3]. This is particularly important for clinicians working in first-response areas, such as emergency departments (EDs), to recognize, so that appropriate initial antimicrobial therapy is not delayed. Several studies have demonstrated that delaying the delivery of pathogen-appropriate antimicrobial therapy to patients with CAP and VAP results in excess mortality [8 10]. Thus, it is essential for physicians working in the ED to distinguish between HCAP and CAP, in order to correctly assess and manage suspected cases of pneumonia. This approach to HCAP also applies to other health care associated infections in which the pathogens are more similar to hospital-acquired organisms than to community-acquired ones [6, 11]. This supplement to Clinical Infectious Diseases represents the proceedings of a panel of investigators whose goal was to assess the quality of evidence in support of the clinical classification of HCAP as a distinct entity and the need for specific therapeutic interventions for HCAP. Ten clinical practice statements were drafted by the chair (M.H.K.) and the 2 workshop leaders (L.E.M. and R.P.B.) and were subsequently evaluated by the 11-member panel made up of leaders in infectious diseases, pulmonary and critical care medicine, and pharmacology (table 1). Before the summit was convened, each participant was assigned a statement and instructed to systematically review and summarize the evidence supporting or refuting that statement. In the first phase of the live meeting, the simultaneously conducted workshops Defining HCAP and Therapeutic Intervention included a leader and 4 5 content experts and served as a forum for each individual to present the evidence for his or her statement. When the data were presented, primary attention was given to the study methodology, the number of patients enrolled, and the outcome events. After the presentation of data for each statement, workshop members discussed the evidence, graded the strength of the evidence, and assigned the statement a consensus numeric grade for the Nature of the Evidence and the Grade of Recommendation (table 2). In the second phase of the live meeting, all summit panelists reconvened, reviewed the workshop summaries, and discussed each statement further. After each discussion, all participants voted on their individual levels of support, using the grading scheme shown in table 2. In addition to defining the level of evidence in support of Table 1. Health Care Associated Pneumonia (HCAP) Summit clinical practice statements. Workshop 1: Defining HCAP (statements 1 5) 1. The patient in/from a health care associated, nonhospital environment who develops a clinical presentation of pneumonia has HCAP. (J.E.M.) 2. The clinical and microbiological features of HCAP are more similar to HAP and VAP than to CAP. (L.E.M.) 3. The recommended evaluation of HCAP with treatment failures is the same as that for HAP. (Kenneth Leeper) 4. The definitions are the same for HCAP and HAP treatment failures. (D.O.) 5. Severe CAP is not HCAP. (D.E.C.) Workshop 2: Therapeutic Intervention (statements 6 10) 6. Initial empirical therapy for HCAP is the same as that for HAP. (M.S.N.) 7. Patients with HCAP who are at risk for gram-negative bacterial infections should receive dual empirical antibiotic coverage. (D.L.P.) 8. Patients should receive initial empirical therapy that covers MRSA at the time of HCAP diagnosis. (S.T.M.) 9. When microbiological data are unavailable, de-escalation in patients with HCAP should not occur. (R.P.B.) 10. The duration of antibiotic therapy for patients with HCAP with a clinical response should be 7 days. (J.S.) NOTE. CAP, community-acquired pneumonia; HAP, hospital-acquired pneumonia; MRSA, methicillin-resistant Staphylococcus aureus; VAP, ventilator-associated pneumonia. each statement, the panel members also outlined additional data required to further refine the statements for future clinical use. The main intention of this meeting was to provide a framework for future discussion and research in the area of HCAP. Before the summit meeting, clinical perspectives of practicing physicians were measured via a Web-based survey. E-mail polling was done to ascertain their level of support for the same 10 statements. The e-mail invitation to participate in the electronic survey was sent to 3200 members of the Infectious Diseases Society of America (IDSA) (all active e-mail addresses). Of the IDSA members surveyed, 383 (11.9%) responded. The purpose of the electronic surveys was to provide information that would allow for the comparison of data-driven responses from the content experts at the summit with those of clinicians practicing in the field. The summit participants and the surveyed physicians used the same grading scheme to rate the 10 statements (table 2). Note. Although the American Thoracic Society (ATS) IDSA guidelines were intended to apply only to patients with HCAP seen in the acute-care setting, those recommendations were extrapolated to nonhospitalized patients with HCAP for this summit. Accordingly, voting on the grade of evidence for each clinical practice statement was done 3 times: first, for the statement in general; second, for the statement as it applied to hospitalized patients with HCAP; and third, for the statement HCAP Summit Critical Appraisal CID 2008:46 (Suppl 4) S297

Table 2. Workshop and Health Care Associated Pneumonia (HCAP) Summit panel voting schemes. Category I II III IV V A B C D E Nature of evidence Evidence obtained from at least 1 well-designed, randomized, controlled trial Evidence obtained from well-designed cohort or case-control studies Evidence obtained from case series, case reports, or flawed clinical trials Opinions of respected authorities based on clinical experience, descriptive studies, or reports of expert committees Insufficient evidence to form an opinion Level of workshop support for statement There is good evidence to support the statement There is fair evidence to support the statement There is poor evidence to support the statement, but recommendations may be made on other grounds There is fair evidence to reject the statement 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 rationale for including those with community-acquired HCAP was that some data were available for this group, especially for those with NHAP. Therefore, the committee felt that there was sufficient evidence to make recommendations for some of the issues. However, several areas with insufficient information were identified. STATEMENT 1: THE PATIENT IN/FROM A HEALTH CARE ASSOCIATED, NONHOSPITAL ENVIRONMENT WHO DEVELOPS A CLINICAL PRESENTATION OF PNEUMONIA HAS HCAP Rationale and Definition of Statement In defining HCAP as a distinct clinical entity, the most recent ATS-IDSA nosocomial pneumonia guidelines defined a subset of patients at risk for harboring resistant organisms despite their residence in the community [3]. Criteria included hospitalization in an acute-care facility for 2 days within 90 days before the infection; residence in a nursing home or long-termcare facility; recent receipt of intravenous antibiotic therapy, chemotherapy, or wound care, within 30 days before the infection; or attending a hospital or hemodialysis clinic [3]. Although the ATS-IDSA guidelines were intended to apply only to hospitalized patients with HCAP, it is apparent that these concepts are being extrapolated to nonhospitalized patients with HCAP as well [12]. By definition, the ATS-IDSA guidelines apply to patients coming to an acute-care facility from a nonhospital environment, whether the patient is seen in an outpatient facility or ED or is admitted directly to the hospital. However, there is a question regarding whether the guidelines for such patients should also apply to patients who remain in a nonhospital environment, such as a nursing home or longterm-care facility, or who remain in another setting but who meet the other ATS-IDSA criteria for having HCAP [3]. Methods A search of the OVID 1996-present database to identify studies related to descriptions of HCAP was completed on 1 November 2006. The search of the combined term health care associated or healthcare-associated produced a total of 144 articles. Next, the text word search for the term HCAP yielded 66 articles, and the text word search for healthcare-associated pneumonia resulted in 7 articles. At this point, the 2 text word searches were combined with the first combined-term search, and the results were limited to the English language. This produced 82 articles. The same search strategy was then used in the OVID database in process, and an additional 10 articles were identified. By scanning the titles of these 92 articles, 14 relevant articles were noted, and a review of the references for these 14 articles added 4 articles to the total. Thus, 18 articles were considered to be relevant to this statement. Evidence Definitions of HCAP. Several definitions of HCAP are stated or implied in the medical literature. One prevalent use of the term, considered to be irrelevant to this discussion, is the use S298 CID 2008:46 (Suppl 4) Kollef et al.

of health care associated as a replacement for or synonym of nosocomial or hospital associated [13]. A second use of the term is hospitalized with community-acquired pneumonia, which also fails to capture the concept presented in the ATS-IDSA guidelines [14]. The relevant concept is that pneumonia not acquired in an acute-care hospital (traditionally labeled as community-acquired infection ) is more likely to have a spectrum of pathogens that resemble those associated with HAP or VAP than to have a distribution of microbes traditionally associated with CAP. HCAP as a distinct entity. Differences in the likely prevalence of drug-resistant pathogens were highlighted in a study by Friedman et al. [6] of health care associated bloodstream infections in adults, which defined patients with health care associated bacteremia in a fashion similar to the ATS-IDSA guidelines. Patients with health care associated bacteremia were similar to those with hospital-acquired bloodstream infections, with regard to frequency of comorbid conditions, pathogens and their susceptibility, and mortality rates. The authors concluded that a separate category for [health care associated] infections is justified, and this new category will have obvious implications for choices about empirical therapy and infectioncontrol surveillance [6, p. 791]. This theme was echoed and expanded to include pneumonia in a 2004 editorial by Craven, who stated, compared with patients with community-acquired pneumonia (CAP), those with HCAP are often at greater risk for colonization and infection with a wider spectrum of multidrug-resistant organisms [4, p. 153]. However, Grossman et al., in a review of practice guidelines for treatment of lowerrespiratory-tract infections in hospitalized patients, concluded that HCAP is treated similarly to HAP and may be considered with HAP [15, p. 295]. Kollef et al. [2] reviewed a large database of 4543 patients with culture-positive pneumonia and identified 20% as having HCAP. The percentage of patients with a culture positive for Staphylococcus aureus was similar among those with HCAP (46.7%) and those with HAP (47.1%), and mean mortality rates (19.8% and 18.8%, respectively) were similar for these 2 groups of patients as well. The mean length of stay for patients with HCAP was intermediate between that for patients with CAP and that for patients with HAP. The authors concluded that this analysis justified HCAP as a new category of pneumonia [2, p. 3854]. Pop-Vicas et al. [16] noted an increasing prevalence of MDR, gram-negative bacilli recovered at admission to a tertiary-care hospital. Factors independently associated with the isolation of resistant organisms (age 65 years, prior antibiotic therapy for 2 weeks, and residence in a long-term-care facility) were similar to those used to define HCAP. The editorial response to the ATS-IDSA definition of HCAP has been mixed. Hiramatsu and Niederman [1, p. 3786] note that publication of these recommendations has been recognized by the Centers for Medicare and Medicaid Services in their application of core measures for the treatment of CAP. This action has led to the exclusion of patients with HCAP from studies of adherence to antibiotic therapy recommendations for patients with CAP. Fujitani et al. [17, pp. 627 and 630] considered the classification of HCAP as a separate disease entity to be a good idea but noted problems with its execution. They noted that the definitions of HAP, CAP, and HCAP have varied among different large-scale studies and suggest that classification schemes are inherently imprecise because patient groups overlap in the HCAP categories. Wunderink [18, p. 2686] also noted that a distinction between HCAP and CAP has never been totally clear. He concluded, however, by stating that despite these issues, defining the HCAP category has led to more appropriate antibiotic therapy for the majority of patients and clearly assisted decision making [18]. Differences in application of the definition by setting. The previous studies dealt with patients seen in, or admitted to, acute-care hospitals. However, many patients with pneumonia acquired in a nursing home setting are not transferred to an acute-care hospital. For example, Loeb et al. [19] conducted a cluster-randomized controlled trial of different regimens for treatment of pneumonia in nursing home residents in Canada. Only 110 of 661 evaluated patients were hospitalized. The degree to which the HCAP definition applies to patients with pneumonia who remain in nonhospital health care settings, such as nursing homes, is not clear. Mortality rates for NHAP are higher than those for CAP [20, 21], but controlling for different factors that affect this risk is difficult. For example, in a review by El Sohl et al. [22] of 88 patients with cultureconfirmed cases of severe pneumonia, previous use of antibiotics (a component of the ATS-IDSA definition) was found to be predictive of the presence of drug-resistant bacteria. However, the other predictor of drug resistance in this study was a lower Activities of Daily Living (ADL) score, a feature not considered in the ATS-IDSA definition of HCAP. Likewise, at least 1 study suggests that the risk of MDR bacteria being present is no higher for NHAP than for CAP [20]. It was acknowledged that the literature on NHAP is dated and incomplete; this area needs further investigation. Grading of Evidence On the basis of a review of the studies cited above, the 5 members of this workshop agreed that the evidence available to support this statement was category III (a mixture of the 2 following votes) for the statement in general, category IV (primarily from definition) for the statement as it applies to hospitalized patients with HCAP, and category V (insufficient 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 comparison, of the 383 IDSA members who participated in the online survey, 48% accepted the statement completely, 42% accepted the statement with some reservations, 4% accepted the statement with major reservations, 4% rejected the statement with reservations, and 2% rejected the statement completely (figure 1). It was thought by the summit participants that IDSA members were considering the statement primarily for its intended purpose of applicability to patients with HCAP seen in the acute-care hospital setting. Discussion By definition, the ATS-IDSA guidelines apply to patients coming to an acute-care facility from a nonhospital environment, whether the patient is seen in an outpatient facility or ED or is admitted directly to the hospital, and the different panels supported this definition. The concept is presented graphically in figure 2, which represents CAP, HCAP, and HAP as separate entities for which, in general, the likelihood of the presence of MDR organisms increases [23]. Less well documented, but still likely, is that rates of mortality and morbidity also increase as one considers the entities on the right side of the figure. There is, however, overlap between the 3 defined entities; for example, patients with severe CAP might have higher mean mortality rates than do those with HCAP. Similarly, the prevalence of MDR organisms may be high for patients with CAP in some areas where selective pressure due to antimicrobial use is high. It is important to appreciate that these 2 features (severity and Figure 1. Voting comparison for statement 1 ( The patient in/from a health care associated, nonhospital environment who develops a clinical presentation of pneumonia has HCAP ). Summit members refers to the 11-member summit panel; IDSA members refers to the members of the Infectious Diseases Society of America who responded to a Webbased survey. HCAP, health care associated pneumonia. Figure 2. Relationship of health care associated pneumonia (HCAP) to community-acquired pneumonia (CAP), hospital-acquired pneumonia (HAP), and ventilator-associated pneumonia (VAP). Note also the increased risk for colonization and infection with multidrug-resistant (MDR) pathogens, morbidity, and mortality in these groups. Adapted in part from [23]. prevalence of MDR) are not necessarily linked one may be high while the other is not. There is, however, insufficient evidence to decide the validity of the HCAP category as it relates to patients remaining in nursing homes or other non acute-care health settings, as is reflected in the summit participants grading of the evidence. The value of extrapolating the ATS-IDSA definition to these settings requires further study. Likewise, for other non acutecare health settings, including those of specific subsets of patients with HCAP (those receiving hemodialysis, home infusion, wound care, chemotherapy, or recent antibiotics or who have a relative with resistant pathogens), the available data are very limited. Future Directions The paucity of data highlighted in the previous section provides valuable opportunities to determine the relevance of HCAP for the special populations noted and to continue to explore the validity of specific criteria used to define the entity. Of particular note is the observation by Fujitani et al. [17, p. 630], who suggested that a more precise classification to minimize such overlap would allow easier comparison among studies of this entity so a rigorous database can be accumulated for future investigations. STATEMENT 2: THE CLINICAL AND MICROBIOLOGICAL FEATURES OF HCAP ARE MORE SIMILAR TO HAP AND VAP THAN TO CAP Rationale and Definition of Statement Historically, patients with HCAP have been treated with antibiotic regimens recommended by CAP guidelines. As the prevalence of antimicrobial resistance has increased, particularly in S300 CID 2008:46 (Suppl 4) Kollef et al.

patients whose conditions meet HCAP criteria, many clinicians have questioned whether these antibiotic regimens are appropriate. This is of particular importance, given the association between inadequate empirical antibiotic therapy and increased mortality rates. To address these concerns, the ATS-IDSA guidelines recommended broad empirical antibiotic therapy followed by culture-guided de-escalation for patients with HCAP. Although these concepts were intuitive and widely embraced by clinicians, critics expressed concerns regarding the data supporting such significant changes to the guidelines. Because the guidelines cite only 7 references relating to HCAP, this section aims to assess the strength of evidence supporting the assertion that clinical and microbiological features of HCAP are more similar to those of HAP than to those of CAP. Methods HCAP. A PubMed database search to identify studies related to the clinical and microbiological features of HCAP was completed on 24 October 2006. The search terms health care associated pneumonia, healthcare associated pneumonia, health care-associated pneumonia, and healthcare-associated pneumonia gave a total of 48,465 articles. The search terms microbiology and pathogen yielded 551,438 articles. Combining the HCAP search with the microbiology search by use of the AND function produced 138 articles. After limiting these to the English language, 129 articles were reviewed. Only 3 were deemed relevant to the statement. Because HCAP includes multiple entities previously referred to by use of other terminology, several additional searches were conducted. NHAP. The search terms pneumonia and lower respiratory tract infection were combined with the OR function to identify 86,173 articles. The search terms nursing home and long term care were combined with the OR function to identify 44,206 articles. The nursing home and pneumonia searches were combined using the AND function to give 616 articles. When these were combined with the previous microbiology search and limited to the English language, 112 articles were reviewed. Only 5 were deemed relevant to the statement. One article was then added from these articles references, and another recent abstract also was included. Hemodialysis-associated pneumonia. The search terms hemodialysis and dialysis were combined with the OR function to identify 111,259 articles. When these were combined with the prior pneumonia and microbiology searches and limited to the English language, 54 articles were reviewed. One article was deemed relevant to the statement. Home care and wound care associated pneumonia. The search terms home care and wound care were combined with the OR function for a total of 49,986 articles. These were combined with the prior pneumonia and microbiology searches and limited to the English language, yielding 134 articles for review. One article was deemed relevant to the statement. Chemotherapy-associated pneumonia. The search term cancer chemotherapy yielded 311,108 articles. These were combined with the prior pneumonia and microbiology searches to give 348 articles. After limiting these to the English language, 268 articles were reviewed, and 4 were deemed relevant. Queries using multiple search terms relating to pneumonia in patients who have a family member with resistant pathogens and/or patients who have received prior antibiotic therapy did not result in any articles being found. Evidence HCAP. Only 1 study was identified that specifically focused on the microbiology of HCAP [2]. In this retrospective cohort analysis of a multi-institutional database, 4543 cases of culturepositive pneumonia were identified by International Classification of Diseases, Ninth Revision codes. Patients were then stratified as having CAP (49%), HCAP (22%), HAP (18%), or VAP (11%). The most common pathogens in HCAP were methicillin-resistant S. aureus (MRSA) and Pseudomonas aeruginosa (26.5% and 25.3%, respectively), similar to HAP (22.9% and 18.4%; P!.01 for P. aeruginosa). Conversely, Streptococcus pneumoniae and Haemophilus species were seen more frequently in CAP (16.6% and 16.6%) than in HCAP (3.1% and 5.8%; P!.01 for both). The mortality rates among patients with HCAP and patients with HAP were similar (19.8% and 18.8%, respectively; P 1.05) and were significantly higher than that among patients with CAP (10.0%; P!.0001). Limitations of this study included the use of data only for hospitalized patients, inclusion of only patients with early-onset pneumonia, misclassification bias, and exclusion of patients with negative culture results. Also unresolved are the very high rates of Pseudomonas species (17.1%) and methicillin-susceptible S. aureus (17.2%) as the causative pathogens in patients with CAP. The clinical features of HCAP were not assessed in this study. Two additional studies assessed the risk factors for colonization with resistant organisms in hospitalized patients, many of whom did not have pneumonia. The first of these studies assessed variables associated with MDR gram-negative bacillus carriage [16]. In this prospective, case-control study, it was found that predictors of MDR gram-negative bacillus colonization included several subsets of patients also included in the new ATS-IDSA definition of HCAP: residents of long-termcare facilities, patients undergoing hemodialysis, and patients who have recently received antibiotic therapy. Similarly, a prospective surveillance study of MRSA showed that patients whose conditions met HCAP criteria (patients who have recently been hospitalized, residents of long-term-care facilities, patients undergoing dialysis, or patients receiving home nursing HCAP Summit Critical Appraisal CID 2008:46 (Suppl 4) S301

care) accounted for 99% of community-acquired MRSA cases [24]. NHAP. Seven studies of the clinical and microbiological features of NHAP were identified. A prospective case-control study comparing patients with NHAP and age-matched patients with CAP showed that the presentation of pneumonia was strikingly different between groups. Compared with patients with CAP, patients with NHAP were less likely to have a productive cough (61% vs. 35%; P!.05), chills (58% vs. 24%; P!.05), headache (32% vs. 5%; P!.05), sore throat (19% vs. 7%; P!.05), myalgia (33% vs. 7%; P!.05), or arthralgia (10% vs. 0%; P!.05). Although the difference was reported as being statistically nonsignificant, patients with NHAP were almost twice as likely to have confusion (70% vs. 37%). Patients with NHAP were also more likely to die in the hospital (32% vs. 14%; P!.05) [21]. A retrospective cohort analysis comparing the clinical presentations of NHAP and CAP found that patients with NHAP were more likely to have altered mental status (55.9% vs. 11.3%; P!.001), tachypnea (40.9% vs. 22.8%; P!.001), and hypotension (7.0% vs. 1.1%; P!.001) [25]. The presence of subjective variables, such as cough, dyspnea, and pleuritic chest pain, could not be assessed. Patients with NHAP also had a significantly higher mortality rate (18.6% vs. 8.0%; P!.001). In a prospective cohort of 437 consecutive patients with pneumonia, 40 (9%) of the patients resided in nursing homes [20]. These patients with NHAP were less likely than were those with other types of pneumonia to have a productive cough (OR, 0.4; P p.02) or pleuritic pain (OR, 0.1; P p.03) but were more likely to be confused (OR, 2.6; P!.001). Compared with age-matched control individuals living in the community, the patients with NHAP had a significantly higher mortality rate (53.0% vs. 13.4%; P!.001). An article reviewing 18 primary studies published between 1978 and 1994 evaluated the etiology of pneumonia in residents of long-term-care facilities [26]. In this study, the most common pathogens were gram-negative bacilli (18%), S. pneumoniae (16%), Haemophilus influenzae (11%), and S. aureus (6%). Mycoplasma, Chlamydia, and Legionella species accounted for!1% of cases, and 29% of cases did not have an identifiable pathogen. The primary studies showed marked variability in the frequency of causative pathogens: gram-negative bacilli isolation varied from 0% to 55% across studies; that of S. pneumoniae ranged from 0% to 39%; that of S. aureus, from 0% to 33%; and that of Legionella species, from 0% to 6%. The primary studies evaluations of the causative pathogens were widely discrepant: some had no microbiological criteria, others required a high-quality sputum specimen, and some allowed positive blood culture results to suffice if sputum results were negative. None of the studies rigorously pursued the isolation of atypical organisms. A prospective cohort of 104 very elderly patients (mean age SD, 82.3 5.5 years) admitted to the intensive care unit (ICU) with severe pneumonia requiring mechanical ventilation identified a pathogen in 55 patients (53%) by use of an aggressive and invasive approach that included bronchoalveolar lavage (BAL) [27]. Although no formal statistical comparisons of community residents and long-term-care facility residents were performed, patients with NHAP had higher rates of altered mental status (76% vs. 42%) and fever (65% vs. 44%) but a lower rate of chest pain (5% vs. 20%) at admission. Compared with patients with CAP, fewer patients with NHAP had S. pneumoniae isolated (8.5% vs. 14.0%), but more patients with NHAP had S. aureus isolated (29.7% vs. 7.0%). All Staphylococcus isolates from patients with CAP were methicillin susceptible, whereas 78.6% of Staphylococcus isolates (11 of 14) from patients with NHAP were methicillin resistant. In a similar study by the same authors, patients with NHAP requiring mechanical ventilation underwent BAL in an attempt to identify those at risk for harboring resistant pathogens [22]. The most common pathogens included S. aureus (23.9%, of which 61.9% were MRSA) and S. pneumoniae (18.2%). Predictors of infection with resistant pathogens included functional dependence and prior antibiotic exposure. Another recent study assessed the risk factors for colonization with MDR organisms in residents of long-term-care facilities [28]. In a point-prevalence study of 84 individuals, surveillance nasal and rectal cultures were assessed for organisms resistant to 3 frequently prescribed antibiotics. The prevalence of colonization with MDR organisms was 51%, with the most common organisms being Providencia stuartii (31% of isolates), Proteus mirabilis (21%), Escherichia coli (19%), and Morganella morganii (19%). Independent predictors of colonization by multivariate regression analysis included fecal incontinence (OR, 3.78; P p.038) and prior antibiotic exposure (OR, 2.5; P p.047). PFGE identified high rates of identical or related strain types, which suggested substantial horizontal transmission. Dialysis-associated pneumonia. Only 1 study was identified as dealing specifically with pneumonia in patients undergoing long-term hemodialysis [29]. This retrospective cohort analysis linked the waves 1, 3, and 4 Dialysis Morbidity and Mortality Study data sets with Medicare claims to identify 3101 hospital admissions for pneumonia in patients undergoing long-term hemodialysis. Overall, the frequency of microbiological confirmation was very poor (18.2%). In patients with microbiologically confirmed pneumonia, the most common pathogens were S. pneumoniae (18.7%), P. aeruginosa (15.4%), Klebsiella species (8.8%), and H. influenzae (8.2%). Despite high rates of colonization with MRSA in the dialysis population, Staphylococcus species were infrequently the causative pathogen (2.2%). S302 CID 2008:46 (Suppl 4) Kollef et al.

Pneumonia in patients receiving home infusion therapy or wound care. One study was identified that specifically assessed pneumonia in patients receiving home nursing care. In this prospective case-control study of 175 patients with MRSA infection, 41 patients had pneumonia [30]. Multivariate regression analysis identified a highly significant association between MRSA infection and prior receipt of home nursing care (OR, 3.7; P!.001). Other independent risk factors included prior hospitalization and transfer from another institution, such as a nursing home. Pneumonia in patients undergoing chemotherapy. Three studies were identified as relating specifically to pneumonia in patients undergoing chemotherapy. In a prospective observational cohort study of 52 consecutive pneumonia cases among patients with acute leukemia undergoing chemotherapy, the presentation was relatively subtle [31]. The signs and symptoms present in more than half of patients included fever (98%), dyspnea (79%), rales (77%), chills (73%), cough (65%), and sputum production (58%). A causative pathogen was found in 71% of cases, but only 52% were identified antemortem. The most common organisms were fungi (25.0%), Pseudomonas species (23.1%), and Klebsiella species (13.4%). In another prospective cohort of 242 consecutive pneumonia cases among patients with malignancy undergoing antineoplastic chemotherapy, the clinical presentation was similarly subtle [32]. Clinical presentation in more than half of patients included fever (90%), a positive radiographic finding (83%), and rales (65%). Gram-negative bacilli accounted for 90% of cases, with the most common pathogens being Klebsiella species (31.8%) and Pseudomonas species (18.6%). The final study was a prospective surveillance study of neutropenic patients with bacteremic pneumonia [33]. Although 408 cases of pneumonia were identified, clinical and microbiological data were reported only for the 40 patients with concurrent bacteremia. The only sign of pneumonia present in more than half of patients was fever (95%). Cough was the most common symptom of pneumonia and was present in only 47% of patients. The most common pathogens identified were P. aeruginosa (42.5%), S. pneumoniae (30.0%), and E. coli (12.5%). Pneumonia in patients with a relative harboring MDR pathogens. No studies were identified as specifically assessing either the clinical presentation or microbiological features of pneumonia in patients who have a relative with known MDR pathogens. Pneumonia in patients who have recently received antibiotics. No studies were identified as specifically assessing either the clinical presentation or microbiological features of pneumonia in patients who have recently received antibiotics. However, several of the previously cited studies identified prior antibiotic exposure as a risk factor for colonization or infection with resistant pathogens [16, 22, 28]. Grading of Evidence On the basis of a review of the 15 studies cited above, the 5 members of this workshop agreed that the evidence available to support this statement was category II for the statement in general, category II for the statement as it applies to hospitalized patients with HCAP, and category V for the statement as it applies to nonhospitalized patients with HCAP (table 2). Level of Support When voting on the support for this statement, 9% of the summit participants voted to accept the statement completely, 64% voted to accept the statement with some reservations, 18% voted to accept the statement with major reservations, and 9% voted to reject the statement with reservations. In comparison, of the 383 IDSA members who participated in the online survey, 40% voted to accept the statement completely, 47% voted to accept the statement with some reservations, 7% voted to accept the statement with major reservations, 5% voted to reject the statement with reservations, and 1% voted to reject the statement completely (figure 3). Discussion This statement is of key importance, given that the relevance of the remaining statements discussed at the summit hinges on the assertion that HCAP constitutes a distinct clinical entity with unique microbiological features. At present, there is limited conclusive evidence supporting this statement, as is reflected in the summit participants grading of the evidence. All of the reviewed studies support the assertion that the clinical features of HCAP are different from those of CAP. Although patients with HCAP are generally less likely to have Figure 3. Voting comparison for statement 2 ( The clinical and microbiological features of HCAP are more similar to HAP and VAP than to CAP ). Summit members refers to the 11-member summit panel; IDSA members refers to the members of the Infectious Diseases Society of America who responded to a Web-based survey. CAP, community-acquired pneumonia; HAP, hospital-acquired pneumonia; HCAP, health care associated pneumonia; VAP, ventilator-associated pneumonia. HCAP Summit Critical Appraisal CID 2008:46 (Suppl 4) S303

symptoms, the fever response is preserved, and the likelihood of altered mental status is increased. This combination of factors may lead to delayed recognition and initiation of therapy, thereby explaining the increased rates of hypoxemia, systemic hypotension, and death. Presently, there is only 1 study of the microbiology of HCAP as it is specifically defined by the ATS-IDSA guidelines [2]. Although this study has several limitations, it corroborates the assertion of earlier, less rigorous studies concluding that HCAP is more likely to be caused by organisms that are particularly virulent and/or resistant to antibiotic therapy. Of the individual subsets grouped together under the HCAP umbrella, NHAP provides the richest data in terms of the published literature. However, these studies were also the most likely to be confounded by variables such as comorbid illness or prior antibiotic therapy. These studies routinely had limited microbiological data that were of very poor quality. Another concern is the possible obsolescence of older studies, given the changes in pathogen susceptibilities over time. Although nursing home residents have very high rates of colonization with MDR pathogens and these organisms are seen more frequently in patients with NHAP CAP pathogens are also frequently isolated from these patients. The present NHAP knowledge base also suffers from a hospitalization bias; the available studies have rigorously evaluated the causative organisms only in hospitalized patients. This is problematic, because prior therapy has frequently failed for these patients at nursing homes, thereby artificially increasing the frequency of virulent and/or resistant organisms. There is also an extensive literature base showing the good clinical responses of many patients with NHAP who receive in-facility CAP therapy. In all, NHAP appears to be a hybrid entity, blending conventional CAP organisms with increased rates of HAP pathogens. For the remaining subsets of patients with HCAP (those receiving hemodialysis, home infusion, wound care, chemotherapy, or recent antibiotics or who have a relative with resistant pathogens), the available data are very limited and likely suffer from obsolescence. Although it is intuitive to group these patients together, given their increased contact with the health system, the data do not clearly justify doing so. The high rate of fungal infections in patients undergoing chemotherapy reinforces that HCAP subgroups although clearly distinct from CAP are also different from one another. Future Directions Future directions discussed by the summit members reflect many of the limitations of previously discussed studies. Appropriately designed epidemiologic studies with rigorous microbiological criteria clearly are needed to better delineate the causative pathogens of CAP, HAP, and HCAP. Although the use of standardized diagnostic and laboratory criteria would be essential, these criteria do not exist. These large, observational cohorts would need to be followed longitudinally to assess changes in pathogens and resistance patterns over time. STATEMENT 3: THE RECOMMENDED EVALUATION OF HCAP WITH TREATMENT FAILURES IS THE SAME AS THAT FOR HAP Rationale and Definition of Statement Nonresolving pneumonia is variably defined but represents a clinical syndrome in which focal infiltrates persist with signs and symptoms of acute pulmonary infection (e.g., fever, expectoration, malaise, or dyspnea). Despite receiving a minimum of 10 days of antibiotic therapy, patients either do not improve or worsen clinically, or radiographic opacities fail to resolve within 12 weeks after the onset of pneumonia [34 36]. Nonresolving pneumonia often represents treatment failure or a superinfection [37, 38]. In addition to being the result of initial therapy failure or a noninfectious etiology, nonresolving pneumonia may also be the result of an overwhelming immune response to a specific pathogen. It is critical to identify patients at risk for nonresponding pneumonia, to institute early appropriate therapy. Patients with severe HCAP, underlying comorbidities, and certain etiologic agents (viral, atypical) are at greater risk for nonresolving pneumonia and may benefit from alternative supportive approaches (e.g., early tracheostomy) as well as from immune modulation in specific circumstances (e.g., progression to acute lung injury or pneumococcal sepsis). Methods The original PubMed search was conducted in November 2006 and was augmented with a search performed in April 2007. By selection of articles published in English on the duration of nonresolving pneumonia, 50 references focusing on both CAP and HCAP were identified. These were reviewed along with their bibliographies for additional references. Evidence The use of the clinical pulmonary infection score (CPIS) to define resolution of nosocomial pneumonia was evaluated by Luna et al. [39]. These investigators prospectively evaluated 63 patients with microbiologically confirmed VAP. CPISs were followed serially and were noted to improve as early as the third day of therapy in the group of survivors. Patients who did not survive did not demonstrate any improvement in their CPIS, particularly in oxygenation. Patients without treatment response were also significantly more likely to receive inadequate initial treatment and had a higher mortality rate, compared with patients with treatment response. This study suggests that a clinical scoring system may be useful in the early identification of patients with pneumonia whose conditions are unlikely to S304 CID 2008:46 (Suppl 4) Kollef et al.

respond to therapy or who have delayed resolution, in part related to inadequate initial therapy. Resolution can also be defined microbiologically. On the basis of serial quantitative cultures from respiratory secretions, the eradication or persistence of an organism can be demonstrated. In the prospective series studied by Garrard and A Court [40], nonbronchoscopic lung lavage specimens were obtained from 83 patients with nosocomial pneumonia. The investigators found that serial culture results correlated well with the scored clinical responses. Culture counts increased in the few days before the onset of therapy and decreased dramatically after its initiation. In most cases, the culture counts had decreased by 24 h, but they decreased no later than 72 h in all cases of resolving pneumonia. Nonresolving pneumonia was thus equally well defined by both clinical and microbiological criteria, although clinical nonresponse required more time to determine. Menéndez et al. [41] identified factors associated with failure of empirical treatment and determined the incidence of both early (!72 h) and late treatment failure and related implications on the outcome. A prospective, multicenter cohort study was performed involving 1424 hospitalized patients from 15 hospitals. Treatment failure occurred in 215 patients (15.1%): 134 (62.3%) had early failures and 81 (37.7%) had late failures. The causes were infectious in 86 patients (40%), noninfectious in 34 patients (15.8%), and undetermined in 95 patients (44.2%). The independent risk factors associated with treatment failure in a stepwise logistic regression analysis were liver disease, pneumonia risk class, leukopenia, multilobar CAP, pleural effusion, and radiologic signs of cavitation. Independent factors associated with a lower risk of treatment failure were influenza vaccination, initial treatment with fluoroquinolones, and chronic obstructive pulmonary disease. Mortality was significantly higher in patients with treatment failure than in those without treatment failure (25% vs. 2%). Failure of empirical treatment increased the rate of mortality due to CAP 11-fold after adjustment for risk class. Rosón et al. [42] performed an observational analysis of a prospective series of 1383 nonimmunosuppressed hospitalized adults with CAP to identify and categorize causes and factors associated with early failure. At 48 72 h, 238 patients (18%) remained febrile, but most of them responded without further changes in antibiotic therapy, and 81 patients (6%) had early failure. The main causes of early failure were progressive pneumonia ( ), pleural empyema ( ), lack of response n p 54 n p 18 ( ), and uncontrolled sepsis ( ). Independent factors n p 13 n p 9 associated with early failure were older age (165 years) (OR, 0.35), multilobar pneumonia (OR, 1.81), Pneumonia Severity Index (PSI) score 190 (OR, 2.75), Legionella pneumonia (OR, 2.71), gram-negative bacillary pneumonia (OR, 4.34), and discordant antimicrobial therapy (OR, 2.51). Compared with patients with treatment response, patients with early treatment failure had significantly higher rates of complications (58% vs. 24%) and overall mortality (27% vs. 4%) ( P!.001 for both). An etiologic diagnosis was established in 598 patients with early treatment response (48%) and 55 patients with early treatment failure (68%) ( P!.01). Of patients with an etiologic diagnosis, 316 (53%) with early response and 48 (87%) with early failure were classified as definitive. The most frequently identified pathogens in the early-response and early-failure groups were S. pneumoniae (23% and 22%, respectively), Legionella species (6% and 21%), H. influenzae (6% and 5%), and organisms associated with aspiration pneumonia (6% and 6%). Legionella pneumophila and gram-negative bacilli were found more frequently in patients with early failure ( P!.001 and P p.03, respectively). Most patients were initially treated with a single antimicrobial agent, mainly in the early-response group (77% of those with early responses and 65% of those with early failures). The antibiotics most frequently prescribed were the b-lactams (mainly ceftriaxone and amoxicillin-clavulanate). Overall, of the 81 patients for whom treatment failed, concordance of therapy could be determined in 52 patients. In general, patients with early failure received discordant antimicrobial therapy more frequently (16 [31%] of 52 patients) than did patients with early response (52 [9%] of 584 patients). Treatment failed in 1 patient owing to resistance to a recommended regimen; he experienced breakthrough levofloxacin-resistant S. pneumoniae bacteremia (MIC of levofloxacin, 64 mg/ml) after 48 h of intravenous levofloxacin therapy. Because most studies of resolution have included only patients with CAP, the normal resolution of nosocomial pneumonia is more uncertain. Several investigators, however, have identified risk factors for poor outcomes, including death. By inference, the factors promoting a poor outcome may be linked to delayed resolution. Celis et al. [43] identified prognostic factors for nosocomial pneumonia. They reported that respiratory failure, the presence of a fatal underlying condition, age 160 years, and the presence of bilateral radiographic involvement were associated with a significantly increased risk of mortality. Additionally, infection with high-risk organisms, such as P. aeruginosa, S. aureus, other gram-negative bacilli, Candida species, or Aspergillus species, was associated with worse outcomes. In addition to observing longer resolution times with gramnegative bacterial infections, Graybill et al. [44] noted the significance of certain host factors, such as cardiovascular disease, a variety of malignant neoplasms, prior cerebrovascular accident, alcoholism, chronic obstructive pulmonary disease, renal impairment requiring hemodialysis, and diabetes. In his 1973 study of 82 patients with nosocomial pneumonia, prolonged resolution was defined as radiographic abnormalities extending HCAP Summit Critical Appraisal CID 2008:46 (Suppl 4) S305