American Thoracic Society Documents Guidelines for the Management of Adults with Hospital-acquired, Ventilator-associated, and Healthcare-associated Pneumonia This official statement of the American Thoracic Society and the Infectious Diseases Society of America was approved by the ATS Board of Directors, December 2004 and the IDSA Guideline Committee, October 2004 CONTENTS Executive Summary Introduction Methodology Used to Prepare the Guideline Epidemiology Incidence Etiology Major Epidemiologic Points Pathogenesis Major Points for Pathogenesis Modifiable Risk Factors Intubation and Mechanical Ventilation Aspiration, Body Position, and Enteral Feeding Modulation of Colonization: Oral Antiseptics and Antibiotics Stress Bleeding Prophylaxis, Transfusion, and Glucose Control Major Points and Recommendations for Modifiable Risk Factors Diagnostic Testing Major Points and Recommendations for Diagnosis Diagnostic Strategies and Approaches Clinical Strategy Bacteriologic Strategy Recommended Diagnostic Strategy Major Points and Recommendations for Comparing Diagnostic Strategies Antibiotic Treatment of Hospital-acquired Pneumonia General Approach Initial Empiric Antibiotic Therapy Appropriate Antibiotic Selection and Adequate Dosing Local Instillation and Aerosolized Antibiotics Combination versus Monotherapy Duration of Therapy Major Points and Recommendations for Optimal Antibiotic Therapy Specific Antibiotic Regimens Antibiotic Heterogeneity and Antibiotic Cycling Response to Therapy Modification of Empiric Antibiotic Regimens Defining the Normal Pattern of Resolution Reasons for Deterioration or Nonresolution Evaluation of the Nonresponding Patient Major Points and Recommendations for Assessing Response to Therapy Suggested Performance Indicators EXECUTIVE SUMMARY Since the initial 1996 American Thoracic Society (ATS) guide- line on nosocomial pneumonia, a number of new developments Am J Respir Crit Care Med Vol 171. pp 388���416, 2005 DOI: 10.1164/rccm.200405-644ST Internet address: www.atsjournals.org have appeared, mandating a new evidence-based guideline for hospital-acquired pneumonia (HAP), including healthcare-asso- ciated pneumonia (HCAP) and ventilator-associated pneumonia (VAP). This document, prepared by a joint committee of the ATS and Infectious Diseases Society of America (IDSA), fo- cuses on the epidemiology and pathogenesis of bacterial pneu- monia in adults, and emphasizes modifiable risk factors for infec- tion. In addition, the microbiology of HAP is reviewed, with an emphasis on multidrug-resistant (MDR) bacterial pathogens, such as Pseudomonas aeruginosa, Acinetobacter species, and methicillin-resistant Staphylococcus aureus. Controversies about diagnosis are discussed, emphasizing initial examination of lower respiratory tract samples for bacteria, and the rationale for both clinical and bacteriologic approaches, using either ���semiquanti- tative��� or ���quantitative��� microbiologic methods that help direct selection of appropriate antibiotic therapy. We also provide rec- ommendations for additional diagnostic and therapeutic evalua- tions in patients with nonresolving pneumonia. This is an evi- dence-based document that emphasizes the issues of VAP, because there are far fewer data available about HAP in nonintu- bated patients and about HCAP. By extrapolation, patients who are not intubated and mechanically ventilated should be man- aged like patients with VAP, using the same approach to identify risk factors for infection with specific pathogens. The major goals of this evidence-based guideline for the man- agement of HAP, VAP, and HCAP emphasize early, appropriate antibiotics in adequate doses, while avoiding excessive antibiot- ics by de-escalation of initial antibiotic therapy, based on micro- biologic cultures and the clinical response of the patient, and shortening the duration of therapy to the minimum effective period. The guideline recognizes the variability of bacteriology from one hospital to another and from one time period to an- other and recommends taking local microbiologic data into ac- count when adapting treatment recommendations to any specific clinical setting. The initial, empiric antibiotic therapy algorithm includes two groups of patients: one with no need for broad- spectrum therapy, because these patients have early-onset HAP, VAP, or HCAP and no risk factors for MDR pathogens, and a second group that requires broad-spectrum therapy, because of late-onset pneumonia or other risk factors for infection with MDR pathogens. Some of the key recommendations and principles in this new, evidence-based guideline are as follows: ��� HCAP is included in the spectrum of HAP and VAP, and patients with HCAP need therapy for MDR pathogens. ��� A lower respiratory tract culture needs to be collected from all patients before antibiotic therapy, but collection of cultures should not delay the initiation of therapy in critically ill patients. ��� Either ���semiquantitative��� or ���quantitative��� culture data can be used for the management of patients with HAP. ��� Lower respiratory tract cultures can be obtained broncho-

American Thoracic Society Documents 389 scopically or nonbronchoscopically, and can be cultured quantitatively or semiquantitatively. ��� Quantitative cultures increase specificity of the diagnosis of HAP without deleterious consequences, and the specific quantitative technique should be chosen on the basis of local expertise and experience. ��� Negative lower respiratory tract cultures can be used to stop antibiotic therapy in a patient who has had cultures obtained in the absence of an antibiotic change in the past 72 hours. ��� Early, appropriate, broad-spectrum, antibiotic therapy should be prescribed with adequate doses to optimize anti- microbial efficacy. ��� An empiric therapy regimen should include agents that are from a different antibiotic class than the patient has re- cently received. ��� Combination therapy for a specific pathogen should be used judiciously in the therapy of HAP, and consideration should be given to short-duration (5 days) aminoglycoside therapy, when used in combination with a -lactam to treat P. aeruginosa pneumonia. ��� Linezolid is an alternative to vancomycin, and uncon- firmed, preliminary data suggest it may have an advantage for proven VAP due to methicillin-resistant S. aureus. ��� Colistin should be considered as therapy for patients with VAP due to a carbapenem-resistant Acinetobacter species. ��� Aerosolized antibiotics may have value as adjunctive ther- apy in patients with VAP due to some MDR pathogens. ��� De-escalation of antibiotics should be considered once data are available on the results of lower respiratory tract cul- tures and the patient���s clinical response. ��� A shorter duration of antibiotic therapy (7 to 8 days) is recommended for patients with uncomplicated HAP, VAP, or HCAP who have received initially appropriate therapy and have had a good clinical response, with no evidence of infection with nonfermenting gram-negative bacilli. INTRODUCTION As with all guidelines, these new recommendations, although evidence graded, need validation for their impact on the outcome of patients with HAP, VAP, and HCAP. In addition, this guide- line points out areas of incomplete knowledge, which can be used to set an agenda for future research. Hospital-acquired pneumonia (HAP), ventilator-associated pneumonia (VAP), and healthcare-associated pneumonia (HCAP) remain important causes of morbidity and mortality despite ad- vances in antimicrobial therapy, better supportive care modal- ities, and the use of a wide-range of preventive measures (1���5). HAP is defined as pneumonia that occurs 48 hours or more after admission, which was not incubating at the time of admission (1, 3). HAP may be managed in a hospital ward or in the intensive care unit (ICU) when the illness is more severe. VAP refers to pneumonia that arises more than 48���72 hours after endotracheal intubation (2, 3). Although not included in this definition, some patients may require intubation after developing severe HAP and should be managed similar to patients with VAP. HCAP includes any patient who was hospitalized in an acute care hospi- tal for two or more days within 90 days of the infection resided in a nursing home or long-term care facility received recent intravenous antibiotic therapy, chemotherapy, or wound care within the past 30 days of the current infection or attended a hospital or hemodialysis clinic (3, 4, 6). Although this document focuses more on HAP and VAP, most of the principles overlap with HCAP. Because most of the current data have been col- lected from patients with VAP, and microbiologic data from nonintubated patients may be less accurate, most of our informa- tion is derived from those with VAP, but by extrapolation can be applied to all patients with HAP, emphasizing risk factors for infection with specific pathogens. This guideline is an update of the 1996 consensus statement on HAP published by the American Thoracic Society (5). The principles and recommendations are largely based on data pre- sented by committee members at a conference jointly sponsored by the American Thoracic Society (ATS) and the Infectious Disease Society of America (IDSA). The committee was com- posed of pulmonary, critical care, and infectious disease special- ists with clinical and research interests in HAP, VAP, and HCAP. All major aspects of the epidemiology, pathogenesis, bacteriol- ogy, diagnosis, and antimicrobial treatment were reviewed by this group. Therapy recommendations are focused on antibiotic choice and patient stratification adjunctive, nonantibiotic ther- apy of pneumonia is not discussed, but information on this topic is available elsewhere (7). Recommendations to reduce the risk of pneumonia are limited in this document to key, modifiable risk factors related to the pathogenesis of pneumonia to avoid redundancy with the more comprehensive Guidelines for Pre- venting Health-care���associated Pneumonia, prepared by the Cen- ters for Disease Control and Prevention (CDC) and the Hospital Infection Control Practices Advisory Committee (HICPAC) (3). The goal of our document is to provide a framework for the initial evaluation and management of the immunocompetent, adult patient with bacterial causes of HAP, VAP, or HCAP, and excludes patients who are known to be immunosuppressed by human immunodeficiency virus (HIV) infection, hematologic malignancy, chemotherapy-induced neutropenia, organ trans- plantation, and so on. At the outset, the ATS/IDSA Guideline Committee members recognized that currently, many patients with HAP, VAP, or HCAP are infected with multidrug-resistant (MDR) bacterial pathogens that threaten the adequacy of initial, empiric antibiotic therapy. At the same time, the committee members recognized that many studies have shown that exces- sive antibiotic use is a major factor contributing to increased frequency of antibiotic-resistant pathogens. Four major princi- ples underlie the management of HAP, VAP, and HCAP: ��� Avoid untreated or inadequately treated HAP, VAP, or HCAP, because the failure to initiate prompt appropriate and adequate therapy has been a consistent factor associ- ated with increased mortality. ��� Recognize the variability of bacteriology from one hospital to another, specific sites within the hospital, and from one time period to another, and use this information to alter the selection of an appropriate antibiotic treatment regimen for any specific clinical setting. ��� Avoid the overuse of antibiotics by focusing on accurate diagnosis, tailoring therapy to the results of lower respira- tory tract cultures, and shortening duration of therapy to the minimal effective period. ��� Apply prevention strategies aimed at modifiable risk fac- tors. The ATS/IDSA guideline was established for use in the initial management of patients in whom HAP, VAP, or HCAP is sus- pected. Therapeutic algorithms are presented that are based on the expected antimicrobial susceptibility of the common bacte- rial pathogens, and with therapeutic regimens that can commonly lead to initial adequate antibiotic management. This guideline is not meant to replace clinical judgment, but rather to give an organizational framework to patient manage- ment. Individual clinical situations can be highly complex and the judgment of a knowledgeable physician with all available information about a specific patient is essential for optimal clini-

390 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL 171 2005 TABLE 1. EVIDENCE-BASED GRADING SYSTEM USED TO RANK RECOMMENDATIONS Evidence Level Definition Level I (high) Evidence comes from well conducted, randomized controlled trials Level II (moderate) Evidence comes from well designed, controlled trials without randomization (including cohort, patient series, and case-control studies). Level II studies also include any large case series in which systematic analysis of disease patterns and/or microbial etiology was conducted, as well as reports of new therapies that were not collected in a randomized fashion Level III (low) Evidence comes from case studies and expert opinion. In some instances therapy recommendations come from antibiotic susceptibility data without clinical observations Adapted from American Thoracic Society guidelines for the management of adults with community-acquired pneumonia (8). cal management. As more laboratory and clinical data become available, therapy often needs to be streamlined or altered. Fi- nally, our committee realizes that these guidelines will change over time, and that our current recommendations will need to be updated as new information becomes available. METHODOLOGY USED TO PREPARE THE GUIDELINE The ATS/IDSA Guideline Committee originally met as a group, with each individual being assigned a topic for review and pre- sentation to the entire group. Each topic in the guideline was reviewed by more than one committee member, and after pre- sentation of information, the committee discussed the data and formulated recommendations. Two committee members pre- pared each section of the document, and a draft document incor- porating all sections was written and distributed to the committee for review and suggestions. The guideline was then revised and circulated to the committee for final comment. This final state- ment represents the results of this process and the opinions of the majority of committee members. The grading system for our evidence-based recommendations was previously used for the updated ATS Community-acquired Pneumonia (CAP) statement, and the definitions of high-level (Level I), moderate-level (Level II), and low-level (Level III) evidence are summarized in Table 1 (8). All available and rele- vant, peer-reviewed studies published until July 2004 were con- sidered. Much of the literature is observational, and only a few therapy trials have been conducted in a prospective, randomized fashion. Nearly all of the evidence-based data on risk factors for bacte- rial HAP have been collected from observational studies, which cannot distinguish causation from noncausal association. Most of the studies have focused on patients with VAP, but the com- mittee extrapolated the relationship between risk factors and bacteriology to all patients with HAP, including those with HCAP. Ultimate proof of causality, and ideally the best strate- gies for prevention of HAP, VAP, and HCAP, should be based on prospective, randomized trials. However, recommendations are further compromised when such trials provide conflicting results, often as a result of differences in definitions, study design, and the specific population studied. In addition, evidence-based recommendations are dynamic and may change as new therapies become available and as new interventions alter the natural history of the disease. EPIDEMIOLOGY Incidence HAP is usually caused by bacteria, is currently the second most common nosocomial infection in the United States, and is associ- ated with high mortality and morbidity (3). The presence of HAP increases hospital stay by an average of 7 to 9 days per patient and has been reported to produce an excess cost of more than $40,000 per patient (9���11). Although HAP is not a reportable illness, available data suggest that it occurs at a rate of between 5 and 10 cases per 1,000 hospital admissions, with the incidence increasing by as much as 6- to 20-fold in mechanically ventilated patients (9, 12, 13). It is often difficult to define the exact incidence of VAP, because there may be an overlap with other lower respiratory tract infections, such as infectious tra- cheobronchitis in mechanically ventilated patients. The exact incidence varies widely depending on the case definition of pneu- monia and the population being evaluated (14). For example, the incidence of VAP may be up to two times higher in patients diagnosed by qualitative or semiquantitative sputum cultures compared with quantitative cultures of lower respiratory tract secretions (9, 15). HAP accounts for up to 25% of all ICU infections and for more than 50% of the antibiotics prescribed (16). VAP occurs in 9���27% of all intubated patients (9, 11). In ICU patients, nearly 90% of episodes of HAP occur during mechanical ventilation. In mechanically ventilated patients, the incidence increases with duration of ventilation. The risk of VAP is highest early in the course of hospital stay, and is estimated to be 3%/day during the first 5 days of ventilation, 2%/day during Days 5 to 10 of ventilation, and 1%/day after this (17). Because most mechanical ventilation is short term, approximately half of all episodes of VAP occur within the first 4 days of mechanical ventilation. The intubation process itself contributes to the risk of infection, and when patients with acute respiratory failure are managed with noninvasive ventilation, nosocomial pneumonia is less common (18���20). Time of onset of pneumonia is an important epidemiologic variable and risk factor for specific pathogens and outcomes in patients with HAP and VAP . Early-onset HAP and VAP, defined as occurring within the first 4 days of hospitalization, usually carry a better prognosis, and are more likely to be caused by antibiotic- sensitive bacteria. Late-onset HAP and VAP (5 days or more) are more likely to be caused by multidrug-resistant (MDR) pathogens, and are associated with increased patient mortality and morbidity. However, patients with early-onset HAP who have received prior antibiotics or who have had prior hospitalization within the past 90 days are at greater risk for colonization and infection with MDR pathogens and should be treated similar to patients with late-onset HAP or VAP (Table 2) (21). The crude mortality rate for HAP may be as high as 30 to 70%, but many of these critically ill patients with HAP die of their underlying disease rather than pneumonia. The mortality related to the HAP or ���attributable mortality��� has been estimated to be between 33 and 50% in several case-matching studies of VAP. Increased mortality rates were associated with bacteremia, especially with Pseudomonas aeruginosa or Acinetobacter species, medical rather than surgical illness, and treatment with ineffective antibiotic therapy (22, 23). Other studies using similar methodol- ogy failed to identify any attributable mortality due to VAP,

American Thoracic Society Documents 391 TABLE 2. RISK FACTORS FOR MULTIDRUG-RESISTANT PATHOGENS CAUSING HOSPITAL-ACQUIRED PNEUMONIA, HEALTHCARE-ASSOCIATED PNEUMONIA, AND VENTILATOR-ASSOCIATED PNEUMONIA ��� Antimicrobial therapy in preceding 90 d ��� Current hospitalization of 5 d or more ��� High frequency of antibiotic resistance in the community or in the specific hospital unit ��� Presence of risk factors for HCAP: Hospitalization for 2 d or more in the preceding 90 d Residence in a nursing home or extended care facility Home infusion therapy (including antibiotics) Chronic dialysis within 30 d Home wound care Family member with multidrug-resistant pathogen ��� Immunosuppressive disease and/or therapy suggesting a variable outcome impact, according to the severity of underlying medical conditions (24���26). Etiology HAP, VAP, and HCAP may be caused by a wide spectrum of bacterial pathogens, may be polymicrobial, and are rarely due to viral or fungal pathogens in immunocompetent hosts (9, 12, 27���32). Common pathogens include aerobic gram-negative ba- cilli, such as P. aeruginosa, Escherichia coli, Klebsiella pneumo- niae, and Acinetobacter species. Infections due to gram-positive cocci, such as Staphylococcus aureus, particularly methicillin- resistant S. aureus (MRSA), have been rapidly emerging in the United States (16, 33). Pneumonia due to S. aureus is more common in patients with diabetes mellitus, head trauma, and those hospitalized in ICUs (34). Significant growth of oropharyngeal commensals (viridans group streptococci, coagulase-negative staphylococci, Neisseria species, and Corynebacterium species) from distal bronchial specimens is difficult to interpret, but these organisms can pro- duce infection in immunocompromised hosts and some immuno- competent patients (35). Rates of polymicrobial infection vary widely, but appear to be increasing, and are especially high in patients with adult respiratory distress syndrome (ARDS) (9, 12, 36���38). The frequency of specific MDR pathogens causing HAP may vary by hospital, patient population, exposure to antibiotics, type of ICU patient, and changes over time, emphasizing the need for timely, local surveillance data (3, 8, 10, 21, 39���41). HAP involving anaerobic organisms may follow aspiration in nonintu- bated patients, but is rare in patients with VAP (28, 42). Elderly patients represent a diverse population of patients with pneumonia, particularly HCAP. Elderly residents of long- term care facilities have been found to have a spectrum of patho- gens that more closely resemble late-onset HAP and VAP (30, 31). In a study of 104 patients age 75 years and older with severe pneumonia, El-Solh found S. aureus (29%), enteric gram-nega- tive rods (15%), Streptococcus pneumoniae (9%), and Pseudo- monas species (4%) as the most frequent causes of nursing home- acquired pneumonia (30). In another study of 52 long-term care residents aged 70 years and above who failed to respond to 72 hours of antibiotics, MRSA (33%), gram-negative enterics (24%), and Pseudomonas species (14%) were the most frequent pathogens isolated by invasive diagnostics (bronchoscopy) (31). In the latter study, 72% had at least two comorbidities whereas 23% had three or more. Few data are available about the bacteriology and risk factors for specific pathogens in patients with HAP and HCAP, and who are not mechanically ventilated. Data from comprehensive hospital-wide surveillance of nosocomial infections at the Uni- versity of North Carolina have described the pathogens causing both VAP and nosocomial pneumonia in nonintubated patients during the years 2000���2003 (D. Weber and W. Rutala, unpub- lished data). Pathogens were isolated from 92% of mechanically ventilated patients with infection, and from 77% of nonventi- lated patients with infection. In general, the bacteriology of nonventilated patients was similar to that of ventilated patients, including infection with MDR pathogens such as methicillin- resistant S. aureus (MRSA), P. aeruginosa, Acinetobacter spe- cies, and K. pneumoniae. In fact, some organisms (MRSA and K. pneumoniae) were more common in nonventilated than venti- lated patients, whereas certain resistant gram-negative bacilli were more common in patients with VAP (P. aeruginosa, Steno- trophomonas maltophilia, and Acinetobacter species). However, the latter group of more resistant gram-negative bacilli occurred with sufficient frequency in nonventilated patients that they should be considered when designing an empiric therapy regi- men. Studies in nonventilated patients have not determined whether this population has risk factors for MDR pathogens that differ from the risk factors present in ventilated patients. Emergence of selected multidrug-resistant bacteria. Rates of HAP due to MDR pathogens have increased dramatically in hospitalized patients, especially in intensive care and transplant patients (16). Risk factors for colonization and infection with MDR pathogens are summarized in Table 2 (21, 43). Data on mechanisms of antibiotic resistance for specific bacterial patho- gens have provided new insight into the adaptability of these pathogens. Pseudomonas aeruginosa. P. aeruginosa, the most common MDR gram-negative bacterial pathogen causing HAP/VAP, has intrinsic resistance to many antimicrobial agents (44���46). This resistance is mediated by multiple efflux pumps, which may be expressed all the time or may be upregulated by mutation (47). Resistance to piperacillin, ceftazidime, cefepime, other oxy- imino- -lactams, imipenem and meropenem, aminoglycosides, or fluoroquinolones is increasing in the United States (16). De- creased expression of an outer membrane porin channel (OprD) can cause resistance to both imipenem and meropenem or, de- pending on the alteration in OprD, specific resistance to imi- penem, but not other -lactams (48). At present, some MDR isolates of P. aeruginosa are susceptible only to polymyxin B. Although currently uncommon in the United States, there is concern about the acquisition of plasmid-mediated metallo- -lactamases active against carbapenems and antipseudomonal penicillins and cephalosporins (49). The first such enzyme, IMP-1, appeared in Japan in 1991 and spread among P. aeruginosa and Serratia marcescens, and then to other gram-negative pathogens. Resistant strains of P. aeruginosa with IMP-type enzymes and other carbapenemases have been reported from additional coun- tries in the Far East, Europe, Canada, Brazil, and recently in the United States (50). Klebsiella, Enterobacter, and Serratia species. Klebsiella species are intrinsically resistant to ampicillin and other amino- penicillins and can acquire resistance to cephalosporins and az- treonam by the production of extended-spectrum -lactamases (ESBLs) (51). Plasmids encoding ESBLs often carry resistance to aminoglycosides and other drugs, but ESBL-producing strains remain susceptible to carbapenems. Five to 10% of oxyimino- -lactam-resistant K. pneumoniae do not produce an ESBL, but rather a plasmid-mediated AmpC-type enzyme (52). Such strains usually are carbapenem susceptible, but may become resistant by loss of an outer membrane porin (53). Enterobacter species have a chromosomal AmpC -lactamase that is inducible and also easily expressed at a high level by mutation with consequent resistance to oxyimino- -lactams and -methoxy- -lactams,

392 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL 171 2005 such as cefoxitin and cefotetan, but continued susceptibility to carbapenems. Citrobacter and Serratia species have the same inducible AmpC -lactamase and the same potential for resis- tance development. Although the AmpC enzyme of E. coli is not inducible, it can occasionally be hyperexpressed. Plasmid- mediated resistance, such as ESBL production, is a more common mechanism for -lactam resistance in nosocomial isolates, and is increasingly recognized not only in isolates of K. pneumoniae and E. coli, but also Enterobacter species (54). Acinetobacter species, Stenotrophomonas maltophilia, and Burkholderia cepacia. Although generally less virulent than P. aeruginosa, Acinetobacter species have nonetheless be- come problem pathogens because of increasing resistance to commonly used antimicrobial agents (55). More than 85% of isolates are susceptible to carbapenems, but resistance is increas- ing due either to IMP-type metalloenzymes or carbapenemases of the OXA type (49). An alternative for therapy is sulbactam, usually employed as an enzyme inhibitor, but with direct antibac- terial activity against Acinetobacter species (56). S. maltophilia, which shares with B. cepacia a tendency to colonize the respira- tory tract rather than cause invasive disease, is uniformly resistant to carbapenems, because of a ubiquitous metallo- -lactamase. S. maltophilia and B. cepacia are most likely to be susceptible to trimethoprim���sulfamethoxazole, ticarcillin���clavulanate, or a fluoroquinolone (55). B. cepacia is also usually susceptible to ceftazidime and carbapenems. Methicillin-resistant Staphylococcus aureus. In the United States, more than 50% of the ICU infections caused by S. aureus are with methicillin-resistant organisms (16, 33). MRSA produces a penicillin-binding protein with reduced affinity for -lactam antibiotics that is encoded by the mecA gene, which is carried by one of a family of four mobile genetic elements (57, 58). Strains with mecA are resistant to all commercially available -lactams and many other antistaphylococcal drugs, with considerable country-to-country variability (59, 60). Al- though vancomycin-intermediate S. aureus, with a minimal inhib- itory concentration (MIC) of 8���16 g/ml, and high-level vanco- mycin-resistant S. aureus, with an MIC of 32���1,024 g/ml or more, have been isolated from clinical specimens, none to date have caused respiratory tract infection and all have been sensi- tive to linezolid (61, 62). Unfortunately, linezolid resistance has emerged in S. aureus, but is currently rare (63). Streptococcus pneumoniae and Haemophilus influenzae. S. pneumoniae and H. influenzae cause early-onset HAP in pa- tients without other risk factors, are uncommon in late-onset infection, and frequently are community acquired. At present, many strains of S. pneumoniae are penicillin resistant due to altered penicillin-binding proteins. Some such strains are resis- tant as well to cephalosporins, macrolides, tetracyclines, and clindamycin (64). Despite low and moderate levels of resistance to penicillins and cephalosporins in vitro, clinical outcomes in patients with pneumococcal pneumonia and bacteremia treated with these agents have been satisfactory (65). All of the multi- drug-resistant strains in the United States are currently sensitive to vancomycin or linezolid, and most remain sensitive to broad- spectrum quinolones. Resistance of H. influenzae to antibiotics other than penicillin and ampicillin is sufficiently rare so as not to present a problem in therapy. Legionella pneumophila. The evidence for Legionella pneu- mophila as a cause of HAP is variable, but is increased in immu- nocompromised patients, such as organ transplant recipients or patients with HIV disease, as well as those with diabetes mellitus, underlying lung disease, or end-stage renal disease (29, 66���69). HAP due to Legionella species is more common in hospitals where the organism is present in the hospital water supply or where there is ongoing construction (3, 29, 66���69). Because de- tection is based on the widespread use of Legionella urinary antigen, rather than culture for Legionella, disease due to sero- groups other than serogroup 1 may be underdiagnosed. Detailed strategies for prevention of Legionella infections and eradication procedures for Legionella species in cooling towers and the hos- pital water supply are outlined in the CDC/HICPAC Guidelines for Preventing Health-care���associated Pneumonia (3). Fungal pathogens. Nosocomial pneumonia due to fungi, such as Candida species and Aspergillus fumigatus, may occur in organ transplant or immunocompromised, neutropenic patients, but is uncommon in immunocompetent patients (70���75). Nosocomial Aspergillus species infections suggest possible airborne transmis- sion by spores, and may be associated with an environmental source such as contaminated air ducts or hospital construction. By comparison, isolation of Candida albicans and other Candida species from endotracheal aspirates is common, but usually rep- resents colonization of the airways, rather than pneumonia in immunocompetent patients, and rarely requires treatment with antifungal therapy (70). Viral pathogens. The incidence of HAP and VAP due to viruses is also low in immunocompetent hosts. Outbreaks of HAP, VAP, and HCAP due to viruses, such as influenza, parainflu- enza, adenovirus, measles, and respiratory syncytial virus have been reported and are usually seasonal. Influenza, pararinflu- enza, adenovirus, and respiratory syncytial virus account for 70% of the nosocomial viral cases of HAP, VAP, and HCAP (3, 76���78). Respiratory syncytial virus outbreaks of bronchiolitis and pneu- monia are more common in children���s wards and rare in immuno- competent adults (76). Diagnosis of these viral infections is often made by rapid antigen testing and viral culture or serologic assays. Influenza A is probably the most common viral cause of HAP and HCAP in adult patients. Pneumonia in patients with influenza A or B may be due to the virus, to secondary bacterial infection, or both. Influenza is transmitted directly from person to person when infected persons sneeze, cough, or talk or indi- rectly by person���fomite���person transmission (3, 79���81). The use of influenza vaccine along with prophylaxis and early antiviral therapy among at-risk healthcare workers and high-risk patients with amantadine, rimantadine, or one of the neuraminidase in- hibitors (oseltamivir and zanamivir) dramatically reduces the spread of influenza within hospital and healthcare facilities (3, 81���90). Amantadine and rimantadine are effective only for treat- ment and prophylaxis against influenza A strains, whereas neura- minidase inhibitors are effective against both influenza A and B. Major Epidemiologic Points 1. Many patients with HAP, VAP, and HCAP are at in- creased risk for colonization and infection with MDR pathogens (Level II) (2���4, 6, 9, 11���13, 21, 22). 2. It is often difficult to define the exact incidence of HAP and VAP, because there may be an overlap with other lower respiratory tract infections, such as tracheobronchi- tis, especially in mechanically ventilated patients (Level III) (9, 12���14). 3. The exact incidence of HAP is usually between 5 and 15 cases per 1,000 hospital admissions depending on the case definition and study population the exact incidence of VAP is 6- to 20-fold greater than in nonventilated patients (Level II) (9, 12���14). 4. HAP and VAP are a frequent cause of nosocomial infec- tion that is associated with a higher crude mortality than other hospital-acquired infections (Level II) (3, 9, 16). 5. Patients with late-onset HAP and VAP are more likely to be infected with MDR pathogens and have higher