1.American Thoracic Society DocumentsGuidelines for the Management of Adults withHospital-acquired, Ventilator-associated, andHealthcare-associated PneumoniaThis ofcial statement of the American Thoracic Society and the Infectious Diseases Society of America was approvedby the ATS Board of Directors, December 2004 and the IDSA Guideline Committee, October 2004CONTENTS have appeared, mandating a new evidence-based guideline for hospital-acquired pneumonia (HAP), including healthcare-asso-Executive Summary ciated pneumonia (HCAP) and ventilator-associated pneumoniaIntroduction (VAP). This document, prepared by a joint committee of theMethodology Used to Prepare the GuidelineEpidemiology ATS and Infectious Diseases Society of America (IDSA), fo- Incidence cuses on the epidemiology and pathogenesis of bacterial pneu- Etiologymonia in adults, and emphasizes modiable risk factors for infec- Major Epidemiologic Pointstion. In addition, the microbiology of HAP is reviewed, with anPathogenesis emphasis on multidrug-resistant (MDR) bacterial pathogens, Major Points for Pathogenesis such as Pseudomonas aeruginosa, Acinetobacter species, andModiable Risk Factors methicillin-resistant Staphylococcus aureus. Controversies about Intubation and Mechanical Ventilation diagnosis are discussed, emphasizing initial examination of lower Aspiration, Body Position, and Enteral Feedingrespiratory tract samples for bacteria, and the rationale for both Modulation of Colonization: Oral Antiseptics and Antibioticsclinical and bacteriologic approaches, using either semiquanti- Stress Bleeding Prophylaxis, Transfusion, and Glucose Control tative or quantitative microbiologic methods that help direct Major Points and Recommendations for Modiableselection of appropriate antibiotic therapy. We also provide rec- Risk Factorsommendations for additional diagnostic and therapeutic evalua-Diagnostic Testing tions in patients with nonresolving pneumonia. This is an evi- Major Points and Recommendations for Diagnosisdence-based document that emphasizes the issues of VAP,Diagnostic Strategies and Approaches because there are far fewer data available about HAP in nonintu- Clinical Strategy bated patients and about HCAP. By extrapolation, patients who Bacteriologic Strategyare not intubated and mechanically ventilated should be man- Recommended Diagnostic Strategy aged like patients with VAP, using the same approach to identify Major Points and Recommendations for Comparing risk factors for infection with specic pathogens. Diagnostic Strategies The major goals of this evidence-based guideline for the man-Antibiotic Treatment of Hospital-acquired Pneumonia General Approachagement of HAP, VAP, and HCAP emphasize early, appropriate Initial Empiric Antibiotic Therapyantibiotics in adequate doses, while avoiding excessive antibiot- Appropriate Antibiotic Selection and Adequate Dosingics by de-escalation of initial antibiotic therapy, based on micro- Local Instillation and Aerosolized Antibioticsbiologic cultures and the clinical response of the patient, and Combination versus Monotherapyshortening the duration of therapy to the minimum effective Duration of Therapy period. The guideline recognizes the variability of bacteriology Major Points and Recommendations for Optimalfrom one hospital to another and from one time period to an- Antibiotic Therapyother and recommends taking local microbiologic data into ac- Specic Antibiotic Regimens count when adapting treatment recommendations to any specic Antibiotic Heterogeneity and Antibiotic Cycling clinical setting. The initial, empiric antibiotic therapy algorithmResponse to Therapyincludes two groups of patients: one with no need for broad- Modication of Empiric Antibiotic Regimensspectrum therapy, because these patients have early-onset HAP, Dening the Normal Pattern of ResolutionVAP, or HCAP and no risk factors for MDR pathogens, and a Reasons for Deterioration or Nonresolutionsecond group that requires broad-spectrum therapy, because of Evaluation of the Nonresponding Patient late-onset pneumonia or other risk factors for infection with Major Points and Recommendations for AssessingMDR pathogens. Response to Therapy Some of the key recommendations and principles in this new,Suggested Performance Indicators evidence-based guideline are as follows:EXECUTIVE SUMMARY HCAP is included in the spectrum of HAP and VAP, andpatients with HCAP need therapy for MDR pathogens.Since the initial 1996 American Thoracic Society (ATS) guide- A lower respiratory tract culture needs to be collectedline on nosocomial pneumonia, a number of new developmentsfrom all patients before antibiotic therapy, but collectionof cultures should not delay the initiation of therapy incritically ill patients. Either semiquantitative or quantitative culture dataAm J Respir Crit Care Med Vol 171. pp 388416, 2005DOI: 10.1164/rccm.200405-644STcan be used for the management of patients with HAP.Internet address: www.atsjournals.org Lower respiratory tract cultures can be obtained broncho-

2. American Thoracic Society Documents389 scopically or nonbronchoscopically, and can be culturednonintubated patients may be less accurate, most of our informa- quantitatively or semiquantitatively.tion is derived from those with VAP, but by extrapolation can Quantitative cultures increase specicity of the diagnosis be applied to all patients with HAP, emphasizing risk factors of HAP without deleterious consequences, and the specic for infection with specic pathogens. quantitative technique should be chosen on the basis ofThis guideline is an update of the 1996 consensus statement local expertise and experience.on HAP published by the American Thoracic Society (5). The Negative lower respiratory tract cultures can be used to principles and recommendations are largely based on data pre- stop antibiotic therapy in a patient who has had culturessented by committee members at a conference jointly sponsored obtained in the absence of an antibiotic change in the pastby the American Thoracic Society (ATS) and the Infectious 72 hours.Disease Society of America (IDSA). The committee was com- Early, appropriate, broad-spectrum, antibiotic therapy posed of pulmonary, critical care, and infectious disease special- should be prescribed with adequate doses to optimize anti- ists with clinical and research interests in HAP, VAP, and HCAP. microbial efcacy. All major aspects of the epidemiology, pathogenesis, bacteriol- An empiric therapy regimen should include agents that areogy, diagnosis, and antimicrobial treatment were reviewed by from a different antibiotic class than the patient has re- this group. Therapy recommendations are focused on antibiotic cently received. choice and patient stratication; adjunctive, nonantibiotic ther- Combination therapy for a specic pathogen should be apy of pneumonia is not discussed, but information on this topic used judiciously in the therapy of HAP, and considerationis available elsewhere (7). Recommendations to reduce the risk should be given to short-duration (5 days) aminoglycosideof pneumonia are limited in this document to key, modiable therapy, when used in combination with a -lactam to treatrisk factors related to the pathogenesis of pneumonia to avoid P. aeruginosa pneumonia. redundancy with the more comprehensive Guidelines for Pre- Linezolid is an alternative to vancomycin, and uncon-venting Health-careassociated Pneumonia, prepared by the Cen- rmed, preliminary data suggest it may have an advantage ters for Disease Control and Prevention (CDC) and the Hospital for proven VAP due to methicillin-resistant S. aureus. Infection Control Practices Advisory Committee (HICPAC) (3). Colistin should be considered as therapy for patients with The goal of our document is to provide a framework for the VAP due to a carbapenem-resistant Acinetobacter species. initial evaluation and management of the immunocompetent, Aerosolized antibiotics may have value as adjunctive ther- adult patient with bacterial causes of HAP, VAP, or HCAP, apy in patients with VAP due to some MDR pathogens.and excludes patients who are known to be immunosuppressed De-escalation of antibiotics should be considered once databy human immunodeciency virus (HIV) infection, hematologic are available on the results of lower respiratory tract cul- malignancy, chemotherapy-induced neutropenia, organ trans- tures and the patients clinical response. plantation, and so on. At the outset, the ATS/IDSA Guideline A shorter duration of antibiotic therapy (7 to 8 days) isCommittee members recognized that currently, many patients recommended for patients with uncomplicated HAP, VAP,with HAP, VAP, or HCAP are infected with multidrug-resistant or HCAP who have received initially appropriate therapy(MDR) bacterial pathogens that threaten the adequacy of initial, and have had a good clinical response, with no evidenceempiric antibiotic therapy. At the same time, the committee of infection with nonfermenting gram-negative bacilli. members recognized that many studies have shown that exces-sive antibiotic use is a major factor contributing to increasedINTRODUCTIONfrequency of antibiotic-resistant pathogens. Four major princi-ples underlie the management of HAP, VAP, and HCAP:As with all guidelines, these new recommendations, although Avoid untreated or inadequately treated HAP, VAP, orevidence graded, need validation for their impact on the outcome HCAP, because the failure to initiate prompt appropriateof patients with HAP, VAP, and HCAP. In addition, this guide- and adequate therapy has been a consistent factor associ-line points out areas of incomplete knowledge, which can be ated with increased mortality.used to set an agenda for future research. Recognize the variability of bacteriology from one hospitalHospital-acquired pneumonia (HAP), ventilator-associated to another, specic sites within the hospital, and from onepneumonia (VAP), and healthcare-associated pneumonia (HCAP) time period to another, and use this information to alter theremain important causes of morbidity and mortality despite ad- selection of an appropriate antibiotic treatment regimen forvances in antimicrobial therapy, better supportive care modal- any specic clinical setting.ities, and the use of a wide-range of preventive measures (15). Avoid the overuse of antibiotics by focusing on accurateHAP is dened as pneumonia that occurs 48 hours or more after diagnosis, tailoring therapy to the results of lower respira-admission, which was not incubating at the time of admission tory tract cultures, and shortening duration of therapy to(1, 3). HAP may be managed in a hospital ward or in the intensive the minimal effective period.care unit (ICU) when the illness is more severe. VAP refers to Apply prevention strategies aimed at modiable risk fac-pneumonia that arises more than 4872 hours after endotracheal tors.intubation (2, 3). Although not included in this denition, somepatients may require intubation after developing severe HAP The ATS/IDSA guideline was established for use in the initialand should be managed similar to patients with VAP. HCAPmanagement of patients in whom HAP, VAP, or HCAP is sus-includes any patient who was hospitalized in an acute care hospi- pected. Therapeutic algorithms are presented that are based ontal for two or more days within 90 days of the infection; resided the expected antimicrobial susceptibility of the common bacte-in a nursing home or long-term care facility; received recent rial pathogens, and with therapeutic regimens that can commonlyintravenous antibiotic therapy, chemotherapy, or wound care lead to initial adequate antibiotic management.within the past 30 days of the current infection; or attended a This guideline is not meant to replace clinical judgment, buthospital or hemodialysis clinic (3, 4, 6). Although this document rather to give an organizational framework to patient manage-focuses more on HAP and VAP, most of the principles overlap ment. Individual clinical situations can be highly complex andwith HCAP. Because most of the current data have been col-the judgment of a knowledgeable physician with all availablelected from patients with VAP, and microbiologic data frominformation about a specic patient is essential for optimal clini- 3. 390 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL 171 2005TABLE 1. EVIDENCE-BASED GRADING SYSTEM USED TO RANK RECOMMENDATIONSEvidence LevelDefinitionLevel I (high) Evidence comes from well conducted, randomized controlled trialsLevel 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 fashionLevel III (low)Evidence comes from case studies and expert opinion. In some instances therapy recommendations come from antibiotic susceptibility data without clinical observationsAdapted from American Thoracic Society guidelines for the management of adults with community-acquired pneumonia (8).cal management. As more laboratory and clinical data become more than $40,000 per patient (911). Although HAP is not aavailable, therapy often needs to be streamlined or altered. Fi-reportable illness, available data suggest that it occurs at a ratenally, our committee realizes that these guidelines will change of between 5 and 10 cases per 1,000 hospital admissions, with theover time, and that our current recommendations will need toincidence increasing by as much as 6- to 20-fold in mechanicallybe updated as new information becomes available.ventilated patients (9, 12, 13). It is often difcult to dene theexact incidence of VAP, because there may be an overlap withMETHODOLOGY USED TO PREPARE THE GUIDELINE other lower respiratory tract infections, such as infectious tra-cheobronchitis in mechanically ventilated patients. The exactThe ATS/IDSA Guideline Committee originally met as a group,incidence varies widely depending on the case denition of pneu-with each individual being assigned a topic for review and pre-monia and the population being evaluated (14). For example,sentation to the entire group. Each topic in the guideline wasthe incidence of VAP may be up to two times higher in patientsreviewed by more than one committee member, and after pre-diagnosed by qualitative or semiquantitative sputum culturessentation of information, the committee discussed the data andcompared with quantitative cultures of lower respiratory tractformulated recommendations. Two committee members pre-secretions (9, 15).pared each section of the document, and a draft document incor-HAP accounts for up to 25% of all ICU infections and forporating all sections was written and distributed to the committeemore than 50% of the antibiotics prescribed (16). VAP occursfor review and suggestions. The guideline was then revised andin 927% of all intubated patients (9, 11). In ICU patients, nearlycirculated to the committee for nal comment. This nal state-90% of episodes of HAP occur during mechanical ventilation.ment represents the results of this process and the opinions ofIn mechanically ventilated patients, the incidence increases withthe majority of committee members.duration of ventilation. The risk of VAP is highest early in theThe grading system for our evidence-based recommendationswas previously used for the updated ATS Community-acquiredcourse of hospital stay, and is estimated to be 3%/day duringPneumonia (CAP) statement, and the denitions of high-level the rst 5 days of ventilation, 2%/day during Days 5 to 10 of(Level I), moderate-level (Level II), and low-level (Level III) ventilation, and 1%/day after this (17). Because most mechanicalevidence are summarized in Table 1 (8). All available and rele- ventilation is short term, approximately half of all episodes ofvant, peer-reviewed studies published until July 2004 were con- VAP occur within the rst 4 days of mechanical ventilation. Thesidered. Much of the literature is observational, and only a fewintubation process itself contributes to the risk of infection, andtherapy trials have been conducted in a prospective, randomized when patients with acute respiratory failure are managed withfashion.noninvasive ventilation, nosocomial pneumonia is less commonNearly all of the evidence-based data on risk factors for bacte-(1820).rial HAP have been collected from observational studies, whichTime of onset of pneumonia is an important epidemiologiccannot distinguish causation from noncausal association. Most variable and risk factor for specic pathogens and outcomes inof the studies have focused on patients with VAP, but the com-patients with HAP and VAP . Early-onset HAP and VAP, denedmittee extrapolated the relationship between risk factors and as occurring within the rst 4 days of hospitalization, usually carrybacteriology to all patients with HAP, including those with a better prognosis, and are more likely to be caused by antibiotic-HCAP. Ultimate proof of causality, and ideally the best strate- sensitive bacteria. Late-onset HAP and VAP (5 days or more) aregies for prevention of HAP, VAP, and HCAP, should be basedmore likely to be caused by multidrug-resistant (MDR) pathogens,on prospective, randomized trials. However, recommendations and are associated with increased patient mortality and morbidity.are further compromised when such trials provide conicting However, patients with early-onset HAP who have received priorresults, often as a result of differences in denitions, study design,antibiotics or who have had prior hospitalization within the pastand the specic population studied. In addition, evidence-based 90 days are at greater risk for colonization and infection withrecommendations are dynamic and may change as new therapies MDR pathogens and should be treated similar to patients withbecome available and as new interventions alter the natural late-onset HAP or VAP (Table 2) (21).history of the disease. The crude mortality rate for HAP may be as high as 30 to70%, but many of these critically ill patients with HAP die ofEPIDEMIOLOGYtheir underlying disease rather than pneumonia. The mortalityrelated to the HAP or attributable mortality has been estimatedIncidence to be between 33 and 50% in several case-matching studies ofHAP is usually caused by bacteria, is currently the second most VAP. Increased mortality rates were associated with bacteremia,common nosocomial infection in the United States, and is associ-especially with Pseudomonas aeruginosa or Acinetobacter species,ated with high mortality and morbidity (3). The presence of medical rather than surgical illness, and treatment with ineffectiveHAP increases hospital stay by an average of 7 to 9 days perantibiotic therapy (22, 23). Other studies using similar methodol-patient and has been reported to produce an excess cost ofogy failed to identify any attributable mortality due to VAP, 4. American Thoracic Society Documents391TABLE 2. RISK FACTORS FOR MULTIDRUG-RESISTANT hospital-wide surveillance of nosocomial infections at the Uni-PATHOGENS CAUSING HOSPITAL-ACQUIRED PNEUMONIA,versity of North Carolina have described the pathogens causingHEALTHCARE-ASSOCIATED PNEUMONIA, ANDVENTILATOR-ASSOCIATED PNEUMONIAboth VAP and nosocomial pneumonia in nonintubated patientsduring the years 20002003 (D. Weber and W. Rutala, unpub- Antimicrobial therapy in preceding 90 d lished data). Pathogens were isolated from 92% of mechanically Current hospitalization of 5 d or moreventilated patients with infection, and from 77% of nonventi- High frequency of antibiotic resistance in the community or lated patients with infection. In general, the bacteriology ofin the specific hospital unitnonventilated patients was similar to that of ventilated patients, Presence of risk factors for HCAP: Hospitalization for 2 d or more in the preceding 90 dincluding infection with MDR pathogens such as methicillin- Residence in a nursing home or extended care facilityresistant S. aureus (MRSA), P. aeruginosa, Acinetobacter spe- Home infusion therapy (including antibiotics)cies, and K. pneumoniae. In fact, some organisms (MRSA and Chronic dialysis within 30 d K. pneumoniae) were more common in nonventilated than venti- Home wound carelated patients, whereas certain resistant gram-negative bacilli Family member with multidrug-resistant pathogenwere more common in patients with VAP (P. aeruginosa, Steno- Immunosuppressive disease and/or therapytrophomonas maltophilia, and Acinetobacter species). However,the latter group of more resistant gram-negative bacilli occurredwith sufcient frequency in nonventilated patients that theyshould be considered when designing an empiric therapy regi-suggesting a variable outcome impact, according to the severity men. Studies in nonventilated patients have not determinedof underlying medical conditions (2426). whether this population has risk factors for MDR pathogensthat differ from the risk factors present in ventilated patients.EtiologyEmergence of selected multidrug-resistant bacteria. Rates ofHAP, VAP, and HCAP may be caused by a wide spectrum ofHAP due to MDR pathogens have increased dramatically inbacterial pathogens, may be polymicrobial, and are rarely due hospitalized patients, especially in intensive care and transplantto viral or fungal pathogens in immunocompetent hosts (9, 12, patients (16). Risk factors for colonization and infection with2732). Common pathogens include aerobic gram-negative ba-MDR pathogens are summarized in Table 2 (21, 43). Data oncilli, such as P. aeruginosa, Escherichia coli, Klebsiella pneumo-mechanisms of antibiotic resistance for specic bacterial patho-niae, and Acinetobacter species. Infections due to gram-positivegens have provided new insight into the adaptability of thesecocci, such as Staphylococcus aureus, particularly methicillin- pathogens.resistant S. aureus (MRSA), have been rapidly emerging in the Pseudomonas aeruginosa. P. aeruginosa, the most commonUnited States (16, 33). Pneumonia due to S. aureus is moreMDR gram-negative bacterial pathogen causing HAP/VAP, hascommon in patients with diabetes mellitus, head trauma, and intrinsic resistance to many antimicrobial agents (4446). Thisthose hospitalized in ICUs (34).resistance is mediated by multiple efux pumps, which maySignicant growth of oropharyngeal commensals (viridans be expressed all the time or may be upregulated by mutationgroup streptococci, coagulase-negative staphylococci, Neisseria (47). Resistance to piperacillin, ceftazidime, cefepime, other oxy-species, and Corynebacterium species) from distal bronchial imino- -lactams, imipenem and meropenem, aminoglycosides,specimens is difcult to interpret, but these organisms can pro-or uoroquinolones is increasing in the United States (16). De-duce infection in immunocompromised hosts and some immuno-creased expression of an outer membrane porin channel (OprD)competent patients (35). Rates of polymicrobial infection varycan cause resistance to both imipenem and meropenem or, de-widely, but appear to be increasing, and are especially high in pending on the alteration in OprD, specic resistance to imi-patients with adult respiratory distress syndrome (ARDS) (9, 12,penem, but not other -lactams (48). At present, some MDR3638). isolates of P. aeruginosa are susceptible only to polymyxin B.The frequency of specic MDR pathogens causing HAP mayAlthough currently uncommon in the United States, therevary by hospital, patient population, exposure to antibiotics, type is concern about the acquisition of plasmid-mediated metallo-of ICU patient, and changes over time, emphasizing the need -lactamases active against carbapenems and antipseudomonalfor timely, local surveillance data (3, 8, 10, 21, 3941). HAPpenicillins and cephalosporins (49). The rst such enzyme, IMP-1,involving anaerobic organisms may follow aspiration in nonintu- appeared in Japan in 1991 and spread among P. aeruginosa andbated patients, but is rare in patients with VAP (28, 42).Serratia marcescens, and then to other gram-negative pathogens.Elderly patients represent a diverse population of patients Resistant strains of P. aeruginosa with IMP-type enzymes andwith pneumonia, particularly HCAP. Elderly residents of long- other carbapenemases have been reported from additional coun-term care facilities have been found to have a spectrum of patho- tries in the Far East, Europe, Canada, Brazil, and recently ingens that more closely resemble late-onset HAP and VAP (30, 31).the United States (50).In a study of 104 patients age 75 years and older with severe Klebsiella, Enterobacter, and Serratia species. Klebsiellapneumonia, El-Solh found S. aureus (29%), enteric gram-nega-species are intrinsically resistant to ampicillin and other amino-tive rods (15%), Streptococcus pneumoniae (9%), and Pseudo- penicillins and can acquire resistance to cephalosporins and az-monas species (4%) as the most frequent causes of nursing home- treonam by the production of extended-spectrum -lactamasesacquired pneumonia (30). In another study of 52 long-term care(ESBLs) (51). Plasmids encoding ESBLs often carry resistanceresidents aged 70 years and above who failed to respond toto aminoglycosides and other drugs, but ESBL-producing strains72 hours of antibiotics, MRSA (33%), gram-negative enterics remain susceptible to carbapenems. Five to 10% of oxyimino-(24%), and Pseudomonas species (14%) were the most frequent -lactam-resistant K. pneumoniae do not produce an ESBL, butpathogens isolated by invasive diagnostics (bronchoscopy) (31). rather a plasmid-mediated AmpC-type enzyme (52). Such strainsIn the latter study, 72% had at least two comorbidities whereas usually are carbapenem susceptible, but may become resistant23% had three or more.by loss of an outer membrane porin (53). Enterobacter speciesFew data are available about the bacteriology and risk factorshave a chromosomal AmpC -lactamase that is inducible andfor specic pathogens in patients with HAP and HCAP, andalso easily expressed at a high level by mutation with consequentwho are not mechanically ventilated. Data from comprehensiveresistance to oxyimino- -lactams and -methoxy- -lactams, 5. 392AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL 171 2005such as cefoxitin and cefotetan, but continued susceptibility totection is based on the widespread use of Legionella urinarycarbapenems. Citrobacter and Serratia species have the same antigen, rather than culture for Legionella, disease due to sero-inducible AmpC -lactamase and the same potential for resis- groups other than serogroup 1 may be underdiagnosed. Detailedtance development. Although the AmpC enzyme of E. coli is strategies for prevention of Legionella infections and eradicationnot inducible, it can occasionally be hyperexpressed. Plasmid-procedures for Legionella species in cooling towers and the hos-mediated resistance, such as ESBL production, is a more commonpital water supply are outlined in the CDC/HICPAC Guidelinesmechanism for -lactam resistance in nosocomial isolates, and is for Preventing Health-careassociated Pneumonia (3).increasingly recognized not only in isolates of K. pneumoniae and Fungal pathogens. Nosocomial pneumonia due to fungi, suchE. coli, but also Enterobacter species (54).as Candida species and Aspergillus fumigatus, may occur in organAcinetobacter species, Stenotrophomonas maltophilia,transplant or immunocompromised, neutropenic patients, but isand Burkholderia cepacia. Although generally less virulentuncommon in immunocompetent patients (7075). Nosocomialthan P. aeruginosa, Acinetobacter species have nonetheless be-Aspergillus species infections suggest possible airborne transmis-come problem pathogens because of increasing resistance tosion by spores, and may be associated with an environmentalcommonly used antimicrobial agents (55). More than 85% of source such as contaminated air ducts or hospital construction.isolates are susceptible to carbapenems, but resistance is increas- By comparison, isolation of Candida albicans and other Candidaing due either to IMP-type metalloenzymes or carbapenemases species from endotracheal aspirates is common, but usually rep-of the OXA type (49). An alternative for therapy is sulbactam,resents colonization of the airways, rather than pneumonia inusually employed as an enzyme inhibitor, but with direct antibac- immunocompetent patients, and rarely requires treatment withterial activity against Acinetobacter species (56). S. maltophilia,antifungal therapy (70).which shares with B. cepacia a tendency to colonize the respira-Viral pathogens. The incidence of HAP and VAP due totory tract rather than cause invasive disease, is uniformly resistantviruses is also low in immunocompetent hosts. Outbreaks ofto carbapenems, because of a ubiquitous metallo- -lactamase.HAP, VAP, and HCAP due to viruses, such as inuenza, parainu-S. maltophilia and B. cepacia are most likely to be susceptibleenza, adenovirus, measles, and respiratory syncytial virus haveto trimethoprimsulfamethoxazole, ticarcillinclavulanate, or auoroquinolone (55). B. cepacia is also usually susceptible tobeen reported and are usually seasonal. Inuenza, pararinu-ceftazidime and carbapenems.enza, adenovirus, and respiratory syncytial virus account for 70%Methicillin-resistant Staphylococcus aureus. In the of the nosocomial viral cases of HAP, VAP, and HCAP (3, 7678).United States, more than 50% of the ICU infections caused byRespiratory syncytial virus outbreaks of bronchiolitis and pneu-S. aureus are with methicillin-resistant organisms (16, 33). MRSA monia are more common in childrens wards and rare in immuno-produces a penicillin-binding protein with reduced afnity forcompetent adults (76). Diagnosis of these viral infections is often-lactam antibiotics that is encoded by the mecA gene, which made by rapid antigen testing and viral culture or serologic assays.is carried by one of a family of four mobile genetic elements Inuenza A is probably the most common viral cause of(57, 58). Strains with mecA are resistant to all commercially HAP and HCAP in adult patients. Pneumonia in patients withavailable -lactams and many other antistaphylococcal drugs, inuenza A or B may be due to the virus, to secondary bacterialwith considerable country-to-country variability (59, 60). Al-infection, or both. Inuenza is transmitted directly from personthough vancomycin-intermediate S. aureus, with a minimal inhib- to person when infected persons sneeze, cough, or talk or indi-itory concentration (MIC) of 816 g/ml, and high-level vanco- rectly by personfomiteperson transmission (3, 7981). The usemycin-resistant S. aureus, with an MIC of 321,024 g/ml orof inuenza vaccine along with prophylaxis and early antiviralmore, have been isolated from clinical specimens, none to datetherapy among at-risk healthcare workers and high-risk patientshave caused respiratory tract infection and all have been sensi-with amantadine, rimantadine, or one of the neuraminidase in-tive to linezolid (61, 62). Unfortunately, linezolid resistance has hibitors (oseltamivir and zanamivir) dramatically reduces theemerged in S. aureus, but is currently rare (63). spread of inuenza within hospital and healthcare facilities (3,Streptococcus pneumoniae and Haemophilus inuenzae. 8190). Amantadine and rimantadine are effective only for treat-S. pneumoniae and H. inuenzae cause early-onset HAP in pa- ment and prophylaxis against inuenza A strains, whereas neura-tients without other risk factors, are uncommon in late-onset minidase inhibitors are effective against both inuenza A and B.infection, and frequently are community acquired. At present,many strains of S. pneumoniae are penicillin resistant due to Major Epidemiologic Pointsaltered penicillin-binding proteins. Some such strains are resis-tant as well to cephalosporins, macrolides, tetracyclines, and1. Many patients with HAP, VAP, and HCAP are at in-clindamycin (64). Despite low and moderate levels of resistancecreased risk for colonization and infection with MDRto penicillins and cephalosporins in vitro, clinical outcomes in pathogens (Level II) (24, 6, 9, 1113, 21, 22).patients with pneumococcal pneumonia and bacteremia treated 2. It is often difcult to dene the exact incidence of HAPwith these agents have been satisfactory (65). All of the multi- and VAP, because there may be an overlap with otherdrug-resistant strains in the United States are currently sensitivelower respiratory tract infections, such as tracheobronchi-to vancomycin or linezolid, and most remain sensitive to broad-tis, especially in mechanically ventilated patients (Levelspectrum quinolones. Resistance of H. inuenzae to antibiotics III) (9, 1214).other than penicillin and ampicillin is sufciently rare so as not3. The exact incidence of HAP is usually between 5 and 15to present a problem in therapy. cases per 1,000 hospital admissions depending on the caseLegionella pneumophila. The evidence for Legionella pneu-denition and study population; the exact incidence ofmophila as a cause of HAP is variable, but is increased in immu- VAP is 6- to 20-fold greater than in nonventilated patientsnocompromised patients, such as organ transplant recipients or (Level II) (9, 1214).patients with HIV disease, as well as those with diabetes mellitus, 4. HAP and VAP are a frequent cause of nosocomial infec-underlying lung disease, or end-stage renal disease (29, 6669). tion that is associated with a higher crude mortality thanHAP due to Legionella species is more common in hospitalsother hospital-acquired infections (Level II) (3, 9, 16).where the organism is present in the hospital water supply or 5. Patients with late-onset HAP and VAP are more likelywhere there is ongoing construction (3, 29, 6669). Because de-to be infected with MDR pathogens and have higher 6. American Thoracic Society Documents 393 crude mortality than patients with early-onset disease; mon (107, 108). Hematogenous spread from infected intravascu- patients with early-onset HAP who have recently re- lar catheters or bacterial translocation from the gastrointestinal ceived antibiotics or had an admission to a healthcaretract lumen are quite rare. facility are at risk for colonization and infection with MDR pathogens (Level II) (3, 9, 21, 22).Major Points for Pathogenesis6. An increase in crude and attributable mortality for HAP1. Sources of pathogens for HAP include healthcare devices, and VAP is associated with the presence of MDR patho- the environment (air, water, equipment, and fomites), and gens (Level II) (3, 5, 913, 2123).commonly the transfer of microorganisms between the7. Bacteria cause most cases of HAP, VAP, and HCAP and patient and staff or other patients (Level II) (3, 9, 12, 13, many infections are polymicrobial; rates are especially 27, 66, 92, 93). high in patients with ARDS (Level I) (2, 4, 6, 9, 12,2. A number of host- and treatment-related colonization fac- 3638). tors, such as the severity of the patients underlying disease,8. HAP, VAP, and HCAP are commonly caused by aerobic prior surgery, exposure to antibiotics, other medications, gram-negative bacilli, such as P. aeruginosa, K. pneumo- and exposure to invasive respiratory devices and equip- niae, and Acinetobacter species, or by gram-positive cocci, ment, are important in the pathogenesis of HAP and VAP such as S. aureus, much of which is MRSA; anaerobes (Level II) (40, 93, 94). are an uncommon cause of VAP (Level II) (9, 12, 28,3. Aspiration of oropharyngeal pathogens, or leakage of se- 3640, 42, 91). cretions containing bacteria around the endotracheal tube9. Rates of L. pneumophila vary considerably between hos- cuff, are the primary routes of bacterial entry into the pitals and disease occurs more commonly with serogroup lower respiratory tract (Level II) (9598). 1 when the water supply is colonized or there is ongoing4. Inhalation or direct inoculation of pathogens into the lower construction (Level II) (29, 6669). airway, hematogenous spread from infected intravenous 10. Nosocomial virus and fungal infections are uncommon catheters, and bacterial translocation from the gastrointes- causes of HAP and VAP in immunocompetent patients. Outbreaks of inuenza have occurred sporadically andtinal tract lumen are uncommon pathogenic mechanisms risk of infection can be substantially reduced with wide- (Level II) (107, 108). spread effective infection control, vaccination, and use 5. Infected biolm in the endotracheal tube, with subsequent of antiinuenza agents (Level I) (3, 7075, 7990). embolization to distal airways, may be important in the 11. The prevalence of MDR pathogens varies by patient pop-pathogenesis of VAP (Level III) (105, 106). ulation, hospital, and type of ICU, which underscores the6. The stomach and sinuses may be potential reservoirs of need for local surveillance data (Level II) (3, 9, 41). nosocomial pathogens that contribute to bacterial coloni- 12. MDR pathogens are more commonly isolated from pa- zation of the oropharynx, but their contribution is contro- tients with severe, chronic underlying disease, those withversial, may vary by the population at risk, and may be risk factors for HCAP, and patients with late-onset HAP decreasing with the changing natural history and manage- or VAP (Level II) (9, 21, 22, 30, 31, 39, 40, 91).ment of HAP (Level II) (94, 99104, 109).PATHOGENESIS MODIFIABLE RISK FACTORSFor HAP to occur, the delicate balance between host defenses Risk factors for the development of HAP can be differentiatedand microbial propensity for colonization and invasion must shiftinto modiable and nonmodiable conditions. Risk factors mayin favor of the ability of the pathogens to persist and invade the also be patient related (male sex, preexisting pulmonary disease,lower respiratory tract. Sources of infection for HAP includeor multiple organ system failure) or treatment related (intuba-healthcare devices or the environment (air, water, equipment,tion or enteral feeding). Modiable risk factors for HAP areand fomites) and can occur with transfer of microorganisms obvious targets for improved management and prophylaxis inbetween staff and patients (3, 9, 12, 13, 27, 66, 92, 93). A numberseveral studies and in the comprehensive Guidelines for Pre-of host- and treatment-related colonization factors, such as the venting Health-careassociated Pneumonia, published by theseverity of the patients underlying disease, prior surgery, expo- Centers for Disease Control (3, 93, 110). Effective strategiessure to antibiotics, other medications, and exposure to invasive include strict infection control, alcohol-based hand disinfection,respiratory devices and equipment, are important in the patho- use of microbiologic surveillance with timely availability of datagenesis of HAP and VAP (40, 93, 94)on local MDR pathogens, monitoring and early removal of inva-HAP requires the entry of microbial pathogens into the lower sive devices, and programs to reduce or alter antibiotic-prescrib-respiratory tract, followed by colonization, which can then over-ing practices (3, 92, 93, 100, 110113).whelm the hosts mechanical (ciliated epithelium and mucus), Intubation and Mechanical Ventilationhumoral (antibody and complement), and cellular (polymorpho-nuclear leukocytes, macrophages, and lymphocytes and their Intubation and mechanical ventilation increase the risk of HAPrespective cytokines) defenses to establish infection (9, 94). 6- to 21-fold and therefore should be avoided whenever possibleAspiration of oropharyngeal pathogens or leakage of bacteria (3, 94, 110, 114). Noninvasive positive-pressure ventilation, usingaround the endotracheal tube cuff is the primary route of bacte- a face mask, is an attractive alternative for patients with acuterial entry into the trachea (9598). The stomach and sinuses exacerbations of chronic obstructive pulmonary disease or acutehave been suggested as potential reservoirs for certain bacteria hypoxemic respiratory failure, and for some immunosuppressedcolonizing the oropharynx and trachea, but their importancepatients with pulmonary inltrates and respiratory failure (18, 20,remains controversial (99104). Some investigators postulate 115119). Data suggest that use of noninvasive ventilation tothat colonization of the endotracheal tube with bacteria encased avoid reintubation after initial extubation may not be a goodin biolm may result in embolization into the alveoli during strategy (115).suctioning or bronchoscopy (105, 106). Inhalation of pathogens Specic strategies have been recommended to reduce thefrom contaminated aerosols, and direct inoculation, are less com-duration of mechanical ventilation, such as improved methods 7. 394 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL 171 2005of sedation and the use of protocols to facilitate and accelerateModulation of Colonization: Oral Antiseptics and Antibioticsweaning (120124). These interventions are dependent on ade- The progression from colonization to tracheobronchitis to pneu-quate ICU stafng. Reintubation should be avoided, if possible,monia is a dynamic equilibrium and the possibility to discernas it increases the risk of VAP (114). the different entities depends on the specicity of diagnosticAttention to the specic type of endotracheal tube, its mainte-tools. Oropharyngeal colonization, either present on admissionnance, and the site of insertion may also be valuable. The use or acquired during ICU stay, has been identied as an indepen-of oral endotracheal and orogastric tubes, rather than nasotra-dent risk factor for the development of ICU-acquired HAPcheal and nasogastric tubes, can reduce the frequency of nosoco- caused by enteric gram-negative bacteria and P. aeruginosamial sinusitis and possibly HAP, although causality between(101). In a randomized trial, DeRiso and coworkers demon-sinusitis and HAP has not been rmly established (109, 125). strated that the use of the oral antiseptic chlorhexidine signi-Efforts to reduce the likelihood of aspiration of oropharyngealcantly reduced rates of nosocomial infection in patients undergo-bacteria around the endotracheal tube cuff and into the lowering coronary artery bypass surgery (148).respiratory tract include limiting the use of sedative and paralytic Modulation of oropharyngeal colonization, by combinationsagents that depress cough and other host-protective mechanisms,of oral antibiotics, with or without systemic therapy, or by selec-and maintaining endotracheal cuff pressure at greater than 20 cm tive decontamination of the digestive tract (SDD), is also effec-H2O (98, 126). Continuous aspiration of subglottic secretions, tive in signicantly reducing the frequency of HAP, althoughthrough the use of a specially designed endotracheal tube, has methodologic study quality appeared to be inversely related tosignicantly reduced the incidence of early-onset VAP in several the magnitude of the preventive effects (93, 149155).studies (97, 127130). In two prospective randomized trials SDD was associatedVAP may also be related to colonization of the ventilatorwith higher ICU survival among patients receiving SDD (156,circuit (131). A large number of prospective, randomized trials157). In the rst study patients with a midrange APACHE IIhave shown that the frequency of ventilator circuit change doesscore on admission had a lower ICU mortality, although ICUnot affect the incidence of HAP, but condensate collecting inmortality rates of all patients included did not differ signicantlythe ventilator circuit can become contaminated from patient(156). In the largest study performed so far, SDD administeredsecretions (98, 132135). Therefore, vigilance is needed to pre- to 466 patients in one unit was associated with a relative riskvent inadvertently ushing the condensate into the lower airwayfor ICU mortality of 0.65 and with a relative risk of hospitalor to in-line medication nebulizers when the patient turns ormortality of 0.78, when compared with 472 patients admitted inthe bedrail is raised (98, 131134, 136). Passive humidiers ora control ward (157). In addition, infections due to antibiotic-heatmoisture exchangers decrease ventilator circuit coloniza- resistant microorganisms occurred more frequently in the controltion but have not signicantly reduced the incidence of VAPward. Importantly, levels of antibiotic-resistant pathogens were(128, 135139).low in both wards, with complete absence of MRSA. Moreover, a small preexisting difference in outcome between two wardsAspiration, Body Position, and Enteral Feeding and the absence of a cross-over design warrant conrmation ofSupine patient positioning may also facilitate aspiration, which these benecial effects of SDD.may be decreased by a semirecumbent positioning (140142). The preventive effects of selective decontamination of theUsing radioactive labeled enteral feeding, cumulative numbersdigestive tract for HAP have also been considerably lower inof endotracheal counts were higher when patients were placed ICUs with high endemic levels of antibiotic resistance. In suchin the completely supine position (0 ) as compared with a semire-a setting, selective decontamination of the digestive tract maycumbent position (45 ) (140, 141). One randomized trial demon- increase the selective pressure for antibiotic-resistant micro-strated a threefold reduction in the incidence of ICU-acquired organisms (158164). Although selective decontamination of theHAP in patients treated in the semirecumbent position com- digestive tract reduces HAP, routine prophylactic use of antibiot-pared with patients treated completely supine (143). Infection ics should be discouraged, especially in hospital settings wherein patients in the supine position was strongly associated withthere are high levels of antibiotic resistance.the simultaneous administration of enteral nutrition. Thus, intu-The role of systemic antibiotics in the development of HAPbated patients should be managed in a semirecumbent position,is less clear. In one study, prior administration of antibiotics hadparticularly during feeding. an adjusted odds ratio of 3.1 (95% condence interval, 1.46.9)Enteral nutrition has been considered a risk factor for thefor development of late-onset ICU-acquired HAP (165). More-development of HAP, mainly because of an increased risk of over, antibiotics clearly predispose patients to subsequent coloni-aspiration of gastric contents (3, 144). However, its alternative, zation and infection with antibiotic-resistant pathogens (21). Inparenteral nutrition, is associated with higher risks for intravas-contrast, prior antibiotic exposure conferred protection (riskcular device-associated infections, complications of line inser- ratio, 0.37; 95% condence interval, 0.270.51) for ICU-acquiredtions, higher costs, and loss of intestinal villous architecture,HAP in another study (17). In addition, antibiotic use at thewhich may facilitate enteral microbial translocation. Although time of emergent intubation may prevent pneumonia within thesome have advised feeding critically ill patients enterally as early rst 48 hours of intubation (166). Preventive effects of intrave-as possible, a strategy of early (i.e., Day 1 of intubation andnous antibiotics were evaluated in only one randomized trial:ventilation) enteral feeding was, when compared with late ad-administration of cefuroxime for 24 hours, at the time of intuba-ministration (i.e., Day 5 of intubation), associated with a higher tion; and it reduced the incidence of early-onset, ICU-acquiredrisk for ICU-acquired VAP (145, 146). Seven studies have evalu-HAP in patients with closed head injury (167). However, circum-ated the risks for ICU-acquired HAP in patients randomized tostantial evidence of the efcacy of systemic antibiotics also followseither gastric or postpyloric feeding (147). Although signicant from the results of metaanalyses of selective decontaminationdifferences were not demonstrated in any individual study, post- of the digestive tract, which have suggested that the intravenouspyloric feeding was associated with a signicant reduction incomponent of the regimens was largely responsible for improvedICU-acquired HAP in metaanalysis (relative risk, 0.76; 95% survival (149). In summary, prior administration of antibiotics forcondence interval, 0.59 to 0.99) (147). short duration may be benecial in some patient groups, but when 8. American Thoracic Society Documents 395given for prolonged periods may well place others at risk for Major Points and Recommendations for Modifiablesubsequent infection with antibiotic-resistant microorganisms.Risk FactorsStress Bleeding Prophylaxis, Transfusion, and Glucose Control General prophylaxis.Both histamine Type 2 (H2) antagonists and antacids have been1. Effective infection control measures: staff education, com-identied as independent risk factors for ICU-acquired HAP. pliance with alcohol-based hand disinfection, and isolationSucralfate has been used for stress bleeding prophylaxis, as it to reduce cross-infection with MDR pathogens should bedoes not decrease intragastric acidity or signicantly increase used routinely (Level I) (3, 93, 100, 110, 111).gastric volume. Numerous randomized trials, using different doses2. Surveillance of ICU infections, to identify and quantifyand various study populations, have provided controversial re-endemic and new MDR pathogens, and preparation ofsults on the benets of specic stress bleeding prophylaxis agentstimely data for infection control and to guide appropriate,in relation to the increased risk of VAP (38, 99, 103, 104, 155,antimicrobial therapy in patients with suspected HAP or168). One large randomized trial comparing antacids, H2 block-other nosocomial infections, are recommended (Level II)ers, and sucralfate reported no differences in rates of early-onset (3, 92, 93, 100, 110113).VAP, but rates of late-onset VAP were lower among patientsIntubation and mechanical ventilation.treated with sucralfate (103). In one multicenter study of VAP 1. Intubation and reintubation should be avoided, if possible,in patients with ARDS, sucralfate and duration of exposure to as it increases the risk of VAP (Level I) (3, 12, 93, 94,sucralfate were associated with an increased risk of VAP (38).114).A large, double-blind, randomized trial comparing ranitidine 2. Noninvasive ventilation should be used whenever possiblewith sucralfate demonstrated a trend to toward lower rates of in selected patients with respiratory failure (Level I) (18,VAP with sucralfate, but clinically signicant gastrointestinal 20, 115119).bleeding was 4% higher in the sucralfate group (104). Thus, if 3. Orotracheal intubation and orogastric tubes are preferredstress ulcer prophylaxis is indicated, the risks and benets ofover nasotracheal intubation and nasogastric tubes to pre-each regimen should be weighed before prescribing either H2vent nosocomial sinusitis and to reduce the risk of VAP,blockers or sucralfate.although direct causality has not been proved (Level II)A landmark prospective randomized trial comparing liberal(3, 93, 94, 109, 125).and conservative triggers to transfusion in ICU patients not 4. Continuous aspiration of subglottic secretions can reduceexhibiting active bleeding and without underlying cardiac diseasethe risk of early-onset VAP, and should be used, if avail-demonstrated that awaiting a hemoglobin level of 7.0 g/dl asable (Level I) (97, 128, 130).opposed to a level of 9.0 g/dl before initiating transfusion resulted 5. The endotracheal tube cuff pressure should be maintainedin less transfusion and no adverse effects on outcome (169). Inat greater than 20 cm H2O to prevent leakage of bacterialfact, in those patients less severely ill, as judged by low APACHEpathogens around the cuff into the lower respiratory tractII scores, mortality was improved in the restricted transfusion(Level II) (98, 126).group, a result thought to result from immunosuppressive effects 6. Contaminated condensate should be carefully emptiedof nonleukocyte-depleted red blood cell units with consequentfrom ventilator circuits and condensate should be pre-increased risk for infection. Multiple studies have identied ex-vented from entering either the endotracheal tube or in-posure to allogeneic blood products as a risk factor for postoper-ative infection and postoperative pneumonia, and the length ofline medication nebulizers (Level II) (98, 131, 132).time of blood storage as another factor modulating risk (1707. Passive humidiers or heatmoisture exchangers decrease174). In one prospective randomized control trial the use ofventilator circuit colonization, but have not consistentlyleukocyte-depleted red blood cell transfusions resulted in a re-reduced the incidence of VAP, and thus they cannot beduced incidence of postoperative infections, and specically aregarded as a pneumonia prevention tool (Level I) (135reduced incidence of pneumonia in patients undergoing colo- 139).rectal surgery (172). Routine red blood cell transfusion should be 8. Reduced duration of intubation and mechanical ventila-conducted with a restricted transfusion trigger policy. Whether tion may prevent VAP and can be achieved by protocolsleukocyte-depleted red blood cell transfusions will further re- to improve the use of sedation and to accelerate weaningduce the incidence of pneumonia in broad populations of pa- (Level II) (93, 120122, 124).tients at risk remains to be determined. 9. Maintaining adequate stafng levels in the ICU can reduceHyperglycemia, relative insulin deciency, or both may di-length of stay, improve infection control practices, andrectly or indirectly increase the risk of complications and poorreduce duration of mechanical ventilation (Level II) (121outcomes in critically ill patients. van den Berghe and coworkers 124).randomized surgical intensive care unit patients to receive eitherAspiration, body position, and enteral feeding.intensive insulin therapy to maintain blood glucose levels be- 1. Patients should be kept in the semirecumbent positiontween 80 and 110 mg/dl or to receive conventional treatment (3045 ) rather than supine to prevent aspiration, espe-(175). The group receiving intensive insulin therapy had reducedcially when receiving enteral feeding (Level I) (140144).mortality (4.6 versus 8%, p 0.04) and the difference was greater 2. Enteral nutrition is preferred over parenteral nutrition toin patients who remained in the intensive care unit more than reduce the risk of complications related to central intrave-5 days (10.6 versus 20.2%, p 0.005). When compared with the nous catheters and to prevent reux villous atrophy of thecontrol group, those treated with intensive insulin therapy had intestinal mucosa that may increase the risk of bacteriala 46% reduction of bloodstream infections, decreased frequencytranslocation (Level I) (3, 93, 145, 146).of acute renal failure requiring dialysis by 41%, fewer antibiotictreatment days, and signicantly shorter length of mechanical Modulation of colonization: oral antiseptics and antibiotics.ventilation and ICU stay. Although the same degree of benet 1. Routine prophylaxis of HAP with oral antibiotics (selec-may not be seen among patients with VAP as in other popula- tive decontamination of the digestive tract or SDD), withtions, aggressive treatment of hyperglycemia has both theoretical or without systemic antibiotics, reduces the incidence ofand clinical support. ICU-acquired VAP, has helped contain outbreaks of 9. 396AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL 171 2005MDR bacteria (Level I), but is not recommended for rou- of antibiotic therapy led to a reduced incidence of subsequenttine use, especially in patients who may be colonized withpneumonia and mortality (181).MDR pathogens (Level II) (149154, 156159, 161164,The diagnosis of HAP is difcult, and most studies of nonintu-176). bated patients have involved clinical diagnosis, with sputum cul- 2. Prior administration of systemic antibiotics has reducedture, but bronchoscopy has been used less often, making the reliabil-the risk of nosocomial pneumonia in some patient groups,ity of the bacteriologic information uncertain and the specicitybut if a history of prior administration is present at the time of the diagnosis undened (182). The accuracy of the clinicalof onset of infection, there should be increased suspiciondiagnosis of VAP has been investigated on the basis of autopsyof infection with MDR pathogens (Level II) (157159,ndings or quantitative cultures of either protected specimen161164). brush (PSB) or bronchoalveolar lavage (BAL) samples as the 3. Prophylactic administration of systemic antibiotics for 24standard for comparison (183186). Some studies have investi-hours at the time of emergent intubation has been demon-gated the accuracy of a single clinical nding, whereas othersstrated to prevent ICU-acquired HAP in patients withincluded multiple criteria in their denition of pneumonia. Theseclosed head injury in one study, but its routine use is not studies indicate that the diagnostic criteria of a radiographicrecommended until more data become available (Level I)inltrate and at least one clinical feature (fever, leukocytosis,(167).or purulent tracheal secretions) have high sensitivity but low 4. Modulation of oropharyngeal colonization by the use ofspecicity (especially for VAP). Combinations of signs and symp-oral chlorhexidine has prevented ICU-acquired HAP intoms may increase the specicity. A study in which the diagnosticselected patient populations such as those undergoing cor-standard was histology plus positive microbiologic cultures ofonary bypass grafting, but its routine use is not recom-immediate postmortem lung samples, the presence of chest inl-mended until more data become available (Level I) (148).trates, plus two of three clinical criteria resulted in 69% sensitiv- 5. Use daily interruption or lightening of sedation to avoid ity and 75% specicity (187). When the three clinical variablesconstant heavy sedation and try to avoid paralytic agents,were used the sensitivity declined, whereas the use of only onevariable led to a decline in specicity.both of which can depress cough and thereby increase theFor patients diagnosed with ARDS, suspicion of pneumoniarisk of HAP (Level II) (120).should be high and the presence of only one of the three clinicalStress bleeding prophylaxis, transfusion, and hyperglycemia.criteria described should lead to more diagnostic testing (188). 1. Comparative data from randomized trials suggest a trend A high index of suspicion should also be present in patients whotoward reduced VAP with sucralfate, but there is a slightly have unexplained hemodynamic instability or deterioration ofhigher rate of clinically signicant gastric bleeding, com- blood gases during mechanical ventilation. In the absence of anypared with H2 antagonists. If needed, stress bleeding pro-of these ndings, no further investigations are required. Thephylaxis with either H2 antagonists or sucralfate is accept-incidence of colonization in hospitalized patients in general andable (Level I) (99104, 155, 177179).even more in patients requiring endotracheal intubation is high 2. Transfusion of red blood cell and other allogeneic blood(107). Antibiotic treatment of simple colonization is stronglyproducts should follow a restricted transfusion trigger pol-discouraged. Routine monitoring of tracheal aspirate cultures toicy; leukocyte-depleted red blood cell transfusions can helpanticipate the etiology of a subsequent pneumonia has also beento reduce HAP in selected patient populations (Level I) found to be misleading in a signicant percentage of cases (189).(169174).Although these criteria should raise suspicion of HAP, con- 3. Intensive insulin therapy is recommended to maintain se-rmation of the presence of pneumonia is much more difcult,and clinical parameters cannot be used to dene the microbio-rum glucose levels between 80 and 110 mg/dl in ICU pa-logic etiology of pneumonia. The etiologic diagnosis generallytients to reduce nosocomial blood stream infections, dura-requires a lower respiratory tract culture, but rarely may betion of mechanical ventilation, ICU stay, morbidity, andmade from blood or pleural uid cultures. Respiratory tractmortality (Level I) (175).cultures can include endotracheal aspirates, BAL or PSB speci-mens. Overall, the sensitivity of blood cultures is less than 25%,DIAGNOSTIC TESTINGand when positive, the organisms may originate from an extra-pulmonary source in a large percentage, even if VAP is alsoDiagnostic testing is ordered for two purposes: to dene whetherpresent (190). Although an etiologic diagnosis is made from aa patient has pneumonia as the explanation for a constellation of respiratory tract culture, colonization of the trachea precedesnew signs and symptoms and to determine the etiologic pathogendevelopment of pneumonia in almost all cases of VAP, and thuswhen pneumonia is present. Unfortunately, currently available a positive culture cannot always distinguish a pathogen from atools cannot always reliably provide this information.colonizing organism. However, a sterile culture from the lower The diagnosis of HAP is suspected if the patient has a radio-respiratory tract of an intubated patient, in the absence of agraphic inltrate that is new or progressive, along with clinical recent change in antibiotic therapy, is strong evidence that pneu-ndings suggesting infection, which include the new onset ofmonia is not present, and an extrapulmonary site of infectionfever, purulent sputum, leukocytosis, and decline in oxygenation. should be considered (191, 192). In addition, the absence ofWhen fever, leukocytosis, purulent sputum, and a positive cul-MDR microorganisms from any lower respiratory specimen inture of a sputum or tracheal aspirate are present without a new intubated patients, in the absence of a change in antibioticslung inltrate, the diagnosis of nosocomial tracheobronchitis within the last 72 hours, is strong evidence that they are notshould be considered (180). When this denition has been ap-the causative pathogen. The time course of clearance of theseplied to mechanically ventilated patients, nosocomial tracheo-difcult-to-treat microorganisms is usually slow, so even in thebronchitis has been associated with a longer length of ICU stay face of a recent change in antibiotic therapy sterile cultures mayand mechanical ventilation, without increased mortality (180).indicate that these organisms are not present (193). For theseAntibiotic therapy may be benecial in this group of patients reasons, a lower respiratory tract sample for culture should be(180, 181). In one prospective randomized trial of intubatedcollected from all intubated patients when the diagnosis of pneu-patients with community-acquired bronchial infection, the use monia is being considered. The diagnostic yield and negative 10. American Thoracic Society Documents 397predictive value of expectorated sputum in nonintubated pa-The goals of diagnostic approaches in patients with suspectedtients have not been determined. HAP are to identify which patients have pulmonary infection; to ensure collection of appropriate cultures; to promote the useMajor Points and Recommendations for Diagnosis of early, effective antibiotic therapy, while allowing for stream-1. All patients should have a comprehensive medical historylining or de-escalation when possible; and to identify patients obtained and undergo physical examination to dene thewho have extrapulmonary infection (Figure 1). The committee severity of HAP, to exclude other potential sources ofconsidered two different approaches to management, a clinical infection, and to reveal the presence of specic conditions strategy and a bacteriologic strategy, and have incorporated fea- that can inuence the likely etiologic pathogens (Level II) tures from both in the nal recommendations. (9, 16, 194). Clinical Strategy2. All patients should have a chest radiograph, preferably posteroanterior and lateral if not intubated, as portable When the clinical approach is used, the presence of pneumonia chest radiographs have limited accuracy. The radiograph is dened by new lung inltrate plus clinical evidence that the can help to dene the severity of pneumonia (multilobar inltrate is of an infectious origin. The presence of a new or or not) and the presence of complications, such as effu-progressive radiographic inltrate plus at least two of three clini- sions or cavitation (Level II) (5, 195).cal features (fever greater than 38 C, leukocytosis or leukopenia,3. Purulent tracheobronchitis may mimic many of the clini- and purulent secretions) represents the most accurate combina- cal signs of HAP and VAP, and may require antibiotiction of criteria for starting empiric antibiotic therapy (187). Al- therapy, but prospective, randomized trials are neededthough sensitivity for the presence of pneumonia is increased if (Level III) (180). Tracheal colonization is common in only one criterion is used, this occurs at the expense of specicity, intubated patients, but in the absence of clinical ndingsleading to signicantly more antibiotic treatment. Requiring all is not a sign of infection, and does not require therapythree clinical criteria is too insensitive and will result in many or diagnostic evaluation (Level II) (40, 107).patients with true pneumonia not receiving therapy.4. Arterial oxygenation saturation should be measured in all The etiologic cause of pneumonia is dened by semiquantita- patients to determine the need for supplemental oxygen. tive cultures of endotracheal aspirates or sputum with initial Arterial blood gas should be determined if concern exists microscopic examination. Tracheal aspirate cultures consistently regarding either metabolic or respiratory acidosis, and grow more microorganisms than do invasive quantitative cul- this test generally is needed to manage patients who re-tures, and most microbiology laboratories report the results in quire mechanical ventilation. These results, along with other a semiquantitative fashion, describing growth as light, moderate, laboratory studies (complete blood count, serum electro-or heavy. In general, it is rare that a tracheal aspirate culture lytes, renal and liver function), can point to the presence does not contain the pathogen(s) found in invasive quantitative of multiple organ dysfunction and thus help dene the cultures (191, 199, 200). Gram staining of polymorphonuclear severity of illness (Level II) (38, 188). leukocytes and macrophages and careful examination of the5. All patients with suspected VAP should have blood cul-morphology of any bacteria found to be present, may improve tures collected, recognizing that a positive result can indi- diagnostic accuracy when correlated with culture results (201, cate the presence of either pneumonia or extrapulmonary 202). Conversely, a negative tracheal aspirate (absence of bacte- infection (Level II) (190). ria or inammatory cells) in a patient without a recent (within6. A diagnostic thoracentesis to rule out a complicating em- 72 hours) change in antibiotics has a strong negative predictive pyema or parapneumonic effusion should be performed value (94%) for VAP (203). A reliably performed Gram stain if the patient has a large pleural effusion or if the patient of tracheal aspirates has been demonstrated to result in a low with a pleural effusion appears toxic (Level III) (5).incidence of inappropriate therapy when used to guide initial7. Samples of lower respiratory tract secretions should be empiric antibiotic therapy (9, 198). obtained from all patients with suspected HAP, andThe clinical strategy emphasizes prompt empiric therapy for should be collected before antibiotic changes. Samplesall patients suspected of having HAP. The driving force behind can include an endotracheal aspirate, bronchoalveolar this strategy is the consistent nding that delay in the initiation lavage sample, or protected specimen brush sample of appropriate antibiotic therapy for patients with HAP is associ- (Level II) (183, 184, 192, 196, 197). ated with increased mortality (37, 112, 204). The selection of8. In the absence of any clinical suspicion of HAP or nosoco- initial antibiotic therapy is based on risk factors for specic mial tracheobronchitis, no respiratory tract cultures should pathogens, modied by knowledge of local patterns of antibiotic be obtained (Level III). resistance and organism prevalence. Therapy is modied on the9. A sterile culture of respiratory secretions in the absence basis of the clinical response on Days 2 and 3, and the ndings of a new antibiotic in the past 72 hours virtually rules of semiquantitative cultures of lower respiratory tract secretions. out the presence of bacterial pneumonia, but viral or Legionella infection is still possible (Level II) (192). If This approach requires no specialized microbiologic methods, these patients have clinical signs of infection, an extrapul- and all patients suspected of having pneumonia are treated. This monary site of infection should be investigated (Level II)avoids the problem of not treating some infected individuals. (190, 198). Use of an ICU-specic, broad-spectrum empiric therapy regi- 10. For patients with ARDS, for whom it is difcult to demon- ment can reduce the incidence of inappropriate initial therapy strate deterioration of radiographic images, at least one ofto less than 10% (198, 205). the three clinical criteria or other signs of pneumonia, such The major limitation to the clinical approach is that it consis- as hemodynamic instability or deterioration of blood gases, tently leads to more antibiotic therapy than when therapy deci- should lead to more diagnostic testing (Level II) (38). sions are based on the ndings (microscopy and quantitative cultures) of invasive (bronchoscopic) lower respiratory tract sam- ples (198). The clinical approach is overly sensitive, and patientsDIAGNOSTIC STRATEGIES AND APPROACHES can be treated for pneumonia when another noninfectious pro-Because clinical suspicion of HAP/VAP is overly sensitive, fur-cess is responsible for the clinical ndings. These processes mayther diagnostic strategies are required for optimal management.include congestive heart failure, atelectasis, pulmonary thrombo- 11. 398AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL 171 2005Figure 1. Summary of the managementstrategies for a patient with suspectedhospital-acquired pneumonia (HAP), ven-tilator-associated pneumonia (VAP), orhealthcare-associated pneumonia (HCAP).The decision about antibiotic discontinu-ation may differ depending on the typeof sample collected (PSB, BAL, or endotra-cheal aspirate), and whether the resultsare reported in quantitative or semiquan-titative terms (see text for details).embolism, pulmonary drug reactions, pulmonary hemorrhage, sooner, is necessary, because patients who are improving willor ARDS. Even if the patient has pneumonia, reliance on semi- have signs of a good clinical response by this time point (193,quantitative cultures, which may not reliably separate true patho-208). Singh and coworkers have shown that some patients withgens from colonizers, can lead to either more or broader spec-a low clinical suspicion of VAP (CPIS of 6 or less) can havetrum antibiotic therapy than with a quantitative approach (198).antibiotics safely discontinued after 3 days, if the subsequentThese cultures have their greatest value if they are negative and course suggests that the probability of pneumonia is still lowthe patient has not received new antibiotics within the past 72 (207). The modied CPIS used by Singh and coworkers appearshours. One other concern is that reliance on nonquantitative cul- to be an objective measure to dene patients who can receivetures could lead to a failure to recognize extrapulmonary infection a short duration of therapy.at an early time point. Major points and recommendations for the clinical strategy. In an effort to improve the specicity of clinical diagnosis, 1. A reliable tracheal aspirate Gram stain can be used to directPugin and coworkers developed the clinical pulmonary infectioninitial empiric antimicrobial therapy and may increase thescore (CPIS), which combines clinical, radiographic, physiologi-diagnostic value of the CPIS (Level II) (191, 199, 201, 209).cal (PaO2/FiO2), and microbiologic data into a single numerical2. A negative tracheal aspirate (absence of bacteria or in-result (206). When the CPIS exceeded 6, good correlation with ammatory cells) in a patient without a recent (within 72the presence of pneumonia, as dened by quantitative cultures hours) change in antibiotics has a strong negative pre-of bronchoscopic and nonbronchoscopic BAL specimens, wasdictive value (94%) for VAP and should lead to a searchfound. However, in a subsequent study that used histology plusfor alternative sources of fever (Level II) (203).immediate postmortem quantitative lung cultures as the refer-3. The presence of a new or progressive radiographic inl-ence standard, the CPIS had a sensitivity of 77% and a specicity trate plus at least two of three clinical features (feverof 42% (187). One prospective study evaluated 79 episodes ofgreater than 38 C, leukocytosis or leukopenia, and puru-suspected VAP, using the CPIS, and compared the ndings withlent secretions) represent the most accurate clinical criteriadiagnoses established by BAL culture. Overall, the sensitivityfor starting empiric antibiotic therapy (Level II) (187).and specicity of the score were low, although it improved if a4. If a clinical strategy is used, reevaluation of the decisionGram stain of a deep respiratory tract culture was added to the to use antibiotics based on the results of semiquantitativeevaluation (201). lower respiratory tract cultures and serial clinical evalua- The original description of the CPIS required microbiologictions, by Day 3 or sooner, is necessary (Level II) (193,data, and thus could not be used to screen for HAP. Singh and 205, 207, 208).colleagues used a modied CPIS that did not rely on culture5. A modied CPIS of 6 or less for 3 days, proposed by Singhdata to guide clinical management (207). Another approach was and coworkers, is an objective criterion to select patientsto calculate the score by using the results of a Gram stain of aat low risk for early discontinuation of empiric treatmentBAL specimen or blind protected telescoping catheter sample,of HAP, but still requires validation in patients with moreand score the ndings as either positive or negative. Using thissevere forms of VAP (Level I) (201, 207).approach, the CPIS for patients with conrmed VAP was signi-cantly higher than the value for nonconrmed VAP (201). Bacteriologic Strategy If a clinical strategy is used, reevaluation of the decision toThe bacteriologic strategy uses quantitative cultures of loweruse antibiotics based on serial clinical evaluations, by Day 3 or respiratory secretions (endotracheal aspirates, BAL or PSB speci- 12. American Thoracic Society Documents399mens collected with or without a bronchoscope) to dene both Postmortem studies have also demonstrated that VAP is oftenthe presence of pneumonia and the etiologic pathogen. Growth in multiple different phases of evolution at different sites atabove a threshold concentration is required to diagnose VAP/ the same time (216). Prior antibiotic therapy can inuence theHAP and to determine the causative microorganism(s). Growthnumber of bacteria found in lung tissue, and patients who havebelow the threshold is assumed to be due to colonization ordied in spite of prolonged therapy are likely to have organismscontamination. The bacteriologic strategy has been used to guide resistant to the agents used, whereas patients started on therapydecisions about whether to start antibiotic therapy, which patho-within 24 (and up to 72) hours may have negative cultures,gens are responsible for infection, which antimicrobial agents toespecially if the therapy is adequate (192). The multifocal natureuse, and whether to continue therapy.of VAP suggests that BAL and endotracheal aspirates can pro-Because the bacteriologic approach emphasizes avoidance of vide more representative samples than the protected specimenthe problem of overtreatment with antibiotics by trying to sepa- brush (PSB), which samples only a single bronchial segment.rate colonizing from infecting pathogens, use of this method has Because of the diffuse bilateral nature of VAP and predomi-consistently led to nding fewer microorganisms growing abovenance in dependent lung segments, blind BAL and PSB maythe diagnostic threshold than are present in nonqualitative cul- be as accurate as bronchoscopic sampling in some patients (219).tures of tracheal aspirates. When therapy decisions have beenAnother issue with the bacteriologic strategy is that culturebased on these data, fewer patients have been treated with antibi- results are not available immediately. Ancillary tests such asotics, and a potentially narrower spectrum of therapy was used,Giemsa stain for intracellular microorganisms, Gram stain, orcompared with the clinical approach (198, 210). Quantitative differential cell counts can be used to increase the likelihood ofcultures have been demonstrated to have good diagnostic utilitya subsequent positive culture and can be used to guide the needfor the presence of pneumonia, especially in patients with a low for antibiotic therapy before culture results. In some studies,or equivocal clinical suspicion of infection (211, 212). this approach has led to less use of antibiotics with no adverseThe major concern with the bacteriologic approach is that aoutcomes, and a tendency to improved mortality (198, 201). Notfalse negative culture can lead to a failure to treat either a specic all investigators agree about the safety of withholding therapypatient or a specic pathogen, and that the results are not always until quantitative results are available, and are positive, or toconsistent and reproducible (213215). A major factor causingwithdrawing therapy if cultures are negative, after empiricallyfalse negative quantitative cultures is a recent starting of orstarting antimicrobials for suspected infection (198, 220222).change in antibiotic therapy, especially in the preceding 24 hours,Clinically, these decisions have been guided by the degree ofbut up to 72 hours (192, 212). Therefore, ideally all quantitative certainty of the diagnosis of pneumonia at the time of testingcultures should be obtained before any antibiotic manipulation.(pretest probability), and on the severity of illness of the patientThis may not be possible in all situations, and in this setting a(198). Thus, most investigators agree that patients with signs ofchange in the diagnostic threshold may be helpful (212). For infection, who are clinically unstable, should receive therapy,BAL, use of a threshold 10-fold lower than usual may avoid regardless of the initial bronchoscopic ndings (198, 212).some false negative results in patients given antibiotics before The diagnostic threshold to discriminate infection from colo-testing. However, some patients with pneumonia will have cul-nization varies with the technique used, and possibly by theture growth below threshold, even without recent antibioticclinical probability of infection (212). The threshold may bechanges, especially in early forms of infection (215217). lowered if the patient has recently had a change in antibioticMethodologic issues involved in the inconsistent results oftherapy or if the probability of infection is high. Endotrachealpublished studies have been summarized in a meta-analysisaspirates can be cultured quantitatively, and with a threshold of(184). These include the evaluation of patients who did not106 cfu/ml or more the sensitivity of this method for the presencemeet recognized clinical criteria for the presence of pneumonia; of pneumonia has varied from 38 to 82%, with a mean of 76prolonged time between the performance of a diagnostic test9%, and with a specicity ranging from 72 to 85%, with a meanand the collection of conrmatory histopathologic information; of 75 28% (209).inclusion of patients who had received antibiotic therapy before Bronchoscopic BAL studies have typically used a diagnosticdiagnostic testing, often without correcting for the duration of threshold of 104 or 105 cfu/ml. Samples contaminated by upperantibiotic therapy; and inclusion of patients studied by BAL airway secretions, as reected by a high percentage of squamousperformed with insufcient lavage volume (less than 140 ml). A epithelial cells, should be used with caution. A few studies havemajor problem with all studies of HAP diagnosis is the absence ofshown the technique to be reproducible, but not all bacteria area gold standard with which diagnostic results can be compared. recovered above the diagnostic threshold when the procedureEven the best criteria for the presence of pneumonia, immediatehas been repeated in the same patient at the same site (223).postmortem histologic evaluation with microbiologic conrma- An evidence-based review of 23 prospective studies of BAL intion of infection, can be inaccurate. In addition, only a subgroup suspected VAP showed a sensitivity of 4293%, with a mean ofof patients with severe VAP is included in these types of studies. 73 18% (186), and a specicity of 45100%, with a mean ofIn a prospective study of 148 patients receiving mechanical82 19%. In 12 studies, the detection of intracellular organismsventilation and in whom infectious pneumonia was suspected,in 25% of recovered cells was used to diagnose pneumonia,Gibot and coworkers used a rapid immunoblot technique on with a mean sensitivity of 6920% and a specicity of 75BAL uid, and found that levels of soluble triggering receptor 28% (186). The advantage of looking for intracellular organismsexpressed on myeloid cells (sTREM-1) were the strongest inde-is the ability to obtain information of high predictive value in apendent predictor of pneumonia (odds ratio, 41.5) (218). Whenrapid time frame, without waiting for the results of cultures tocommercially available, this marker, coupled with the classicdene the presence of pneumonia, although not the specicclinical criteria and results of microbiologic cultures, may be aidentity of the etiologic pathogen.valuable tool with which to increase the specicity and maintain Quantitative cultures of PSB samples have used a diagnosticthe sensitivity of HAP diagnosis (197).threshold of 103 cfu/ml or more. The quality of the PSB sampleHistologic data have demonstrated several characteristics of is difcult to measure, and the reproducibility is not exact, withVAP pertinent to diagnostic testing, such as the nding that as many as 25% of results on different sides of the diagnosticthe process is often multifocal, frequently involving both lungs,threshold, when comparing two samples collected from the samegenerally in the posterior and lower segments (191, 215, 216). site in the same patient (183). The sensitivity and specicity range 13. 400 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL 171 2005from 33 to 100% (mean, 66 19%) and from 50 to 100% (mean,antibiotic use, and potentially reducing mortality. In the trial,90 15%). PSB appears to be more specic than sensitive for about 10% of the patients managed with a quantitative strategythe presence of pneumonia, and a positive result greatly increases received antibiotic therapy regardless of bronchoscopic ndingsthe likelihood of pneumonia being present (186). because of the presence of clinical instability and signs of sepsis. The bacteriologic strategy does require specialized laboratoryConsidering the available methods for diagnostic testing andand clinical skills. In many clinical settings, bronchoscopy isthe goals of using appropriate therapy in a timely manner, with-not immediately available, especially in the evenings, and the out overusing antibiotics, the committee has combined featurescollection of blind, nonbronchoscopic samples is an appealingof the clinical and bacteriologic approach into an algorithmalternative. Blind sampling can be done by BAL or PSB, or ashown in Figure 1. The decision to discontinue antibiotics, usingblind bronchial suction sample can be taken. When BAL samples this algorithm, may differ depending on the type of respiratoryare obtained nonbronchoscopically, the threshold varies by tech- tract sample that is collected and whether the culture results arenique and may be different from that of bronchoscopic BAL. reported in quantitative or semiquantitative terms. AdvocatesThe sensitivities of blind bronchial suction, blind mini-BAL, andblind PSB are 7497, 63100, and 5886%, respectively (224). of the bacteriologic approach support the discontinuation ofThe specicity of these methods has varied from 74 to 100% antibiotics in clinically stable patients whose quantitative culturefor blind bronchial suction, from 66 to 96% for mini-BAL, andresults of deep lung samples (BAL or PSB) fall below a diagnos-from 71 to 100% for blind PSB. In general, these techniquestic threshold. The utility of quantitative endotracheal aspiratesprovide data similar to those of samples collected bronchoscopi- for this decision is not as well dened. Advocates of the clinicalcally, although with a trend toward more cultures above thestrategy generally make a decision about antibiotic discontinua-diagnostic threshold. Side effects should be no greater and possi- tion based on the clinical course of the patient, supplementedbly less than with bronchoscopically collected samples.by data from either quantitative or semiquantitative cultures Recommendation for the bacteriologic strategy. Quantitative from a lower respiratory tract sample, which could include ancultures can be performed on endotracheal aspirates or samples endotracheal aspirate, as well as a BAL or PSB sample.collected either bronchoscopically or nonbronchoscopically, andeach technique has its own diagnostic threshold and methodo- Major Points and Recommendations for Comparinglogic limitations. The choice of method depends on local expertise,Diagnostic Strategiesexperience, availability, and cost (Level II) (197, 198, 214, 224).1. A patients with suspected VAP should have a lower respi-Recommended Diagnostic Strategyratory tract sample sent for culture, and extrapulmonaryTo date, several decision analyses, one retrospective study, and infection should be excluded, as part of the evaluation be-four prospective studies have evaluated the impact of diagnostic fore administration of antibiotic therapy (Level II) (198).strategies on the use of antibiotics and the outcomes of patients 2. If there is a high pretest probability of pneumonia, or in thewith suspected VAP (198, 211, 212, 220222, 225). In three ran-10% of patients with evidence of sepsis, prompt therapydomized single-center studies, no differences in mortality wereis required, regardless of whether bacteria are found onfound when invasive techniques (PSB and/or BAL) were com-microscopic examination of lower respiratory tract sam-pared with either quantitative or semiquantitative endotrachealples (Level II) (197, 198).aspirate culture techniques (220222). However, these studies 3. Diagnostic techniques that identify etiologic pathogens onincluded few patients (51, 76, and 88, respectively) and antibiotics the basis of qualitative cultures will lead to therapy forwere continued in all patients, even those with negative cultures, more organisms than diagnostic techniques based on quan-thereby negating one of the potential advantages of the bacterio-titative cultures (Level I) (198, 220222).logic strategy. In fact, several prospective studies have concluded 4. Semiquantitative cultures of tracheal aspirates cannot bethat antibiotics can be safely stopped in patients with negative used as reliably as quantitative cultures to dene the pres-quantitative cultures, with no adverse impact on mortality (15,ence of pneumonia and the need for antibiotic therapy198, 226). (Level I) (198, 220222).One large, prospective randomized trial did show an advan-5. If bronchoscopic sampling is not immediately available,tage to the quantitative bronchoscopic approach, when com- nonbronchoscopic sampling can reliably obtain lower re-pared with a clinical approach in a multicenter study of 413patients suspected of having HAP (198). Compared with patients spiratory tract secretions for quantitative cultures, whichmanaged clinically, those receiving invasive management had acan be used to guide antibiotic therapy decisions (Levellower mortality rate on Day 14 (16 and 25%; p 0.02), but II) (224).not on Day 28, and lower mean sepsis-related organ failure6. The use of a bronchoscopic bacteriologic strategy has beenassessment scores on Days 3 and 7 (p 0.04). At 28 days, theshown to reduce 14-day mortality, compared with a clinicalquantitative culture group had signicantly more antibiotic-free strategy, in one study of suspected VAP (Level I) (198).days (11 9 versus 7 7 days; p 0.001), but only a multivariate 7. Delays in the initiation of appropriate antibiotic therapyanalysis showed a signicant difference in mortality (hazard ra- can increase the mortality of VAP and thus therapy shouldtio, 1.54; 95% condence interval, 1.10 to 2.16; p 0.01). Onenot be postponed for the purpose of performing diagnosticstrength of the study was that a high percentage of patients instudies in patients who are clinically unstable (Level II)both arms received adequate initial antibiotics, although