© 2005 American Thoracic Society doi: 10.1164/rccm.200405-644ST
Guidelines for the Management of Adults with Hospital-acquired, Ventilator-associated, and Healthcare-associated Pneumonia
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
Since the initial 1996 American Thoracic Society (ATS) guideline on nosocomial pneumonia, a number of new developments have appeared, mandating a new evidence-based guideline for hospital-acquired pneumonia (HAP), including healthcare-associated pneumonia (HCAP) and ventilator-associated pneumonia (VAP). This document, prepared by a joint committee of the ATS and Infectious Diseases Society of America (IDSA), focuses on the epidemiology and pathogenesis of bacterial pneumonia in adults, and emphasizes modifiable risk factors for infection. 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 "semiquantitative" or "quantitative" microbiologic methods that help direct selection of appropriate antibiotic therapy. We also provide recommendations for additional diagnostic and therapeutic evaluations in patients with nonresolving pneumonia. This is an evidence-based document that emphasizes the issues of VAP, because there are far fewer data available about HAP in nonintubated patients and about HCAP. By extrapolation, patients who are not intubated and mechanically ventilated should be managed 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 management of HAP, VAP, and HCAP emphasize early, appropriate antibiotics in adequate doses, while avoiding excessive antibiotics by de-escalation of initial antibiotic therapy, based on microbiologic 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 another and recommends taking local microbiologic data into account 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:
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 guideline 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 advances in antimicrobial therapy, better supportive care modalities, 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 hospital 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 collected from patients with VAP, and microbiologic data from nonintubated patients may be less accurate, most of our information 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 presented 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 composed of pulmonary, critical care, and infectious disease specialists with clinical and research interests in HAP, VAP, and HCAP. All major aspects of the epidemiology, pathogenesis, bacteriology, diagnosis, and antimicrobial treatment were reviewed by this group. Therapy recommendations are focused on antibiotic choice and patient stratification; adjunctive, nonantibiotic therapy 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 Preventing Health-care–associated Pneumonia, prepared by the Centers 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 transplantation, 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 excessive antibiotic use is a major factor contributing to increased frequency of antibiotic-resistant pathogens. Four major principles underlie the management of HAP, VAP, and HCAP:
The ATS/IDSA guideline was established for use in the initial management of patients in whom HAP, VAP, or HCAP is suspected. Therapeutic algorithms are presented that are based on the expected antimicrobial susceptibility of the common bacterial 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 management. 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 clinical management. As more laboratory and clinical data become available, therapy often needs to be streamlined or altered. Finally, 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.
The ATS/IDSA Guideline Committee originally met as a group, with each individual being assigned a topic for review and presentation to the entire group. Each topic in the guideline was reviewed by more than one committee member, and after presentation of information, the committee discussed the data and formulated recommendations. Two committee members prepared each section of the document, and a draft document incorporating 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 statement 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 relevant, peer-reviewed studies published until July 2004 were considered. 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 bacterial 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 committee 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 strategies 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.
Incidence HAP is usually caused by bacteria, is currently the second most common nosocomial infection in the United States, and is associated 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 tracheobronchitis in mechanically ventilated patients. The exact incidence varies widely depending on the case definition of pneumonia 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 methodology failed to identify any attributable mortality due to VAP, suggesting a variable outcome impact, according to the severity of underlying medical conditions (24–26).
Etiology 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 produce infection in immunocompromised hosts and some immunocompetent 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 nonintubated 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 pathogens 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-negative rods (15%), Streptococcus pneumoniae (9%), and Pseudomonas 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 University 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, unpublished data). Pathogens were isolated from 92% of mechanically ventilated patients with infection, and from 77% of nonventilated 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 species, and K. pneumoniae. In fact, some organisms (MRSA and K. pneumoniae) were more common in nonventilated than ventilated patients, whereas certain resistant gram-negative bacilli were more common in patients with VAP (P. aeruginosa, Stenotrophomonas 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 regimen. 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.
PSEUDOMONAS AERUGINOSA. Although currently uncommon in the United States, there is concern about the acquisition of plasmid-mediated metallo-ß-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 countries in the Far East, Europe, Canada, Brazil, and recently in the United States (50).
KLEBSIELLA, ENTEROBACTER, AND SERRATIA SPECIES.
ACINETOBACTER SPECIES, STENOTROPHOMONAS MALTOPHILIA, AND BURKHOLDERIA CEPACIA.
METHICILLIN-RESISTANT STAPHYLOCOCCUS AUREUS.
STREPTOCOCCUS PNEUMONIAE AND HAEMOPHILUS INFLUENZAE.
LEGIONELLA PNEUMOPHILA.
Fungal pathogens.
Viral pathogens. 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 indirectly 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 inhibitors (oseltamivir and zanamivir) dramatically reduces the spread of influenza within hospital and healthcare facilities (3, 81–90). Amantadine and rimantadine are effective only for treatment and prophylaxis against influenza A strains, whereas neuraminidase inhibitors are effective against both influenza A and B.
Major Epidemiologic Points
For HAP to occur, the delicate balance between host defenses and microbial propensity for colonization and invasion must shift in favor of the ability of the pathogens to persist and invade the lower respiratory tract. Sources of infection for HAP include healthcare devices or the environment (air, water, equipment, and fomites) and can occur with transfer of microorganisms between staff and patients (3, 9, 12, 13, 27, 66, 92, 93). A number of host- and treatment-related colonization factors, such as the severity of the patient's underlying disease, prior surgery, exposure to antibiotics, other medications, and exposure to invasive respiratory devices and equipment, are important in the pathogenesis of HAP and VAP (40, 93, 94) HAP requires the entry of microbial pathogens into the lower respiratory tract, followed by colonization, which can then overwhelm the host's mechanical (ciliated epithelium and mucus), humoral (antibody and complement), and cellular (polymorphonuclear leukocytes, macrophages, and lymphocytes and their respective cytokines) defenses to establish infection (9, 94). Aspiration of oropharyngeal pathogens or leakage of bacteria around the endotracheal tube cuff is the primary route of bacterial entry into the trachea (95–98). The stomach and sinuses have been suggested as potential reservoirs for certain bacteria colonizing the oropharynx and trachea, but their importance remains controversial (99–104). Some investigators postulate that colonization of the endotracheal tube with bacteria encased in biofilm may result in embolization into the alveoli during suctioning or bronchoscopy (105, 106). Inhalation of pathogens from contaminated aerosols, and direct inoculation, are less common (107, 108). Hematogenous spread from infected intravascular catheters or bacterial translocation from the gastrointestinal tract lumen are quite rare.
Major Points for Pathogenesis
Risk factors for the development of HAP can be differentiated into modifiable and nonmodifiable conditions. Risk factors may also be patient related (male sex, preexisting pulmonary disease, or multiple organ system failure) or treatment related (intubation or enteral feeding). Modifiable risk factors for HAP are obvious targets for improved management and prophylaxis in several studies and in the comprehensive Guidelines for Preventing Health-care–associated Pneumonia, published by the Centers for Disease Control (3, 93, 110). Effective strategies include strict infection control, alcohol-based hand disinfection, use of microbiologic surveillance with timely availability of data on local MDR pathogens, monitoring and early removal of invasive devices, and programs to reduce or alter antibiotic-prescribing practices (3, 92, 93, 100, 110–113).
Intubation and Mechanical Ventilation Specific strategies have been recommended to reduce the duration of mechanical ventilation, such as improved methods of sedation and the use of protocols to facilitate and accelerate weaning (120–124). These interventions are dependent on adequate ICU staffing. Reintubation should be avoided, if possible, as it increases the risk of VAP (114). Attention to the specific type of endotracheal tube, its maintenance, and the site of insertion may also be valuable. The use of oral endotracheal and orogastric tubes, rather than nasotracheal and nasogastric tubes, can reduce the frequency of nosocomial sinusitis and possibly HAP, although causality between sinusitis and HAP has not been firmly established (109, 125). Efforts to reduce the likelihood of aspiration of oropharyngeal bacteria around the endotracheal tube cuff and into the lower respiratory tract include limiting the use of sedative and paralytic agents that depress cough and other host-protective mechanisms, and maintaining endotracheal cuff pressure at greater than 20 cm H2O (98, 126). Continuous aspiration of subglottic secretions, through the use of a specially designed endotracheal tube, has significantly reduced the incidence of early-onset VAP in several studies (97, 127–130). VAP may also be related to colonization of the ventilator circuit (131). A large number of prospective, randomized trials have shown that the frequency of ventilator circuit change does not affect the incidence of HAP, but condensate collecting in the ventilator circuit can become contaminated from patient secretions (98, 132–135). Therefore, vigilance is needed to prevent inadvertently flushing the condensate into the lower airway or to in-line medication nebulizers when the patient turns or the bedrail is raised (98, 131–134, 136). Passive humidifiers or heat–moisture exchangers decrease ventilator circuit colonization but have not significantly reduced the incidence of VAP (128, 135–139).
Aspiration, Body Position, and Enteral Feeding Enteral nutrition has been considered a risk factor for the development of HAP, mainly because of an increased risk of aspiration of gastric contents (3, 144). However, its alternative, parenteral nutrition, is associated with higher risks for intravascular device-associated infections, complications of line insertions, higher costs, and loss of intestinal villous architecture, which may facilitate enteral microbial translocation. Although some have advised feeding critically ill patients enterally as early as possible, a strategy of early (i.e., Day 1 of intubation and ventilation) enteral feeding was, when compared with late administration (i.e., Day 5 of intubation), associated with a higher risk for ICU-acquired VAP (145, 146). Seven studies have evaluated the risks for ICU-acquired HAP in patients randomized to either gastric or postpyloric feeding (147). Although significant differences were not demonstrated in any individual study, postpyloric feeding was associated with a significant reduction in ICU-acquired HAP in metaanalysis (relative risk, 0.76; 95% confidence interval, 0.59 to 0.99) (147).
Modulation of Colonization: Oral Antiseptics and Antibiotics Modulation of oropharyngeal colonization, by combinations of oral antibiotics, with or without systemic therapy, or by selective decontamination of the digestive tract (SDD), is also effective in significantly reducing the frequency of HAP, although methodologic study quality appeared to be inversely related to the magnitude of the preventive effects (93, 149–155). In two prospective randomized trials SDD was associated with higher ICU survival among patients receiving SDD (156, 157). In the first study patients with a midrange APACHE II score on admission had a lower ICU mortality, although ICU mortality rates of all patients included did not differ significantly (156). In the largest study performed so far, SDD administered to 466 patients in one unit was associated with a relative risk for ICU mortality of 0.65 and with a relative risk of hospital mortality of 0.78, when compared with 472 patients admitted in a control ward (157). In addition, infections due to antibiotic-resistant microorganisms occurred more frequently in the control ward. Importantly, levels of antibiotic-resistant pathogens were low in both wards, with complete absence of MRSA. Moreover, a small preexisting difference in outcome between two wards and the absence of a cross-over design warrant confirmation of these beneficial effects of SDD. The preventive effects of selective decontamination of the digestive tract for HAP have also been considerably lower in ICUs with high endemic levels of antibiotic resistance. In such a setting, selective decontamination of the digestive tract may increase the selective pressure for antibiotic-resistant microorganisms (158–164). Although selective decontamination of the digestive tract reduces HAP, routine prophylactic use of antibiotics should be discouraged, especially in hospital settings where there are high levels of antibiotic resistance. The role of systemic antibiotics in the development of HAP is less clear. In one study, prior administration of antibiotics had an adjusted odds ratio of 3.1 (95% confidence interval, 1.4–6.9) for development of late-onset ICU-acquired HAP (165). Moreover, antibiotics clearly predispose patients to subsequent colonization and infection with antibiotic-resistant pathogens (21). In contrast, prior antibiotic exposure conferred protection (risk ratio, 0.37; 95% confidence interval, 0.27–0.51) for ICU-acquired HAP in another study (17). In addition, antibiotic use at the time of emergent intubation may prevent pneumonia within the first 48 hours of intubation (166). Preventive effects of intravenous antibiotics were evaluated in only one randomized trial: administration of cefuroxime for 24 hours, at the time of intubation; and it reduced the incidence of early-onset, ICU-acquired HAP in patients with closed head injury (167). However, circumstantial evidence of the efficacy of systemic antibiotics also follows from the results of metaanalyses of selective decontamination of the digestive tract, which have suggested that the intravenous component of the regimens was largely responsible for improved survival (149). In summary, prior administration of antibiotics for short duration may be beneficial in some patient groups, but when given for prolonged periods may well place others at risk for subsequent infection with antibiotic-resistant microorganisms.
Stress Bleeding Prophylaxis, Transfusion, and Glucose Control A landmark prospective randomized trial comparing liberal and conservative "triggers" to transfusion in ICU patients not exhibiting active bleeding and without underlying cardiac disease demonstrated that awaiting a hemoglobin level of 7.0 g/dl as opposed to a level of 9.0 g/dl before initiating transfusion resulted in less transfusion and no adverse effects on outcome (169). In fact, in those patients less severely ill, as judged by low APACHE II scores, mortality was improved in the "restricted transfusion" group, a result thought to result from immunosuppressive effects of non–leukocyte-depleted red blood cell units with consequent increased risk for infection. Multiple studies have identified exposure to allogeneic blood products as a risk factor for postoperative infection and postoperative pneumonia, and the length of time of blood storage as another factor modulating risk (170–174). In one prospective randomized control trial the use of leukocyte-depleted red blood cell transfusions resulted in a reduced incidence of postoperative infections, and specifically a reduced incidence of pneumonia in patients undergoing colorectal surgery (172). Routine red blood cell transfusion should be conducted with a restricted transfusion trigger policy. Whether leukocyte-depleted red blood cell transfusions will further reduce the incidence of pneumonia in broad populations of patients at risk remains to be determined. Hyperglycemia, relative insulin deficiency, or both may directly or indirectly increase the risk of complications and poor outcomes in critically ill patients. van den Berghe and coworkers randomized surgical intensive care unit patients to receive either intensive insulin therapy to maintain blood glucose levels between 80 and 110 mg/dl or to receive conventional treatment (175). The group receiving intensive insulin therapy had reduced mortality (4.6 versus 8%, p < 0.04) and the difference was greater in patients who remained in the intensive care unit more than 5 days (10.6 versus 20.2%, p = 0.005). When compared with the control group, those treated with intensive insulin therapy had a 46% reduction of bloodstream infections, decreased frequency of acute renal failure requiring dialysis by 41%, fewer antibiotic treatment days, and significantly shorter length of mechanical ventilation and ICU stay. Although the same degree of benefit may not be seen among patients with VAP as in other populations, aggressive treatment of hyperglycemia has both theoretical and clinical support.
Major Points and Recommendations for 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 hyperglycemia.
Diagnostic testing is ordered for two purposes: to define whether a patient has pneumonia as the explanation for a constellation of new signs and symptoms and to determine the etiologic pathogen when pneumonia is present. Unfortunately, currently available tools cannot always reliably provide this information. The diagnosis of HAP is suspected if the patient has a radiographic infiltrate that is new or progressive, along with clinical findings suggesting infection, which include the new onset of fever, purulent sputum, leukocytosis, and decline in oxygenation. When fever, leukocytosis, purulent sputum, and a positive culture of a sputum or tracheal aspirate are present without a new lung infiltrate, the diagnosis of nosocomial tracheobronchitis should be considered (180). When this definition has been applied to mechanically ventilated patients, nosocomial tracheobronchitis has been associated with a longer length of ICU stay and mechanical ventilation, without increased mortality (180). Antibiotic therapy may be beneficial in this group of patients (180, 181). In one prospective randomized trial of intubated patients with community-acquired bronchial infection, the use of antibiotic therapy led to a reduced incidence of subsequent pneumonia and mortality (181). The diagnosis of HAP is difficult, and most studies of nonintubated patients have involved clinical diagnosis, with sputum culture, but bronchoscopy has been used less often, making the reliability of the bacteriologic information uncertain and the specificity of the diagnosis undefined (182). The accuracy of the clinical diagnosis of VAP has been investigated on the basis of autopsy findings or quantitative cultures of either protected specimen brush (PSB) or bronchoalveolar lavage (BAL) samples as the standard for comparison (183–186). Some studies have investigated the accuracy of a single clinical finding, whereas others included multiple criteria in their definition of pneumonia. These studies indicate that the diagnostic criteria of a radiographic infiltrate and at least one clinical feature (fever, leukocytosis, or purulent tracheal secretions) have high sensitivity but low specificity (especially for VAP). Combinations of signs and symptoms may increase the specificity. A study in which the diagnostic standard was histology plus positive microbiologic cultures of immediate postmortem lung samples, the presence of chest infiltrates, plus two of three clinical criteria resulted in 69% sensitivity and 75% specificity (187). When the three clinical variables were used the sensitivity declined, whereas the use of only one variable led to a decline in specificity. For patients diagnosed with ARDS, suspicion of pneumonia should be high and the presence of only one of the three clinical criteria described should lead to more diagnostic testing (188). A high index of suspicion should also be present in patients who have unexplained hemodynamic instability or deterioration of blood gases during mechanical ventilation. In the absence of any of these findings, no further investigations are required. The incidence of colonization in hospitalized patients in general and even more in patients requiring endotracheal intubation is high (107). Antibiotic treatment of simple colonization is strongly discouraged. Routine monitoring of tracheal aspirate cultures to anticipate the etiology of a subsequent pneumonia has also been found to be misleading in a significant percentage of cases (189). Although these criteria should raise suspicion of HAP, confirmation of the presence of pneumonia is much more difficult, and clinical parameters cannot be used to define the microbiologic etiology of pneumonia. The etiologic diagnosis generally requires a lower respiratory tract culture, but rarely may be made from blood or pleural fluid cultures. Respiratory tract cultures can include endotracheal aspirates, BAL or PSB specimens. Overall, the sensitivity of blood cultures is less than 25%, and when positive, the organisms may originate from an extrapulmonary source in a large percentage, even if VAP is also present (190). Although an etiologic diagnosis is made from a respiratory tract culture, colonization of the trachea precedes development of pneumonia in almost all cases of VAP, and thus a positive culture cannot always distinguish a pathogen from a colonizing organism. However, a sterile culture from the lower respiratory tract of an intubated patient, in the absence of a recent change in antibiotic therapy, is strong evidence that pneumonia is not present, and an extrapulmonary site of infection should be considered (191, 192). In addition, the absence of MDR microorganisms from any lower respiratory specimen in intubated patients, in the absence of a change in antibiotics within the last 72 hours, is strong evidence that they are not the causative pathogen. The time course of clearance of these difficult-to-treat microorganisms is usually slow, so even in the face of a recent change in antibiotic therapy sterile cultures may indicate that these organisms are not present (193). For these reasons, a lower respiratory tract sample for culture should be collected from all intubated patients when the diagnosis of pneumonia is being considered. The diagnostic yield and negative predictive value of expectorated sputum in nonintubated patients have not been determined.
Major Points and Recommendations for Diagnosis
Because clinical suspicion of HAP/VAP is overly sensitive, further diagnostic strategies are required for optimal management. The goals of diagnostic approaches in patients with suspected HAP are to identify which patients have pulmonary infection; to ensure collection of appropriate cultures; to promote the use of early, effective antibiotic therapy, while allowing for streamlining or de-escalation when possible; and to identify patients who have extrapulmonary infection (Figure 1). The committee considered two different approaches to management, a clinical strategy and a bacteriologic strategy, and have incorporated features from both in the final recommendations.
Clinical Strategy When the clinical approach is used, the presence of pneumonia is defined by new lung infiltrate plus clinical evidence that the infiltrate is of an infectious origin. The presence of a new or progressive radiographic infiltrate plus at least two of three clinical features (fever greater than 38°C, leukocytosis or leukopenia, and purulent secretions) represents the most accurate combination of criteria for starting empiric antibio |
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EXECUTIVE SUMMARY
-methoxy-ß-lactams, such as cefoxitin and cefotetan, but continued susceptibility to carbapenems. Citrobacter and Serratia species have the same inducible AmpC ß-lactamase and the same potential for resistance 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 ß-lactam resistance in nosocomial isolates, and is increasingly recognized not only in isolates of K. pneumoniae and E. coli, but also Enterobacter species (