key: cord-0036364-yw9ine1e
authors: Chroneou, Alexandra; Zias, Nikolaos; Gray, Anthony; Gray, Anthony; Craven, Donald E.; Craven, Donald E.
title: Pneumonia
date: 2010
journal: Surgical Intensive Care Medicine
DOI: 10.1007/978-0-387-77893-8_29
sha: a39966baec8b1e39e591e0d4d288fed40f4e0e06
doc_id: 36364
cord_uid: yw9ine1e

Hospital-acquired pneumonia (HAP) is usually caused by bacterial, viral, or fungal pathogens that occur ≥48 h after hospital admission.(1,2) Overall, more than 80% of HAP episodes are related to invasive airway management (in patients with endotracheal intubation or tracheostomy) with mechanical ventilation, which is known as ventilator-associated pneumonia (VAP).(3) VAP is defined as pneumonia developing more than 48 h after intubation and mechanical ventilation. Healthcare-associated pneumonia (HCAP) is part of the continuum of pneumonia, which includes patients who were hospitalized in an acute-care hospital for ≥2 days within 90 days of the infection; resided in a 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.(1,2) Although this document focuses more on HAP and VAP, many of the principles are also relevant to the management of HCAP. HAP, VAP, and HCAP are the second most common nosocomial infections after urinary tract infection, but are the leading causes of mortality due to hospital-acquired infections.(4,5)

with the duration of mechanical ventilation and attack rates have been estimated to be approximately 3% per day during the first 5 days and 2% per day thereafter. 8 We are entering an era with greater pressure for public reporting of healthcare-associated infections, but rates may depend on the definitions and denominators used. Eggimann et al. examined several ways to report healthcare-associated infection rates and suggested some caveats for benchmarking rates of VAP. In a prospective cohort of 1,068 medical ICU patients, 127 episodes of VAP developed in 106 (23.5%) of 451 mechanically ventilated patients. 10 The incidence of first episode of VAP was 22.8/1,000 patient-days; 29.6/1,000 patient days at risk, 35.7/1,000 ventilator days, and 44.0/1,000 ventilator days at risk. When considering all 127 episodes of VAP, infection rates increased from 22.8 to 27.3 episodes/1,000 ICU days and from 35.7 to 42.8 episodes/1,000 ventilator days. These data demonstrate the importance of the denominator chosen and may differ by as much as 40-60%. These rates have decreased in the past 3 years due to better prevention measures.

Crude mortality rates for VAP pneumonia range from 20 to 60%, reflecting, in large part, the severity of underlying disease, organ failure, and specific pathogen(s) and study populations. 1, 2, 6, 11, 12 In two major studies of VAP, the mortality rate varied between 4% in patients without prior antibiotic exposure to 73% in those with VAP due to MDR pathogens (e.g., P. aeruginosa or A. baumannii), and attributable mortality ranged from 6 to 14%. 13 Prevention programs for VAP are critically important for patient safety. Preventing VAP not only improves clinical outcomes, but also significantly reduces healthcare costs and liability. Rello et al. demonstrated that an average episode of VAP increased hospitalization by 12 days, mechanical ventilation by 10 days, ventilator days by 6 days, and ICU stay by 6 days at a hospital cost of $40,000; similar results have been reported from a suburban hospital by Warren et al. 12, 14 Pathogenesis Pathogenesis of HAP involves the direct interaction between the pathogen(s) with the host and epidemiologic variables that facilitate this dynamic. There are several mechanisms that contribute to the pathogenesis of HAP, and the relative contribution of each pathway remains controversial and varies by population at risk and the infecting pathogen(s) (Fig. 29.1 ). 1, 2 Microaspiration in nonventilated patients is the primary route of bacterial entry into the lower respiratory tract. 1, 2 In addition, patients who are sedated, postoperative, or have abnormal swallowing are at higher risk for aspiration. 1, 2 Direct inoculation, bacteremic spread, or translocation of bacteria from the gastrointestinal tract are less common modes of acquisition. High concentrations of bacteria refluxed from the gastric reservoir or infected sinuses may be aspirated and increase levels of bacteria colonizing the oropharynx, but the relative contribution of these sites remains controversial. The current practice of maintaining patients in the semi-upright position, especially while providing enteral feeding, probably reduces the contribution of gastric colonization to VAP. Bacterial adherence and colonization of the oropharynx clearly are important for bacterial entry into the lower respiratory tract. 1, 15, 16 Colonization with gram-negative bacilli was present in 16% of moderately ill patients versus 57% of critically ill patients, and rates of pneumonia increased sixfold in ICU patients with bacterial colonization. Host factors, types of bacteria colonizing the pharynx, and the use of antibiotics may alter colonization and adherence of gram-negative bacilli. Oral epithelial cells rich in fibronectin bind gram-positive organisms, such as streptococci and S. aureus; conversely, those poor in fibronectin preferentially bind gram-negative bacilli such as P. aeruginosa. 16 In the mechanically ventilated patient, inhalation of aerosols, contaminated tubing condensate, leakage of bacteria, and oral secretions around the endotracheal cuff are routes of bacterial entry into the lower respiratory tract (Fig. 29.2) . 18, 19 In addition, local trauma and inflammation from the endotracheal tube increase tracheal colonization and reduce clearance of organisms and secretions from the lower respiratory tract. The development of biofilm-encased bacteria over time on the endotracheal tube lumen may increase the risk of bacterial embolization into the alveoli following suctioning or bronchoscopy 20 (Fig. 29. 3).

In mechanically ventilated patients, the stomach and gastrointestinal tract may contribute to oropharyngeal and tracheal colonization with gram-negative bacilli, although some investigators question their importance. 1, 15, [21] [22] [23] The stomach often is sterile when the pH is <2 because of the potent bactericidal activity of hydrochloric acid. An increase in gastric colonization occurs with achlorhydria, and various gastrointestinal diseases, malnutrition, or use of antacids or histamine-2 (H2) blockers. In mechanically ventilated patients, colonization may reach 1-100 million gram-negative bacilli/ml of gastric juice when the pH is >4. 23 2. An intubated patient with oropharyngeal colonization. Subglottic secretions pooled above the endotracheal tube (ETT) cuff may leak around the cuff or be introduced directly into the trachea, resulting in either colonization. Depending on level of bacterial colonization, using semiquantitative samples of endotracheal aspirates (SQ-ETA) or quantitative-ETA, a diagnosis of ventilator-associated tracheobronchitis (VAT) and ventilator-associated pneumonia (VAP) can be made. Quantitative diagnostic sampling of the alveolar space by bronchoscopic of non-bronchoscopic, bronchoalveolar lavage (BAL), or protected specimen brush (PSB) may also be used to diagnose VAP. NG: nasogastric tube. The pathogenesis of lower respiratory tract infections often begins with tracheal colonization, which may progress to ventilator-associated tracheobronchitis (VAT), and, in selected patients, to VAP. 24, 25 In addition, discrimination between VAT and VAP may be difficult due to poor and overlapping definitions. VAT is defined as the presence of clinical signs of lower respiratory tract infection (fever, leukocytosis, and purulent sputum) with a quantitative endotracheal sputum sample with more than 106 organisms/ml of a respiratory pathogen, in the absence of a new or progressive infiltrate on chest X-ray ( Fig. 29.2 ). Monitoring endotracheal aspirates used to identify pathogens colonizing the lower airway is needed to diagnose and initiate early, appropriate antibiotic therapy. Recent data suggest that VAT appears to be an important risk factor for VAP and that targeted antibiotic therapy for VAT may be a new paradigm for VAP prevention and better patient outcomes. 24, 25 Immune Defenses in the Lung The response of pulmonary host defenses to invading microorganisms plays an integral part in the pathogenesis and outcome of infection ( Fig. 29.1 ). 2, 6, 26, 27 Mucociliary and mechanical clearances in the upper airway are important factors in the defense against infection. Bacterial antigens and cytokines that alter the activity and efficacy of ciliary cells in clearing bacteria from the lower airway need further study. The ability of macrophages and polymorphonuclear leukocytes to eliminate bacterial pathogens, and the interaction of these cells with inflammatory cytokines, probably play important roles in the pathogenesis of pneumonia. Cell-mediated immune response is controlled by a complex array of lipids, peptides, and cytokines, including interleukin-1 and -2 interferons, growth factors, and chemotactic factors. Leukotrienes complement components, and platelet-activating factor also assist in the inflammatory response and contribute to the pathogenesis of pneumonia.

The wide spectrum of etiologic agents causing HAP/VAP varies by hospital, type of ICU, and patient population studied, emphasizing the importance of current local surveillance data 1, 2, 6, 9, 12, 28, 29 (Table 29 .1). Bacteria causing HAP/VAP may originate from various sources, including the patient's endogenous flora, other patients, staff, contaminated devices, or the environment. 7, 30, 31 Prior hospitalization, exposure to chronic care facilities, and antibiotic therapy also are important predisposing factors for MDR pathogens. [32] [33] [34] [35] In the absence of these factors, early onset HAP, occurring during the first 5 days of the hospital stay, is usually caused by Streptococcus pneumoniae, Moraxella catarrhalis, Haemophilus influenzae, or anaerobic bacteria ( Gram-negative bacilli have been implicated in more than 60% of reported episodes of HAP, and S. aureus (often MRSA) accounts for 20-40% of episodes but is increasing rapidly in the United States. 1, 5, 9 Isolation rates of these bacteria vary considerably depending on the population at risk, location, hospital size, ICU type, and method of diagnosis. However, overall rates of MDR pathogen infections are increasing rapidly in the United States and many other countries. 5, 37, 38 Most episodes of bacterial nosocomial pneumonia are caused by more than one species of bacteria because of aspiration or leakage of mixed bacterial flora from the oropharynx. 1, 2, 6, 12 More recently, pneumonia due to community-acquired MRSA (CA-MRSA) has emerged in children and adults. [39] [40] [41] [42] In contrast to healthcare-associated (HA)-MRSA, CA-MRSA isolates are genetically distinct and almost uniformly carry the Panton-Valentine leukocidin (PVL), which may be associated with greater virulence. These strains also have been identified as an emerging source of infection spreading within hospitals. There is also concern over the evolution of vancomycin or glycopeptide-intermediate S. aureus (VISA/GISA) isolates of S. aureus that have been increasing. 39, 43 Diagnosis Accurate data regarding etiologic agents, epidemiology, and treatment of HAP/VAP are limited by the lack of a diagnostic gold standard. Although clinical criteria and semiquantitative sputum culture criteria for the diagnosis of VAP are the current standard for diagnosis in most hospitals, there are concerns about lack of diagnostic specificity. 2, 6, 44 Atelectasis, pulmonary edema, pulmonary emboli, neoplastic processes, and some autoimmune diseases can mimic HAP and VAP and, therefore, microbiologic diagnosis is critical. In addition, chest radiographic changes may be difficult to evaluate due to adult respiratory distress syndrome (ARDS) or congestive heart failure, making the clinical diagnosis of pneumonia more difficult ( Fig. 29.4a, b) . The use of a computerized tomographic (CT) scan improves imaging but quality sputum samples for Gram stain and culture are also of paramount importance for providing clues to possible pathogens. Sputum may be produced spontaneously, induced by nebulized saline, or obtained by bronchoscopy in the non-intubated patient. For patients in mechanically ventilated ICUs, there has been considerable controversy regarding the benefits and risks of clinical diagnosis using semiquantitative evaluation of endotracheal aspirates versus quantitative cultures obtained from either bronchoscopic bronchoalveolar lavage (B-BAL) or protective specimen brush (B-PSB) or non-bronchoscopic BAL/PSB (NB-BAL or NB-PSB). 2 These diagnostic approaches are discussed below.

The clinical diagnosis of pneumonia is defined as the presence of a new or progressive radiographic infiltrate plus at least two of three clinical features (fever >38°C, leukocytosis or leukopenia, and purulent secretions). While sensitivity for the presence of pneumonia is increased if only one criterion is used, specificity is reduced, leading to significantly increased use of antibiotics. Requiring all three clinical criteria is too insensitive, resulting in under-prescribing for patients with HAP.

The clinical pulmonary infection score (CPIS), used in some ICUs, gives points for clinical, radiographic, physiologic (PaO 2 /FiO 2 ), and microbiologic data for a single numerical result. 36 When the CPIS score was greater than 6, good correlation was found with the presence of pneumonia. 45 Singh et al. used a modified CPIS score that did not rely on culture data to guide clinical management. 46 Patients with a low clinical suspicion of VAP (CPIS 6) were randomized to therapy with ciprofloxacin compared to conventional therapy. The ciprofloxacin group had antibiotics discontinued after 3 days if there was no deterioration in their clinical status or CPIS score. 46 The modified CPIS score appears to be an objective measure to define patients who can receive shorter courses of therapy (3 days), achieving better overall outcomes.

Most microbiology laboratories report sputum culture results in a semiquantitative fashion, describing growth as light, moderate, or heavy. Moderate to heavy growth is most consistent with a diagnosis of VAT or VAP, especially if the Gram stain has many polymorphonuclear leukocytes and bacteria. The presence of bacteria on Gram stain (smear) correlates with 10 5 bacteria/ml by bronchoscopic alveolar lavage (BAL). Also, the morphology of the bacteria is a clue to the offending bacteria (i.e., gram-positive cocci in clusters suggest S. aureus and gram-negative bacilli may suggest Klebsiella spp, E. coli, or P. aeruginosa). It is also important to correlate these findings with aerobic culture results, because anaerobic cultures are not routinely performed. A Gram stain of sputum or tracheal aspirate without bacteria or inflammatory cells has a strong negative predictive value for VAP and may suggest another cause for the patient's fever, leukocytosis, and infiltrate on chest X-ray. Use of the endotracheal aspirates for the diagnosis of VAP allows prompt, empiric therapy, and may reduce mortality. However, it may not effectively separate lower airway colonization (purulent tracheobronchitis) from VAP (Table 29. 2). Semiquantitative criteria suggesting VAP are moderate to heavy growth.

By comparison, quantitative endotracheal aspirates, or cultures of lower respiratory secretions using bronchoscopic or non-bronchoscopic BAL or PSB to define VAP, are more specific than semiquantitative endotracheal aspirates. 2,6 VAP is defined as growth of >10 5 -10 6 CFU/ml for endotracheal aspirates, >10 3 CFU/ml for PSB, and >10 3 CFU/ml for BAL. Growth below the threshold suggests colonization or contamination with some exceptions. For example, patients who have had a recent change in antibiotics may have a false-negative BAL/PSB, perhaps early VAP, inadequate BAL technique, or other causes, such as Legionella pneumophila, viruses, or anaerobic bacteria. However, the quantitative approach may improve de-escalation of antibiotics by targeting the specific pathogens that are causing VAP. In one large, prospective, randomized trial of 413 patients with suspected VAP, patients receiving invasive management compared to those managed clinically had a lower mortality rate at day 14 (16 and 25%; p = 0.02, but not at day 28), lower mean sepsis-related organ failure assessment scores (p = 0.04), and significantly more antibiotic-free days (11 ± 9 vs. 7 ± 7; p < 0.001). 47 Multivariate analysis demonstrated significantly reduced mortality (hazards ratio, 1.54 [CI, 1.10-2.16]; p = 0.01). Although a high percentage of patients in both arms received adequate initial antibiotics, more patients in the invasive group received adequate therapy than in the clinical group, and the impact of this difference on the observed mortality is of concern.

This study suggests that the quantitative approach is safe, leads to less antibiotic use, and may potentially reduce mortality.

On the contrary, a recent randomized study by a Canadian Critical Care Trials group compared quantitative and semiquantitative techniques for diagnosing VAP in 740 patients who were randomized to specifically target antibiotic therapy. 48 Although there were many patients excluded from the study, including those with MRSA and P. aeruginosa colonization, the clinical outcomes in terms of length of stay in the hospital/ICU and the 28-day mortality were similar between the two groups.

Current management principles for HAP and VAP summarized in the 2005 American Thoracic Society & Infectious Diseases Society (ATS/IDSA) Guidelines include early, appropriated, initial antibiotic therapy, followed by de-escalating antibiotics based on clinical response and microbiologic data and reducing duration of therapy to 7-8 days in responders. 2 An alternative management strategy has been suggested that focuses on treating VAT before the development of VAP using targeted antibiotic therapy when a quantitative endotracheal aspirate has a pathogen(s) 10 6 organisms/ml, but such a strategy needs further investigation. 24, 25 Early, Appropriate, and Adequate Initial Empiric Antibiotic Therapy As soon as HAP/VAP is suspected, the collection of respiratory samples and the prompt initiation of appropriate antibiotics, in adequate doses, are suggested ( Fig. 29 .5 and Table 29 .2). It has been shown that the shorter the time between diagnosis and initiation of treatment the better the impact on prognosis, length of hospital stay, and cost. [49] [50] [51] [52] Appropriate therapy means that the pathogen is susceptible to the chosen regimen, whereas adequate therapy means that appropriate drugs, with good lung penetration, are given in optimal doses via the correct route. Choosing an initial, appropriate intravenous antibiotic regimen depends on the likelihood of infection with MDR pathogens, such as P. aeruginosa, A. baumannii,

Risk factors for MDR pathogens include prior hospitalization, late-onset infection, prior antibiotic therapy, and chronic dialysis, and are more for residents of chronic care facilities and for immunocompromised patients. Patients without MDR risk factors and early onset HAP or VAP usually can be treated with a more limited spectrum of antibiotics, such as ceftriaxone plus azithromycin, a third-or fourth-generation quinolone (i.e., levofloxacin), or ampicillin-sulbactam (Table 29. 2). By comparison, broader initial antibiotic therapy is suggested if patients are at risk for MDR pathogens (Table 29. 3). Finally, it is important to use doses of antibiotics that will achieve adequate concentrations in the lung parenchyma, which are outlined in the ATS/IDSA Guideline. 2 Assessing Clinical Response, Cultures, and Antibiotic De-escalation While initial antibiotic coverage should be liberal and broad enough to cover all suspected pathogens, de-escalation or streamlining antibiotic therapy, based on the patient's clinical response and microbiologic data, is of critical importance to improve patient outcomes and minimize antibiotic use 2,46 ( Fig. 29.5 ). Patients without evidence of HAP or VAP should have their antibiotics stopped. If necessary, further work-up and treatment for other sources of fever should be initiated.

In a recent randomized trial of patients with VAP, patients randomized to 8 days of antibiotic therapy had fewer recurrences and less resistance overall than those randomized to 15 days of therapy. 53 No significant differences were noted in mortality or clinical response parameters, but rates of recurrence for those patients with VAP due to P. aeruginosa infection were higher in the group treated for 8 rather than 15 days. The ATS/IDSA guideline recommends 7-8 days of therapy for uncomplicated HAP or VAP with close follow-up for any signs of relapse, especially for patients with HAP or VAP due to P. aeruginosa 2 (Fig. 29.5 ).

This pathogen is distinguished by its capacity to develop resistance to all known classes of antibiotics even while the patient is still on therapy. It is unclear if this problem could be avoided with the use of combination therapy. 54, 55 The only supporting data comes from a study of P. aeruginosa bacteremia (few cases Antimicrobial therapy in preceding 90 days Current hospitalization of at least 5 days High frequency of antibiotic resistance in the community or in the specific hospital unit Hospitalization for at least 2 days in the preceding 90 days Residence in a nursing home or extended care facility Home infusion therapy (including antibiotics) Chronic dialysis within 30 days Home wound care Family member with infection involving MDR pathogen Immunosuppressive disease and/or therapy of which were due to pneumonia), which showed that patients receiving combination therapy were less likely to die. 56 Cometta et al., 55 in a prospective study, compared combination therapy of an aminoglycoside and a carbapenem versus monotherapy with carbapenem, which did not show improved outcomes, or a difference in the rate of developing resistance. Of note is that no study has used single daily dosing of the aminoglycoside, or the maximal effective dose recommended by ATS/IDSA. Also, no data are available comparing a fluoroquinolone-based combination therapy, with b-lactam monotherapy. However, if P. aeruginosa is isolated, combination therapy should be used until antibiotic sensitivity is available.

The choices of treatment of Acinetobacter species pneumonia are limited because of its native resistance to many classes of antibiotics. Carbapenems, polymyxins, and the sulbactam component of ampicillin-sulbactam are considered the most effective antibiotic classes. Wood and coworkers demonstrated equivalent rates of clinical cure in a population with trauma surgery with ampicillin-sulbactam, compared with imipenem, including patients with imipenem-resistant isolates. 57 The emergence of carbapenem-resistant clones suggests the need for use of optimal doses of carbapenem. Polymyxins are significantly nephrotoxic, limiting their widespread intravenous use; there may be some benefit from aerosolized polymyxin. 58, 59 Extended-Spectrum -Lactamase Producers

The hallmark of ESBL-producing enterobacteriaceae, such as Klebsiella pneumoniae, Escherichia coli, and Enterobacter species, is a variable response to cephalosporins, and therefore third-and fourth-generation agents should be avoided as monotherapy when these pathogens are suspected or isolated. 60 Third-generation cephalosporins (e.g., cefotaxime) should not be used for treatment of Enterobacter spp. because of the high frequency of resistance of this pathogen to this therapy. 61 The use of the fourth-generation cephalosporin (e.g., cefepime) is also not recommended. 60,62 A most reliable empiric choice is a carbapenem, such as imipenem, meropenem, or etrapenem. 63 

Although vancomycin is considered the standard therapy for MRSA pneumonia, clinical trials and studies from different centers have reported clinical failure rates of greater than 40% with a standard dose of 1 g every 12 h. [64] [65] [66] This treatment failure may be related to inadequate dosing. 64 Many physicians have therefore tried to achieve a trough concentration of 15 mg/l or more, but without prospective clinical data supporting this practice. Combination therapy with rifampin, aminoglycosides, and other agents has been tried, but without well-documented value. 67 The use of continuous vancomycin infusions has not been proved to be advantageous compared with twice-daily dosing in severe MRSA infections. 68 Linezolid is another agent that has been used in the treatment of patients with MRSA VAP. Two large multicenter trials demonstrated equivalence to vancomycin in the treatment of these patients. 69, 70 When these studies were combined and analyzed by multivariate techniques, linezolid was associated with a better clinical cure and lower mortality. Although the superiority of linezolid over vancomycin needs further validation in randomized trials, it has higher lung penetration, as measured by epithelial lining fluid analysis when compared with vancomycin. 58, 71 Linezolid should be considered in patients with renal failure or a documented lack of response to vancomycin. Dosing vancomycin in patients with fluctuating renal function is difficult, and requires frequent monitoring of drug levels. Notably, the presence of renal insufficiency was a significant predictor of vancomycin failure in a multivariate analysis of patients with VAP, 69 and there is also concern about increased nephrotoxicity in patients receiving vancomycin and other nephrotoxic medications, such as aminoglycosides. 68, 72, 73 Other approved new agents for nosocomial MRSA infections are quinupristin/dalfopristin. Daptomycin should not be used in the treatment of MRSA pneumonia, as it was found inferior in clinical trials. Tigecycline has excellent activity against MRSA in vitro, and clinical studies of VAP are in progress. Ceftobiprole and dalbavancin also have in vitro activity against MRSA, but are not currently approved for use in the United States. [74] [75] [76] There are also new concerns over the emergence and rapid spread of a new strain of community-acquired MRSA that can cause serious pneumonia in healthy children and adults, and superinfection in individuals with influenza A virus infection. [77] [78] [79] Community-acquired MRSA has caused outbreaks in nursing homes, hospitals, schools, prisons, athletic teams, and the military. This strain may continue to spread in the community and is likely to become a major healthcare-associated pathogen. 39, 79, 80 Community-acquired MRSA isolates have increased virulence that may be related, in part, to the presence of the Panton-Valentine leukocidin. Furthermore, the combination of increasing hospital-acquired MRSA in healthcare settings and the rapid spread of community-acquired MRSA in selected high-risk populations and in acute and chronic healthcare settings requires close attention. Finally, the encapsulated pathogens S. pneumoniae and S. aureus, which may cause HAP, are common causes of bacterial superinfection following the yearly influenza outbreaks, and there is even greater concern over both hospital-acquired and community-acquired MRSA in the setting of a future bird flu pandemic. 81 Lack of Response to Initial Therapy In most patients, clinical improvement takes 24-48 h. Therefore, the selected antimicrobial regimen should not be changed during this time unless there is evidence of progressive deterioration. 84 used successfully a self-study module, in-service teaching programs that were coordinated with ICU staff meetings, along with fact sheets and posters, which were placed in the ICU and respiratory care departments. Rates of VAP dropped nearly 58%, and the cost savings were estimated to be between $425,606 and >$4,000,000. Babcock et al., using an extension of this program in an Integrated Health Care System, reported a 46% reduction in VAP over an 18-month period. 85 Staffing in the ICU is important, which is under-appreciated 1,4 , and must be sufficient for patient care and compliance with infection control practices. [85] [86] [87] Use of proper isolation techniques and effective infection control practices are cornerstones for prevention of HAP. 1, 7, 86 Infection control programs have repeatedly demonstrated efficacy in reducing infection and colonization due to MDR organisms. 1, 4, 30, [88] [89] [90] Unfortunately, staff compliance with proven infection control measures, such as hand hygiene, remains inconsistent in many hospitals. Also, surveillance of ICU infections to identify and quantify endemic and new MDR organisms with timely feedback of data is critical. 10, 88, [91] [92] [93] Timely communication of current data among clinicial, laboratory, pharmacy, and infection control staff is essential. Organism-specific strategies may need to be complemented by more aggressive eradication methods. 41, 43, 94 Studies are beginning to implicate the inanimate environment as an indirect contributor to pathogen acquisition. 86 Special interventions, including targeted environmental sampling and more aggressive environmental disinfection, may be indicated during outbreaks, particularly those involving MDR organisms or organisms that are more resistant to routine cleaning. 95 Antibiotic stewardship programs play an extremely important role in the overall effort to control healthcare-associated infections, reduce emergence of MDR organisms, and control spiraling healthcare costs. 96 Antibiotic stewardship should be focused, dynamic, and carefully monitored in order to adjust for specific MDR pathogens. 23, 97 An infectious disease pharmacist in the ICU, or a computerized decision support program to optimize drug regimens, has reduced inappropriate antibiotic use. 1, 2 By comparison, antibiotic cycling or rotation programs are more difficult to evaluate because of study design issues. 2,97-100

Risk factors for the development of HAP can be differentiated into modifiable and non-modifiable conditions as will be discussed later. Aspiration -the primary route of bacterial entry into the lung -is common and increased during hospitalization, with sedation, neuromuscular blockers, head trauma, intubation, enteral feeding, and following surgery. 1 , 101-105 Supine patient positioning may facilitate aspiration, which can be decreased by maintaining a semirecumbent patient position. One randomized trial demonstrated a threefold reduction in the incidence of ICU-acquired VAP in patients kept in a semirecumbent position versus supine position. 106 VAP rates reached 50% in patients maintained in the supine position while simultaneously receiving enteral nutrition.

Although maintaining mechanically ventilated and/or enterally fed patients in a 30-45° position continues to be strongly recommended, 1,2,106 recent studies have suggested that this may not be practical, at least at the levels currently recommended. A study by van Nieuwenhoven et al. in ventilated patients who were randomly assigned to backrest elevation of 45° versus the standard of 10°, demonstrated barriers to implementing this strategy. 107 The targeted backrest elevation of 45° was not reached and the actual achieved difference was 28° versus 10°, which did not reduce VAP. Perhaps, further studies measuring the impact of maintaining ventilated and/or enterally fed patients in a semirecumbent position are more attainable targets.

Oral care has been studied and recommended to prevent VAP. [108] [109] [110] [111] In a recent study, Mori et al. compared rates of VAP in a nonrandomized group compared to historic controls. 112 The incidence of VAP in the oral care group was 3.9 episodes/1,000 days versus 10.4 in the control group. Although there are concerns about the study design, oral care has intuitive benefits and limited cost, but more randomized, controlled studies are needed.

Oropharyngeal colonization is the primary source of pathogens causing HAP and VAP, and therefore reducing levels of colonization or eliminating potential pathogens is an obvious risk-reduction strategy. In a randomized trial, DeRiso et al. demonstrated that the use of the oral antiseptic chlorhexidine (CHX) significantly reduced rates of hospital-acquired infections in patients undergoing coronary artery bypass graft surgery. 113 Although topical antiseptics, such as chlorhexidine (CHX), provide an attractive alternative to antibiotics, the initial reported success in patients who have undergone cardiac surgery could not be confirmed by other studies. A recent study by Koeman et al. provides important data from a multicenter, double-blind, randomized clinical trial of VAP outcomes for subjects treated with 2% CHX paste versus patients randomized to 2% CHX + 2% colistin (COL) paste to provide greater activity against gram-negative bacilli compared to placebo. 114 Compared to the placebo group, the daily risk of VAP was reduced by 65% in the CHX group (p = 0.01) and 55% in the CHX-COL group (p < 0.03). This impressive result for an inexpensive, nontoxic, topically applied modality warrants further attention, but is difficult to reconcile with the absence of effect on ventilator days, length of stay, or mortality. It is important to measure how prophylactic use of CHX and CHX-COL complement other effective prevention strategies, and resistance could become an important issue over time.

Data from seven randomized controlled trials by Chan et al., involving 2,144 patients, showed that topical antiseptics are beneficial in preventing VAP; the benefit is most marked in patients who have undergone cardiac surgery. 115 These findings are comparable to those of another recently published review study 116 (limited to topical CHX), which also included seven trials but only 1,650 patients. However, both reviews found that oropharyngeal antiseptics had no impact on mortality or length of stay in the intensive care unit.

Modulation of oropharyngeal colonization by combinations of oral antibiotics, with or without systemic therapy, or selective decontamination of the digestive tract (SDD) is effective in preventing HAP/VAP, although the methodologic study quality, specific regimens used, study populations, and clinical impact differ widely among studies. 1, 2, 108, 110, 117, 118 In two recently published prospective randomized trials, SDD was associated with a higher ICU survival among patients receiving SDD. 118, 119 Also, in two meta-analyses and one additional study, decreased mortality was demonstrated in critically ill surgical patients receiving SDD, including both systemic and local prophylactic antibiotics, 117, 120, 121 raising questions about the relative importance of systemic rather than non-absorbed antibiotics.

Preventive effects of intravenous antibiotics were evaluated in only one randomized trial: Administration of cefuroxime for 24 h at the time of intubation reduced the incidence of early onset HAP in patients with closed head injury. 122 The role of the gastrointestinal tract in the pathogenesis of VAP and the clinical evidence for the efficacy of SDD were recently reviewed by Kallet and Quinn 123 and in a Cochrane review by Liberati et al. 117 In the latter study, the authors concluded that for topical and systemic antibiotic prophylaxis, five patients would need to be treated to prevent one infection and 21 patients would need to be treated to prevent one death. No recommendation was made for topical prophylaxis. In a large study of SDD by de Jonge et al. in 2003, SDD was highly effective in preventing pneumonia without an increase in antibiotic resistance. 119 However, citing concerns over rapid increases in antimicrobial resistance in the hospital setting, coupled with the association between MDR pathogens and poorer patient outcomes, recent guidelines have suggested that SDD should be considered for selected ICU populations and in targeted clinical scenarios, but not be employed "routinely" for VAP prevention. 1, 2, 124 Since VAT appears to be a precursor to VAP, recently there has been greater interest in collecting serial endotracheal aspirates and using targeted antibiotic therapy to treat VAT as a method of preventing VAP and not delaying therapy in patients with chest X-rays that are difficult to interpret. 24, 25 Although these approaches need further investigation, they could be a new paradigm for early treatment, VAP prevention, and better patient outcomes.

Several devices have been identified as risk factors for HAP. Many of these devices are used in mechanically ventilated patients and increase the risk of VAP; intervention strategies are summarized in several review articles. 1, 2, 125 

Continuous aspiration of subglottic secretions (CASS) through use of specially designed endotracheal tubes (ETTs) with a wider elliptic hole helps facilitate drainage (Fig. 29. 3) and has significantly reduced the incidence of early onset VAP in several studies. 1, 2 In a recent meta-analysis, CASS reduced the incidence of VAP by half (risk ratio 0.51, 95% CI 1.7-2.3), shortened ICU stay by 3 days (95% CI 2.1-3.9), and delayed the onset of VAP by 6 days. CASS also was cost effective, saving $4,992 per episode of VAP prevented or $1,872 per patient, but mortality was not affected. 126 Silver Biofilm-encased bacteria that form on the ETT and are protected against killing by antibiotics and host defenses may be a risk factor for VAP. A large, randomized study of 1,509 patients intubated for more that 24 h compared the use of colloidal silver-coated ETT (Bard Pharmaceuticals) -designed to prevent endotracheal tube colonization and biofilm formation -to a conventional ETT. 127 Diagnosis of VAP required confirmation of VAP by a BAL ³ 10 4 organisms/ml. The silver-ETT group had a lower incidence of VAP (4.8% vs. 7.5%, p = 0.03), with a relative risk reduction of 35.9% and an absolute reduction of 2.7%, but did not reduce mortality rates, duration of intubation, ICU stay, or hospital stay. Like CASS, the silver-ETT delayed the onset of VAP, had its greatest effect in patients ventilated for more than 48 h, and was highly active against pathogens, such as P. aeruginosa and MRSA.

Non-invasive positive pressure ventilation (NPPV) provides ventilatory support without the need for intubation and for earlier removal of the endotracheal tube to reduce complications related to prolonged intubation. NPPV using a face mask is an attractive alternative for patients with acute exacerbations of chronic obstructive pulmonary disease (COPD) or acute hypoxemic respiratory failure, and for some immunosuppressed patients with pulmonary infiltrates and respiratory failure. 1,2 Burns et al., in a recent Cochrane review, reported significant benefits: decreased mortality (RR 0.41, 95% CI 0.22-0.76), lower rates of VAP (RR 0.28, 95% CI 0.90-0.85), decreased length of ICU stay and shorter hospital stays, and lower duration of mechanical support. 128 The impact of NPPV is greater in patients with COPD exacerbations or congestive heart failure than for patients with VAP. Recent data also indicate that NPPV may not be a good strategy to avoid re-intubation after initial extubation and is recommended for hospitals with staff who are experienced in this technique. 129 

Efforts to reduce the likelihood of aspiration of oropharyngeal bacteria around the endotracheal tube cuff 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 >20 cm H 2 O. 130 Re-intubation should be avoided, if possible, as it increases the risk of VAP. 131 Efforts to reduce acute lung injury by using smaller tidal volumes and lower pressures have been suggested. 132 Other strategies to reduce the duration of mechanical ventilation include improved methods of sedation and the use of protocols to facilitate and accelerate weaning. 1, [133] [134] [135] These interventions clearly are dependent on adequate ICU staffing. 136, 137 Dries et al., using a standardized weaning protocol, reduced the proportion of days of mechanical ventilation (total ICU days) from 0.47 to 0.33%, number of patients failing extubation (25 vs. 43) , and the rates of VAP (15-5%). 138 Schweickert et al. evaluated seven complications in 128 patients receiving mechanical ventilation and continuous infusions of sedative drug, who were randomized to daily interruption of sedative infusions (N = 66) versus sedation directed by the MICU team without this strategy (N = 60). 7, 133 Daily interrupted sedative infusions reduced the length of stay in ICU (6.2 days vs. 9.9, p < 0.01), duration of mechanical ventilation (4.8 vs. 7.3 days, p < 0.003), and the incidence of complications per patient (13/12 patients vs. 26/19 patients, p < 0.04).

Enteral nutrition has been considered a risk factor for the development of HAP, mainly secondary to the increased risk of aspiration of gastric contents. 1, 139 Parenteral nutrition is associated with a higher risk of intravascular-device-associated infection and complications from central venous catheter insertion, higher costs, and loss of intestinal villous architecture, which may facilitate enteral microbial translocation. Accurate assessment of the patient's nutritional status and the use of enteral feeding, rather than parenteral nutrition, appear to reduce the risk of HAP. 1, 140 Early initiation of enteral feeding may help maintain the gastrointestinal epithelium and prevent bacterial translocation, but it is not without risk. Enteral feeding protocols have been suggested to reduce complications. 4, 141 Early gastrostomy for enteral feedings has been considered as a strategy to reduce VAP in patients with head injury and stroke. 142 

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 et al. randomized patients in surgical ICUs to receive either intensive insulin therapy to maintain blood glucose levels between 80 and 110 mg/dl or to receive conventional treatment. 143 The group receiving intensive insulin therapy had reduced mortality (4.6% vs. 8%, p < 0.04), and the difference was greater in patients who remained in the ICU for more than 5 days (10.6% vs. 20.2%, p = 0.005). When compared to 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 days with antibiotic treatment, and significantly shorter length of mechanical ventilation and ICU stay. While the same degree of benefit may not be seen in VAP as in other populations, aggressive treatment of hyperglycemia has both theoretical and clinical support for SICU patients.

A recent study of intensive insulin therapy in 1,200 medical ICU patients did not significantly reduce overall hospital mortality and actually increased mortality in patients with ICU stays less than 3 days. 144 However, the intensive insulin therapy group had reduced acquired renal failure, duration of mechanical ventilation, and length of ICU and hospital stay. Unfortunately, predicting the length of stay is difficult, and coupled with concerns about the risks of hypoglycemia and with increased resource implications, the benefit of intensive insulin therapy for specific hospital or MICU patients will require further evaluation.

Histamine-type 2 (H 2 ) antagonists and antacids have been identified as independent risk factors for ICU-acquired HAP. Sucralfate has been used for stress bleeding prophylaxis, as it does not increase intragastric acidity or gastric volume, but is less effective in preventing gastrointestinal bleeding. 1, 2 Numerous randomized trials, using different doses and various study populations, have provided controversial results on the benefits of specific stress bleeding prophylaxis agents in relation to the increased risk of VAP and bleeding. 25, 145 One large randomized trial comparing antacids, H 2 blockers, and sucralfate reported no differences in rates of early onset VAP, but rates of late-onset VAP were lower in patients treated with sucralfate. 25 More recently, Bornstain et al. examined risk factors for early onset VAP (from 3 to 7 days) in 747 patients. 146 Several different variables were identified in the univariate analysis, but only sucralfate used in the first 48 h of ICU stay and unplanned extubation were predictors of VAP in the multivariate analysis, and antibiotics were protective. In an earlier multicenter study of VAP in patients with ARDS, sucralfate and duration of exposure to sucralfate were associated with an increased risk of VAP. 147 A recent, large, double-blind, randomized trial comparing ranitidine to sucralfate demonstrated a trend toward lower rates of VAP with sucralfate, but clinically significant gastrointestinal bleeding was 4% higher in the sucralfate group. 145 Data indicate that H 2 blockers and protein pump inhibitors are associated with lower rates of gastrointestinal bleeding when compared to sucralfate, which may be doubly important, as transfusion also is a possible risk factor for VAP.

Concerns have been raised over reports of increased rates of C. difficile infections among persons receiving proton pump inhibitors. 148 A cohort study from a database of 1,187 inpatients at a Montreal teaching hospital showed that patients who had also received proton pump inhibitors other than antibiotics were at increased risk for C. difficile diarrhea.

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. 2 In one prospective randomized control trial, the use of leukocyte-depleted red blood cell transfusions resulted in a lower incidence of postoperative infections and, specifically, a reduced incidence of pneumonia in patients undergoing colorectal surgery. 149 Routine red blood cell transfusion should therefore be conducted with a restricted transfusion trigger policy.

The focus of prevention has been on ICU patients while in the ICU, but these patients are also at increased risk for relapse or re-infection during their rehabilitation. Therefore, efforts should be directed at risk reduction at discharge, such as routine vaccinations and patient education aimed at reducing lifestyle risks, such as smoking cessation, exercise, and weight control.

In spite of the progress in the diagnosis, prevention, and management of HAP/VAP, these diseases still have a significant effect on outcome. Immediate administration of adequate antimicrobials is now considered a critical element in the effort to improve survival in HAP/VAP. The choice of the initial antibiotic regimen should be patient-oriented and guided by directed staining of respiratory samples. Prior hospitalization, presence of comorbidities, and the pressure of index cases are helpful indicators in order to anticipate the presence of MRSA, A. baumanii and P. aeruginosa. Local surveillance data and prior exposure to specific antibiotics (which should be avoided in the initial regimen) help in the choice of the initial antibiotic treatment. Antimicrobial therapy should be adjusted 48-72 h after the onset of pneumonia, based on a combination of quantitative respiratory cultures and resolution assessment. The duration of treatment should also be individualized; however, courses longer than 1 week are rarely justified.

Investing in prevention can pay great dividends in improved quality of life and reduced morbidity and mortality. 1, 2 In addition, prevention can have a huge impact in reducing length of hospital stay and healthcare costs during acute care. Spreading the seeds of prevention into chronic care and rehabilitation facilities also is vitally needed in the increasing diversity of our healthcare settings.

Guidelines for preventing health-care -associated pneumonia, 2003: recommendations of CDC and the Healthcare Infection Control Practices Advisory Committee

Guidelines for the management of adults with hospital-acquired, ventilatory-associated, and health care-associated pneumonia

Hospital-acquired pneumonia in the 21st century: a review of existing treatment options and their impact on patient care

Prevention of hospital-associated pneumonia and ventilator-associated pneumonia

Nosocomial infections in medical intensive care units in the United States. National Nosocomial Infections Surveillance System

Ventilator-associated pneumonia

The pathogenesis of ventilatorassociated pneumonia: its relevance to developing effective strategies for prevention

Incidence of and risk factors for ventilator-associated pneumonia in critically ill patients

A report from the National Nosocomial Infections Surveillance (NNIS) System

Ventilator-associated pneumonia: caveats for benchmarking

Risk factors for pneumonia and fatality in patients receiving continuous mechanical ventilation

Epidemiology and outcomes of ventilator-associated pneumonia in a large US database

The attributable morbidity and mortality of ventilator-associated pneumonia in the critically ill patient. The Canadian Critical Trials Group

Outcome and attributable cost of ventilator-associated pneumonia among intensive care unit patients in a suburban medical center

Prevention of ventilator-associated pneumonia by oral decontamination: a prospective, randomized, double-blind, placebo-controlled study

Changing pharyngeal bacterial flora of hospitalized patients. Emergence of gram-negative bacilli

Severe community-acquired pneumonia: what do we need to know to effectively manage patients?

Contaminated medication nebulizers in mechanical ventilator circuits. Source of bacterial aerosols

Nosocomial pneumonia in mechanically ventilated adult patients: epidemiology and prevention in 1996

Endogenous source of bacteria in tracheal tube and proximal ventilator breathing system in intensive care patients

Devising strategies for preventing nosocomial pneumonia -should we ignore the stomach?

Ventilator-associated pneumonia: do the bacteria come from the stomach?

Nosocomial pneumonia in mechanically ventilated patients receiving antacid, ranitidine, or sucralfate as prophylaxis for stress ulcer. A randomized controlled trial

Antimicrobial treatment for ventilator-associated tracheobronchitis: a randomized, controlled multicenter study

Ventilatorassociated tracheobronchitis (VAT); the impact of targeted antibiotic therapy on patient outcomes

Serial changes in soluble triggering receptor expressed on myeloid cells in the lung during development of ventilator-associated pneumonia

Soluble triggering receptor expressed on myeloid cells and the diagnosis of pneumonia

Incidence, risk, and prognosis factors of nosocomial pneumonia in mechanically ventilated patients

Incidence, etiology, and outcome of nosocomial pneumonia in ICU patients requiring percutaneous tracheotomy for mechanical ventilation

Infection control in intensive care units and prevention of ventilator-associated pneumonia

Epidemiology and control of nosocomial infections in adult intensive care units

Ventilator-associated pneumonia caused by potentially drug-resistant bacteria

Epidemiology and outcomes of health-care-associated pneumonia: results from a large US database of culture-positive pneumonia

What is healthcare-associated pneumonia, and how should it be treated?

Impact of invasive strategy on management of antimicrobial treatment failure in institutionalized older people with severe pneumonia

Diagnosis of ventilatorassociated pneumonia by bacteriologic analysis of bronchoscopic and nonbronchoscopic "blind" bronchoalveolar lavage fluid

Increasing prevalence of antimicrobial resistance in intensive care units

Nursing home-acquired pneumonia

Staphylococcus aureus: times, they are a-changin

The growing menace of community-acquired methicillin-resistant Staphylococcus aureus

Methicillin-resistant Staphylococcus aureus control: we didn't start the fire, but it's time to put it out

Are active microbiological surveillance and subsequent isolation needed to prevent the spread of methicillin-resistant Staphylococcus aureus?

Control and outcome of a large outbreak of colonization and infection with glycopeptideintermediate Staphylococcus aureus in an intensive care unit

Does this patient have ventilator-associated pneumonia?

Diagnosing pneumonia during mechanical ventilation: the clinical pulmonary infection score revisited

Short-course empiric antibiotic therapy for patients with pulmonary infiltrates in the intensive care unit. A proposed solution for indiscriminate antibiotic prescription

Invasive and noninvasive strategies for management of suspected ventilator-associated pneumonia. A randomized trial

Canadian Critical Care Trials Group. A randomized trial of diagnostic techniques for ventilator-associated pneumonia

The influence of mini-BAL cultures on patient outcomes: implications for the antibiotic management of ventilator-associated pneumonia

Efficacy of adequate early antibiotic therapy in ventilator-associated pneumonia: influence of disease severity

Clinical importance of delays in the initiation of appropriate antibiotic treatment for ventilatorassociated pneumonia

Impact of appropriateness of initial antibiotic therapy on the outcome of ventilator-associated pneumonia

Comparison of 8 vs 15 days of antibiotic therapy for ventilator-associated pneumonia in adults: a randomized trial

Treatment of severe pneumonia in hospitalized patients: results of a multicenter, randomized, double-blind trial comparing intravenous ciprofloxacin with imipenem-cilastatin. The Severe Pneumonia Study Group

Prospective randomized comparison of imipenem monotherapy with imipenem plus netilmicin for treatment of severe infections in nonneutropenic patients

Antibiotic therapy for Pseudomonas aeruginosa bacteremia: outcome correlations in a prospective study of 200 patients

Comparison of ampicillin-sulbactam and imipenem-cilastatin for the treatment of acinetobacter ventilator-associated pneumonia

Treatment of nosocomial pneumonia and tracheobronchitis caused by multidrug-resistant Pseudomonas aeruginosa with aerosolized colistin

Treatment of multidrug-resistant Acinetobacter baumannii ventilator-associated pneumonia (VAP) with intravenous colistin: a comparison with imipenem-susceptible VAP

Outcome of cephalosporin treatment for serious infections due to apparently susceptible organisms producing extended-spectrum beta-lactamases: implications for the clinical microbiology laboratory

Enterobacter bacteremia: clinical features and emergence of antibiotic resistance during therapy

Effects of inoculum and beta-lactamase activity in AmpC-and extended-spectrum beta-lactamase (ESBL)-producing Escherichia coli and Klebsiella pneumoniae clinical isolates tested by using NCCLS ESBL methodology

Antibiotic therapy for Klebsiella pneumoniae bacteremia: implications of production of extended-spectrum beta-lactamases

Area under the inhibitory curve and a pneumonia scoring system for predicting outcomes of vancomycin therapy for respiratory infections by Staphylococcus aureus

Prospective randomized comparison of quinupristin/dalfopristin versus vancomycin. Nosocomial Pneumonia Group

Pneumonia in the surgical intensive care unit: factors determining successful outcome

Slow response to vancomycin or vancomycin plus rifampin in methicillin-resistant Staphylococcus aureus endocarditis

Comparison of continuous with discontinuous intravenous infusion of vancomycin in severe MRSA infections

Linezolid vs vancomycin: analysis of two double-blind studies of patients with methicillin-resistant Staphylococcus aureus nosocomial pneumonia

PNU-100766) versus vancomycin in the treatment of hospitalized patients with nosocomial pneumonia: a randomized, doubleblind, multicenter study

Intrapulmonary pharmacokinetics of linezolid

Nephrotoxicity of vancomycin and aminoglycoside therapy separately and in combination

Mississippi mud in the 1990s: risks and outcomes of vancomycin-associated toxicity in general oncology practice

Pharmacologic treatment options for nosocomial pneumonia involving methicillin-resistant Staphylococcus aureus

Emerging options for treatment of invasive, multidrugresistant Staphylococcus aureus infections

Anti-MRSA beta-lactams in development, with a focus on ceftobiprole: the first anti-MRSA beta-lactam to demonstrate clinical efficacy

Severe Staphylococcus aureus infections caused by clonally related community-acquired methicillin-susceptible and methicillin-resistant isolates

Severe communityonset pneumonia in healthy adults caused by methicillin-resistant Staphylococcus aureus carrying the Panton-Valentine leukocidin genes

Severe methicillin-resistant Staphylococcus aureus community-acquired pneumonia associated with influenza -Louisiana and Georgia

Comparison of community-and health care-associated methicillin-resistant Staphylococcus aureus infection

Preparing for the next pandemic

Preventing ventilator-associated pneumonia in adults: sowing seeds of change

Evidence-based clinical practice guideline for the prevention of ventilator-associated pneumonia

Effect of an education program aimed at reducing the occurrence of ventilator-associated pneumonia

Ventilator-associated pneumonia in a multi-hospital system: differences in microbiology by location

The role of the intensive care unit environment in the pathogenesis and prevention of ventilatorassociated pneumonia

Postoperative complications: does intensive care unit staff nursing make a difference?

Impact of an infection control program on rates of ventilator-associated pneumonia in intensive care units in 2 Argentinean hospitals

Ventilator-associated pneumonia: does surveillance have a role in its management?

Experience with a clinical guideline for the treatment of ventilator-associated pneumonia

Nosocomial infection and multidrug-resistant bacteria surveillance in intensive care units: a survey in France

Surveillance in infection control: are we making progress?

Successful search-and-destroy policy for methicillin-resistant Staphylococcus aureus in The Netherlands

Improved cleaning of patient rooms using a new targeting method

Evaluation of an intervention designed to decrease the rate of nosocomial methicillin-resistant Staphylococcus aureus infection by encouraging decreased fluoroquinolone use

Nosocomial antibiotic resistance in multiple gram-negative species: experience at one hospital with squeezing the resistance balloon at multiple sites

Cycling empirical antimicrobial agents to prevent emergence of antimicrobial-resistant Gram-negative bacteria among intensive care unit patients

Preventing ventilator-associated pneumonia: an evidence-based approach of modifiable risk factors

Scheduled change of antibiotic classes: a strategy to decrease the incidence of ventilator-associated pneumonia

Aspiration and the risk of ventilatorassociated pneumonia

Cisapride decreases gastric content aspiration in mechanically ventilated patients

Endotracheal aspiration in the diagnosis of ventilator-associated pneumonia

Gastric reflux and pulmonary aspiration in anaesthesia

The effect of ventilatorassociated pneumonia on the prognosis of head trauma patients

Supine body position as a risk factor for nosocomial pneumonia in mechanically ventilated patients: a randomised trial

Continuous lateral rotational therapy in the medical intensive care unit

Oral decontamination is cost-saving in the prevention of ventilatorassociated pneumonia in intensive care units

Oral health and care in the intensive care unit: state of the science

The role of oral microbial colonization in ventilator-associated pneumonia. Oral Surg Oral Med Oral Pathol Oral Radiol Endod

Improving oral care in patients receiving mechanical ventilation

Oral care reduces incidence of ventilator-associated pneumonia in ICU populations. Intensive Care Med

Chlorhexidine gluconate 0.12% oral rinse reduces the incidence of total nosocomial respiratory infection and nonprophylactic systemic antibiotic use in patients undergoing heart surgery

Oral decontamination with chlorhexidine reduces the incidence of ventilator-associated pneumonia

Oral decontamination for prevention of pneumonia in mechanically ventilated adults: systematic review and meta-analysis

Topical chlorhexidine for prevention of ventilator-associated pneumonia: a meta-analysis

Antibiotic prophylaxis to reduce respiratory tract infections and mortality in adults receiving intensive care

Selective decontamination of the digestive tract and ventilator-associated pneumonia (part 1)

Effects of selective decontamination of digestive tract on mortality and acquisition of resistant bacteria in intensive care: a randomised controlled trial

Selective decontamination of the digestive tract

Selective decontamination of the digestive tract in surgical patients: a systematic review of the evidence

Protective effect of intravenously administered cefuroxime against nosocomial pneumonia in patients with structural coma

The gastrointestinal tract and ventilatorassociated pneumonia

Selective digestive decontamination should not be routinely employed

Care of the ventilator circuit and its relation to ventilator-associated pneumonia

Subglottic secretion drainage for preventing ventilator-associated pneumonia: a meta-analysis

Silver-coated endotracheal tubes and incidence of ventilator-associated pneumonia: the NASCENT randomized trial

A meta-analysis of noninvasive weaning to facilitate liberation from mechanical ventilation

Noninvasive positive-pressure ventilation for respiratory failure after extubation

Acquired neuromuscular disorders in critically ill patients: a systematic review

Groupe de Reflexion et d'Etude sur les Neuromyopathies En Reanimation

Re-intubation increases the risk of nosocomial pneumonia in patients needing mechanical ventilation

Acute lung injury and bacterial infection

Daily interruption of sedative infusions and complications of critical illness in mechanically ventilated patients

Daily interruption of sedative infusions in critically ill patients undergoing mechanical ventilation

Protocol weaning of mechanical ventilation in medical and surgical patients by respiratory care practitioners and nurses: effect on weaning time and incidence of ventilator-associated pneumonia

Nurse-staffing levels and the quality of care in hospitals

Influence of the quality of nursing on the duration of weaning from mechanical ventilation in patients with chronic obstructive pulmonary disease

Protocol-driven ventilator weaning reduces use of mechanical ventilation, rate of early reintubation, and ventilator-associated pneumonia

Patient selection for clinical investigation of ventilator-associated pneumonia. Criteria for evaluating diagnostic techniques

Optimizing the benefits and minimizing the risks of enteral nutrition in the critically ill: role of small bowel feeding

Implementation of an evidence-based feeding protocol and aspiration risk reduction algorithm

Early gastrostomy reduces the rate of ventilator-associated pneumonia in stroke or head injury patients

Intensive insulin therapy in mixed medical/surgical intensive care units: benefit versus harm

Intensive insulin therapy in the medical ICU

A comparison of sucralfate and ranitidine for the prevention of upper gastrointestinal bleeding in patients requiring mechanical ventilation. Canadian Critical Care Trials Group

Sedation, sucralfate, and antibiotic use are potential means for protection against early-onset ventilator-associated pneumonia

Multicenter prospective study of ventilator-associated pneumonia during acute respiratory distress syndrome. Incidence, prognosis, and risk factors. ARDS Study Group

Risk of Clostridium difficile diarrhea among hospital inpatients prescribed proton pump inhibitors: cohort and case-control studies

Randomised comparison of leucocyte-depleted versus buffy-coat-poor blood transfusion and complications after colorectal surgery

Hospital-acquired pneumonia

Preventing ventilator-associated pneumonia: tiptoeing through a minefield