Published: November 2013
In 2005, the American Thoracic Society (ATS) and Infectious Disease Society of America (IDSA) published an evidenced-based guideline for the management of hospital-acquired pneumonia (HAP), ventilator-associated pneumonia (VAP), and health care–associated pneumonia (HCAP).1 This chapter summarizes the key principles of epidemiology, pathogenesis, diagnosis, and management of nosocomial pneumonia.
HAP is defined as pneumonia that occurs 48 hours or more after hospital admission and that was not present at the time of admission. VAP refers to pneumonia that occurs 48 hours or more after endotracheal intubation. HCAP includes patients who have recently been hospitalized within 90 days of the infection, resided in a nursing home or long-term care facility, or received parenteral antimicrobial therapy, chemotherapy, or wound care within 30 days of pneumonia.1 The term HAP is often used to represent both VAP and HCAP. For practical purposes, most principles for HAP, VAP, and HCAP overlap.
HAP is the second most common nosocomial infection in the United States and is associated with high mortality and morbidity. HAP occurs at a rate between 5 and 15 cases per 1,000 hospital admissions and accounted for approximately 15% of all hospital-acquired infections (HAIs). HAP increases hospital stay by an average of 7 to 9 days per patient and has an associated cost of more than $40,000 per patient. It accounts for 11% of HAIs outside of intensive care units (ICUs) and 26% of HAIs in the ICUs.2,3 HAP carries a crude mortality rate of 30% to 70% with an estimated attributable mortality rate to pneumonia between 27% and 50%.1
Intubation and mechanical ventilation (MV) are the most important risk factors to developing HAP. Incidence of HAP increases by 6-21 fold in mechanically ventilated patients, rendering VAP as the most common nosocomial infection in critically ill patients. Previous studies have demonstrated that nearly 90% of mechanically ventilated patients in ICU were diagnosed with VAP. The exact incidence of VAP is difficult to define due to lack of standardized criteria of VAP diagnosis as well as possible overlap with other lower respiratory infections, such as tracheobronchitis.1,4 Because of the significant risk of MV, most of the research on hospital-associated pneumonia has been focused on VAP for the last 3 decades.
Other major risk factors for developing HAP have been identified, most of which co-exist with mechanically ventilated patients. They can be classified into nonmodifiable and modifiable conditions. Nonmodifiable risk factors include candidates aged older than 70 years, underlying chronic-lung disease, immunosuppresion, and previous thoracoabdominal surgery. Nonmodifiable risk factors include re-intubation, a depressed level of consciousness, malnutrition, oropharyngeal colonization, enteral nutrition, supine patient positioning and stress bleeding prophylaxis.1,3
Pneumonia occurs when the host's ability to fight against invading microbial pathogens is compromised. The reduced state of the immune system could be due to interplay amongst different host factors, including underlying comorbidities, immunosuppressive medications, and a depressed level of consciousness leading to impaired mechanical (ciliated epithelium and mucus), humoral, and cellular host defenses. Bacteria may enter the lower respiratory tract by micro- or bolus-aspiration of oropharyngeal organisms, inhalation of aerosols containing bacteria, or, less frequently, hematogenous spread from a distant body site.3 Of the possible routes, microaspiration is believed to be the most important because of both community-acquired and HAP. Studies have shown that up to 50% of healthy subjects aspirate during sleep. Those with abnormal swallowing will be at a higher risk of aspiration. Hospitalized patients, particularly those who are mechanically ventilated and in a decreased level of consciousness due to either underlying disease or sedative drugs, are at the highest risk. The types of aspirated microbial pathogens will depend on the bacterial colonization of the oropharynx. Previous studies demonstrated that about 70% of patients who are hospitalized for at least 4 days will have their oropharynx colonized with gram-negative bacilli (GNB) organisms, rendering GNB as the most common pathogen that causes HAP. Gram-negative bacteria account for 55% to 85% of HAP infections, and gram-positive cocci account for 20% to 30%.
In mechanically ventilated patients, aspiration can occur during the intubation process, leakage of colonized oropharyngeal secretions around the endotracheal tube (ET) cuff, or condensation of air particles from a contaminated ventilatory circuit. Whether stomach or sinuses serve as potential reservoirs for bacterial colonization of the oropharynx is still being debated. The ET tube bypasses upper respiratory tract host defenses allowing for pooling of oropharyngeal secretions above the ET cuff. In addition, it is believed there is a biofilm formation over the bacterial colonization of the ET tube, making de-colonization of the ET tube difficult. The development of VAP portends a poor prognosis with a rate of mortality 2 to 10 times higher than those without VAP.
Bacteria have been the most commonly isolated pathogens, although viral and fungal pathogens are potentially found in immunocompromised hosts (patients on chronic immunosuppresed medications, solid organ and bone marrow transplant recipients). In general, the distribution of microbial pathogens varies among institutions, partly because of differences in patient population and local patterns of antimicrobial resistance in hospitals and critical care units. Common bacterial pathogens include aerobic GNB, such as Pseudomonas aeruginosa, Acinetobacter baumanii, Klebsiella pneumoniae, Escherichia coli as well as gram-positive organisms such as Staphylococcus aureus. In patients with early onset pneumonia (within 5 days of hospitalization), they are usually due to antimicrobial-sensitive bacteria such as Enterobacter spp, E. coli, Klebsiella spp, Proteus spp, Serratia marcescens, Community pathogens such as Streptococcus pneumoniae, Haemophilus influenzae, and methicillin-sensitive S. aureus should also be considered.
In critically ill patients, the susceptibility of the bacteria isolated depends on the duration of stay in the ICU and MV. VAP is classified into early and late onset. Early-onset VAP occurs within less than 96 hours of ICU admission and is generally due to antimicrobial-sensitive bacteria. Late-onset VAP occurs after 96 hours of ICU admission and is caused by multidrug-resistant (MDR) pathogens. Potential MDR pathogens include: P. aeruginosa, K. pneumonia (extended spectrum beta-lactamase and Klebsiella-producing carbapanamase strains), Acinetobacter spp, Stenotrophomonas maltophilia, Burkholderia cepacia, and methicillin-resistant S. aureus. Other risk factors of MDR pathogens include prior antibiotic use within the preceding 90 days, high frequency of antibiotic resistance in the community or hospital, HCAP risk factors, and immunocompromised state.
Risk Factors for Multidrug-Resistant Pathogens
Diagnosing of HAP is difficult because it requires a thorough assessment of clinical grounds and microbiological and radiological findings. There are no reliable tools to determine whether the patient has pneumonia. All patients should have a comprehensive medical history and physical exam to help identify the risk factors and the severity of pneumonia. This will help to exclude other potential extrapulmonary infections and rule out the presence of noninfectious causes.1
Clinical findings that suggest the presence of infection include a new onset of fever, leukocytosis or leukopenia, purulent sputum, and decreased arterial oxygenation saturation. Traditionally, the presence of pneumonia is defined as the presence of at least two of the three clinical features (fever greater than 38°C, leukocytosis, and purulent secretions) plus a new or progressing lung infiltrate on a chest radiograph.5 When the clinical findings are present but there is no new lung infiltrate, a diagnosis of nosocomial tracheobronchitis should be considered. Studies have shown that this clinical approach has high sensitivity but low specificity, particularly in critically ill patients because other conditions may mimic pneumonia.6 One study demonstrated 69% sensitivity and 75% specificity when the clinical approach is combined with histological findings plus positive microbiological culture of immediate postmortem lung samples.5 The lack of specificity in the clinical diagnosis gives rise to the need for more reliable diagnostic tools to optimize management, so that fewer patients are treated with antibiotics for noninfectious causes. Although there are many different testing modalities that can be employed, all have their limitations and no single test is sufficiently sensitive and specific enough to be considered a gold standard test.1,7–9
Samples of lower respiratory tract should be obtained when clinical suspicion is high and should be collected before antibiotic therapy is started. Samples can include non-invasive endotracheal aspirate (ETA) or invasive protected specimen brush (PSB), or bronchoalveolar lavage (BAL) in intubated patients. Non-intubated patients are limited to expectorated sputum culture, which is neither sensitive nor specific, making the reliability of microbiologic information in this population uncertain. The bacteriologic strategy is to use quantitative cultures where a certain threshold concentration is required for true pathogen identification. Quantitative cultures of ETA, PSB or BAL are recommended by ATS/IDSA 2005 guidelines because identified pathogens on the basis of semiquantitative or qualitative culture may potentially lead to more antibiotic therapy.1 Each method has its own diagnostic threshold and methodologic limitations.
ETA is the most useful non-invasive test in critically ill patients because it has been shown to have high sensitivity (>95%) and a negative predictive value (NPV) of 94%. Its utility lies in its high NPV to exclude the presence of a true pathogen when the culture is negative, thus minimizing unnecessary use of antibiotics. It is important to be cautious when interpreting the positive culture as one needs to differentiate between colonization or true pathogen. More invasive diagnostic tests such as BAL (from bronchoscopy) and PSB allow clinicians to obtain better protected distal samples from the lower respiratory tract without contamination from upper airway or oral secretions. However, many studies have shown that when BAL and PSB were compared with ETA, they do not appear to differ significantly in terms of sensitivity, specificity or, more importantly, patient morbidity and mortality.10–13
Ruiz et al performed a prospective, open, randomized study in a large tertiary care hospital in Spain to compare quantitative cultures of ETA vs BAL or PSB in 76 mechanically ventilated patients who were receiving empirical antibiotic therapy.10 They found no significant differences in ICU length of stay, duration of MV, or mortality between the two groups. The authors concluded that outcome is not influenced by techniques used for microbial investigation.10 Canadian Critical Care Trials Group performed a prospective, randomized, multicenter trial in the Canada and the United States involving 740 patients in 28 ICUs. They compared BAL with quantitative culture of the fluid and ETA with qualitative culture of the aspirate in mechanically ventilated patients who had suspected VAP after 4 days in the ICUs. There were no significant differences in 28-day mortality rates, targeted therapy, ICU and hospital lengths of stay.11 These findings have led many clinicians to conclude that both noninvasive and invasive tools achieve similar clinical outcomes.
A diagnostic thoracentesis should be performed if patients have enlarging pleural effusions to rule out a complicating empyema or parapneumonic effusion. All patients with HAP should also have blood cultures collected to help indicate the presence of either pneumonia or extrapulmonary infection. However, its reported sensitivity is only 8% to 20%.1 It is important to note that if clinical suspicion of HAP is low, one should not collect respiratory tract cultures as this can lead to the unnecessary use of antimicrobial therapy if cultures are positive given its undefined specificity.
In addition, a scoring system called Clinical Pulmonary Infection Score (CPIS) was first developed by Pugin et al in 1991 in an effort to improve specificity of clinical diagnosis.14 The scoring system was then modified by Singh et al in 2000.15 CPIS consists of clinical, microbiological, and radiological elements. They include temperature, blood leukocytes, tracheal secretions, oxygenation, pulmonary radiography, and microbiological data. When the CPIS exceeded 6, a diagnosis of pneumonia is suggested; although, some studies have demonstrated that the CPIS is still not an optimal diagnostic tool as it has relatively low sensitivity and specificity when histology and immediate postmortem quantitative lung cultures was used as the reference standard.5,16 It also lacks definition for tracheal secretions. In addition, the pulmonary radiography in critically ill patients is done in portable x-rays, which further diminishes its specificity.
Given the limitations and the lack of true gold standard for the diagnosis of pneumonia, a novel approach to look for a reliable new biomarker has been extensively explored in the past decade. Procalcitonin (PCT) has been evaluated in different patient groups and conditions, varying from sepsis to pneumonia in both outpatient and inpatient settings.17 It has been repeatedly shown to have high specificity for bacterial, rather than viral infections, compared with traditional markers such as C-reactive protein, erythrocyte sedimentation rate, and leukocytes.17,18 PCT, a precursor to calcitonin, is released via a direct stimulation of cytokines such tumor necrosis factor-α, and IL-6. Its elevation occurs within 6 to 12 hours upon stimulation, peaks in the second day with subsequent daily decrease during clinical recovery.18 PCT however has its own limitations. It can be falsely elevated in non-infectious causes of systemic inflammation including pancreatitis, burn injury, trauma injury, and major surgery19 and lacks the ability to predict specific bacterial pathogens.20,21 Moreover, optimal diagnostic cutoff points have not been well defined and they vary according to the severity of presentation and clinical settings. For these reasons, serum PCT levels need to be carefully interpreted according to the severity, risk factors, and pretest probability of bacterial pneumonia. It should not be used as a stand-alone test nor replace clinical assessment of patients.18 The utility of PCT may have more pronounced impact in guiding clinicians in deciding about initiation or discontinuation of antibiotics, which will be discussed further in the treatment section below.
Because VAP is a potentially severe infection associated with high mortality, most studies were done in VAP patients. Recommendations for HAP treatment is a data extrapolation from those of VAP studies. When the clinical suspicion of HAP is high, it is essential to promptly start appropriate antimicrobial therapy as both delayed and inadequate treatment have been correlated with increased rate of morbidity and mortality.7,22–26 Previous studies reported a mortality rate of 30% in patients who receive early appropriate therapy compared with a rate of 91% in patients who did not.26
ATS/IDSA 2005 guidelines recommend clinicians start initial empiric antimicrobial coverage based on the clinical severity, the presence of risk factors for MDR organisms, and the time onset of HAP.1,4 Identification of the risk factors of MDR organisms is essential in determining the appropriate antimicrobial therapy. Selection should also predicate on the characteristics of the local patient population, microbial environment, cost, and formulary restrictions. Patients who have stayed in a hospital more than 5 days at the time of diagnosis; have history of prior antibiotics use; have recent hospitalization within 90 days; are admitted from health care–associated facility (nursing home, long-term care facility, dialysis center, etc) should be classified as being at risk for MDR organisms. Health care–associated infections are bacteriologically similar to HAIs. Suggested initial empiric antimicrobials in patients without and with known risk factors for MDR organisms are summarized in the ATS/IDSA guidelines as shown in Table 1 and Table 2, respectively.1
|Potential MDR pathogens||Combination Antibiotics Therapy*|
Antibiotic resistant enteric GNB
Piperacillin/tazobactam 4.5 g every 6 hours
Ceftazidime 2 g every 8 hours
Imipinem 500 mg every 8 hours
Levofloxacin 750 mg daily
Gentamicin 7 mg/kg daily
|Methicillin-resistant Staphylococcus aureus||
Linezolid 600 mg every 12 hours
* Dosages based on normal renal and hepatic function.
† Trough levels for gentamicin and tobramycin should be <1µg/ml, and for amikacin, they should be <4-5µg/ml.
‡ Trough levels for vancomycin should be 15-20µg/ml.
Methicillin-sensitive Staphylococcus aureus
Antibiotic sensitive enteric GNB
Ceftriaxone 2 g daily
ORAmpicillin-sulbactam 3 g every 6 hours
ORLevofloxacin 750 mg daily
ORMoxifloxacin 400 mg daily
ORErtapenem 1 g daily
It is important to note that in severe pneumonia, which is defined by the need for ICU admission; respiratory failure; radiologic progression of pneumonia; severe sepsis or septic shock, a combination of empiric therapy is essential. Critically ill patients who have late-onset VAP tend to be colonized with MDR GNB organisms and at high risk for difficult-to-treat GNB strain.4,9 A randomized multicenter study by Heyland et al demonstrated that a combination therapy is associated with better microbiological and clinical outcomes in late-onset VAP.27 A combination therapy should include agents from different antibiotic classes and consist of a double coverage of MDR gram negatives, plus a coverage for gram positives.9 Targeted gram negative organisms include Pseudomonas aeruginosa, Acinetobacter baumanii, Klebsiella pneumonia (ESBL strain) while targeted gram positive organism includes Methicillin-resistant Staphylococcus aureus. Clinicians should be mindful that the choice of a specific agent for empiric therapy should be based on knowledge of the prevailing pathogens with their susceptibility patterns within the healthcare setting. Moreover, patients who have previously received antibiotics may develop resistance to that same class of antibiotics, thus it is wise to choose a different class of antibiotics.1 In cases of treating MDR GNB pathogens that are highly resistant to antipseudomonal cephalosporins, antipseudomonal carbapenems, beta-lactam/beta lactamase inhibitors, and fluoroquinolones, an alternative antibiotic option such as colistin can be used. Clinicians should also follow the general principles of pharmacokinetics and pharmacodynamics of antimicrobial therapy to achieve optimal dosing and to avoid significant side effects.
The initial antibiotic treatment must be reassessed on day 2 or 3. Depending on the clinical progress and microbiological findings, clinicians should adjust therapy accordingly. Clinical improvement on day 2 or 3 with specific isolated pathogens should prompt clinicians to de-escalate treatment based on the pathogen's susceptibility pattern. If patients do not demonstrate clinical improvement at 48 to 72 hours with no microbiological findings, antibiotics may be safely discontinued, and other sites of infection or non-infectious etiology should be explored.
The implementation of PCT use in optimizing the management of pneumonia is prudent given more robust published data on the protocols using PCT measurements. Several randomized-controlled trials have evaluated PCT for therapeutic decision about initiation and duration of antibiotics.28 In critically ill patients with severe pneumonia, empiric antibiotic therapy should not be delayed for PCT measurement. A careful clinical assessment and periodic monitoring of serum PCT levels after antibiotic initiation is important. Repeated serum PCT levels should be utilized to determine when to discontinue antibiotics. This strategy is different in patients with low pretest probability.18 Initial serum PCT level <0.5µg/L argues against a typical bacterial infection, and other diagnoses should be considered, including viral causes. Serum PCT level may be repeated in 6 to 24 hours. A drop of PCT to <0.5µg/L or by at least 80% to 90% from peak values is a reasonably conservative threshold for stopping antibiotic therapy, assuming patients show clinical improvement. If PCT levels do not decrease by about 50% every 1 to 2 days, treatment failure should be considered and reassessment of patients is recommended.18
There is no consensus regarding the duration of antibiotic treatment for all patients with HAP. Recommendations from the ATS/IDSA guidelines have suggested that the duration of treatment should be guided by severity, time to clinical response, and the pathogenic organism.1 Shorter duration of therapy is preferred when good clinical response is evident. Prolonged antibiotic exposure could potentially lead to emergence of MDR pathogens. Chastre et al performed a prospective, randomized, double blind, multicentre trial that compared 8 versus 15 days of antibiotic treatment for VAP and found no difference in mortality, ICU length of stay, and recurrent infections.29 Those who were found to have recurrent infections had MDR pathogens and received only 8 days of treatment. Those with VAP caused by Pseudomonas aeruginosa also did not have favorable outcomes when treated for 8 days. Serial PCT levels in determining duration of antibiotic treatment in ICU patients is helpful.19,30 A systemic review by Agarwal et al showed that PCT guidance was associated with significantly reduced antimicrobial exposures by 20% to 38% without compromising clinical outcomes.19
Recommendations for Assessing Response to Treatment
Prevention is essential because HAP is associated with high morbidity and mortality. Preventive strategies are generally classified into nonspecific and specific measures. Nonspecific measures include standard preventative measures, such as hand hygiene and proper use of gloves, gown and mask. These measures should be integrated throughout the hospital system to prevent all infections related to health care. Specific preventive measures are tailored to patients with risk factors of HAP. They have three main objectives. The first objective is to reduce the exposure time from MV as much as possible. The second objective is to minimize the frequency of aspirations. The third objective is, to decrease bacterial colonization of the oropharynx.9 Intubation and MV significantly increase risk for HAP; therefore, avoidance of intubation and re-intubation is recommended whenever possible. The combination of sedation and MV weaning protocols has demonstrated a reduction in the duration of MV and thus, VAP frequency.31,32 The use of noninvasive positive pressure ventilation is an alternative choice for patients with acute hypoxemic respiratory failure and exacerbations of chronic obstructive pulmonary disease.1 The role of early tracheostomy is controversial as several clinical trials have not shown any benefit in reducing VAP incidence.33,34
Several preventive measures to reduce the frequency of aspiration have been extensively studied. Semirecumbent patient positioning (30° to 45° elevation of the head of the bed) has been shown to reduce VAP incidence rates. Although data are conflicting, enteral feeding has been considered as a risk factor of HAP with post-pyloric feeding being the preferred route of nutrition to gastric feeding.35 Intermittent subglottic secretion drainage has recently been shown to decrease the VAP incidence rate in a prospective multicentre trial, although the duration of MV and hospital mortality was not reduced.36 Other measures to decrease risk of aspiration include avoidance of unplanned extubation and reintubation, avoidance of gastric overdistention, continuous control of endotracheal cuff pressure of at least 20cm H2O and modest positive end-expiratory pressure have been studied, but more clinical data are still required.37,38
To decrease bacterial colonization of oropharynx, oral endotracheal intubation and orogastric tubes are recommended as opposed to nasotracheal and nasogastric tubes. Oropharyngeal colonization by enteric GNBs and P. aeruginosa is considered as an independent risk factor for HAP development. Antiseptic chlorhexidine and selective digestive decontamination (SDD) of the digestive tract using nonabsorbable antibiotics have been tried as preventive measures. Both showed a decrease in bacterial colonization and VAP incidence.39 The ATS/IDSA guidelines however discouraged the routine use of SDD because it may lead to the development of MDR organisms.1 There are other preventive efforts to reduce bacterial colonization, such as stress bleeding prophylaxis, silver-coated ET, and use of different humidification systems, but all provide controversial results and do not reduce the duration of MV, ICU length of stay, or mortality.1,40 In current efforts to eliminate HAIs and promote patient's safety, as recommended by the Institute for Healthcare Improvement, an implementation of VAP prevention bundles have become a popular strategy to reduce VAP rates. Proposed VAP prevention bundles involve semirecumbent position, stress ulcer prophylaxis, deep vein thrombosis prophylaxis, adjustment of sedation and daily assessment of extubation. A collaborative observational cohort study by Berenholtz et al evaluated the impact of a multifaceted intervention on compliance with the ventilator bundles. They demonstrated that a multifaceted intervention was associated with a significant decrease in VAP rates (71%) and sustained up to 2.5 years.41
Despite numerous attempts at preventive measures, most of the studies did not show a benefit in reducing mortality. Some argue the problem lies in the VAP surveillance and due to its lack of standardized criteria for diagnosis. This results in an inaccurate and unreliable number of VAP cases. The National Healthcare Safety Network, which is the Centers for Disease Control's HAI surveillance system, developed a new algorithm for a more objective and reliable surveillance definition. The new algorithm detects ventilator-associated conditions and its complications, requires a minimum period of time on the ventilator, focuses on objective clinical data, and does not include chest-radiograph findings. The hope is to have an improved surveillance for ventilator-associated events when the new algorithm is implemented.42