Severe Community-Acquired Pneumonia

Even though there is no uniform definition for severe pneumonia, patients who require ventilator support or vasopressor support are generally regarded as having severe pneumonia, but it is more challenging to define severe illness in patients who are not receiving these interventions. However, identifying patients with severe pneumonia is important for proper resource utilization, and outcomes can be improved if these patients are identified early, avoiding delayed admission to the ICU, which is in itself a poor prognostic factor.

Several prognostic scoring systems were developed to predict the mortality risk and guide the site of care decision. The pneumonia severity index (PSI) and the British Thoracic Society’s CURB-65 score help with determining mortality risk for patients with CAP.¹⁴ The PSI was developed to identify patients with a low risk of dying, placing all patients into five classes, based on the demographic characteristics, coexisting illnesses, physical examination findings, laboratory measurements, and radiographic findings. The ICU is most often used for patients in classes IV and V, who have a 30-day mortality risk of 4% to 10% and 27%, respectively.¹⁵ However, the PSI score may overestimate severity of illness in patients with older age, while underestimating severity in young patients without comorbid conditions.¹⁶ The complexity of the PSI contrasts with the simpler bedside scoring system, CURB-65. With this tool, 1 point is assigned each for the presence of confusion, blood urea nitrogen (BUN) greater than 7.0 mol/L (19.6 mg/dL), respiratory rate of 30 or more breaths/minute, systolic blood pressure 90 mm Hg or less, or diastolic blood pressure 60 mm Hg or less, and age 65 years or more.¹⁷ Mortality rate increases proportionately with scores higher than 3 (score 3, 17%; score 4, 41.5%; and score 5, 57%).

Severe pneumonia and the host inflammatory response to infection are determined by several variables, including the identity of the pathogen, the timeliness and appropriateness of therapy, and patient variables. The latter include the genetic makeup of the individual, age, nutritional status, sex, and comorbid medical conditions. Although the PSI and CURB-65 score performed well to determine mortality risk, there is still a need to identify patients who will need ICU level of care at the earliest possible time point.18,19 According to the 2007 ATS/IDSA guidelines, severe CAP is present if a patient requires invasive mechanical ventilation or vasopressors or has any three of the nine minor criteria (Box 42.2).¹⁹ The PIRO score has also been used and is calculated within 24 hours of ICU admission with 1 point assigned for each of comorbid conditions (chronic obstructive pulmonary disease [COPD], immunosuppressed state), age older than 70 years, multilobar opacities on chest radiograph, shock, severe hypoxemia, acute renal failure, bacteremia, and acute respiratory distress syndrome (ARDS). Patients can be stratified into four classes: (1) low, 0 to 2 points; (2) mild, 3 points; (3) high, 4 points; (4) very high, 5 to 8 points. In patients admitted to the ICU, the PIRO score had a better performance than APACHE II and ATS/IDSA criteria to predict 28-day mortality rate.¹⁸

Severe pneumonia is a dynamic inflammatory process, and predicting which stable-appearing patients will require ICU care later is difficult. Hence, critically ill patients who do not have obvious need for ICU care, such as invasive respiratory/vasopressor support (IRVS), must satisfy certain minor criteria in order to be recognized. However, the predictive value of using just three minor criteria alone for making a decision to admit to the ICU is uncertain, and in one study, the use of four minor criteria improved the accuracy of predicting subsequent need for ICU care.20,21 A recent prospective study from Scotland excluded patients with the two major ATS/IDSA criteria present on admission, and demonstrated that each of the nine minor criteria was associated with an increased risk of need for mechanical ventilation, need for vasopressor support, and 30-day mortality.²²

Another system developed in Australia—SMART-COP—can assess the need for intensive respiratory or vasopressor support.²³ The SMART-COP was developed primarily to identify the need for IRVS. Different point scores were assigned to various parameters: low Systolic blood pressure less than 90 mm Hg (2 points), Multilobar pneumonia (1 point), low Albumin level less than 3.5 g/dL (1 point), high Respiratory rate 25 to 30 breaths/minute (1 point), Tachycardia higher than 125 beats/minute (1 point), Confusion (1 point), poor Oxygenation (2 points), and low arterial pH less than 7.35 (2 points). A score of more than 3 points identified 92% of patients requiring IRVS, with a specificity of 62.3%, outperforming PSI and CURB-65 scores to identify this specific end point.²³ The SMART-COP as well as the ATS/IDSA 2007 guidelines are the most accurate for predicting need for ICU care.²⁴

Renaud and coworkers examined risk factors for early admission to the ICU among 6560 patients, who presented to the emergency department and did not require immediate respiratory or circulatory support.²⁵ They identified 11 criteria independently associated with ICU admission: male gender, age younger than 80 years, comorbid conditions, respiratory rate of 30 breaths/minute or higher, heart rate of 125 beats/minute or higher, multilobar infiltrate or pleural effusion, white blood cell count less than 3 or more than 20 g/L, hypoxemia (oxygen saturation <90% or arterial partial pressure of oxygen [PaO₂] <60 mm Hg), BUN of 11 mmol/L or higher, pH less than 7.35, and sodium less than 130 mEq/L. They used these criteria to develop the risk of early admission to ICU index (REA-ICU index), which stratified patients into four risk classes, with the risk of ICU admission on days 1 to 3 ranging from 0.7% to 31%.²⁵

Recent data from the German Competence Network for the Study of CAP (CAPNETZ) Study Group demonstrated that serum biomarkers (PCT) can be used as good predictors for short- and long-term all-cause mortality rates in patients admitted with CAP.²⁶ A low level of PCT value in patients classified as high risk by PSI and CURB-65 scores predicted a low risk of dying, and probably a low need for ICU admission.²⁷ Ramirez and colleagues showed that the ATS/IDSA 2007 minor criteria had comparable predictive value with other scores, such as CURB-65 and SMART-COP, but that the use of biomarkers like PCT and C-reactive protein (CRP), along with minor criteria, helped in predicting the need for delayed ICU admission.²⁸ Pathophysiologic severity markers of severe sepsis, like soluble receptor for advanced glycation end products (SRAGE) along with severity scores have been examined in patients with CAP and are encouraging but need further studies for validation.²⁹

Pneumonia Acquired in the Hospital

Hospital-acquired pneumonia (HAP) is the second most common nosocomial infection in the United States,⁴⁰ and current guidelines have emphasized the importance of the time of onset of the disease and the presence of risk factors for infection due to MDR pathogens in defining the approach to therapy. The major goals are early, appropriate antibiotic therapy in adequate doses and appropriate de-escalation of initial antibiotic therapy, based on microbiologic cultures and the clinical response of the patient.²

Early- and late-onset HAP and VAP are diagnosed 2 to 5 days, and more than 5 days, after hospitalization, respectively. The pathogens associated with early-onset HAP and VAP are a group of “core pathogens,” including Streptococcus pneumoniae, Haemophilus influenzae, methicillin-susceptible Staphylococcus aureus (MSSA), and enteric gram-negative bacilli (Escherichia coli, Klebsiella species, Proteus species, and Enterobacter species). In contrast, late-onset HAP and VAP are caused by all the core pathogens, plus drug-resistant pathogens such as MRSA and MDR gram-negative bacilli (Pseudomonas aeruginosa, Acinetobacter species, Enterobacter species, and extended-spectrum β-lactamase [ESBL]–positive strains).

Unlike CAP, there are no well-studied scoring systems to assess disease severity in patients with HAP and VAP. Clinical studies have used surrogate markers such as the APACHE II, or the Sequential Organ Failure Assessment (SOFA) score as a measure of organ dysfunction and severity assessment.⁴¹ The Clinical Pulmonary Infection Score (CPIS) was originally introduced for diagnoses in patients with VAP (described later in the text), but it has also been used to follow the response of VAP patients to therapy.⁴² The value of APACHE II, SOFA score, and CPIS in the prediction of mortality risk during VAP episodes was assessed in a prospective observational study, which found that an APACHE II score greater than 16 (determined at the time of VAP diagnosis) was the only independent predictor of the mortality risk (OR 5; p = 0.019) in a logistic regression analysis.⁴³ In a prospective study by Lisboa and colleagues from Spain, including 441 patients with VAP in three multidisciplinary ICUs, the mortality risk in patients with VAP was assessed by a simple four-variable VAP PIRO score: comorbid conditions (COPD, immunocompromised state, heart failure, cirrhosis, or chronic renal failure); bacteremia; systolic blood pressure less than 90 mm Hg; and ARDS.⁴⁴ Patients were stratified into three levels of risk: (1) mild, 0 to 1 points; (2) high, 2 points (hazard ratio, 2.14); and (3) very high, 3 to 4 points (hazard ratio, 4.63). More recently, a newer and easier scoring system, the IBMP-10, was proposed and is based on the presence of immunodeficiency; (2) blood pressure less than 90 mm Hg (systolic) or less than 60 mm Hg (diastolic); multilobar infiltrates noted on a chest radiograph; platelet count less than 100,000/µL; and duration of hospitalization before the onset of VAP of more than 10 days.⁴⁵ IBMP-10 score was comparable to the APACHE II score in its ability to predict mortality risk in patients with VAP but needs further validation in prospective studies.

Health Care–Associated Pneumonia

The ATS/IDSA guidelines included HCAP as a form of nosocomial pneumonia because these patients were at risk for infection with MDR pathogens because of recent contact with the health care environment. HCAP includes patients who were hospitalized in an acute care hospital for 2 or more days within 90 days of the infection; those who reside in a nursing home or long-term care facility; individuals who received recent intravenous antibiotic therapy, chemotherapy, or wound care within the past 30 days; and those attending a hospital or hemodialysis clinic. Recent clinical investigations have shown that HCAP includes a diverse group of patients, with some at risk for MDR organisms and others not. In fact, many HCAP patients have been treated successfully with a monotherapy regimen or with regimens used for CAP.¹³ Patients in the HCAP population who are at risk for MDR pathogens were those with severe illness or those with other risk factors including hospitalization in the past 90 days, antibiotic therapy in the past 6 months, poor functional status as defined by activities of daily living score, and immune suppression.

General Overview

The respiratory system has both innate and adaptive immunity, which helps prevent potentially harmful pathogens from adhering to the respiratory mucosa and proliferating. Multiple defense barriers in the conducting and gas exchange surfaces of the respiratory tract filter out invading pathogens. The combined effects of the physical, innate, and acquired host defense systems serve to recognize, localize, kill, and remove pathogens. The pathogens that reach the conducting airways are exposed to the soluble constituents in airway fluids. Multiple antimicrobial peptides, such as lysozyme (lytic to bacterial membranes); lactoferrin (which excludes iron from bacterial metabolism); IgA and IgG; and defensins are present in the airway mucosa and pathogens are expelled by the coordinated mucociliary system and cough reflex. Particles 1 µm and smaller reach the alveolar surface and interact with the alveolar macrophages and other components such as IgG, complement, surfactant, and surfactant-associated proteins. Bacteria are opsonized by IgG, complement, or surfactant proteins SP-A and SP-D and are ingested by alveolar macrophages. Pathogen recognition is mediated by toll-like receptors. They initiate local inflammatory response by releasing interleukins and cytokines and carry microbial antigens into the interstitium and to regional lymph nodes where they are taken up by specialized dendritic cells and presented to responding lymphocytes to initiate adaptive immune responses.⁶⁷

Pneumonia develops when these host defenses are overwhelmed by the invading microorganisms (Fig. 42.1). This may occur because the patient has an inadequate immune response, often as the result of underlying comorbid illness, which can lead to anatomic abnormalities (endobronchial obstruction, bronchiectasis), disease-associated immune impairment, or therapy-induced dysfunction of the immune system (corticosteroids, endotracheal intubation).^2,68,69 Pneumonia can also occur in patients who have an adequate immune system if the host defense system is overwhelmed by a large inoculum of bacteria (massive aspiration) or by a particularly virulent organism to which the patient has no preexisting immunity (such as an endemic virus) or to which the patient has an inability to form an adequate immune response. With this paradigm in mind, it is easy to understand why previously healthy individuals develop infection with virulent pathogens such as viruses (influenza), Legionella pneumophila, Mycoplasma pneumoniae, Chlamydophila pneumoniae, and S. pneumoniae. However, for chronically ill patients, it is possible for them to be infected not only by these virulent organisms but also by organisms that are not highly virulent. Owing to host defense impairments, organisms that commonly colonize these patients can cause infection as a result of an inadequate immune response. These organisms include enteric gram-negative bacteria (E. coli, Klebsiella pneumoniae, P. aeruginosa, Acinetobacter spp.) and fungi (Aspergillus and Candida spp.). There can also be genetic variations in the immune response, making some patients prone to overwhelming infection, due to an inadequate response, and others prone to acute lung injury, due to an excessive immune response.³² In fact, the failure to localize the immune response to the respiratory site of initial infection may explain why some patients develop acute lung injury and sepsis as the inflammatory response extends to the entire lung and systemic circulation.⁷⁰

Route of Entry

Bacteria can enter the lung via several routes, but aspiration from a previously colonized oropharynx is the most common way that patients develop pneumonia. Although most pneumonias result from microaspiration, patients can also aspirate large volumes of bacteria if they have impaired neurologic protection of the upper airway (stroke, seizure), or if they have gastrointestinal illnesses that predispose to vomiting. Other routes of entry include inhalation, which applies primarily to viruses, L. pneumophila, and Mycobacterium tuberculosis; hematogenous dissemination from extrapulmonary sites of infection (right-sided endocarditis); and direct extension from contiguous sites of infection. In critically ill hospitalized patients, bacteria can also enter the lung from a colonized stomach (spreading retrogradely to the oropharynx, followed by aspiration), from a colonized or infected maxillary sinus, from colonization of dental plaque, or directly via the endotracheal tube (from the hands of staff members). Studies have also shown that the use of nasal tubes (into the stomach or trachea), can predispose to sinusitis and pneumonia, but that a gastric source of pneumonia pathogens in ventilated patients is not common.71,72

Colonization of the Upper Respiratory System and Digestive Tract

Colonization of the upper respiratory and digestive tracts with pathogenic microorganisms is a major risk factor for the development of pneumonia.⁷³ Factors enhancing airway colonization include antibiotic therapy, endotracheal intubation, smoking, malnutrition, general surgery, dental plaque, and therapies that elevate the gastric pH.⁷⁴ The stomach can be the source of 30% of the enteric gram-negative bacteria that colonize the trachea of intubated patients, but it is difficult to decide if such colonization leads to pneumonia. In a recent multicenter randomized controlled study by Lacherade and colleagues, the use of intermittent subglottic secretion drainage resulted in a significant reduction in microbiologically confirmed VAP compared to control subjects (14.8% vs. 25.6%; P = 0.02),⁷⁵ without a significant difference in the duration of mechanical ventilation and hospital mortality rate. The findings suggest that interruption of gastric to oral to tracheal transmission of bacteria can help to prevent VAP. The importance of oral colonization in VAP pathogenesis was shown in a study by DeRiso and coworkers, which demonstrated that the use of the oral antiseptic chlorhexidine in 353 patients undergoing coronary artery bypass surgery significantly reduced the incidence of respiratory tract infections by 69%.⁷⁶ It has become difficult to separate colonization from infection in intubated patients, particularly with the recognition of ventilator-associated tracheobronchitis (VAT).⁷⁷ VAT patients have an infection, with clinical signs (fever, leukocytosis, and purulent sputum) and microbiologic findings (Gram stain with bacteria and leukocytes, with either a positive semiquantitative or a quantitative sputum culture) but the absence of a new infiltrate on chest radiograph. It remains uncertain if VAT can progress to VAP, or if the two events are independent of one another. If VAT is a precursor of VAP, then serial surveillance cultures of endotracheal aspirates could identify MDR pathogens for targeted antibiotic treatment when VAT is present, in an effort to prevent VAP.⁷⁸

The Role of Respiratory Therapy Equipment and Endotracheal Tubes

The endotracheal tube bypasses the filtration and host defense functions of the upper airway and can act as a conduit for direct inoculation of bacteria into the lung. This route may be particularly important if bacteria form a biofilm and colonize the inside of the endotracheal tube itself.79,80 This can occur if tracheobronchial organisms reach the endotracheal tube, a site where they are able to proliferate free from any impediment by the host defense system. Bacteria commonly do grow at this location in a biofilm, which promotes the growth of MDR organisms.⁸⁰ The biofilm represents a “sequestered nidus” of infection on the inside of the endotracheal tube, and particles can be dislodged every time the patient is suctioned. This is one of the mechanisms explaining the strong association between endotracheal intubation and pneumonia. Given the presence of biofilm in endotracheal tubes, it may be tempting to regularly reintubate patients and use a fresh tube, but this approach is not recommended because reintubation is itself a risk factor for VAP.⁸¹ Afessa and colleagues reported that the use of the silver-coated tube reduced the mortality rate of patients who developed VAP despite having the silver tube in place, compared with the mortality rate of patients who developed VAP with a standard tube in place (14% vs. 36%; P = 0.03).⁸² However, the overall mortality rate was high in patients with the silver tube, and the rate of death from respiratory failure was higher in the silver tube–treated patients than those with the standard tube (19% vs. 11%, P = 0.02), raising doubts on the impact of using the silver-coated tube on VAP patients. Other interventions, such as use of devices to remove biofilm from the tube interior and the coating of tubes with mimics of antimicrobial peptides (ceragenins), are in development to interrupt the pathogenesis of VAP.⁸³

Just as a patient’s own tracheobronchial flora can spread to the endotracheal tube and amplify to large numbers, a similar phenomenon can occur in respiratory therapy equipment and in ventilator circuits.84,85 Ventilator circuit colonization has been studied and the greatest bacterial numbers are found at sites nearest to the patient, not the ventilator, suggesting that circuit contamination originates from the patient.⁸⁴ One highly contaminated site is the condensate in the tubing, and this material can inadvertently be inoculated into patients if the tubing is not handled carefully. Because condensate colonization occurs in 80% of tubings within 24 hours, it does not appear that frequent ventilator circuit changes are useful or even able to reduce the risk of pneumonia; in one study, tubing changes every 24 hours (rather than every 48 hours) served as a risk factor for pneumonia.⁸⁶ Although most patients have ventilator tubing changed every 48 hours, several studies have shown no increased risk of infection if tubing is never changed or changed infrequently.^87,88 The use of heat moisture exchangers may be one way to avoid this problem, but they have had an inconsistent effect on preventing VAP. In addition, frequent changes of heat moisture exchangers (i.e., every 24 hours) have not been shown to have an impact on the incidence of VAP, and heat moisture exchangers should be changed no more frequently than every 48 hours.⁸⁹

Historical Information

Pneumonia is generally characterized by symptoms of fever, cough, purulent sputum production, and dyspnea in a patient with a new or progressive lung infiltrate, with or without an associated pleural effusion. In nonventilated patients, cough is the most common finding and is present in up to 80% of all CAP patients, but is less common in those who are elderly, those with serious comorbid conditions, and individuals coming from nursing homes. Patients with CAP and an intact immune system generally have classic pneumonia symptoms, but the elderly patient can have a nonrespiratory presentation with symptoms of confusion, falling, failure to thrive, altered functional capacity, or deterioration in a preexisting medical illness, such as congestive heart failure.⁹⁰ The absence of clear-cut respiratory symptoms and an afebrile status have themselves been identified as predictors of an increased risk of death. Pleuritic chest pain is also commonly seen in patients with CAP, and in one study, its absence was also identified as a poor prognostic finding.⁹¹ A recent study pointed out that nonsteroidal anti-inflammatory drugs prior to hospitalization were associated with a higher chance of developing pleuropulmonary complications (OR = 8.1).⁹²

Certain clinical conditions are associated with specific pathogens in patients with CAP, and these associations should be evaluated when obtaining a history (Box 42.6).¹⁹ For example, if the presentation is subacute, following contact with birds, rats, or rabbits, then the possibility of psittacosis, leptospirosis, tularemia, or plague, respectively, should be considered. Coxiella burnetti (Q fever) is a concern with exposure to parturient cats, cattle, sheep, or goats; hantavirus with exposure to mice droppings in endemic areas; and Legionella with exposure to contaminated water sources (saunas). Following influenza, superinfection with pneumococcus, S. aureus (including MRSA), and H. influenzae should be considered. With travel to endemic areas in Asia, the onset of respiratory failure after a preceding viral illness should lead to suspicion of a viral pneumonia, which could be severe acute respiratory syndrome (SARS) or avian influenza.⁹³ Endemic fungi (coccidioidomycosis, histoplasmosis, and blastomycosis) occur in well-defined geographic areas and may present acutely with symptoms that overlap with acute bacterial pneumonia. Clinicians should also be cognizant of the risk of bioterrorism and be able to detect clinical features of Bacillus anthracis, Yersinia pestis, and Francisella tularensis.

Nosocomial pneumonia often presents with less definitive clinical findings, particularly in those who are mechanically ventilated, in which the clinical diagnosis is made in patients with a new or progressive radiographic infiltrate, along with some indication that infection is present (fever, purulent sputum, or leukocytosis). In addition, some patients can have purulent sputum and fever, without a new infiltrate, and be diagnosed as having purulent tracheobronchitis, an infectious complication of mechanical ventilation (VAT) that may also require antibiotic therapy, but is not pneumonia.² In taking a history from a patient with nosocomial pneumonia, it is important to identify if there are risk factors present for drug-resistant organisms. For ventilated patients, these factors include prolonged ICU stay (≥5 days), recent antibiotic therapy, and the presence of HCAP risks.^2,60 In CAP patients, risk factors for drug-resistant pneumococcus include recent β-lactam therapy, exposure to a child in day care, alcoholism, immune suppression, and multiple medical comorbid conditions.^94,95

Physical Examination

Physical findings of pneumonia include tachypnea, crackles, rhonchi, and signs of consolidation (egophony, bronchial breath sounds, dullness to percussion). Patients should also be evaluated for signs of pleural effusion. In addition, extrapulmonary findings should be sought to rule out metastatic infection (arthritis, endocarditis, meningitis) or to add to the suspicion of an “atypical” pathogen, such as M. pneumoniae or C. pneumoniae, which can lead to such complications as bullous myringitis, skin rash, pericarditis, hepatitis, hemolytic anemia, or meningoencephalitis. One of the most important ways to recognize severe CAP early in the course of illness is to carefully count the respiratory rate.96,97 In the elderly, an elevation of respiratory rate can be the initial presenting sign of pneumonia, preceding other clinical findings by as much as 1 to 2 days and tachypnea is present in over 60% of all patients, being present more often in the elderly than in younger patients with pneumonia.⁹⁷ In addition, the counting of respiratory rate can identify the patient with severe illness, who commonly has a rate more than 30 breaths/minute. Gurgling sounds heard during quiet breathing or speech have been independently associated with HAP.⁹⁸ Overall, the clinical diagnosis of pneumonia has moderate sensitivity (79%) and specificity (66%),⁹⁹ and in general, definitive imaging studies are required in critically ill patients.

Community-Acquired Pneumonia

The microorganisms causing CAP may vary according to geographic area and underlying patient risk factors. Even with extensive diagnostic testing, an etiologic agent is defined in only about half of all patients with CAP, pointing out the limited value of diagnostic testing, and the possibility that we do not know all the organisms that can cause CAP. The most common cause of CAP is pneumococcus (S. pneumoniae), an organism that is frequently (at least 40% of the time) resistant to penicillin or other antibiotics, leading to the term drug-resistant Streptococcus pneumoniae (DRSP). Fortunately, most penicillin resistance in the United States is still more commonly of the “intermediate” type (penicillin minimum inhibitory concentration, or MIC, of 0.1 to 1.0 mg/L) and not of the high-level type (penicillin MIC of 2.0 mg/L or more).¹⁰⁰ Pneumococcal resistance to other antibiotics is also common, including macrolides and trimethoprim-sulfamethoxazole, but the clinical relevance and impact on outcome of these in vitro findings is uncertain, and most experts believe that only organisms with a penicillin MIC of 4 mg/L or more are associated with an increased risk of death.¹⁰¹ Recently, the U.S. definitions of resistance have changed for nonmeningeal infection, with sensitive being defined by a penicillin MIC of 2 mg/L or less, intermediate as an MIC of 4 mg/L, and resistant as an MIC of 8 mg/L or more. With these new definitions of resistance, very few pathogens will be defined as resistant, but those that are may affect outcome.

All patients with severe CAP should be considered to be at risk for DRSP, and in addition, those admitted to the ICU can have infection with atypical pathogens, which account for up to 20% of infections, either as primary infection or as copathogens. The identity of these organisms varies over time and geography. In some areas, Legionella is a common cause of severe CAP, although in others C. pneumoniae or M. pneumoniae predominate.³⁰ Other important causes of severe CAP include H. influenzae, S. aureus, which includes MRSA (especially after influenza), and enteric gram-negative organisms (including P. aeruginosa) in patients with appropriate risk factors (particularly bronchiectasis and steroid-treated COPD).

Recently, a toxin-producing strain of MRSA has been described to cause CAP in patients after influenza and other viral infections (Fig. 42.2). This community-acquired MRSA (CA-MRSA) is biologically and genetically distinct from the MRSA that causes nosocomial pneumonia, being more virulent and necrotizing, and associated with the production of the Panton-Valentine leukocidin (PVL).^102,103 Viruses can be a cause of severe CAP, including influenza virus, as well as parainfluenza virus and epidemic viruses such as coronavirus (which caused SARS) and avian influenza.⁹³ Viral pneumonia (SARS and influenza) can lead to respiratory failure, and occasionally tuberculosis or endemic fungi can result in severe pneumonia. Recent experience with the 2009 pandemic influenza A (H1N1) infection showed that critical illness was associated with severe hypoxemia and that multisystem organ failure occurred rapidly after hospital admission and mostly in young adults and pregnant patients.¹⁰⁴

Unusual etiologic organisms should be considered, especially in patients who have epidemiologic risk factors for specific pathogens, as discussed earlier. In addition, certain “modifying factors” may be present that increase the likelihood of CAP caused by certain pathogens.² Thus, the risk factors for DRSP include β-lactam therapy in the past 3 months, alcoholism, age older than 65 years, immune suppression, multiple medical comorbid conditions, and contact with a child in day care.⁹⁴ Risk factors for gram-negative infections include residence in a nursing home, underlying cardiopulmonary disease, multiple medical comorbid conditions, probable aspiration, recent hospitalization, and recent antibiotic therapy. Many of these patients who are at risk for gram-negative infections would now be reclassified as having HCAP.^2,105

Some ICU patients are at risk for pseudomonal infection, although others are not, and the risk factors for P. aeruginosa infection are structural lung disease (bronchiectasis), corticosteroid therapy (>10 mg prednisone/day), broad-spectrum antibiotic therapy for more than 7 days in the past month, previous hospitalization, and malnutrition.² Although aspiration has often been considered a risk factor for anaerobic infection, a study of severe CAP in elderly patients with aspiration risk factors found that this population was very likely to have gram-negative infection, and that, using sensitive microbiologic methods, anaerobes were uncommon.¹⁰⁶ Previous studies looking at microbiologic causes in patients admitted with CAP to the ICU have shown wide variation in the results, with a limitation being that not all microbiologic tests were applied systematically for all patients. A recent prospective observational study by Cillóniz and coworkers on 362 consecutive adult patients with CAP admitted to the ICU within 24 hours of presentation reported that 11% of all cases were polymicrobial, with S. pneumoniae, respiratory viruses, and P. aeruginosa being the commonest isolated pathogens.¹⁰⁷ Other studies have also shown a high frequency of multiple pathogens, including a mixture of bacterial and “atypical” pathogens, which may explain why most patients with severe CAP need to be treated empirically for both groups of organisms. Chronic respiratory disease and ARDS criteria were independent predictors of polymicrobial causes and inappropriate initial antimicrobial treatment was more frequent in the polymicrobial infection group compared with the monomicrobial infection group (39% vs. 10%, P < 0.001).

Nosocomial Pneumonia

All patients with this illness are at risk for infection with a group of bacteria referred to as “core pathogens,” which include pneumococcus, H. influenzae, MSSA, and nonresistant gram-negative organisms (E. coli, Klebsiella spp., Enterobacter spp., Proteus spp., and Serratia marcescens). In addition, some patients are also at risk for infection with other organisms, depending on the presence of risk factors such as prolonged hospitalization (≥5 days), prior antibiotic therapy, recent hospitalization (within 90 days), recent antibiotic therapy, residence in a nursing home, or need for chronic care outside the hospital.2,60 Patients with these risk factors can possibly be infected with MDR gram-positive and gram-negative organisms including MRSA, P. aeruginosa and Acinetobacter spp. Recognition of the multiple risk factors associated with these resistant pathogens has made it clear that patients with either early-onset or late-onset nosocomial pneumonia can be infected with MDR organisms. In addition, up to 40% of patients with VAP have polymicrobial infection, involving multiple pathogens.¹⁰⁸ In immunosuppressed patients uncommon pathogens such as Aspergillus species, Candida species, L. pneumophila, Pneumocystis jiroveci, Nocardia species, and viruses such as cytomegalovirus should be suspected.⁷⁴

Most data on nosocomial pneumonia bacteriology come from patients with VAP, and the cause in nonventilated patients is presumed to be similar, based on the presence of risk factors for drug-resistant pathogens. In patients with VAP, infection with enteric gram-negative organisms is more common than infection with gram-positive organisms, although the frequency of MRSA infection is increasing in this population, as is infection with Acinetobacter spp.¹⁰⁹ In a recent prospective study comparing the clinical and microbiologic characteristics of 315 episodes of ICU-acquired pneumonia (VAP 52% vs. non-VAP 48%) the types of etiologic pathogens and outcome were similar regardless of whether pneumonia is or is not acquired during mechanical ventilation.¹¹⁰

HCAP patients have been included in the nosocomial pneumonia guidelines as being a group at risk for infection with MDR gram-positive and gram-negative organisms.² Although many ICU-admitted patients with this illness are infected with these organisms, one study of nursing home patients requiring mechanical ventilation for severe pneumonia showed that these organisms were not present if the patient with severe pneumonia had not received antibiotics in the preceding 6 months and was also of a good functional status (as defined by activities of daily living).¹¹¹ In approaching the bacteriology of nosocomial pneumonia, it is important to recognize that each hospital, and each ICU within a given hospital, can have its own unique flora and antibiotic susceptibility patterns, and thus therapy needs to be adapted to the organisms in a given institution, which can change over time.¹¹² In addition, it is especially important to know this information because antibiotic resistance is a common factor contributing to initially inappropriate empiric antibiotic therapy. Choosing the wrong empiric therapy has been a particular problem for organisms such as P. aeruginosa, Acinetobacter spp., and MRSA.⁵³ These highly resistant organisms can be present in as many as 60% of patients who develop VAP after at least 7 days of ventilation and who have also received prior antibiotic therapy.^2,60

Isolation of Patients with Pneumonia

Patients with certain suspected pathogens should be placed in respiratory isolation to protect both the staff and other patients from infection with these organisms. This practice includes primarily airborne pathogens that spread via the aerosol route and includes any patient who is suspected of having tuberculosis, influenza, respiratory syncytial virus (RSV), or any other epidemic viral infection. Tuberculosis should be considered in any patient with a history of a preceding indolent pneumonia, and in those with severe pneumonia and a history of human immunodeficiency virus (HIV) infection or recent immigration from endemic areas of infection. Patients with MRSA and highly resistant gram-negative infections may need gown, glove, and mask precautions to avoid spread of these difficult-to-treat bacteria.

General Considerations

Therapy of severe pneumonia should be started empirically, and laboratory and imaging studies should be done to corroborate the diagnosis and identify the etiologic agent when possible. A specific causal diagnosis is obtained in less than 50% of patients with CAP and the major focus of diagnostic testing is to assess the severity of illness and allow early identification of pneumonia-related complications.¹⁴ However, in most cases of VAP an etiologic agent can be demonstrated, but the presence of a positive culture cannot reliably distinguish infection from colonization.

Radiographic Evaluation

In all forms of pneumonia, a chest radiograph is used to identify the presence of a lung infiltrate, but in some clinical settings, especially in suspected VAP, there can be noninfectious causes for the radiographic abnormality. A chest radiograph is used to identify complicated and severe illness, such as multilobar infiltrates, cavitation, or a loculated pleural effusion (suggesting an empyema). Chest radiographic patterns are generally not useful for identifying the cause of CAP, although hematogenous dissemination will have bilateral peripheral infiltrates, and aspiration most commonly involves the superior segment of the right lower lobe or posterior segment of the right upper lobe. Findings such as pleural effusion (pneumococcus, H. influenzae, M. pneumoniae, pyogenic streptococci) and cavitation (P. aeruginosa, S. aureus, anaerobes, MRSA, tuberculosis) can suggest certain groups of organisms. The chest radiograph may be suboptimal in patients with early infection, severe granulocytopenia, and bullous emphysema and in obese patients. In those instances, it is reasonable to repeat a chest radiograph in 24 to 48 hours.¹⁹ A computed tomography (CT) scan of the chest has better sensitivity in diagnosing an infiltrate (Fig. 42.3), but routine CT scan has not been shown to be associated with improved outcomes. Thin-section CT cannot reliably distinguish bacterial pneumonias from other causes, especially in patients with underlying lung diseases or immunocompromised conditions except in cases of Pneumocystis pneumonia, which has a characteristic pattern.^113,114 Chest ultrasound is progressively being used to identify the safe site for sampling of the pleural fluid. In the ICU, radiographs are often done at the bedside, and are of such poor quality that pneumonia may be missed or confused with other diagnoses.

Routine Laboratory Tests

A complete blood count, chemistry panel, and arterial blood gas analysis are necessary for all patients admitted to the ICU. Leukopenia is seen in patients with severe pneumonia and sepsis caused by pneumococcus or by gram-negative organisms. Both leukocytosis and leukopenia are associated with poor prognosis in patients with CAP¹⁹ and with thrombocytosis and thrombocytopenia.¹¹⁵ Hyponatremia (serum sodium <130 mEq/L) on admission is associated with poor outcome in CAP patients.¹¹⁶ Elevated liver function tests can be seen in a variety of viral and bacterial pneumonias secondary to atypical agents such as Legionella spp. and Mycoplasma spp., Q fever, tularemia, and psittacosis, as well as in pneumococcal infection.

Role of Biomarkers

Open Lung Biopsy

This procedure is rarely needed unless there is persistence of infiltrates on imaging and suspicion for atypical organisms (such as Aspergillus, cytomegalovirus, Cryptococcus spp., Nocardia, and Toxoplasma gondii) is high in an immunocompromised host with progressive disease not responding to standard treatment regimens. Open lung biopsy is also useful if a pneumonia mimic (inflammatory lung disease, pulmonary hemorrhage, or malignancy) is suspected.

Recommended Testing for Community-Acquired Pneumonia

The ATS/IDSA guidelines recommend that all CAP patients admitted to the ICU should have a chest radiograph, blood and lower respiratory tract (sputum, endotracheal aspirate, bronchoalveolar lavage, or bronchoscopic specimen) cultures, and Legionella and pneumococcal urine antigen testing. If the patient has a moderate-sized pleural effusion, this should be tapped and the fluid sent for culture and biochemical analysis. Those with a cavitary infiltrate on chest imaging should have fungal cultures and tuberculosis testing performed.

Severity assessment scores such as ATS/IDSA 2007 guidelines or SMART-COP can be used to determine the severity of the disease and serum biomarkers like PCT should be used to guide site of care decisions. In patients with no response to treatment or unrelenting high levels of biomarkers, further imaging or invasive diagnostic methods such as bronchoscopy and thoracentesis should be performed and an alternate diagnosis other than CAP should be considered. A suggested diagnostic/treatment approach is provided in Figure 42.4.

Recommended Testing for Nosocomial Pneumonia

Nosocomial pneumonia is diagnosed when a patient has been in the hospital for at least 48 to 72 hours and then develops a new or progressive infiltrate on chest radiograph, accompanied by at least two of the following three: fever, leukocytosis, and purulent sputum. As mentioned, these clinical findings may be sensitive but not specific for infection, and efforts to improve the clinical diagnosis of pneumonia have involved the previously mentioned CPIS.¹²⁸ The CPIS uses six criteria (fever, purulence of sputum, white blood cell count, oxygenation, degree of radiographic abnormality, and presence of pathogens in the sputum), with each scored on a scale from 0 to 2, and pneumonia is diagnosed with a total score of at least 6 (out of a maximum of 12). The CPIS was modified by Singh and coworkers to include radiographic progression in order to improve diagnostic accuracy (Table 42.1).¹²⁹ The CPIS at 72 hours was calculated on the basis of all seven variables and took into consideration the progression of the infiltrate and culture results of the tracheal aspirate specimen. A CPIS greater than 6 at baseline and at 72 hours was considered suggestive of pneumonia and indicated the need for a full course of antibiotic therapy. However, subsequent studies showed that CPIS has a low sensitivity and specificity for diagnosing VAP compared to quantitative cultures of bronchoalveolar lavage fluid, with considerable interobserver variability.¹³⁰ Thus, the use of CPIS remains controversial and has been most successfully used in guiding treatment decisions for patients with a low likelihood of VAP and in guiding the duration of therapy and defining the response to treatment.^42,131

Many studies have documented that VAP is diagnosed more often clinically than can be confirmed microbiologically, and the diagnosis is further obscured by the fact that most mechanically ventilated patients are colonized by enteric gram-negative bacteria, and thus the finding of potential pathogens in the sputum has limited diagnostic value. Many patients with suspected nosocomial pneumonia can have other diagnoses, which can be suggested by the rapidity of the clinical response and by the nature of the clinical findings. These diagnoses include atelectasis and congestive heart failure (very rapid clinical resolution), or in the case of a lack of response to therapy, inflammatory lung diseases, extrapulmonary infection (sinusitis, central-line infection, intra-abdominal infection), or the presence of an unusual or drug-resistant pathogen. The ATS/IDSA guidelines for nosocomial pneumonia have recommended that all patients have a lower respiratory tract sample collected prior to starting therapy and that the technique and culture method be one that the clinician is expert at performing and interpreting. Lower respiratory tract cultures can be obtained bronchoscopically or nonbronchoscopically and can be cultured quantitatively or semiquantitatively. A suggested algorithm for diagnosis and treatment of nosocomial pneumonia is provided in Figure 42.5.

General Considerations

Timely initiation of appropriate antibiotics has significant mortality benefit for both severe CAP and VAP patients. The ATS and IDSA have developed algorithms for initial empiric therapy, based on the most likely etiologic pathogens in a given clinical setting.2,19 If diagnostic testing reveals a specific etiologic pathogen, then therapy can be focused on those results. De-escalation of antibiotics is valuable in the management of VAP because most patients are at risk for infection with MDR pathogens, requiring empiric broad-spectrum antibiotics, and this can lead to antibiotic overuse and further development of resistance if therapy is not adjusted once culture and clinical response data become available.⁶⁴

Microbial Resistance

Patients in the ICU are at a high risk of developing infection, which is often due to antibiotic-resistant pathogens. The incidence of resistance is related to several factors: (1) induction of resistant strains (e.g., emergence of resistance during treatment because of the selection of new mutations), (2) selection of resistant strains (e.g., antimicrobial treatment may select and favor overgrowth of preexisting resistant flora), (3) introduction of resistant strains (e.g., cross-transmission from other patients or health care workers), and (4) dissemination of resistant strains (e.g., suboptimal infection control).¹³² There is growing concern about MDR pathogens in the United States, belonging to the group of “ESKAPE” organisms (Enterococcus faecium, S. aureus, K. pneumoniae, Acinetobacter baumanii, P. aeruginosa, and Enterobacter species).^133,134 A recent prospective interventional study evaluated the effect of antimicrobial diversity on resistance caused by the ESKAPE pathogens in patients with VAP. The study was conducted over 44 months and examined three different antimicrobial strategies implemented consecutively: (1) a patient-specific period, when therapy was based on preexisting risk factors; (2) a 24-month scheduling period, in which antipseudomonal β-lactams were selected and prioritized quarterly during the first 12 months (prioritization periods) and restricted during the next 12 months (restriction periods); and (3) a mixing period over the next 10 months. VAP due to the ESKAPE pathogens increased significantly during scheduling compared with patient-specific and mixing periods (RR, 2.67 and 3.84, respectively).¹³⁵ During the periods in which a diverse prescription pattern was implemented, there was a lower incidence of VAP due to ESKAPE organisms and the authors concluded that antibiotic strategies promoting diversity may prevent the emergence of MDR organisms.

Antibiotic Considerations

All patients with severe pneumonia treated in the ICU should receive initial empiric combination therapy. The rationale for this approach is to provide broad antimicrobial coverage to assure appropriate therapy. In addition, there has been the hope that, in the therapy of nosocomial pneumonia, combination therapy could prevent the emergence of resistance during therapy and potentially provide synergistic activity if a β-lactam antibiotic is combined with an aminoglycoside (for P. aeruginosa pneumonia). However, only with bacteremic P. aeruginosa pneumonia has combination therapy (generally with an aminoglycoside and a β-lactam) been shown to be superior to monotherapy.136,137 In the absence of bacteremia, an older meta analysis found no therapeutic benefit to adding an aminoglycoside to a β-lactam in critically ill patients, but the impact on appropriateness of therapy was not evaluated.¹³⁷ Currently, with the high prevalence of MDR pathogens in nosocomial pneumonia, combination therapy increases the likelihood of appropriate therapy, compared to monotherapy. In fact, in the Canadian Clinical Trials group study of VAP, even though combination therapy did not reduce mortality rates, compared to monotherapy, it led to appropriate therapy 84% of the time when MDR pathogens were present, compared to 11% of the time when these organisms were treated with monotherapy.¹³⁸

One practical problem to using aminoglycosides is that they have a narrow therapeutic-to-toxic ratio and a high incidence of nephrotoxicity, particularly in elderly patients. When these drugs are used, it is important to achieve high peak serum levels to optimize efficacy, but to also avoid elevated trough levels, which correlate with toxicity. When peak serum levels have been monitored, levels of more than 7 µg/mL for gentamicin and tobramycin and more than 28 µg/mL for amikacin have been associated with more favorable outcomes.¹³⁹ One other limitation of aminoglycosides is their relatively poor penetration into bronchial secretions, achieving only 40% of the serum concentrations in the lung. In addition, antimicrobial activity is reduced at the low pH levels that are common in the bronchial secretions of patients with pneumonia.¹⁴⁰ To address some of these concerns, it has now become standard to administer aminoglycosides by combining the total 24-hour dose into a single dose, rather than in divided doses. This approach is theoretically possible because bactericidal activity of aminoglycosides is optimized by high peak concentrations, and once-daily dosing relies on the prolonged postantibiotic effect of aminoglycosides. This approach might not only improve efficacy but also reduce (or at least not increase) toxicity because of low trough levels, and reduce the need for monitoring of serum levels. In one meta-analysis, this approach proved to have little advantage with regard to efficacy or safety.¹⁴¹ However, once-daily dosing is now standard, and optimizing drug pharmacokinetics and pharmacodynamics is important in ICU patients, and this goal can be achieved by using maximal doses of antibiotics while choosing proper drug delivery schemes. This means using once-daily dosing of aminoglycosides, and prolonged infusion of high-dose β-lactams, the latter taking advantage of the time-dependent killing of β-lactams, in contrast to the concentration-dependent killing by aminoglycosides. In one study that used an optimized approach to antibiotic dosing and delivery versus standard therapy, infection-related mortality rate was reduced (8.5% vs. 21.6%).¹⁴²

Initial empiric therapy of CAP treated in the ICU should also be with a combination of agents, usually directed at bacterial pathogens and atypical pathogens. In severe CAP, even with documented pneumococcal bacteremia, dual therapy is associated with reduced mortality rate compared to monotherapy. In the selection of a second agent, a macrolide may be preferred over a quinolone, possibly due to its anti-inflammatory properties, with the main exception being a preference for quinolones if Legionella is suspected.

Although initial therapy of severe pneumonia usually requires multiple agents, once culture data are available, as part of a de-escalation strategy, monotherapy can often be used. Even patients with severe nosocomial pneumonia can be converted to monotherapy, provided that certain high-risk organisms are absent (P. aeruginosa, Acinetobacter spp., and MRSA), but the antibiotics that have been effective as monotherapy for severe VAP include imipenem, meropenem, doripenem, cefepime, ciprofloxacin, high-dose levofloxacin (750 mg daily), and piperacillin/tazobactam.2,121,143–147 Circumstances in which monotherapy should not be used include the following: (1) in any patient with severe CAP, in which the efficacy of this approach has not been demonstrated; (2) in suspected or documented bacteremic infection with P. aeruginosa; (3) in the empiric therapy of VAP if the patient has risk factors for infection with MDR pathogens; and (4) if the patient has nosocomial pneumonia and both S. aureus and P. aeruginosa are identified in culture as the etiologic pathogens. Monotherapy of nosocomial infection should never be attempted with a third-generation cephalosporin because of the possibility of emergence of resistance during therapy as a result of production of chromosomal β-lactamases by the Enterobacteriaceae group of organisms.²

If P. aeruginosa is the target organism, then antibiotics with efficacy against this pathogen are needed. Antipseudomonal β-lactam antibiotics include the penicillins—piperacillin, azlocillin, mezlocillin, ticarcillin, and carbenicillin; the third-generation cephalosporins ceftazidime and cefoperazone; the fourth-generation cephalosporin cefepime; the carbapenems imipenem, doripenem, and meropenem; the monobactam aztreonam (which can be used in the penicillin-allergic patient); and the β-lactam/β-lactamase inhibitor combinations ticarcillin/clavulanate and piperacillin/tazobactam. Other antipseudomonal agents include the quinolone ciprofloxacin, high-dose levofloxacin (750 mg/day), and the aminoglycosides (amikacin, gentamicin, tobramycin).

In patients with suspected MRSA pneumonia, therapy should be with either vancomycin or linezolid (a bacteriostatic, oxazolidinone antibiotic). Early subgroup analysis of two prospective randomized, controlled trials suggested that linezolid led to higher cure and survival rates, compared to vancomycin in patients with documented MRSA VAP.¹⁴⁸ A subsequent prospective study of patients with suspected MRSA VAP, randomized to receive either linezolid, 600 mg, or vancomycin, 1 g every 12 hours, showed trends in favor of linezolid for bacteriologic cure and survival that were not statistically significant.¹⁴⁹ The comparison between linezolid and vancomycin has been evaluated by several meta analyses, which showed no definitive difference, except for a trend in favor of linezolid for clinical success.¹⁵⁰ Recently, a large multicenter trial comparing linezolid to optimally dosed vancomycin was completed, including nearly 400 patients with documented MRSA VAP and HCAP. In that trial, linezolid led to a significantly higher rate of clinical response than vancomycin, but no difference in mortality rate.¹⁵¹ In the study, vancomycin caused more nephrotoxicity, a problem that has been increasingly common when trough levels are pushed above 15 mg/L. Telavancin is another agent that has been studied in MRSA VAP, but when compared to vancomycin, it had no clear advantage and a similar rate of nephrotoxicity but did lead to better clinical responses when MRSA was intermediately sensitive to vancomycin, with MIC values higher than 1 mg/L.¹⁵² In fact, recent studies have shown that the frequency of MRSA with these higher MIC values is increasing, and this is further challenging the efficacy of vancomycin.¹⁵³ Tigecycline has efficacy against MRSA, but has not shown efficacy in VAP, although daptomycin is active against MRSA when it causes bacteremia but is inactivated by pulmonary surfactant, and thus cannot be used to treat pneumonia.

Acinetobacter spp. are inherently resistant to cephalosporins, penicillins, and aminoglycosides.¹⁵⁴ In the past, the most reliable therapy for these agents was a carbapenem, but now resistance to carbapenems is more common, necessitating the use of polymixin B and E (colistin). Acinetobacter is sensitive in vitro to tigecycline, but in a clinical trial, tigecycline monotherapy was inferior to imipenem in the therapy of VAP, including when Acinetobacter was present, and thus if this agent is used, it is probably best as part of a combination regimen, along with a carbapenem, sulbactam, colistin, or an aminoglycoside.¹⁵⁵

Role of Corticosteroids

The fact that inflammatory markers such as IL-6, IL-8, and IL-10 are elevated in patients with severe CAP and decrease in the first few days of appropriate antibiotic therapy favored the possible use of immunomodulators and anti-inflammatory medications such as macrolides, or steroids as an adjunct to reduce the proinflammatory cytokines. One randomized controlled trial of 48 patients compared hydrocortisone infusion (240 mg/day) to placebo, and found that steroid therapy reduced mortality rates, length of stay, and duration of mechanical ventilation.¹⁵⁶ Subsequent studies have not consistently shown benefit for the use of corticosteroids as routine therapy in severe CAP. A meta analysis of available data concluded that there was no definite benefit but also no adverse consequences,¹⁵⁷ although a prospective randomized controlled trial showed a higher frequency of late clinical failure when steroids were used as adjunctive therapy in CAP.¹⁵⁸ Corticosteroids were also used as adjunctive therapy in patients with severe H1N1 pneumonia with ARDS, and were associated with an increased mortality rate, suggesting harm from their use.¹⁵⁹ Given the currently available data, corticosteroids should not be part of routine therapy of severe CAP. In special situations, however, steroids may have value. Patients with pneumonia and pneumococcal meningitis may benefit from adjunctive corticosteroid therapy (dexamethasone) if it is started prior to the initiation of antibiotic therapy, because it may lead to improved long-term neurologic outcomes.^160,161 Patients with P. jiroveci pneumonia also benefit from corticosteroid therapy, if the initial arterial oxygen tension is less than 70 mm Hg, by attenuating some of the inflammation that is induced by antibiotic killing of the organisms. In patients with pneumonia and refractory shock some investigators have considered using corticosteroids to treat relative adrenal insufficiency, but a large prospective randomized trial could not demonstrate benefit.¹⁶²

Nonpharmacologic Measures

Adjunctive therapeutic measures are needed in some patients, including oxygen, chest physiotherapy (if at least 30 mL of sputum daily, and a poor cough response), mucolytic agents, and aerosolized bronchodilators.

Community-Acquired Pneumonia Therapy Algorithm (see Fig. 42.4)

For ICU-admitted CAP patients, initial therapy should be directed at DRSP, Legionella, and other atypical pathogens in all patients, and for selected patients, enteric gram-negative and other organisms should also be targeted, based on epidemiologic risk assessment. Therapy falls into two categories, depending on whether the patient is at risk for P. aeruginosa (structural lung disease such as bronchiectasis, therapy with broad-spectrum antibiotics for more than 7 days in the last month, use of corticosteroids [more than 10 mg of prednisone daily], malnutrition, or HIV infection). In certain circumstances, such as pneumonia complicating influenza, therapy should also include empiric coverage for S. aureus (including MRSA).

Nosocomial Pneumonia Therapy Algorithm (see Fig. 42.5)

In defining therapy for patients with nosocomial pneumonia, it is important to evaluate (a) time of onset of infection, (b) underlying comorbid conditions, (c) severity of disease—based on scoring systems, and (d) risk factors for MDR pathogens. Antibiotic therapy should be given at the first clinical suspicion of infection, and empiric therapy should be dictated by dividing patients into a group not at risk for MDR pathogens, and a group that is at risk. Those who are not at risk for MDR pathogens include patients with both early onset of infection, and no risks for HCAP such as recent hospitalization, treatment in a health care–associated facility (nursing home, dialysis center, etc.), and no history of recent antibiotic therapy in the past month. Patients with either late-onset infection or the presence of any of the other MDR risk factors are treated empirically for infection with MDR gram-negative and gram-positive pathogens. Not all HCAP patients are at risk for MDR pathogens, and those who are not can receive a narrow-spectrum regimen, similar to that used for CAP. The HCAP patient who is at risk for MDR pathogens is the patient with severe pneumonia and any additional MDR risk such as antibiotic therapy or hospitalization in the past 3 months, poor functional status, and immune suppression. MDR pathogens are not likely in HCAP patients with severe pneumonia who do not have any of these other risks present.¹⁰⁶

Community-Acquired Pneumonia

Prevention through vaccination and smoking cessation assumes importance for all groups of patients, but especially for the elderly patient and those with comorbid conditions (COPD, cardiovascular disease, diabetes, cigarette smokers, alcoholism), who are at risk for both a higher frequency of infection and a more severe course of illness. Appropriate patients should be vaccinated with both pneumococcal and influenza vaccines. Even for the patient who is recovering from CAP, immunization while in the hospital is appropriate to prevent future episodes of infection, and the evaluation of all patients for vaccination need and the provision of information about smoking cessation are now performance standards used to evaluate the hospital care of CAP patients.

Nosocomial Pneumonia

Although no single method is able to prevent nosocomial pneumonia reliably, multiple small interventions may have benefit, especially those focused on modifiable risk factors for infection. Recently, these interventions have been combined into “ventilator bundles,” which have been demonstrated to reduce the incidence of VAP, if applied carefully.187,188 Most of these bundles include multiple interventions, so it is difficult to know which individual manipulations are most valuable. Successful bundles have included interventions such as elevation of the head of the bed to 30 degrees (to avoid the risk of aspiration present with the supine position), daily interruption of sedation to attempt weaning, peptic ulcer disease prophylaxis, endotracheal tube suctioning (possibly with a closed suction system), hand washing, careful oral care (including oral chlorhexidine), and tight control of blood glucose.⁴⁰ In spite of the success of this approach, one recent randomized study has demonstrated a lack of benefit and feasibility of routine elevation of the head of the bed.¹⁸⁹ The efficacy of this approach has led to a movement to aim for “zero VAP” in all ICUs, but it remains uncertain if this goal is really achievable, and if hospitals that consistently report this result have simply changed the diagnostic criteria for VAP, because in many instances, the incidence of VAP has been reduced, without a reduction in associated outcomes such as mortality rate and ICU length of stay.

Other widely used measures in mechanically ventilated patients are avoidance of large inocula of bacteria into the lung (careful handling of ventilator circuit tubing), mobilization of respiratory secretions (frequent suctioning, use of rotational bed therapy in selected individuals), nutritional support (enteral preferred over parenteral), placing of feeding tubes into the small bowel (to avoid aspiration, which is more likely with stomach tubes), and avoidance of large gastric residuals when giving enteral feeding. In addition, any tube inserted into the stomach or trachea should be inserted through the mouth and not the nose, whenever possible, to avoid obstructing the nasal sinuses, and to prevent nosocomial sinusitis, which can lead to nosocomial pneumonia.⁴⁰ A specially adapted endotracheal tube that allows for continuous aspiration of subglottic secretions may interrupt the oropharyngeal to tracheal transfer of bacteria and reduce the incidence of pneumonia.¹⁹⁰ In addition, modifications of the endotracheal tube have been developed, including silver coating of the tube and a focus on maintaining endotracheal tube cuff pressure to avoid leakage of tracheal secretions to the lung, and both approaches have had some success. In addition, new devices to remove biofilm from the surface of the endotracheal tube are in development, but their clinical benefit is not yet defined. Because endotracheal intubation is a risk for pneumonia, noninvasive positive-pressure ventilation should be used whenever possible, and this approach is associated with a lower pneumonia risk than traditional mechanical ventilation. Early tracheostomy has been considered a potentially effective means of VAP prevention, but a large randomized trial did not confirm such a benefit.¹⁹¹ There is no specific role for prophylactic systemic or topical antibiotics, but some data suggest that patients with coma due to stroke or head trauma and those who may have aspirated during an emergent intubation may benefit from a 24-hour course of systemic antibiotics.¹⁹² The use of selective digestive decontamination (SDD), which involves the use of prophylactic systemic and topical (mouth and intestinal tract) antimicrobials, has been a controversial strategy for VAP prevention for many years. Although one large trial has recently reported benefit, there are many concerns with this approach, including the development of antibiotic resistance, and the possibility that the use of oral chlorhexidine and ventilator bundles may be just as effective as the entire SDD regimen.^193,194

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