Introduction
Community-acquired pneumonia (CAP) is a frequent infectious respiratory disease. Although many patients with CAP can be treated as outpatients, the mortality of CAP in those who do require hospitalization ranges from 5% to 15% and increases to 20% to 50% in patients who require intensive care unit (ICU) care. Hospital-acquired pneumonia (HAP) is the second most common and most frequently fatal nosocomial infection.
A clinical diagnosis of pneumonia can usually be established on the basis of signs, symptoms, and chest radiographs, although distinguishing CAP or HAP from conditions such as congestive heart failure, pulmonary embolism, and chemical aspiration pneumonia is sometimes difficult. Defining an etiologic agent is also challenging. Although early empirical therapy is necessary, it is important to identify the causative pathogen in patients who require hospitalization, both to confirm the appropriateness of therapy and to reduce unnecessary antimicrobial use.
Diagnosis and management of pneumonia has become more complex due to the growing number of aged and comorbid, debilitated, institutionalized, and immunocompromised individuals, to the diverse array of microorganisms that cause pneumonia, and to increasing antimicrobial resistance.
Pathophysiology and Pathogenesis
Aspiration of oropharyngeal or nasopharyngeal secretions is the main mechanism of contamination of lower airways by bacteria. While a person is awake, glottal reflexes prevent aspiration; during sleep, 50% of normal persons aspirate small volumes of pharyngeal secretions. Because oropharyngeal secretions may contain 10 7 to 10 11 microorganisms per milliliter, aspiration of as little as 0.001 mL may carry more than 100,000 bacteria.
The oropharynx of healthy individuals is colonized by diverse microorganisms that vary in their potential virulence. The ability of microorganisms to colonize the oropharynx and to cause lower respiratory tract infections is determined in part by the interaction of specific microbial adhesins with cellular receptors. For example, Streptococcus pneumoniae, which contains multiple adhesions, binds to the receptor for platelet-activating factor on epithelial cells, and this interaction is enhanced by cigarette smoke, infection with respiratory viruses, and particulate air pollutants, all of which are linked to increased risk for pneumococcal pneumonia. Likewise, Staphylococcus aureus expresses multiple adhesins that bind host extracellular matrix proteins. Gram-negative bacterial pathogens also possess specific adhesins, many of which form macromolecular structures, termed pili . Klebsiella pneumoniae exploits two distinct pili to adhere to epithelial cells: type 1 pili bind to diverse host target molecules with exposed mannose residues, and type 3 pili interact with extracellular matrix proteins.
Several mechanisms in the airways prevent adherence and colonization by potential bacterial pathogens. Respiratory epithelial cells synthesize and secrete peptides, termed defensins and cathelicidins , that possess broad-spectrum antimicrobial activity. In the distal airways and alveoli, pulmonary surfactant proteins A and C can inhibit bacterial binding to host cells and also promote phagocytosis of selected bacteria. The presence of complement and immunoglobulins (particularly immunoglobulin A [IgA]), also prevents colonization of the oropharynx. In addition to protection provided by host factors, the upper airway microbiota may modulate susceptibility to pathogens, as indicated by the evidence that broad-spectrum antimicrobial therapy predisposes to colonization and infection. The effects of the microbiota operate through competition for binding sites or nutritional resources, or by modulating expression of specific host defense molecules. Interactions between the virulence and quantity of aspirated or inhaled microorganisms and the individual’s innate and adaptive immune responses determine whether pneumonia develops.
As an alternative to aspiration of bacteria of the upper airways, Mycoplasma pneumoniae, Chlamydophila species, Coxiella burnetii, Legionella, and Mycobacterium tuberculosis enter the lower respiratory tract by inhalation . Inhalation pneumonia is most often due to microorganisms that survive suspended in the air for prolonged periods, are present in droplet nuclei smaller than 5 µm, and are able to evade innate immune responses.
Epidemiology
Community-Acquired Pneumonia
The true incidence of CAP is uncertain because the illness is not reportable and only 20% to 50% of patients require hospitalization. Estimates of the incidence of CAP range from 2 to 15 cases per 1000 persons per year, with substantially higher rates in older adults.
Although the severity of disease is influenced by the patient’s age and by the presence and type of coexisting conditions, the severity of disease is also related to the pathogen. M. pneumoniae, S. pneumoniae, Chlamydophila pneumoniae, Haemophilus influenzae, and viruses are causes of mild CAP ( Table 33-1 ), whereas S. pneumoniae, M. pneumoniae, and H. influenzae can cause CAP severe enough to warrant hospitalization ( Table 33-2 ). The most frequently identified pathogens causing severe CAP (i.e., CAP requiring ICU care) include S. pneumoniae , enteric gram-negative bacilli, S. aureus, Legionella pneumophila, M. pneumoniae, H. influenzae, and respiratory viruses ( Table 33-3 ). Up to 20% of severe CAP episodes are caused by polymicrobial infection. Even if extensive diagnostic procedures are performed, the responsible pathogen is not isolated in up to 50% to 60% of patients with severe CAP.
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* Severity of disease warranting treatment in an intensive care unit.
Gram-negative enteric bacilli, S. aureus, Legionella species, and respiratory viruses are uncommon causes of CAP, although local outbreaks can markedly increase the incidence of Legionella . Methicillin-resistant Staphylococcus aureus (MRSA), originally a nosocomial pathogen, has appeared in the community where it is referred to as community-acquired MRSA. Community-acquired MRSA can lead to severe pulmonary infections, including necrotizing and hemorrhagic pneumonia. Pseudomonas aeruginosa infection is uncommon in the absence of specific risk factors (recent antibiotic treatment, acquired immunodeficiency syndrome [AIDS], and severe pulmonary comorbidity, especially bronchiectasis, cystic fibrosis, and severe chronic obstructive pulmonary disease [COPD]).
The likely etiology of severe CAP varies in differing patient populations, depending on age and comorbidities, including HIV infection.
Age-Related Factors
Pneumonia remains one of the major causes of morbidity in children. In Europe, there are more than 2.5 million cases of childhood pneumonia yearly, which account for about 50% of hospital admissions for children. Radiographically defined pneumonia is present in 7.5% of febrile illnesses in infants up to 3 months old and in 13% of infectious illnesses during the first 2 years of life. In children younger than 2 years, S. pneumoniae and respiratory syncytial virus are the most frequent microorganisms, whereas M. pneumoniae is a leading cause of pneumonia in older children and young adults.
In adults, increased age is associated with a change in the distribution of microbial causes and an increase in the frequency and severity of pneumonia. The annual incidence of CAP in noninstitutionalized older adults is estimated between 18 and 44 per 1000 compared with 4.7 to 11.6 per 1000 in the general population. Although older adults are particularly at risk for pneumococcal pneumonia, they also have increased rates of pneumonia due to group B streptococci, Moraxella catarrhalis, H. influenzae, L. pneumophila, gram-negative bacilli, C. pneumoniae, and polymicrobial infections. Although the absolute rate of infection by M. pneumoniae does not decrease with age, this pathogen accounts for a smaller proportion of pneumonia in older adults than in younger populations. In patients older than 80 years, there is a higher incidence of aspiration pneumonia and lower incidence of infection with Legionella species than in younger patients.
Personal Habits
Alcohol consumption is an important risk factor for CAP because of its potential to impair level of consciousness, thus increasing the risk for aspiration of oropharyngeal contents. In addition, diverse effects of alcoholism on innate and adaptive immunity have been reported, which may contribute to increased risk. Alcoholism has been shown to be an independent risk factor for increased rate and severity of pneumonia, especially that due to S. pneumoniae. This predisposition persists several months after cessation of alcohol consumption.
Smoking is one of the most important risk factors for CAP and is associated with an increased frequency of CAP due to S. pneumoniae, L. pneumophila, and influenza. Smoking alters mucociliary transport and humoral and cellular defenses, affects epithelial cells, and increases adhesion of S. pneumoniae and H. influenzae to the oropharyngeal epithelium.
Comorbidities
The most frequent comorbidity associated with CAP is COPD. Patients with COPD have an increased risk for CAP, due to alterations in mechanical and cellular defenses that allow bacterial colonization of the lower airways. Patients with severe COPD (forced expiratory volume in 1 second < 30% of predicted) and bronchiectasis have an increased risk for pneumonia caused by H. influenzae and P. aeruginosa. In patients with COPD treated with oral corticosteroids for long periods, the risk for infection with Aspergillus species is increased.
Pneumonia remains the major cause of morbidity and mortality in patients with cystic fibrosis. During the first decade of life, S. aureus and nontypeable H. influenzae are the most common pathogens, although P. aeruginosa is occasionally isolated in infants. By 18 years of age, 80% of patients with cystic fibrosis harbor P. aeruginosa and 3.5% harbor Burkholderia cepacia. Stenotrophomonas maltophilia, Achromobacter xylosoxidans, and nontuberculous mycobacteria are emerging pathogens in this population.
Other comorbidities associated with increased rates of CAP and consequent mortality include congestive heart failure, chronic kidney or liver disease, cancer, diabetes, dementia, cerebrovascular diseases, and immunodeficiencies (e.g., neutropenia, lymphoproliferative diseases, immunoglobulin deficiencies, and human immunodeficiency virus [HIV] infection).
Geographic and Occupational Considerations
Geographic factors, seasonal timing, travel history, and occupational or unusual exposures modify the risk of various microbial etiologies of CAP. For example, an increased frequency of S. pneumoniae is found in soldiers, painters, and South African gold miners. Burkholderia pseudomallei (melioidosis) is endemic in the rural tropics. Exposure to pet birds or work on a poultry (especially turkey) farm or processing plant increases the risk of psittacosis ( Chlamydophila psittaci ), while contact with horses or other large mammals including cattle, swine, sheep, goats, or deer increases exposure to Rhodococcus . Rodent contact suggests the possibility of infection with Yersinia pestis (plague) in the rural southwestern United States and Francisella tularensis (tularemia) in rural Arkansas or Nantucket, Massachusetts. Exposure to sheep, dogs, and cats should prompt evaluation for Coxiella burnetii (Q fever). The role of seasonal timing is illustrated by the increased incidence of lower respiratory tract infections due to S. pneumoniae and H. influenzae in winter months. Pneumonia causing the severe acute respiratory syndrome (SARS) due to a coronavirus emerged in epidemic form in Southeast Asia, and another coronavirus causes the emerging Middle East respiratory syndrome (MERS). Finally, the infectious agents that cause anthrax, tularemia, and plague may be used for bioterrorism or biowarfare purposes and cause lower respiratory tract infections.
Hospital-Acquired (Nosocomial) Pneumonia
Early-onset HAP (<5 days of hospitalization) is most often due to microorganisms that are also associated with CAP, such as S. pneumoniae, H. influenzae, and anaerobes. Late-onset HAP (>5 days of hospitalization) is mainly caused by MRSA, enteric gram-negative bacilli, P. aeruginosa, nonfermenters such as Acinetobacter baumannii and S. maltophilia, and polymicrobial infections. Factors that increase the risk for HAP include antibiotic exposure, old age, severe comorbidities, underlying immunosuppression, colonization of the oropharynx by virulent microorganisms, conditions that promote pulmonary aspiration or inhibit coughing (e.g., thoracoabdominal surgery, endotracheal intubation, insertion of nasogastric tube, supine position), and exposure to contaminated respiratory equipment. A recent study suggests that multidrug-resistant microorganisms are more frequent in early-onset HAP than was initially thought and that risk factors for early-onset pneumonia should be reappraised.
Health Care–Associated Pneumonia
Health care now reflects a continuum with many traditional inpatient services provided in outpatient settings. Physicians often categorize new infections in such subjects as “community-acquired.” However, these health care–associated infections have a unique epidemiology more like that of hospital-acquired infections, and this has resulted in health care–acquired pneumonia (HCAP) being recognized as a separate entity by the American Thoracic Society (ATS) and Infectious Diseases Society of America (IDSA). S. aureus (both methicillin-sensitive and methicillin-resistant) and P. aeruginosa are the most frequent associated microorganisms. Compared with CAP, HCAP patients have more severe disease, higher mortality, greater length of hospital stay, and greater cost of care.
Clinical Presentation
Pneumonia is characterized by the presence of fever, altered general well-being, and respiratory symptoms, such as cough (90%), sputum production (66%), dyspnea (66%), pleuritic pain (50%), and hemoptysis (15%). In older and immunocompromised patients, the signs and symptoms of pulmonary infection may be muted and overshadowed by nonspecific complaints. Temperature greater than 38.5° C or accompanied by chills should never be attributed to bronchitis without examining a chest radiograph.
Occasionally, there is a “classic” history, such as that of the patient with pneumococcal infection who presents with sudden onset of rigor followed by pleuritic chest pain, dyspnea, and cough with rusty sputum. Similarly, a patient with Legionella pneumonia may complain predominantly of diarrhea, fever, headache, confusion, and myalgia. For M. pneumoniae infection, extrapulmonary manifestations such as myringitis, encephalitis, uveitis, iritis, and myocarditis may be present. However, only rarely does the clinical history clearly suggest a specific etiologic diagnosis.
Information obtained from the clinical history and physical examination is not sufficient to confirm the diagnosis of pneumonia. A definitive diagnosis requires the finding of a new opacity on the chest radiograph.
In older patients, especially those with multiple comorbidities, pneumonia may present with general weakness, decreased appetite, altered mental status, incontinence, or decompensation due to underlying disease. The presence of tachypnea may precede other signs of pneumonia by 1 to 2 days. Tachycardia is another common initial sign but is less frequent and specific than tachypnea. Fever is absent in 30% to 40% of older patients. Owing to the lack of specific symptoms, the diagnosis of CAP is frequently delayed in older adults. Older patients with pneumonia who present with altered mental status without fever can have a delay in receiving antibiotics by more than 4 hours after arrival; this delay increases mortality.
Typical Versus Atypical Pneumonia
The division of CAP into typical and atypical syndromes has been used to predict the likely pathogens and select appropriate empirical therapy. The clinical picture of “typical” CAP is that of disease characteristically caused by bacteria such as S. pneumoniae, H. influenzae, and K. pneumoniae. The initial presentation is frequently acute, with an intense chill. Productive cough is present, and the sputum is purulent or bloody. Pleuritic pain may suggest S. pneumoniae. Physical examination reveals typical findings of pulmonary consolidation (see Chapter 16 ). Blood tests show leukocytosis with neutrophilia and the presence of band forms in most cases. Chest radiography shows lobar consolidation with air bronchograms ( Fig. 33-1 ).
In contrast, the syndrome of gradual onset of fever, nonproductive cough, and a relatively normal white blood cell count in a patient without a readily demonstrable bacterial pathogen has been called “atypical pneumonia.” Frequently, systemic complaints are more prominent than the respiratory ones. The atypical syndrome is characteristic of infections by pathogens such as M. pneumoniae, Chlamydophila species, C. burnetii, and viruses. However, several studies, including one that included patients with mild CAP treated on an outpatient basis, have found that neither the clinical symptoms nor the radiographic manifestations are sufficiently sensitive or specific to guide pathogen-directed antibiotic treatment against “typical” versus “atypical” microorganisms. Therefore, current guidelines do not emphasize the use of the typical versus atypical classification to determine initial empirical antibiotic treatment for CAP.
Patient Evaluation
Clinical Evaluation
The clinical findings that best differentiate CAP from other acute respiratory tract infections are cough, fever, tachypnea, tachycardia, and pulmonary crackles; CAP is present in 20% to 50% of persons who have all five factors. Specific signs of pulmonary consolidation are present in only one third of the cases that warrant hospitalization and are frequently absent in patients that are less ill. Early in the evolution of disease, pain and cough may be absent and the physical examination may be normal other than for fever. In debilitated older patients, vague clinical manifestations of pneumonia are common and the presence of fever with no apparent source, especially when accompanied by confusion or tachypnea, justifies obtaining a chest radiograph.
Clues to the etiologic diagnosis may lie outside the respiratory tract. Bradycardia in relation to the amount of fever (pulse should increase by 10 beats/min/°C of temperature elevation) has been associated with pneumonia due to Legionella, C. psittaci, Mycoplasma, or F. tularensis . M. pneumoniae infection may present with extrapulmonary manifestations including arthralgia, cervical lymphadenopathy, bullous myringitis, diarrhea, myalgia, myocarditis, hepatitis, nausea, pericarditis, and vomiting. Skin lesions of erythema multiforme or erythema nodosum suggest Mycoplasma infection (as well as tuberculosis and endemic fungal infection), whereas lesions of ecthyma gangrenosum are most often seen with P. aeruginosa infection. Finally, the examiner must look for the presence of complications such as pleural effusion, pericarditis, endocarditis, arthritis, and central nervous system involvement, which may necessitate further diagnostic procedures and, potentially, a change in therapy.
Laboratory Evaluation
Once the patient is suspected to have pneumonia, laboratory studies should include blood cell counts, serum glucose and electrolyte measurements, and pulse oximetry or arterial blood gas assays. These data provide a basis for making decisions regarding the need for hospitalization. The increased incidence of CAP in HIV-infected individuals provides an additional rationale for HIV testing, particularly in patients with no other risk factors for CAP.
Marked leukocytosis with a leftward shift is more often encountered with infections caused by S. pneumoniae, H. influenzae, and gram-negative bacilli than with M. pneumoniae, Chlamydophila species, Coxiella, or nonbacterial causes of pneumonia. Leukopenia may be seen with overwhelming pneumococcal or gram-negative bacillary pneumonia. The serum level of C-reactive protein and the erythrocyte sedimentation rate are increased to higher values with bacterial than with viral pneumonias. Thrombocytopenia and thrombocytosis are associated with a greater severity of pneumonia and higher mortality.
Procalcitonin (PCT), a precursor of calcitonin, is present at increased concentrations in the blood of persons with bacterial infections, and PCT assays have been used to evaluate the severity, prognosis, and evolution of pneumonia. Importantly, procalcitonin is used to deescalate antibiotics or to stop antibiotics when the levels decrease to a certain cutoff point. A randomized trial of a PCT-guided strategy compared with a guideline-based algorithm, revealed equivalent primary outcomes of treatment of lower respiratory tract infections, but the PCT-guided strategy resulted in reduced antibiotic exposure and duration, fewer adverse effects of antibiotic treatment, and shorter length of stay.
Radiographic Evaluation
Radiographic evaluation is necessary to establish the presence of pneumonia, because there is no combination of historical data, physical findings, or laboratory results that reliably confirms the diagnosis. Limitations of chest radiography include interobserver variability and suboptimal specificity, particularly in patients with the acute respiratory distress syndrome (ARDS). Conversely, the sensitivity of the chest radiograph is decreased in (1) patients with emphysema, bullae, or structural abnormalities of the lung, who may present with delayed or subtle radiographic changes; (2) obese patients, in whom it may be difficult to discern the existence of pneumonia; and (3) patients with very early infection, severe dehydration, or profound granulocytopenia. Computed tomography (CT) of the chest provides a more sensitive means of detecting minor radiographic abnormalities. However, a chest CT is not recommended for patients with suspected pneumonia who have an apparently normal chest radiograph.
Although several radiographic patterns have been associated with pneumonia caused by specific microorganisms, the presence of a certain pattern is not a reliable method for diagnosing a specific pathogen. Nonetheless, the presence of air bronchograms and a lobar ( eFig. 33-1 ) or segmental pattern is more characteristic of typical than atypical causes of pneumonia. In contrast, a mixed pattern (alveolar and interstitial disease ( eFig. 33-2 ) is more frequently observed with atypical pneumonias. Pneumonia complicating aspiration (frequently from anaerobes) ( eFig. 33-3 ) most often involves the superior segment of the right lower lobe or posterior segment of the right upper lobe, or both, as well as the corresponding segments on the left. Infections developing from hematogenous seeding often appear as multiple rounded, small opacities, sometimes with cavities, with a basal predominance, where the distribution of blood flow is greatest. Demonstration of a lung abscess ( eFig. 33-4 ), cavitation, or necrotizing pneumonia suggests infection by anaerobes, S. aureus, Streptococcus pyogenes, or gram-negative bacilli. Pleural effusion frequently accompanies pneumonia; the size of the pleural effusion on the chest radiograph helps determine whether thoracentesis should be performed.
Microbiologic Evaluation
Identification of the infecting microorganism facilitates the use of specific therapy instead of unnecessarily broad-spectrum antimicrobial agents. Although the utility of sputum examination is debated (see later), pleural fluid (if present) and two sets of blood cultures should be obtained in patients hospitalized for CAP. Optimal culture results require that specimens be obtained before initiation of antimicrobial therapy. Sputum samples must be carefully collected, transported, and processed in order to optimize the recovery of common bacterial pathogens. These recommendations are summarized in Tables 33-4 and 33-5 .
| PATIENTS WHO DO NOT REQUIRE HOSPITALIZATION |
| None * |
| PATIENTS WHO REQUIRE HOSPITALIZATION |
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| ADDITIONAL TESTS FOR PATIENTS WHO REQUIRE TREATMENT IN AN ICU |
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* Gram stain and culture should be strongly considered in patients with risk factors for infection by an antimicrobial-resistant organism or unusual pathogen.
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* Gram stain and culture of valid sputum sample, endotracheal aspirate, or bronchoscopically obtained specimens using a protected specimen brush or bronchoalveolar lavage (if patient is intubated).
Sputum Examination
Microscopic examination of expectorated sputum is the easiest and most rapidly available method of evaluating the microbiology of lower respiratory tract infections. A valid expectorated sputum specimen can be obtained in about 40% of patients hospitalized with CAP. When interpreting sputum cultures, it is crucial to ensure that oropharyngeal contents do not unduly contaminate the specimens. The presence of more than 10 squamous epithelial cells per low-power field (×100 magnification) indicates excessive oropharyngeal contamination and the specimen should be discarded because it is not representative of the pulmonary milieu. A specimen with few or no squamous cells and many polymorphonuclear white blood cells (>25 cells/low-power field in a sample from a patient who is not granulocytopenic ) is ideal (see Fig. 33-3 ). Gram-stained expectorated sputum specimens of acceptable quality should be carefully examined using ×1000 magnification (oil immersion objective). Specific fluorescent antibodies are used to evaluate sputum or other respiratory tract specimens for the presence of Legionella and selected other pathogens (see Chapter 17 ) .
When acceptable sputum is obtained, the specificity of the Gram stain for pneumococcal pneumonia is estimated to be greater than 80%. Because the fastidious nature of S. pneumoniae and H. influenzae leads to the death of these organisms, the sensitivity of sputum culture may be lower than that of sputum Gram stain examination for S. pneumoniae or H. influenzae. In contrast, S. aureus and gram-negative bacilli may dominate even if they are not the cause of the patient’s illness, because these bacteria are hardier and may proliferate during sample transport and processing. True pneumonia due to S. aureus or gram-negative bacilli is doubtful if the Gram stain of a valid sputum specimen does not corroborate the presence of these bacteria. In good quality Gram-stained sputum, the presence of a single or a preponderant morphotype of bacteria (≥90%) is considered diagnostic. In the absence of an informative Gram stain, the predictive value of sputum culture is very low.
The latest IDSA/ATS guidelines recommend obtaining a sputum sample for Gram stain and culture in hospitalized patients with the clinical indications listed in Table 33-6 but are optional for patients without these conditions.
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For patients with HAP or ventilator-associated pneumonia (VAP), the range of potential pathogens is so broad and antimicrobial susceptibility patterns so diverse that vigorous diagnostic measures are justified. In ventilated patients, the equivalent of sputum is the endotracheal aspirate for which the criteria for validity are the same as those for sputum. Although the Gram stain and qualitative cultures of endotracheal aspirates have excellent sensitivity, they have poor specificity. Quantitative cultures of endotracheal aspirate samples may help distinguish colonization from infection. However, there has been difficulty in choosing a quantitative threshold for VAP; some have chosen to consider a range of quantitative cultures, from 10 3 to 10 6 CFU/mL, rather than a single cutoff.
Some bacterial agents of pneumonia cannot be cultivated on conventional laboratory media. For example, Legionella requires buffered charcoal yeast extract agar for isolation, whereas recovery of Chlamydophila species and C. burnetii requires culture in mammalian cell lines. When necessary, specimens can be sent to specialized or reference laboratories for appropriate procedures. Culture of certain agents of bacterial pneumonia poses major health risks to laboratory workers (e.g., F. tularensis, Bacillus anthracis, C. burnetii ) . Specimens suspected to harbor one of these agents should be dealt with carefully in a biologic safety hood, and isolation of the pathogens should be reserved for specialized laboratories.
Blood and Pleural Fluid Cultures
Although the overall yield of blood cultures is less than 20% in patients hospitalized for CAP, a positive culture of blood or pleural fluid establishes the etiologic diagnosis of pneumonia. Not surprisingly, the detected rate of bacteremia is lower in patients with mild CAP and higher in patients with severe CAP, especially those warranting ICU care. Prior antibiotic treatment decreases the yield of blood cultures. The latest IDSA/ATS guidelines recommend obtaining blood samples for culture in hospitalized patients with the clinical indications listed in Table 33-6 but are optional for patients without these conditions.
In up to 40% of CAP cases, a pleural effusion may be present. Although the specificity of pleural exudate cultures is very high, the sensitivity is low because of the low incidence of invasion of the pleura. Diagnostic thoracentesis should be performed when a significant pleural effusion is present. Gram stain of pleural fluid may produce an indication of the infecting organisms within 1 hour, while culture identification may require 24 to 48 hours.
Antigen Detection
Commercial assays can be used to detect capsular polysaccharide antigens of S. pneumoniae or L. pneumophila serogroup 1 in urine, and can require less than 1 hour. The sensitivity of these tests is little affected by prior antibiotic treatment; indeed, results may remain positive several weeks after successful treatment. For L. pneumophila serogroup 1, the sensitivity is 60% to 80%, and the specificity is greater than 95%. Urinary antigen testing is currently the most helpful rapid test for the diagnosis of Legionella infections. The major limitation of urinary antigen tests is that currently available tests are intended to detect L. pneumophila serogroup 1 antigen only, although this is the most common cause of Legionella infection.
The sensitivity of S. pneumoniae urinary antigen detection is 50% to 80% and the specificity is 90%. The degree of positivity for the S. pneumoniae urinary antigen test correlates with the Pneumonia Severity Index (PSI). The S. pneumoniae antigen test may also be applied on pleural fluid with a sensitivity and specificity of almost 100%. Urine specimens of children, frequent carriers of S. pneumoniae in the nasopharynx, may test positive in the absence of evidence of pneumonia, and the test should therefore be interpreted with caution in children. The most recent IDSA/ATS guidelines recommend S. pneumoniae and L. pneumophila urinary antigen detection in hospitalized patients with the clinical indications listed in Table 33-6 , but are optional for patients without these conditions.
Antigens for the many common respiratory viruses, influenza virus, respiratory syncytial virus, adenovirus, and parainfluenza viruses can be detected by direct immunofluorescence or by enzyme-linked immunoassay. A rapid antigen detection test for influenza can provide an etiologic diagnosis within 15 to 30 minutes. Test performance varies according to the test used, viral strain, sample type, duration of illness, and patient age. Most show a sensitivity ranging from 50% to 70% and a specificity approaching 100% in adults (see Chapter 17 ).
Nucleic Acid Amplification Tests
Culture procedures for viruses and fastidious bacteria, M. pneumoniae, C. pneumoniae, L. pneumophila, and Bordetella pertussis, which normally do not colonize in the human respiratory tract, are too insensitive and too slow to be helpful in guiding therapy. These pathogens should be detected by nucleic acid amplification tests; their sensitivity is generally superior to that of the traditional procedures and some are considered as the “gold standard.” Real-time multiplex polymerase chain reaction assays detect respiratory viruses in both immunocompetent and immunosuppressed hosts. (See Chapter 17 for detailed information on nucleic acid amplification tests for respiratory pathogens.)
Serologic Evaluation
Before the development of nucleic acid amplification tests, serologic techniques were used to establish a microbiologic diagnosis for pneumonia caused by pathogens that cannot be readily cultured. Examples include common pathogens such as M. pneumoniae, C. pneumoniae, and L. pneumophila, and less common causes of pneumonia such as those caused by the agents of tularemia, brucellosis, and psittacosis, and certain viruses. Diagnosis usually requires that a convalescent specimen demonstrate a fourfold increase in immunoglobulin (Ig) G titer above that present in an acute specimen. These tests are not helpful in initial patient management but are of utility in defining the epidemiology of the pertinent infectious agents. Because IgM antibodies appear earlier than IgG antibodies, the detection of pathogen-specific IgM in serum has been used for the early serologic diagnosis of certain acute infections.
Invasive Diagnostic Techniques
Because of problems encountered with the use of expectorated sputum, it may be necessary to perform an invasive procedure to obtain suitable material for microscopy and cultures. This may be important in the management of patients with life-threatening CAP in whom diagnostic materials cannot otherwise be obtained, patients with progressive pneumonia despite seemingly appropriate antimicrobial therapy, immunocompromised patients, and patients with HAP, especially in the setting of endotracheal intubation. Although qualitative culture of materials obtained by endotracheal suction has excellent sensitivity, the specificity of such cultures is poor; thus, overreliance on these cultures can lead to antibiotic overtreatment.
Bronchoscopic Samples
The reliability of bronchoscopic procedures to determine the microbial etiology of pneumonia depends on the technique used and the organism sought. When compared with sputum cultures, optimally processed bronchoscopic specimens demonstrate improved sensitivity and equal specificity for the culture of pathogenic fungi and mycobacteria. However, such materials have unacceptably poor specificity for routine bacterial cultures owing to oropharyngeal contamination. Semiquantitative or quantitative cultures of materials obtained bronchoscopically with a protected sheath brush or through bronchoalveolar lavage (BAL) and by direct lung aspiration have been successfully used for aerobic and anaerobic bacterial cultures (see Chapters 17 and 22 ). For protected sheath brush cultures, a threshold of 10 3 colony-forming units (CFU)/mL has been recommended to distinguish colonization from infection. However, 14% to 40% of duplicate samples yield disparate quantitative results.
BAL fluid can be quantitatively cultured for bacteria and qualitatively cultured for fungi, mycobacteria, and viruses. A concentrate can be stained for cytochemical and fluorescence evaluation. In one study, the threshold of 10 3 CFU/mL for diagnosing bacterial pneumonia correlated well with diagnoses based on protected sheath brush results and histologic examination of the lung. BAL permits identification of contaminated specimens (i.e., those with greater than 1% squamous epithelial cells), the immediate diagnosis of infection (i.e., intracellular bacteria in more than 2% to 5% of examined polymorphonuclear leukocytes), and the exclusion of infection (i.e., the absence of bacterial pathogens in culture of BAL fluid, although the sensitivity is reduced by prior antibiotic administration).
In one study, the use of quantitative cultures obtained by protected sheath brush and BAL, compared with qualitative cultures of endotracheal aspirates and clinical evaluation, was associated with lower 14-day mortality rates, earlier reversal of organ dysfunction, and less antibiotic use. However, other randomized trials on the use of quantitative cultures of protected sheath brush and BAL specimens, rather than quantitative cultures of endotracheal aspirates, in patients with VAP have not replicated these findings. The use of a sophisticated algorithm (i.e., Clinical Pulmonary Infection Score) increases the diagnostic accuracy of clinical judgment.
Transthoracic Lung Aspiration
Transthoracic lung aspiration obtains specimens suitable for microbiologic and cytologic examination directly from lung parenchyma ( eFig. 33-5 ). It is more widely used for diagnosing malignant pulmonary lesions than infectious diseases, for which, in immunocompetent hosts, the diagnostic yield by transthoracic lung aspiration is approximately 50%. Serious complications of transthoracic lung aspiration include pneumothorax and hemoptysis, even when small-gauge needles are used.
Differential Diagnosis
Several diseases may present with fever and chest radiographic opacities and mimic CAP ( eTable 33-1 ) ; such diseases should be suspected when the radiographic resolution is unusually quick or when there is a lack of response to initial or subsequent antibiotic treatments. In patients with HAP, and particularly in those with VAP, the classic signs and symptoms of pneumonia (including new radiographic changes, fever, leukocytosis or leukopenia, and purulent pulmonary secretions) are neither sufficiently sensitive nor specific to confirm the presence of a pulmonary infection. Atelectasis, pulmonary hemorrhage, ARDS, and pulmonary embolism, among others, are conditions that may mimic pneumonia. In patients with suspected HAP or VAP, the microbiologic confirmation of pneumonia is important in order to avoid unnecessary treatments and increased antibiotic resistance.
| Pulmonary edema |
| Pulmonary infarction |
| Acute respiratory distress syndrome |
| Pulmonary hemorrhage |
| Lung cancer or metastatic cancer |
| Atelectasis |
| Radiation pneumonitis |
| Drug reactions involving the lung |
| Extrinsic allergic alveolitis |
| Pulmonary vasculitis |
| Pulmonary eosinophilia |
| Organizing pneumonia |
Therapeutic Approach to Pneumonia
Once the diagnosis of pneumonia is made, the clinician must decide the appropriate treatment setting: outpatient, general hospital bed, or ICU. Applying prediction rules can facilitate this decision. The second key initial decision is the selection of initial antimicrobial therapy.
Assessment of Severity
The PSI ( eTable 33-2 ) is a scoring system derived from a retrospective analysis of a cohort of 14,199 patients with CAP and prospectively validated in a separate cohort of 38,039 patients with CAP. The PSI is heavily weighted by age, which means it is less useful at extremes of age and is not valid in children. Outpatient treatment is recommended for patients with a PSI score of 70 or less (class I or II). Patients with a PSI score of 71 to 90 (class III) may benefit from brief hospitalization, while inpatient care is appropriate for patients with a score greater than 90 (class IV and V). Prospective studies in both community and teaching hospitals demonstrate that the hospital admission decisions based on PSI may be safely and effectively applied in clinical practice. The PSI is complex and often needs decision support tools for efficient use in a busy emergency department.
| Patient Characteristic | Points Assigned |
|---|---|
| DEMOGRAPHIC FACTORS | |
| Males | Age (yr) |
| Females | Age (yr) − 10 |
| Nursing home residents | Age (yr) + 10 |
| COMORBID ILLNESSES | |
| Neoplastic disease | +30 |
| Liver disease | +20 |
| Congestive heart failure | +10 |
| Cerebrovascular disease | +10 |
| Renal disease | +10 |
| PHYSICAL EXAMINATION FINDINGS | |
| Altered mental status | +20 |
| Respiratory rate 30/min or greater | +20 |
| Systolic blood pressure <90 mm Hg | +20 |
| Temperature <35° C or ≥40° C | +15 |
| Pulse 125/min or greater | +10 |
| LABORATORY FINDINGS | |
| pH <7.35 | +30 |
| BUN >10.7 mmol/L | +20 |
| Sodium <130 mEq/L | +20 |
| Glucose >13.9 mmol/L | +10 |
| Hematocrit <30% | +10 |
| P o 2 <60 mm Hg or O 2 saturation <90% | +10 |
| Pleural effusion | +10 |
* A risk score is obtained by summing the patient’s age in years (age − 10 for females) and the points for each applicable patient characteristic. Patients with a score <50 are candidates for outpatient treatment, whereas those with scores >90 warrant hospitalization. Proper management of patients with scores of 70 to 90 requires careful application of clinical judgment.
The British Thoracic Society validated the simpler CURB-65 score for admission triage decisions. Their algorithm assigns 1 point for each of the following findings at presentation: (1) confusion; (2) urea higher than 7 mmol/L (equal to BUN more than 20 mg/dL); (3) respiratory rate of 30/min or more; (4) low systolic (<90 mm Hg) or diastolic (≤60 mm Hg) blood pressure; and (5) age 65 years or older. Outpatient treatment is recommended for 0-1 points, brief inpatient or supervised outpatient care is recommended for 2 points, and hospitalization is recommended for 3 or greater, with consideration of ICU care for patients with scores of 4 or 5.
Risk stratification for both PSI and CURB-65 was based on associated mortality. They are therefore not sensitive to logistic and social issues such as reliability of oral intake, including antibiotics, and home support.
Patients initially admitted to a general floor with subsequent transfer to the ICU have higher mortality than patients with equivalent severity of illness admitted directly to the ICU. Neither PSI nor CURB-65 are accurate for determining need for ICU care in patients without an obvious indication such as the need for mechanical ventilation or vasopressor support while still in the emergency department. Several scores have been developed for this critical decision. These scores share many common risk factors ( Table 33-7 ) and appear to be equally effective, and management of severe CAP per these guidelines has been associated with decreased mortality. The optimal use of these scores is to identify at-risk patients who need additional evaluation or monitoring even if not initially admitted to the ICU.
| Respiratory rate > 30 breaths/min * † ‡ § |
| Pa o 2 /F io 2 ratio < 250 or arterial saturation ≤90% on room air * † ‡ § |
| Multilobar or bilateral radiographic involvement or pleural effusion * † ‡ § |
| Confusion or disorientation * † ‡ |
| Uremia (BUN level > 20 mg/dL) * † ‡ |
| Leukopenia (WBC count < 4000 cells/dL) or extreme leukocytosis (>20,000 cells/dL) * § |
| Thrombocytopenia (platelet count < 100,000 cells/dL) * |
| Hypothermia (core temperature < 36° C) * |
| Hypotension requiring aggressive fluid resuscitation * |
| Acidosis (pH < 7.30) † ‡ § |
| Hypoalbuminemia (albumin < 3.5 g/dL) † |
| Hyponatremia (sodium < 130 mEq/L) § |
| Tachycardia (>125/min) † § |
Selection of Antimicrobial Agents
Whenever possible, treatment for pneumonia should use the antibiotic with the narrowest spectrum possible, selected on the basis of the underlying pathogen. However, pathogens are rarely identified at the time of presentation, especially when pneumonia is managed in the outpatient setting. Because optimal outcomes are associated with a rapid initiation of antibiotics, initial treatment for patients with pneumonia must be empirical. In selecting initial empirical antimicrobial therapy, physicians should consider the setting in which the pneumonia arose (e.g., community, hospital, nursing home), the severity of illness, age of the patient, presence of comorbidities and immunosuppression, recent antimicrobial therapy, and specific clinical manifestations of the illness. Geographic and facility-specific factors, such as the local prevalence of specific microorganisms (e.g., C. burnetii, L. pneumophila, endemic mycoses, and multidrug-resistant [MDR] pathogens), may also affect the initial treatment choice.
In hospitalized patients, specimens for cultures of blood, sputum, and pleural fluid (if present) should be obtained before treatment. A brief delay in starting therapy while performing diagnostic procedures is reasonable in patients who are not hypotensive. However, delays of more than 4 to 8 hours may increase the length of hospitalization and have been associated with increased mortality.
Community-Acquired Pneumonia
The standard therapy for inpatient empirical antibiotic coverage of CAP is one of two regimens: the combination of a second- or third-generation cephalosporin combined with a macrolide or one of the fluoroquinolones with efficacy against respiratory pathogens (levofloxacin, moxifloxacin, gatifloxacin). Either therapy should be effective against penicillin-resistant S. pneumoniae . The North American guidelines recommend that any empirical regimen for CAP should be active against “atypical” pathogens such as M. pneumoniae, C. pneumoniae, and L. pneumophila. Retrospective analyses of patients hospitalized with CAP indicate that regimens that cover “atypical” pathogens and those that follow recommendations made by the ATS and the IDSA are associated with improved clinical outcomes. In contrast, some Northern European guidelines suggest atypical coverage is not needed unless patients have clinical features more common to atypical pathogens. It is important to recognize that all CAP treatment guidelines are based on broad epidemiologic considerations that may vary by location. Variation from these regimens should be based on specific epidemiologic or clinical characteristics that strongly suggest one of the less common CAP pathogens such as mixed aerobic-anaerobic flora due to aspiration or presence of gram-negative Enterobacteriaceae or P. aeruginosa in patients with specified risk factors.
When tuberculosis is a possibility, fluoroquinolones should be used cautiously in CAP, because as little as 10 days of fluoroquinolone administration is sufficient to select for fluoroquinolone-resistant M. tuberculosis .
The greatest factor to consider in the choice of regimens is a history of recent use of any of the agents. Widespread fluoroquinolone use, especially in subtherapeutic doses, and use of ciprofloxacin has been associated with fluoroquinolone resistance in up to 13% of S. pneumoniae isolates in Hong Kong. Fluoroquinolone resistance and subsequent treatment failures are reported in pneumococcal CAP, but this is less common with use of the fluoroquinolones that have improved activity against respiratory pathogens. In contrast, the frequency of macrolide resistance in S. pneumoniae is increasing, and a macrolide should not be used for monotherapy of S. pneumoniae infection unless in vitro testing confirms that the patient’s strain is susceptible to macrolides.
Empirical antibiotic treatment of severe CAP (SCAP) remains controversial, predominantly due to a lack of treatment studies specifically focused on SCAP. The spectrum of etiologies is clearly greater in SCAP. Even so, penicillin-sensitive pneumococci are still the most likely etiology. Whether SCAP justifies more aggressive diagnostic testing or broader spectrum empirical treatment in all cases has not been established. Retrospective studies suggest combination therapy specifically for severe pneumococcal pneumonia and for SCAP in general are associated with lower mortality. In a large cohort of older patients with CAP needing hospitalization, antibiotic treatment including azithromycin was associated with a lower 90-day risk mortality compared with other antibiotics.
Summaries of the recent IDSA/ATS guideline CAP antibiotic recommendations are presented in eTable 33-3 and eTable 33-4 , respectively.
| BRITISH THORACIC SOCIETY |
|
| AMERICAN THORACIC SOCIETY |
| INFECTIOUS DISEASES SOCIETY OF AMERICA |
|
| DRUG-RESISTANT STREPTOCOCCUS PNEUMONIAE THERAPEUTIC WORKING GROUP |
|
| CANADIAN INFECTIOUS DISEASES SOCIETY AND CANADIAN THORACIC SOCIETY |
|
* American Thoracic Society comorbidities (modifying factors) include cardiopulmonary disease and age older than 65 years, receipt of a β-lactam antimicrobial within the prior 3 months, alcoholism, prior immunosuppressive therapy, multiple medical comorbidities, exposure to a child in a daycare center, residence in a nursing home, underlying cardiopulmonary disease, multiple comorbidities or recent antimicrobial therapy. Infectious Diseases Society of America comorbidities include only COPD, diabetes, renal or congestive heart failure, and malignancy.
† Advanced macrolides are azithromycin and clarithromycin. Telithromycin has similar antimicrobial activity, but is associated with a higher risk of toxicity and its indications are limited.
§ High-dose amoxicillin (3 to 4 g/day), high-dose amoxicillin-clavulanate (2 g amoxicillin plus 125 mg clavulanic acid every 12 hr), cefpodoxime, cefprozil, or cefuroxime.
‖ Because of increasing macrolide resistance, erythromycin cannot be relied upon to ensure coverage of β-lactamase–producing Haemophilus influenzae. A combination of a β-lactam/β-lactamase inhibitor is preferred.
¶ Antipneumococcal fluoroquinolones include levofloxacin, and moxifloxacin.
# Levofloxacin or moxifloxacin.
** Available oral second-generation cephalosporins include cefaclor, cefuroxime axetil, cefprozil, cefonocid, and loracarbef.
| MILD TO MODERATE DISEASE |
|
| SEVERE DISEASE |
|
* Antipneumococcal fluoroquinolones include levofloxacin, gatifloxacin, and moxifloxacin.
† Advanced macrolides are azithromycin and clarithromycin.
‡ Modifying factors include those considered to increase the risk of infection by a penicillin-resistant pneumococcus (age older than 65 years, exposure to a β-lactam antimicrobial within the prior 3 months, alcoholism, prior immunosuppressive therapy, multiple medical comorbidities, exposure to a child in a daycare center or to infection by an enteric gram-negative bacillus (residence in a nursing home, underlying cardiopulmonary disease, multiple comorbidities, or recent antimicrobial therapy).
§ Preferred regimen may be determined by whether the patient has received antibiotics within the prior 3 months.
‖ Antianaerobic agents include clindamycin, metronidazole, and β-lactam/β-lactamase inhibitor combinations.
¶ Acceptable cephalosporins include second-generation agents (e.g., cefuroxime, cefamandole), third-generation agents (cefotaxime or ceftriaxone), or fourth-generation agents (cefepime or cefpirome, neither of which is available in the United States).
†† American Thoracic Society risk factors for Pseudomonas aeruginosa are structural lung disease (i.e., bronchiectasis, cystic fibrosis), corticosteroid use (>10 mg prednisone/day), broad-spectrum antibiotic therapy for more than 7 days in the past month, or malnutrition. The Infectious Diseases Society of American risk factors for P. aeruginosa include only structural lung disease or recent completion of a course of antibiotics or steroids. The Canadian risk factors include only structural lung disease, recent antibiotic therapy, or recent hospitalization in an intensive care unit.
‡‡ Antipseudomonal β-lactams include ceftazidime, cefepime, imipenem, meropenem, mezlocillin, piperacillin, and piperacillin-tazobactam.
Hospital-Acquired Pneumonia and Ventilator-Associated Pneumonia
Empirical therapy for VAP is necessarily broad because the range of potential pathogens is large and mortality is increased when the responsible pathogen is resistant to the initial empirical antibiotic regimen ( Table 33-8 ). Recommended empirical regimens include expanded-spectrum β-lactam agents, usually in combination with aminoglycosides and with MRSA coverage. The empirical β-lactam should be based on antibiotic sensitivity patterns for common gram-negative pathogens in the relevant institution or specific unit.
| Setting | Core Pathogens | Antimicrobial Choices |
|---|---|---|
| 2 to 5 Days in Hospital | ||
| Mild to moderate pneumonia † Severe pneumonia “low-risk” † | Enterobacteriaceae Streptococcus pneumoniae Haemophilus influenzae Methicillin-sensitive Staphylococcus aureus | β-Lactam/β-lactamase inhibitor ‡ or ceftriaxone or fluoroquinolone § All ± an aminoglycoside |
| ≥5 Days in Hospital | ||
| Mild to moderate pneumonia | As above | As above |
| ≥5 Days in Hospital | ||
| Severe HAP “low risk” | Pseudomonas aeruginosa Enterobacter spp. Acinetobacter spp. | Carbapenem or β-lactam/β l -lactamase inhibitor † or cefepime |
| All plus amikacin or fluoroquinolone § | ||
| ≥2 Days in Hospital | ||
| Severe HAP “high risk” | As above | As above |
| Special Circumstances | ||
| Recent abdominal surgery or witnessed aspiration | Anaerobes | As per Table 33-9 |
| Other sites of infection with MRSA or prior use of antistaphylococcal antibiotics | MRSA | As per Table 33-9 |
| Prolonged ICU stay or prior use of broad-spectrum antibiotics or structural lung disease (cystic fibrosis, bronchiectasis) | P. aeruginosa | As per Table 33-9 |
| Endemicity within facility and either impaired cell-mediated immunity or failure to respond to antibiotics | Legionella | As per Table 33-9 |
* High-risk criteria include age older than 65 years, pancreatitis, chronic obstructive pulmonary disease, central nervous system dysfunction (stroke, drug overdose, coma, status epilepticus), congestive heart failure, malnutrition, diabetes mellitus, endotracheal intubation, renal failure, complicated thoracoabdominal surgery, and alcoholism. All other patients are considered to be at low risk.
† Antimicrobial treatment should also be sufficient to cover core pathogens.
‡ Ticarcillin-clavulanate and piperacillin-tazobactam are the preferred β-lactam/β-lactamase inhibitors for the treatment of nosocomial pneumonia. Ampicillin-sulbactam lacks adequate activity against many nosocomial enteric gram-negative bacilli.
§ Levofloxacin (IV or PO), gatifloxacin (IV or PO), moxifloxacin (IV or PO), or gemifloxacin (PO only) are preferred for Streptococcus pneumoniae. When used for severe HAP, levofloxacin should be dosed at 750 mg IV daily. Ciprofloxacin has the best in vitro activity against Pseudomonas aeruginosa.
Empirical antibiotics for HAP are less well studied. HAP in nonintubated patients is a mixture of CAP pathogens and the pathogens found in VAP, although the frequency of the latter is likely lower, especially in cases that present early after admission. The greatest risk for MDR pathogens in nonintubated patients with HAP is recent antibiotic therapy, and monotherapy is probably adequate for most patients without recent antibiotic exposure. Anaerobes appear to play a slightly greater role in HAP than VAP because of the risk of macroaspiration, but specific anaerobic coverage is not necessary if an appropriate β-lactam is used. Unless Legionella is known to be endemic in the institution, targeted therapy for this pathogen is seldom necessary in the empirical treatment of HAP. Efforts to identify the cause of infection are especially crucial in patients with HAP or VAP, to allow selection of optimal antimicrobial therapy and minimize the duration of empirical broad-spectrum coverage.
Health Care–Associated Pneumonia
The optimal approach to empirical coverage for HCAP remains controversial, due to variations in health care systems and definitions. Pneumonia in nursing home and chronic care facility residents is seen in a bimodal pattern. Ambulatory patients who are able to take care of most of their activities of daily living have disease that resembles CAP, while in contrast, severely debilitated patients with tracheostomies, feeding tubes, frequent and recent acute care hospital admissions, and frequent exposure to antibiotics are at high risk for MDR pathogens and should be treated with VAP regimens. Culture-negative HCAP patients have equivalent or better outcomes when treated with CAP antibiotics as with broader spectrum treatment, but are difficult to identify at admission. If started on broader therapy, deescalation to CAP therapy after culture results return negative appears safe.
Other Pneumonia Syndromes
On initial presentation, a variety of other infectious pulmonary syndromes may not be readily differentiated from acute bacterial pneumonia. Examples include influenza A, severe acute respiratory syndrome, hantavirus pulmonary syndrome, and other viral pneumonias. Milder cases of viral pneumonia may be distinguished by a low PCT level and antibiotics can be safely withheld or withdrawn in these patients.
Concerns about potential bioterrorism or biowarfare require attention to the epidemiologic, clinical, and microbiologic significance of pneumonia due to B. anthracis (anthrax), F. tularensis (tularemia), and Y. pestis (plague). These infectious agents are individually discussed later in this chapter. Further information may be obtained from organizations such as the Centers for Disease Control and Prevention ( www.cdc.gov ) , IDSA ( www.idsociety.org ), and the World Health Organization ( www.who.org ) (see Chapter 40 ).
Adjustments in Antimicrobial Therapy
If the etiologic agent of a patient’s pneumonia has been identified, the initial antimicrobial regimen should be adjusted based on the results of in vitro susceptibility testing. The ideal drug for a known pathogen has the narrowest spectrum of activity and is the most efficacious, least toxic, and least costly. Pathogen-based modification of therapy is particularly important in HAP because prolonged use of broad-spectrum empirical agents promotes the emergence of MDR pathogens. Recommendations for specific drug choices for specific microorganisms are discussed under the sections devoted to individual microorganisms and are summarized in Table 33-9 . If a pathogen is not identified, reevaluation of the initial therapeutic regimen must take into account the patient’s response to therapy. Change from parenteral to oral antimicrobial therapy can safely be made in hospitalized CAP patients when clinically stable and able to absorb effective oral antimicrobials ; this is often achieved within 3 days. In-hospital observation after switching from intravenous to oral antibiotics for CAP patients is not needed. Because HAP pathogens are frequently resistant to available oral antimicrobials, enteral absorption is less predictable, and the severity of illness is greater, initial oral antimicrobial therapy is much less frequently appropriate.
| Type of Infection | Preferred Agent(s) | Alternative Agent(s) |
|---|---|---|
| COMMUNITY-ACQUIRED PNEUMONIA | ||
| Streptococcus pneumoniae | ||
| PCN-susceptible | Penicillin G, amoxicillin, clindamycin, doxycycline | Cephalosporin, macrolide, * (MIC < 2 g/mL) fluoroquinolone † |
| PCN-resistant | Agents identified using in vitro susceptibility tests, including cefotaxime, ceftriaxone, vancomycin, and fluoroquinolone † | Macrolide, if susceptible |
| Mycoplasma | Doxycycline, macrolide | Fluoroquinolone † |
| Chlamydophila pneumoniae | Doxycycline, macrolide | Fluoroquinolone † |
| Legionella | Azithromycin, fluoroquinolone (including ciprofloxacin), † erythromycin (± rifampin) | Doxycycline ± rifampin |
| Haemophilus influenzae | Second- or third-generation cephalosporin, clarithromycin, doxycycline, β-lactam/β-lactamase inhibitor, trimethoprim-sulfamethoxazole, azithromycin | Fluoroquinolone † |
| Moraxella catarrhalis | Second- or third-generation cephalosporin, trimethoprim-sulfamethoxazole, macrolide doxycycline, β-lactam/β-lactamase inhibitor | Fluoroquinolone † |
| Neisseria meningitidis | Penicillin | Ceftriaxone, cefotaxime, cefuroxime, chloramphenicol, fluoroquinolone † |
| Streptococci (other than S. pneumoniae ) | Penicillin, first-generation cephalosporin | Clindamycin (susceptibility should be confirmed), vancomycin |
| Anaerobes | Clindamycin, β-lactam/β-lactamase inhibitor, β-lactam plus metronidazole | Carbapenem |
| Staphylococcus aureus | ||
| Methicillin-susceptible ‡ | Oxacillin, nafcillin, cefazolin; all ± rifampin or gentamicin ‡ | Cefuroxime, cefotaxime, ceftriaxone, fluoroquinolones, † clindamycin, vancomycin |
| Methicillin-resistant ‡ | Vancomycin ‡ ± rifampin or gentamicin | Linezolid, quinupristin-dalfopristin; trimethoprim-sulfamethoxazole, fluoroquinolones, † and tetracyclines may also show activity (in vitro testing required) |
| Klebsiella pneumoniae and other Enterobacteriaceae (excluding Enterobacter spp.) | Third-generation cephalosporin or cefepime (all ± aminoglycoside) carbapenem | Aztreonam, β-lactam/β-lactamase inhibitor, § fluoroquinolone † |
| HOSPITAL-ACQUIRED INFECTIONS | ||
| Enterobacter spp. | Carbapenem, β-lactam/β-lactamase inhibitor, cefepime, fluoroquinolone; all + aminoglycoside in seriously ill patients | Third-generation cephalosporin + aminoglycoside |
| Pseudomonas aeruginosa | Antipseudomonal β-lactam § + aminoglycoside, carbapenem + aminoglycoside | Ciprofloxacin + aminoglycoside, ciprofloxacin + antipseudomonal β-lactam ‖ |
| Acinetobacter | Aminoglycoside + piperacillin or a carbapenem | Doxycycline, ampicillin-sulbactam, colistin |
| LESS COMMON PATHOGENS | ||
| Nocardia | Trimethoprim-sulfamethoxazole | Imipenem ± amikacin, doxycycline or minocycline, sulfonamide ± minocycline or amikacin |
| Coxiella burnetii (Q fever) | Doxycycline | Fluoroquinolone |
| Chlamydophila psittaci (psittacosis) | Doxycycline | Erythromycin, chloramphenicol |
| Eikenella corrodens | Penicillin | Tetracyclines, β-lactam/β–lactamase inhibitor, second- and third-generation cephalosporins, fluoroquinolones |
* Azithromycin (IV or PO) is the preferred macrolide; clarithromycin (PO) or erythromycin (IV or PO) may also be used.
† Levofloxacin (IV or PO), gatifloxacin (IV or PO), moxifloxacin (IV or PO), or gemifloxacin (PO only) are preferred for Streptococcus pneumoniae . Ciprofloxacin has the best in vitro activity against Pseudomonas aeruginosa .
‡ Rifampin and gentamicin should be reserved for cases of bacteremic Staphylococcus aureus pneumonia, empyema formation, or lung abscesses. Activity of rifampin and gentamicin requires laboratory confirmation for methicillin-resistant S. aureus.
§ Ticarcillin-clavulanate and piperacillin-tazobactam are the preferred β-lactam/β-lactamase inhibitors for the treatment of nosocomial pneumonia due to Enterobacteriaceae. Ampicillin-sulbactam lacks adequate activity against many nosocomial enteric gram-negative bacilli.
‖ Antipseudomonal β-lactams ceftazidime, cefepime, imipenem, meropenem, mezlocillin, piperacillin, or piperacillin-tazobactam.
Common Causes of Pyogenic Pneumonia
Individual pneumonia pathogens may have unique epidemiology, diagnostic tests, and/or treatment. The sections that follow emphasize these unique aspects for selected pathogens (or groups).
Streptococcus pneumoniae (Pneumococcal Pneumonia)
Epidemiology
S. pneumoniae is the most frequent cause of CAP among patients who require hospitalization. The overall incidence of pneumococcal pneumonia is approximately 200 cases per 100,000 persons per year, with 9 to 14 cases per 100,000 cases of bacteremia. This infection accounts for 40,000 deaths annually in the United States with most deaths in the very young and the elderly. Risk factors, particularly in adults, include cigarette smoking, HIV infection (even with preserved CD4 counts), heavy alcohol use, chronic liver disease, genetic defects in host immunity, and malnutrition. Pneumococcal infections present predominantly in the winter and early spring and are often associated with prior infection by influenza or respiratory syncytial virus.
Use of the conjugate pneumococcal vaccine has markedly decreased invasive pneumococcal infections in children, with a secondary reduction in adults. This latter effect probably represents interruption of transmission by aerosolized droplets and direct physical contact, in that the conjugate vaccine is effective in blocking colonization. However, widespread use of the conjugate vaccine in the United States has resulted in an increase in the number and proportion of cases of invasive pneumococcal disease due to isolates with polysaccharide capsule types that are not included in the seven-valent vaccine. Consequently, a conjugate vaccine containing 13 capsular polysaccharide antigens was developed; this was approved by the U.S. Food and Drug Administration in 2012.
Clinical Manifestations
The classic presentation of pneumococcal pneumonia consists of a single rigor followed by sustained fever, cough, dyspnea, and production of rusty or mucoid sputum; gross hemoptysis is unusual. Severe pleuritic chest pain is common. The radiographic appearance of pneumococcal pneumonia is often either lobar consolidation (see Fig. 33-1 and eFig. 33-1 ) or patchy bronchopneumonia ( eFig. 33-6 ). Although pneumococci can cause necrotizing pneumonia, cavitation rarely develops. Small, parapneumonic effusions are frequently found and can progress to frank empyema. Neutropenia may develop in patients with overwhelming infection.
Microbiologic Diagnosis
Although Gram stain of purulent sputum that reveals numerous, characteristic “lancet-shaped” diplococci with blunted ends (commonly seen in pairs and short chains) in the absence of other predominant flora is strongly suggestive of pneumococcal pneumonia ( Fig. 33-2 ), a good quality sputum specimen cannot always be obtained. The organism is recovered from sputum culture in fewer than half of cases, and even a single dose of antibiotics can affect the yield of sputum cultures, which contributes to the discrepancy between sputum Gram stain and culture results. The frequency of positive blood cultures has fallen from 30% of hospitalized patients to less than 10% in many contemporary series. This decrease may reflect a greater percentage of blood cultures drawn after antibiotics because of the emphasis on timely antibiotic doses in the emergency department, deemphasis on blood cultures in CAP in general, and/or a benefit of vaccination on invasive pneumococcal disease.
The rapid urinary antigen S. pneumoniae test offers an alternative approach to the diagnosis of pneumococcal CAP and is becoming more widely used in diagnosis and in narrowing antibiotic therapy. Despite satisfactory sensitivity and specificity, the urinary antigen test is complementary to culture methods, since it cannot provide information on antimicrobial susceptibility of the infecting organism.
Clinical Course
With an appropriate antibiotic, a clinical response is usually expected within 24 to 48 hours. The onset of suppurative complications, such as purulent pericarditis, meningitis, endocarditis, arthritis, and cellulitis after initiation of therapy is uncommon in the modern era. The exception is empyema, which appears to be increased due to serotype replacement in the vaccinated populations by serotypes more often associated with empyema. Pneumococcal pneumonia remains a cause of septic shock and ARDS.
Treatment
Antimicrobial resistance complicates treatment for S. pneumoniae in much of the world, including in the United States. For nonmeningeal isolates of S. pneumoniae, the redefinition of full susceptibility as a minimum inhibitory concentration (MIC) of penicillin less than or equal to 2 µg/mL and high-level resistance as MIC greater than or equal to 8 µg/mL markedly changed the incidence of penicillin resistance. This redefinition was driven by discordance between the previous lower MIC breakpoints and clinical success rates. The rate of increase in the frequency of penicillin resistance may have stabilized, possibly as a consequence of the pneumococcal conjugate vaccine and a shift in the outpatient antibiotic prescription patterns away from β-lactams.
Penicillin resistance in S. pneumoniae is due to alterations in penicillin-binding proteins rather than to β-lactamase production. Unlike other β-lactams, cefotaxime, ceftriaxone, and cefepime retain activity against 75% to 95% of nonmeningeal isolates of S. pneumoniae. S. pneumoniae resistance rates to other antimicrobials can be as high as 30% for trimethoprim-sulfamethoxazole (TMP-SMX), 16% for tetracyclines, 26% for macrolides, and 9% for clindamycin; these rates are higher among penicillin-resistant pneumococci. High-level macrolide resistance (MIC > 64 µg/mL) associated with the MLSB (macrolide, lincosamide, streptogramin B) phenotype is more common in Europe and has been associated with in vitro resistance to clindamycin. S. pneumoniae resistance to fluoroquinolones has also emerged with associated clinical treatment failures.
Recent exposure to an antibiotic increases the likelihood of the patient having a pneumococcal isolate resistant to that antibiotic (or class of antibiotics). Thus, it is important to avoid antibiotics that have been used in the prior 90 days when selecting a regimen for empirical treatment of a pneumococcal infection. Retrospective and prospective observational studies have suggested a benefit to treating severely ill patients with proven pneumococcal infections with both a β-lactam and a macrolide. Explanations that have been proposed to explain those results include nonbactericidal effects, such as inhibiting biofilm production, or an anti-inflammatory effect of the macrolide.
Other Streptococci
Epidemiology
S. pyogenes (group A β-hemolytic streptococcus) can be found in the oropharynx of more than 20% of children and a smaller percentage of adults. Carriage rates increase greatly during epidemics and in crowded conditions. In the United States, the incidence of pneumonia due to S. pyogenes was 0.15 to 0.35 per 100,000 persons per year, but may be as high as 3.6 per 100,000 in children. The organism is easily transferred between contacts, leading to epidemics of group A streptococcal pneumonia in military recruits, nursing homes, and other crowded settings. Pneumonia due to S. pyogenes most often manifests during the late winter and spring months, may follow an episode of influenza, measles, or varicella, and has been associated with increased age, alcohol abuse, diabetes mellitus, cancer, and HIV infection. S. pyogenes can cause necrotizing pneumonia and is associated with pleural empyema.
Group B (i.e., Streptococcus agalactiae ) streptococci are a major cause of neonatal sepsis and pneumonia. In adults, pneumonia accounts for approximately 15% of adult infections by group B streptococci. Most adults with group B streptococcal pneumonia are debilitated and develop pneumonia as a consequence of aspiration. Diabetes, cirrhosis, stroke, decubitus ulcer, and neurogenic bladder are also risk factors.
The Streptococcus milleri group C streptococci (which include S. intermedius, S. anginosus, and S. constellatus ) have emerged as significant respiratory pathogens, predominantly causing empyema ( eFig. 33-7 and 
) and lung abscesses as well as superinfection pneumonia in severe viral pneumonia. Infections with bacteria in this group share many of the features of anaerobic infections, including increased risk with periodontal disease and alcoholism. Other viridans and microaerophilic streptococci (α-hemolytic, nonpneumococcal) are rarely the sole pathogens in patients with pneumonia; they are more commonly found mixed with other facultative and anaerobic organisms in aspiration pneumonia.
Clinical Manifestations
CAP from these pathogens is clinically indistinguishable from pneumococcal pneumonia. Exudative pharyngitis may be evident and unilobar involvement is common with group A streptococcal pneumonia. Pleural effusions in group A streptococcal pneumonia are frequent, may be large, accumulate rapidly, and appear early in the course of the disease, particularly in children. Pneumonia caused by other β-hemolytic streptococci is usually less abrupt and milder; pleural effusions are uncommon, and lung tissue necrosis is rare despite frequent bacteremia. S. milleri infection is predominantly associated with empyema, with or without concomitant pneumonia. Pneumothorax at the time of initial presentation appears to be more common with S. milleri than with other streptococcal empyemas.
Microbiologic Diagnosis
Because streptococci are common in the oropharynx, documentation of infection from these organisms requires isolation from a culture of blood, pleural fluid, or respiratory specimen obtained by means of an invasive procedure ( Fig. 33-3 ). Pleural fluid cultures of children with S. pyogenes pneumonia are frequently positive. Polymerase chain reaction technology holds promise for aiding diagnosis, especially of group A streptococcal infections and S. milleri empyema.
Clinical Course
Empyema and/or pericarditis are seen in 5% to 30% of patients with group A streptococcal pneumonia ; other complications include pneumothorax, mediastinitis, and bronchopleural fistula formation. The only classic nonsuppurative complication that follows S. pyogenes pneumonia is glomerulonephritis.
Treatment
Most of these streptococci are susceptible to penicillin G, ampicillin, and many cephalosporins, although α-hemolytic streptococci may require high dosage, due to the phenomenon of tolerance (growth inhibition without killing, at low and intermediate drug concentrations). Because resistance to clindamycin and erythromycin is found in up to 15% to 20% of isolates, susceptibility testing is advisable before monotherapy with a macrolide or clindamycin. As for empyemas caused by other pathogens, drainage of empyema fluid is an important component of therapy.
Haemophilus influenzae
Epidemiology
Invasive infection, especially pneumonia, due to H. influenzae is estimated to account for approximately 1.2 cases per 100,000 adults per year in the United States, and is one of the more common causes of pneumonia in adults requiring hospitalization. Chronic lung disease, malignancy, HIV infection, and alcoholism are among the most common predisposing conditions to Haemophilus pneumonia. Active smoking appears to particularly increase the risk of H. influenzae pneumonia.
As with S. pneumoniae , vaccination against H. influenzae type b significantly changed the epidemiology of childhood pneumonia. Vaccinated children are still susceptible to unencapsulated (or nontypeable) strains but the incidence of H. influenzae pneumonia has fallen dramatically. Nonbacteremic infection by unencapsulated or non–type b strains is the most common form of H. influenzae pneumonia in adults.
Clinical Manifestations
Haemophilus pneumonia is clinically indistinguishable from other bacterial pneumonias ( eFig. 33-8 ). On radiographs, Haemophilus pneumonia may be multilobar, patchy bronchopneumonia or have areas of frank consolidation. Spherical radiographic opacities (so-called round pneumonia) have been described, but cavitation is uncommon. Small parapneumonic effusions may occasionally progress to empyema. Bacteremia is more common in children than in adults.
Microbiologic Diagnosis
Diagnosing H. influenzae pneumonia by a Gram stain of sputum is difficult, because the small, pleomorphic coccobacilli are often overlooked. Culture of expectorated sputum reveals H. influenzae in only half of well-documented cases of pneumonia. Asymptomatic colonization with nontypeable strains in patients with COPD complicates analysis of Gram stain and sputum cultures ( Fig. 33-4 ).
