An expanded version of this chapter is available online at ExpertConsult.
Introduction
Community-acquired pneumonia (CAP) is a frequent infectious respiratory disease.
1
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 107 to 1011 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,
2
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,3, 4, 5 all of which are linked to increased risk for pneumococcal
pneumonia. Likewise, Staphylococcus aureus expresses multiple adhesins that bind host
extracellular matrix proteins.6, 7 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.
8
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.
9
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.10,
11 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.12, 13, 14, 15 Interactions between the virulence and quantity
of aspirated or inhaled microorganisms and the individual's innate and adaptive immune
responses determine whether pneumonia develops.
16
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.
17
Although the severity of disease is influenced by the patient's age and by the presence
and type of coexisting conditions,18, 19, 20, 21 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
).21, 22, 23 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
).21, 22, 23, 24, 25 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.
Table 33-1
Common Causes of Community-Acquired Pneumonia in Patients Who Do Not Require Hospitalization*
Mycoplasma pneumoniae
Streptococcus pneumoniae
Chlamydophila pneumoniae
Haemophilus influenzae
Respiratory viruses
*
Organisms are listed in the general order of frequency.
Table 33-2
Common Causes of Community-Acquired Pneumonia in Patients Who Require Hospitalization*
Streptococcus pneumoniae
Mycoplasma pneumoniae
Chlamydophila pneumoniae
Haemophilus influenzae
Staphylococcus aureus
Mixed infections
Enteric gram-negative bacilli
Aspiration (anaerobes)
Respiratory viruses
Legionella species
*
Organisms are listed in the general order of frequency.
Table 33-3
Common Causes of Severe Community-Acquired Pneumonia*
†
Streptococcus pneumoniae
Enteric gram-negative bacilli
Staphylococcus aureus
Legionella species
Mycoplasma pneumoniae
Respiratory viruses
Pseudomonas aeruginosa (relative frequency determined by the presence or absence of
specific risk factors)
*
Severity of disease warranting treatment in an intensive care unit.
†
Organisms are listed in the general order of frequency.
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.26, 27
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.
28
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]).21, 22, 24
The likely etiology of severe CAP varies in differing patient populations, depending
on age and comorbidities, including HIV infection.22, 29, 30, 31, 31a
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.
32
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.17,
32, 33 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.17, 24, 34 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.
35
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.
36, 37 This predisposition persists several months after cessation of alcohol consumption.
37
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.
38
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.
4
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.
38
In patients with COPD treated with oral corticosteroids for long periods, the risk
for infection with Aspergillus species is increased.
39
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.
40
Stenotrophomonas maltophilia, Achromobacter xylosoxidans, and nontuberculous mycobacteria
are emerging pathogens in this population.
41
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).42,
43, 44
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.
45
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
46
and Francisella tularensis (tularemia) in rural Arkansas or Nantucket, Massachusetts.
47
Exposure to sheep, dogs, and cats should prompt evaluation for Coxiella burnetii (Q
fever).
48
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,49, 50 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.51, 52
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.
53
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
54
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).
53
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.
55
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.17, 34 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.
56
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.18, 19, 20, 21 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
).
Figure 33-1
Pneumococcal pneumonia with lobar consolidation.
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,
57
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.
57
Therefore, current guidelines do not emphasize the use of the typical versus atypical
classification to determine initial empirical antibiotic treatment for CAP.18, 19,
20, 21, 58
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.
59
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.
60
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.
61
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.18, 19, 20, 21 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.
62
Importantly, procalcitonin is used to deescalate antibiotics or to stop antibiotics
when the levels decrease to a certain cutoff point.
63
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.
64
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.18, 21, 59, 65 Limitations of chest radiography
include interobserver variability and suboptimal specificity, particularly in patients
with the acute respiratory distress syndrome (ARDS).
21
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.
59
However, a chest CT is not recommended for patients with suspected pneumonia who have
an apparently normal chest radiograph.
21
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.66, 67 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
.
Table 33-4
Recommended Microbiologic Evaluation in Patients with Community-Acquired Pneumonia
PATIENTS WHO DO NOT REQUIRE HOSPITALIZATION
None*
PATIENTS WHO REQUIRE HOSPITALIZATION
Two sets of blood cultures (obtained prior to antibiotics)
Gram stain and culture of a valid sputum sample
Urinary antigen test for detection of Legionella pneumophila (in endemic areas or
during outbreaks)
Stain for acid-fast bacilli and culture of sputum (if tuberculosis is suggested by
clinical history or radiologic findings)
Fungal stain and culture of sputum, and fungal serologies (if infection by an endemic
mycosis is suggested by the clinical history or radiologic findings)
Sputum examination for Pneumocystis jirovecii (if suggested by clinical history or
radiologic findings)
Nucleic acid amplification tests for Mycoplasma pneumoniae, Chlamydophila pneumoniae,
Chlamydophila psittaci, Coxiella burnetii, Legionella species, and respiratory viruses
(in endemic areas or during outbreaks)
Culture and microscopic evaluation of pleural fluid (if significant fluid is present)
ADDITIONAL TESTS FOR PATIENTS WHO REQUIRE TREATMENT IN AN ICU
Gram stain and culture of endotracheal aspirate or bronchoscopically obtained specimens
using a protected specimen brush or BAL
Other procedures as for other hospitalized patients
BAL, bronchoalveolar lavage; ICU, intensive care unit.
*
Gram stain and culture should be strongly considered in patients with risk factors
for infection by an antimicrobial-resistant organism or unusual pathogen.
Table 33-5
Recommended Microbiologic Evaluation in Patients with Hospital-Acquired Pneumonia
Two sets of blood cultures
Gram stain and culture of a valid sputum sample*
Urinary antigen test for detection of Legionella pneumophila (in endemic areas or
during outbreaks)
*
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.
18
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
68
) 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%.
69
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
58
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.
Table 33-6
Clinical Indications for More Extensive Testing in Community-Acquired Pneumonia
Intensive care unit admission
Failure of outpatient antibiotic therapy
Radiographic cavities
Leukopenia
Active alcohol abuse
Chronic severe liver disease
Severe obstructive/structural lung disease
Asplenia
Recent travel (within past 2 weeks)
Positive Legionella UAT result
Positive pneumococcal UAT result
Pleural effusion
UAT, urinary antigen test.
From Mandell LA, Wunderink RG, Anzueto A: Infectious Diseases Society of America/American
Thoracic Society Consensus Guidelines on the Management of Community-Acquired Pneumonia.
Clin Infect Dis 44(Suppl 2):S27–S72, 2007.
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.
70
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 103 to
106 CFU/mL, rather than a single cutoff.
71
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.72, 73 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.
74
The latest IDSA/ATS guidelines
58
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.69, 74, 75
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%.
76
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%.
77
The degree of positivity for the S. pneumoniae urinary antigen test correlates with
the Pneumonia Severity Index (PSI).
78
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.
79
The most recent IDSA/ATS guidelines
58
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.”
80
Real-time multiplex polymerase chain reaction assays detect respiratory viruses in
both immunocompetent and immunosuppressed hosts.
81
(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.61, 82 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.
71
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 cultures83, 84, 85 (see Chapters 17 and 22). For protected
sheath brush cultures, a threshold of 103
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.
85
In one study, the threshold of 103 CFU/mL for diagnosing bacterial pneumonia correlated
well with diagnoses based on protected sheath brush results and histologic examination
of the lung.
86
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).87,
88
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.
89
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.90, 91 The use
of a sophisticated algorithm (i.e., Clinical Pulmonary Infection Score) increases
the diagnostic accuracy of clinical judgment.
92
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)
59
; 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.
eTable 33-1
Noninfectious Causes of Fever and Radiographic Changes That May Mimic Community-Acquired
Pneumonia
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.
93
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.94, 95, 96
The PSI is complex and often needs decision support tools for efficient use in a busy
emergency department.
eTable 33-2
Scoring System for Determining Risk of Complications in Patients with Community-Acquired
Pneumonia*
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
Po
2 <60 mm Hg or O2 saturation <90%
+10
Pleural effusion
+10
BUN, blood urea nitrogen; Po
2, oxygen pressure.
*
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.
Adapted from Fine MJ, Auble TE, Yealy DM, et al: A prediction rule to identify low-risk
patients with community-acquired pneumonia. N Engl J Med 336:243–250, 1997.
The British Thoracic Society validated the simpler CURB-65 score for admission triage
decisions.25, 97 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.
98
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.58, 99, 100, 101 These scores share many common risk factors
(Table 33-7
) and appear to be equally effective,
102
and management of severe CAP per these guidelines has been associated with decreased
mortality.103, 104, 105 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.
Table 33-7
Criteria to Consider Admission to an Intensive Care Unit for Patients with Community-Acquired
Pneumonia without Shock or Respiratory Failure
Respiratory rate > 30 breaths/min*
†
‡
§
Pao
2/Fio
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)†
§
BUN, blood urea nitrogen; Fio
2, fractional concentration of oxygen in inspired gas; Pao
2, arterial oxygen pressure; WBC, white blood cell.
*
IDSA/ATS
58
†
SMART-COP
99
‡
CURXO
100
§
REA-ICU
101
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.106, 107
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).
58
Either therapy should be effective against penicillin-resistant S. pneumoniae.
108
The North American guidelines20, 21, 58 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.18, 20,
96, 109, 110 In contrast, some Northern European guidelines suggest atypical coverage
is not needed unless patients have clinical features more common to atypical pathogens.
97
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.24, 111
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.
112
The greatest factor to consider in the choice of regimens is a history of recent use
of any of the agents.
113
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.
114
Fluoroquinolone resistance and subsequent treatment failures are reported in pneumococcal
CAP,114, 115, 116 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.
116a
Summaries of the recent IDSA/ATS guideline CAP antibiotic recommendations are presented
in eTable 33-3 and eTable 33-4, respectively.
58
eTable 33-3
Guidelines for Empirical Oral Outpatient Treatment of Immunocompetent Adults with
Community-Acquired Pneumonia
BRITISH THORACIC SOCIETY
Primary: amoxicillin
Alternatives: erythromycin or clarithromycin
AMERICAN THORACIC SOCIETY
No modifying factors*, #: Advanced macrolide† or doxycycline‡
Comorbidities*, #: β-lactam§ macrolide‖ or doxycycline,‡ or fluoroquinolone¶ alone
INFECTIOUS DISEASES SOCIETY OF AMERICA
No modifying factors*, #: advanced macrolide† or doxycycline
Comorbidities*, #: fluoroquinolone¶ or advanced macrolide†
Antibiotics within 3 months: fluoroquinolone¶ alone or advanced macrolide† β-lactam§
Suspected aspiration: clindamycin or amoxicillin-clavulanate
Influenza with bacterial superinfection: β-lactam§ or fluoroquinolone¶
Nursing home patient: fluoroquinolone¶ alone, or amoxicillin-clavulanate advanced
macrolide
DRUG-RESISTANT STREPTOCOCCUS PNEUMONIAE THERAPEUTIC WORKING GROUP
Primary: macrolide, doxycycline, cefuroxime, amoxicillin, amoxicillin-clavulanate
Alternative: fluoroquinolone#
CANADIAN INFECTIOUS DISEASES SOCIETY AND CANADIAN THORACIC SOCIETY
No modifying factors: macrolide or doxycycline‡
COPD: advanced macrolide† or doxycycline‡
COPD plus recent antibiotics or steroids: fluoroquinolone¶ alone, amoxicillin-clavulanate
macrolide,‡ or second-generation cephalosporin** macrolide‡
Suspected aspiration: amoxicillin-clavulanate macrolide, or fluoroquinolone‡
¶ clindamycin, or metronidazole
Nursing home patient: fluoroquinolone# alone or macrolide‡ plus amoxicillin-clavulanate
or second-generation cephalosporin
COPD, chronic obstructive pulmonary disease.
*
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.
‡
Second-choice agent.
§
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.
eTable 33-4
Guidelines for Empirical Parenteral Inpatient Treatment of Immunocompetent Adults
with Community-Acquired Pneumonia
MILD TO MODERATE DISEASE
British Thoracic Society
Primary: ampicillin or penicillin plus a macrolide
Alternative: fluoroquinolone*
American Thoracic Society
No modifying factors†: azithromycin alone, doxycycline, β-lactam, or fluoroquinolone*
alone
With modifying factors‡: cefotaxime or ceftriaxone or ampicillin-sulbactam or high-dose
ampicillin; macrolide or doxycycline; or fluoroquinolone* alone
Infectious Diseases Society of America
Primary§: cefotaxime, ceftriaxone, ertapenem, or ampicillin/sulbactam plus advanced
macrolide†; or fluoroquinolone* alone
Suspected aspiration: fluoroquinolone* ± antianaerobic agent‖
Drug-Resistant Streptococcus pneumoniae Therapeutic Working Group
Primary: cefuroxime, cefotaxime, ceftriaxone, or ampicillin-sulbactam; macrolide
Alternative: fluoroquinolone*
Canadian Infectious Diseases Society and Canadian Thoracic Society
Fluoroquinolone* or cephalosporin,¶ macrolide**
SEVERE DISEASE
British Thoracic Society
Primary: cefuroxime, cefotaxime, or ceftriaxone; macrolide, rifampin
Alternative: fluoroquinolone* ± penicillin IV
American Thoracic Society
Standard: cefotaxime or ceftriaxone; azithromycin or fluoroquinolone*
At risk for Pseudomonas aeruginosa
††: antipseudomonal β-lactam‡‡ ciprofloxacin or antipseudomonal β-lactam aminoglycoside
plus azithromycin or fluoroquinolone*
Infectious Diseases Society of America
Primary: cefotaxime, ceftriaxone, ertapenem, or ampicillin/sulbactam; advanced macrolide†
or fluoroquinolone*
β-Lactam allergy: fluoroquinolone* ± clindamycin
Pseudomonas risks††: antipseudomonal β-lactam‡‡ ciprofloxacin or antipseudomonal β-lactam‡‡
aminoglycoside; fluoroquinolone* or a macrolide
Pseudomonas risks†† and β-lactam allergy: aztreonam levofloxacin or aztreonam; moxifloxacin
or gatifloxacin ± an aminoglycoside
Drug-Resistant Streptococcus pneumoniae Therapeutic Working Group
Primary: ceftriaxone or cefotaxime, macrolide; or ceftriaxone or cefotaxime, fluoroquinolone*
Alternative (with caution): fluoroquinolone*
Canadian Infectious Diseases Society and Canadian Thoracic Society
Standard: cefotaxime, ceftriaxone or β-lactam/β-lactamase inhibitor; fluoroquinolone*
or macrolide**
Pseudomonas risks††: ciprofloxacin, antipseudomonal β-lactam‡‡ or aminoglycoside or
antipseudomonal β-lactam‡‡ aminoglycoside macrolide**
*
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).
**
Second-choice agent.
††
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.
53
The empirical β-lactam should be based on antibiotic sensitivity patterns for common
gram-negative pathogens in the relevant institution or specific unit.
Table 33-8
Guidelines for Empirical Antibiotic Treatment of Nosocomial Pneumonia*
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/βl-lactamase inhibitor†
or cefepime
All plus amikacin or fluoroquinolone§
≥2 Days in Hospital
Severe HAP “high risk”
As above
As above
Special Circumstances
19, 58
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
This protocol does not address the treatment of neutropenic or HIV-infected persons.
Severe pneumonia requiring care in an ICU is characterized by rapid radiographic progression,
multilobar disease, or cavitation. All other cases of nosocomial pneumonia are considered
mild to moderate.
HAP, hospital-acquired pneumonia; ICU, intensive care unit; MRSA, methicillin-resistant
Staphylococcus aureus.
*
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.
Modified from American Thoracic Society: Hospital-acquired pneumonia in adults: Diagnosis
assessment of severity, initial antimicrobial therapy, and preventative strategies.
Am J Respir Crit Care Med 153:1711–1725, 1995.
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.55, 117, 118, 119 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,
29
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,
119
but are difficult to identify at admission. If started on broader therapy, deescalation
to CAP therapy after culture results return negative appears safe.
120
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,49, 50 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.
121
Concerns about potential bioterrorism or biowarfare require attention to the epidemiologic,
clinical, and microbiologic significance of pneumonia due to B. anthracis (anthrax),
51
F. tularensis (tularemia),
52
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 antimicrobials122, 123; 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.
Table 33-9
Agents for Specific Therapy of Selected Respiratory Pathogens
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
MIC, minimum inhibitory concentration.
*
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.
Modified from Bartlett JG, Dowell SF, Mandell LA, et al: Practice guidelines for the
management of community-acquired pneumonia in adults: Infectious Diseases Society
of America. Clin Infect Dis 31:347−382, 2000.
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.21,
22 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.124, 125 Pneumococcal
infections present predominantly in the winter and early spring and are often associated
with prior infection by influenza or respiratory syncytial virus.
126
Use of the conjugate pneumococcal vaccine has markedly decreased invasive pneumococcal
infections in children, with a secondary reduction in adults.127, 127a 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.
128
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.
129
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.
125
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.
130
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
20
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.
Figure 33-2
Gram stain of sputum from a patient with pneumococcal pneumonia.
The predominant organisms are gram-positive lancet-shaped diplococci.
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.74, 75, 77, 131 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.
132
Pneumococcal pneumonia remains a cause of septic shock and ARDS.
133
Treatment
Antimicrobial resistance complicates treatment for S. pneumoniae in much of the world,
including in the United States.
134
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.
135
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.
136
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.
137
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.134, 136 High-level macrolide
resistance (MIC > 64 µg/mL) associated with the MLSB (macrolide, lincosamide, streptogramin
B) phenotype is more common in Europe
138
and has been associated with in vitro resistance to clindamycin.
139
S. pneumoniae resistance to fluoroquinolones has also emerged with associated clinical
treatment failures.113, 136
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.
113
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.76, 140, 141 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.128, 142 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.143, 144 The organism
is easily transferred between contacts, leading to epidemics of group A streptococcal
pneumonia in military recruits, nursing homes, and other crowded settings.
142
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.143,
144
S. pyogenes can cause necrotizing pneumonia
145
and is associated with pleural empyema.
146
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.
147
Most adults with group B streptococcal pneumonia are debilitated and develop pneumonia
as a consequence of aspiration.
147
Diabetes, cirrhosis, stroke, decubitus ulcer, and neurogenic bladder are also risk
factors.
147
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 Video 33-1
) and lung abscesses as well as superinfection pneumonia in severe viral pneumonia.148,
149 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.
148
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.
147
S. milleri infection is predominantly associated with empyema, with or without concomitant
pneumonia.
148
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
150
and S. milleri empyema.
149
Figure 33-3
Streptococcus.
A, Group A streptococcus (Streptococcus pyogenes, β-hemolytic streptococcus). B, Group
B streptococcus (Streptococcus agalactiae) are indistinguishable from Streptococcus
pneumoniae on Gram stain. Both form long chains containing multiple bacteria.
Clinical Course
Empyema and/or pericarditis are seen in 5% to 30% of patients with group A streptococcal
pneumonia
143
; 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.
151
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.
152
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.
152
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
).
Figure 33-4
Haemophilus influenzae.
Gram stain shows small pleomorphic coccobacilli diffusely across the field that, because
of their size, can be missed on sputum examination.
Clinical Course
The overall mortality rate of H. influenzae pneumonia is 5% to 7% but is higher in
patients with bacteremia or extrapulmonary disease.
152
Associated foci of infection, such as empyema, meningitis, arthritis, pericarditis,
and epiglottitis are more common with encapsulated (type b) H. influenzae.
Treatment
H. influenzae isolates produce β-lactamase in 20% to 50% of cases and are therefore
resistant to ampicillin. Increasing macrolide resistance also compromises empirical
therapy with these agents. Consequently, serious H. influenzae respiratory tract infections
should be treated with a second- or third-generation cephalosporin, β-lactam/β-lactamase
inhibitor, or fluoroquinolone while awaiting results of susceptibility testing.
Mycoplasma pneumoniae
Epidemiology
M. pneumoniae accounts for up to 37% of CAP in persons treated as outpatients and
10% of pneumonias requiring hospitalization.20, 22 In the United States, there is
an estimated 2 cases per year per 1000 individuals. Mycoplasma infections are seen
throughout the year, but outbreaks are most common in the fall. Because Mycoplasma
is readily transmitted from person to person via aerosolized respiratory droplets,
outbreaks are common in families or closed populations.
153
Clinical Manifestations
The clinical picture of M. pneumoniae pneumonia is the paradigm of atypical CAP,18,
21 as described previously. Pharyngitis, cervical adenopathy, and bullous myringitis
may be encountered, although the latter is not more common with Mycoplasma pneumonia
than with pneumococcal pneumonia/otitis. A wide variety of exanthems, including maculopapular
eruptions, urticaria, erythema multiforme, and erythema nodosum, develop in 10% to
25% of patients. The chest radiograph usually shows an interstitial or a mixed pattern
that may be more striking than expected based on chest physical findings (Fig. 33-5
and eFig. 33-9). Other chest radiographic patterns are occasionally encountered as
well (eFig. 33-10).
Figure 33-5
Radiographic findings in Mycoplasma pneumoniae pneumonia are nonspecific.
Bilateral bronchopneumonia is seen in this patient.
Microbiologic Diagnosis
When obtained, sputum generally displays moderate numbers of polymorphonuclear leukocytes
without a predominant organism. Recovery of M. pneumoniae from culture of clinical
specimens requires special media and takes approximately 10 days. Although acute Mycoplasma
pneumonia may stimulate cold agglutinin production in a titer of 32 or greater, this
nonspecific result is also found in various other infectious and noninfectious conditions
including pneumonia due to Legionella, adenovirus, and influenza.
18
The shortcomings of staining, culture, and serology for detection of Mycoplasma pneumoniae
make this pathogen especially suitable for diagnosis by nucleic acid testing. Several
nucleic acid tests for M. pneumoniae are currently available, and their role in management
of CAP is being defined (see Chapter 17).
Clinical Course
Mycoplasma pneumonia is usually a benign, often self-limited infection with an excellent
prognosis for complete recovery. ARDS and death have been reported but are rare. A
unique aspect of M. pneumoniae infection is the frequency of associated autoimmune
disorders including fulminant autoimmune hemolytic anemia, Stevens-Johnson syndrome,
aseptic meningitis, meningoencephalitis, pericarditis, and myocarditis.
154
Treatment
Antimicrobial therapy with a tetracycline, macrolide, or fluoroquinolone shortens
the course of clinical symptoms and hastens resolution of radiographic abnormalities.
To prevent clinical relapse, 2 weeks is the minimum recommended duration for treatment.
18
Respiratory isolation can limit transmission, and azithromycin prophylaxis can prevent
infection in close contacts of patients.
155
Chlamydophila pneumoniae
Epidemiology
C. pneumoniae (formerly Chlamydia pneumoniae) accounts for 5% to 15% of cases of CAP.
22
Seroepidemiologic studies suggest that C. pneumoniae eventually causes infection in
40% to 50% of the general population.
Clinical Manifestations
Primary infection by C. pneumoniae is usually asymptomatic: an acute, mild respiratory
tract infection is observed in only 10% of infected adolescents and young adults.
156
There may be bronchitis, sinusitis, laryngitis, tonsillitis, or exacerbations of asthma,
with or without associated pneumonia. Sore throat with hoarseness is often severe
and may precede pneumonia by up to a week and resolve before pneumonia onset, resulting
in a biphasic illness. The erythrocyte sedimentation rate is elevated, but leukocytosis
or elevated PCT may be absent.
Microbiologic Diagnosis
C. pneumoniae cannot be visualized by Gram stain, and tissue culture is required to
grow the pathogen. Although direct fluorescent antibody detection of C. pneumoniae
is available, nucleic acid testing is emerging as a rapid, sensitive mode of detection
that yields results in a time frame useful for clinical management (see Chapter 17).
Clinical Course and Treatment
Complete recovery following C. pneumoniae infection is the rule; fatalities are principally
seen in patients with mixed infection and preexisting illness.156, 157 When associated
with an exacerbation of asthma, C. pneumoniae can require a prolonged time for recovery.
Two-week treatment with a macrolide, tetracycline, doxycycline, or fluoroquinolone
is recommended.18, 157 Older adults can be reinfected, often with severe symptoms.
Staphylococcus aureus
Epidemiology
S. aureus accounts for less than 10% of cases of CAP,
21
but is the second or third most common etiology in patients with CAP requiring ICU
admission. S. aureus, especially MRSA, accounts for up to 30% of nosocomial pneumonias.
29
Nasal colonization is the major source for pneumonia and other invasive S. aureus
infections: 30% to 50% of healthy adults carry the organism transiently in the anterior
nares. Health care workers may have even higher carriage rates. Although the organism
is easily transferred from person to person by direct hand contact, 67% of patients
in whom MRSA pneumonia develops have nasal colonization on admission, indicating that
most cases of S. aureus HAP are not due to S. aureus transmission in the hospital.
158
A community-acquired strain of MRSA (CA-MRSA) has become an important CAP pathogen.159,
160, 161, 162 In addition to antibiotic resistance, the DNA cassette containing the
mecA gene that confers methicillin resistance to this strain includes other virulence
factors. The combination of antibiotic resistance and multiple virulence factors is
associated with significantly higher mortality.
163
Typical hospital-acquired strains of MRSA also cause CAP but usually in patients with
risk factors for HCAP.
164
The ability to differentiate clinically between hospital- and community-acquired cases
is increasingly difficult because risk factors, such as prior antibiotic therapy,
often overlap.
Factors that predispose patients to acquire staphylococcal pneumonia include underlying
pulmonary disease (e.g., COPD, carcinoma, cystic fibrosis), chronic illness (e.g.,
diabetes mellitus, renal failure), or viral infection (e.g., influenza, measles).
165
S. aureus, including CA-MRSA, is second in frequency to S. pneumoniae as a cause of
postinfluenza bacterial pneumonia. Postinfluenza CAP due to CA-MRSA is associated
with a high frequency of complications and mortality. Pneumonia due to hematogenous
spread of S. aureus is a unique type of pneumonia, usually a consequence of intravenous
drug use or septic embolization from endocarditis or an infected vascular site.
Clinical Manifestations
CA-MRSA pneumonia can be seen in young patients without underlying illnesses. The
clinical presentation in severe cases includes high fever, hypotension, and hemoptysis
with rapidly progressive deterioration and septic shock. Leukopenia, rather than leukocytosis,
is observed in a substantial fraction of cases and is associated with poor outcomes.159,
161, 165 The radiographic features of CA-MRSA pneumonia include multilobar opacities
and/or cavitary lesions (eFig. 33-11).
In cases acquired hematogenously such as in endocarditis or other endovascular infection,
signs and symptoms related to the underlying endovascular infection predominate; if
pulmonary infarction results from a septic embolism, pleuritic chest pain and hemoptysis
are often noted. Otherwise, respiratory tract symptoms are mild or absent. The chest
radiograph in patients with hematogenous staphylococcal pneumonia often reveals multiple,
discrete, and often cavitary shadows with a predilection for the lower lobes (Fig.
33-6
).
166
Figure 33-6
Chest radiograph shows hematogenous staphylococcal pneumonia associated with bacterial
endocarditis.
The pneumonia is characterized by many cavities.
Microbiologic Diagnosis
Purulent sputum with multiple clusters of large gram-positive cocci, particularly
if intracellular, is strongly suggestive of S. aureus pneumonia (Fig. 33-7
). The organism is easily recovered from sputum cultures. Absence of MRSA on culture,
even after several doses of antibiotics, is strong evidence that MRSA is not the causative
pathogen. Fewer than 15% of pneumonias due to aspiration are associated with positive
blood cultures. In contrast, hematogenous staphylococcal pneumonia usually yields
multiple positive blood cultures. CA-MRSA pleural effusions are often exudative rather
than grossly purulent but are still high yield on culture. An important clue to CA-MRSA
is the presence of skin lesions,
167
which are often positive on Gram stain as well.
Figure 33-7
Staphylococcus.
Gram stain of sputum from a patient with staphylococcal pneumonia shows abundant large,
round gram-positive cocci in clusters.
Clinical Course
Even with appropriate antibiotics, the duration of fever and need for ICU care is
often prolonged for S. aureus pneumonia, particularly CA-MRSA. Local complications
of staphylococcal pneumonia include empyema and abscess formation. Infection can spread
hematogenously to the central nervous system, bones, joints, skin, and kidneys. Cavities
and necrotic tissue may prevent adequate local antibiotic penetration, whereas unrecognized
or incompletely drained empyema may prolong fever. Most of these manifestations are
due to strains secreting Panton-Valentine leukocidin or one of the other exotoxins
produced by S. aureus. Pleuroscopy or decortication is required in a large percentage
of cases with empyema.
The mortality of S. aureus CAP is generally higher than most etiologies, with the
mortality in methicillin-sensitive strains about 30%. S. aureus CAP following influenza
has a reported mortality of greater than 60%, even if not methicillin-resistant.
16
Treatment
The treatment of choice for methicillin-susceptible S. aureus pneumonia is a penicillinase-resistant
penicillin (e.g., oxacillin 8 to 12 g/day) or a first-generation cephalosporin. Therapy
for 7 to 10 days is adequate in uncomplicated cases, but 4 to 6 weeks of treatment
is recommended for patients with bacteremia or cavitation. In the penicillin-allergic
patient, clindamycin or linezolid can be used.
Treatment of MRSA pneumonia is more challenging, and the incidence of CAP caused by
both health care–associated MRSA and CA-MRSA strains is increasing. Although resistance
to vancomycin is still rare, the MIC has been shifting upward and MICs greater than
1 µg/mL have been associated with clinical failure. In higher-risk patients, such
as those with VAP or with underlying renal insufficiency, linezolid has been found
to have better clinical response rates than vancomycin, although differences in patient
survival have been variable.168, 169, 170 For CA-MRSA, vancomycin therapy alone has
been associated with a significant failure rate.160, 163 Addition of clindamycin or
use of linezolid has been associated with improved outcomes in small case series.
Unlike in MRSA skin infections, clindamycin, fluoroquinolones, and TMP-SMX are unreliable
in severe CA-MRSA cases. Daptomycin is ineffective for treatment of pneumonia, because
it binds to and is inactivated by pulmonary surfactant.
171
Gram-Negative Bacillary Pneumonia
The term gram-negative bacillary pneumonia refers to infections caused by members
of two groups, the Enterobacteriaceae and Pseudomonadaceae and other aerobic gram-negative
bacilli. Infections caused by Haemophilus, Legionella, and anaerobes are usually excluded
from this categorization.
Enterobacteriaceae
Epidemiology.
While they are more common as causes of HAP, gram-negative bacilli may cause up to
5% to 10% of CAP.21, 24, 111 CAP due to gram-negative bacilli is often severe and
frequently requires ICU care. Patients in an ICU, especially those undergoing mechanical
ventilation, have the highest risk for development of gram-negative bacillary pneumonia.
The Enterobacteriaceae normally colonize the digestive tract, and pneumonia usually
results from aspiration of oropharyngeal flora. Although uncommon in healthy, nonhospitalized
individuals, oropharyngeal colonization by gram-negative bacilli is greatly increased
by hospitalization and antimicrobial use; the risk for aspiration is increased by
comorbidities, such as cerebrovascular accidents, seizures, or anesthesia.
24
Occasionally, contaminated home respiratory therapy equipment directly introduces
gram-negative rods into the respiratory tract. Finally, Enterobacteriaceae pneumonia
may result from hematogenous seeding from infection at other anatomic sites.
Among the Enterobacteriaceae, Escherichia coli is the single most frequent cause of
CAP.
24
The classic cause of community-acquired gram-negative bacillary pneumonia, K. pneumoniae
(Friedlander pneumonia), causes fewer than 10% of CAPs, but more than 20% of nosocomial
pneumonias. Alcohol abuse is the most common underlying condition for community-acquired
K. pneumoniae pneumonia. Other underlying conditions that predispose to Klebsiella
infections are diabetes mellitus and COPD.
Clinical Manifestations.
In Klebsiella CAP, a syndrome of pleuritic chest pain, hemoptysis, and bloody sputum
(occasionally with a “currant jelly” appearance) is classic but rarely seen. The clinical
manifestations of Enterobacteriaceae pneumonias are not sufficiently unique to distinguish
these infections from pneumonias due to other causes.
24
Most laboratory abnormalities are nonspecific, but neutropenia is associated with
a poor prognosis. Chest radiographs often demonstrate lower lobe bronchopneumonia
(eFig. 33-12), which is often bilateral. A classic radiographic appearance of Klebsiella
pneumonia is upper lobe consolidation (especially on the right) (Fig. 33-8
) with a bulging or bowed fissure. This manifestation is now uncommon. Klebsiella
can also cause lung abscess (eFig. 33-13) in patients with HCAP.
Figure 33-8
Klebsiella pneumoniae lobar pneumonia with “bulging” fissure.
Frontal chest radiograph shows dense right upper lobe air-space opacity, which bows
the right minor fissure inferiorly (arrows). The bulging fissure sign at chest radiography
is traditionally associated with Klebsiella pneumoniae infection, but is actually
nonspecific, and can be seen with other pulmonary infectious and noninfectious pulmonary
processes as well.
(Courtesy Michael Gotway, MD.)
Microbiologic Diagnosis.
Enterobacteriaceae pneumonia should be suspected when sputum Gram stain reveals large
numbers of uniform-appearing gram-negative rods (Fig. 33-9
). Sputum culture alone is nonspecific for Enterobacteriaceae in either nonintubated
or intubated patients because of oropharyngeal colonization and is one of the major
reasons for interest in quantitative cultures as an approach to distinguishing colonization
from infection.
Figure 33-9
Klebsiella pneumoniae.
Large gram-negative rods in the sputum of a patient with Klebsiella pneumoniae pneumonia
(arrows).
Clinical Course.
Enterobacteriaceae pneumonia fatality rates are 25% to 50%.
24
Bacteremia, neutropenia, and advanced age contribute to a poor prognosis. Destruction
of pulmonary alveolar septae may lead to cavitation.
Treatment.
Treatment of serious infections due to Enterobacteriaceae is complicated by widespread
antimicrobial resistance. Extended-spectrum β-lactamase, carbapenemase, fluoroquinolone,
and aminoglycoside resistance are all common in patients infected with Enterobacteraceae.172,
173 Due to regional and institutional variations in the frequency of resistance to
specific drugs and classes of drugs, initial therapy of possible Enterobacteriaceae
pneumonia must be selected using knowledge of local antibiotic resistance patterns.
In patients with serious infection, a two-drug regimen of an aminoglycoside with a
broad-spectrum β-lactam or carbapenem is recommended for treatment until susceptibility
results are known. Monotherapy may be reasonable for immunocompetent patients with
mild to moderate disease who are infected with susceptible strains of Proteus, Morganella,
K. pneumoniae, or E. coli. Recommendations for empirical therapy for HAP are listed
in Table 33-8, although local resistance patterns must be taken into account.
Pseudomonas aeruginosa and Related Organisms
Epidemiology.
P. aeruginosa is an uncommon cause of CAP except in specific risk groups. Although
one large study in Spain found that 7% of CAP was due to P. aeruginosa, most studies
have found substantially lower rates.24, 111 One major risk factor for Pseudomonas
CAP is structural lung disease, such as cystic fibrosis, bronchiectasis, and severe
COPD (forced expiratory volume in 1 second <30%). Another risk factor is HIV infection,
especially with a marked deficiency of CD4+ T cells.174, 175, 176
Pseudomonas pneumonia in AIDS patients can be severe, with mortality rates as high
as 50%, and be associated with cavitation, even when the patient has a profound CD4+
T-cell deficiency. The incidence of Pseudomonas pneumonia has decreased with widespread
availability of combination antiretroviral therapy. Pseudomonas pneumonia is rare
in normal hosts, but it can develop after exposure to aerosols of contaminated water
such as in hot tubs.21, 24, 40, 68, 177, 178
P. aeruginosa is a leading cause of nosocomial pneumonia and a particularly frequent
cause of VAP.
179
Prolonged endotracheal intubation and prior antibiotic therapy, especially with broad-spectrum
antibiotics, are major risk factors for Pseudomonas VAP. Other nonfermenters, such
as S. maltophilia and B. cepacia, cause pneumonia in patients after prolonged broad-spectrum
antibiotic therapy, and are associated with a high mortality rate. B. cepacia is also
found in outpatients with cystic fibrosis.
Clinical Manifestations.
The clinical picture of pneumonia due to P. aeruginosa (eFig. 33-14) is indistinguishable
from that of the Enterobacteriaceae. Bacteremia is slightly more common than for other
gram-negative pathogens; physical examination may reveal ecthyma gangrenosum, and
leukopenia is common. Its propensity to invade vascular tissue makes Pseudomonas the
most common cause of cavitary pneumonia (eFigs. 33-15 and 33-16) in hospitalized or
immunocompromised patients, and empyema can develop.
Microbiologic Diagnosis.
Gram-stained sputum from patients with Pseudomonas pneumonia typically shows many
slender, gram-negative bacilli (Fig. 33-10
); neutrophils are commonly abundant in the sputum except in neutropenic patients.
Since Pseudomonas and other gram-negative bacilli colonize the oropharynx in hospitalized
or debilitated patients, Gram stain results in these patients can be misleading. In
endotracheally intubated patients, the absence of Pseudomonas on culture is strong
evidence against Pseudomonas as the cause of the patient's pneumonia, because the
organism is typically easy to recover.
Figure 33-10
Pseudomonas.
Gram stain of sputum showing slender gram-negative bacilli (arrows).
Clinical Course.
Mortality from community-acquired P. aeruginosa pneumonia can exceed 25%,
24
and in persons with VAP due to P. aeruginosa, mortality rates are 40% to 70%. The
prognosis in neutropenic patients with P. aeruginosa pneumonia is particularly poor.
180
P. aeruginosa VAP can recur in 25% to 50% of cases, approximately half due to a new
strain.
Treatment.
P. aeruginosa pneumonia should initially be treated with two antimicrobial agents
expected to be active against isolates in the region, such as an aminoglycoside and
an antipseudomonal β-lactam antibiotic; this is especially true for bacteremic or
neutropenic patients.
180
Amikacin is the most reliably active aminoglycoside in most regions. The β-lactam
antibiotics, in descending order of probable activity against P. aeruginosa, are the
carbapenems (imipenem and meropenem), the acylureidopenicillins (e.g., piperacillin),
cefepime, and ceftazidime.
181
Although fluoroquinolones (particularly ciprofloxacin) initially possessed good intrinsic
activity against P. aeruginosa, resistance is now common, making empirical fluoroquinolone
monotherapy hazardous. Resistance can emerge in Pseudomonas during the course of fluoroquinolone
monotherapy.
S. maltophilia is inherently resistant to most standard antibiotics.
182
TMP-SMX is the most reliable agent, while fluoroquinolones or ticarcillin-clavulanate
have activity against some strains.
180
Isolates of S. maltophilia may become resistant in the face of seemingly effective
therapy. B. cepacia may be susceptible to acylureidopenicillins, ceftazidime, TMP-SMX,
fluoroquinolones, minocycline, and chloramphenicol. Resistance rates are higher in
isolates from patients with cystic fibrosis.
Acinetobacter baumannii
Epidemiology.
A. baumannii may cause either CAP or HAP/VAP. Acinetobacter causes CAP in hot climates,
both dry
183
and humid,45, 184 and has become one of the most common causes of CAP in southeast
Asia. In the United States, Acinetobacter CAP is most commonly seen in male alcoholics.
The risk of Acinetobacter VAP varies widely by region and by health care facility.
Nosocomial infections caused by Acinetobacter show seasonal variation, peaking in
late summer, similar to patterns in CAP.
Clinical Manifestations.
Patients with Acinetobacter CAP often present acutely ill and may have leukopenia,
pleural effusions, and empyema.
185
Nosocomial Acinetobacter pneumonia has a less dramatic presentation, similar to those
of other hospital-acquired gram-negative pneumonias.
45
Microbiologic Diagnosis.
Examination of expectorated sputum, which is usually purulent, may reveal a predominance
of paired gram-negative coccobacilli that resemble Neisseria, Haemophilus, and Moraxella
species. Bacteremia complicates community-acquired more often than nosocomial Acinetobacter
pneumonia.
Clinical Course.
The mortality rate of community-acquired Acinetobacter pneumonia approaches 50%.
45
Patients at greatest risk of death are those with leukopenia or empyema. The fatality
rate for nosocomial Acinetobacter pneumonia is determined by the severity of underlying
disease.
Treatment.
Community isolates of A. baumannii can be susceptible to amikacin, tobramycin, ceftazidime,
carbapenems, and doxycycline.
186
Nosocomial Acinetobacter species are resistant to most β-lactams and aminoglycosides
and therefore are most reliably treated with carbapenems, but poor outcomes are common.
187
Some investigators have reported successful treatment of highly resistant isolates
with ampicillin-sulbactam or colistin.188, 189 Resistance to β-lactam antimicrobials,
carbapenems, aminoglycosides, fluoroquinolones, and even polymyxin B and colistin
189
is increasingly common among nosocomial isolates.
Legionella
Epidemiology
L. pneumophila causes both epidemic and sporadic infections; both patterns may be
seen either in the community or in hospitals. Outbreaks have been linked to contaminated
potable water systems, ultrasonic mist devices, whirlpool baths, air-conditioning
condensates, and water-evaporative systems.
190
Legionella is acquired through inhalation of contaminated aerosols or aspiration.
Sporadic cases of L. pneumophila pneumonia (50% to 80% of which are due to serogroup
1) account for 2% to 6% of CAPs in immunocompetent hosts.
21
L. pneumophila is one of the most common causes of severe CAP in certain communities.
Risk factors include exposure to contaminated water, immunosuppression, cigarette
use, diabetes, cancer, end-stage renal disease, and alcohol use. Infection with L.
pneumophila is more common in specific geographic regions, such as the Mediterranean
or the northeastern United States.
In addition to L. pneumophila, 40 other Legionella species have been identified. Many,
such as Legionella micdadei and Legionella longbeachae, produce a pneumonic illness
indistinguishable from that of L. pneumophila. Much less is known about the epidemiology
of non-pneumophila Legionella infections, but they also appear to be from water or
soil-related sources. Immunosuppression appears to be the major host risk for these
species.
Clinical Manifestations
The incubation period for Legionella pneumonia is 2 to 10 days. Lethargy, headache,
fever, recurring rigors, anorexia, and myalgias are frequent early symptoms. After
several days, cough becomes more pronounced; occasionally, watery or purulent sputum
develops. Dyspnea is prominent in half of cases, and one third of patients complain
of pleuritic chest pain. Extrapulmonary manifestations may overshadow respiratory
complaints; gastrointestinal (watery diarrhea, nausea, vomiting, abdominal pain) and
neurologic symptoms and signs (headache, confusion, obtundation, seizures, hallucinations)
are particularly noteworthy. Patients may appear acutely ill. Temperatures reach 40.5° C
in one third of patients, are typically sustained, and may be accompanied by relative
bradycardia. Physical findings are usually limited to the chest, including pleural
friction rubs, but generalized abdominal tenderness, hepatomegaly, splenomegaly, cutaneous
rash, nuchal rigidity, and focal neurologic deficits have all been described.
Hyponatremia and hypophosphatemia are present in more than half of severe cases. Mild
elevations of serum creatinine, creatine phosphokinase, and liver enzymes are also
common, as are hematuria and proteinuria and occasionally frank rhabdomyolysis. There
may be leukopenia and thrombocytopenia especially in severely ill patients. Cold agglutinins
may be present, as in infection due to M. pneumoniae.
Chest radiographic findings typically lag behind the early clinical illness (Fig.
33-11
). Small pleural effusions develop in 50% and may precede the parenchymal process.
Multilobar opacities are commonly seen (eFig. 33-17), particularly on chest CT. Frank
cavitation rarely is seen.
66
Figure 33-11
Legionella pneumophila pneumonia: unilateral disease.
A, Frontal chest radiograph shows subpleural left upper lobe consolidation (arrows).
B–E, Axial chest CT displayed in soft tissue (B and C) and lung (D and E) windows
confirms left upper lobe consolidation (arrows). A small left pleural effusion (*)
is present.
(Courtesy Michael Gotway, MD.)
Microbiologic Diagnosis
Legionella are obligatory aerobic, fastidious, gram-negative bacilli that stain poorly
with Gram stain (see Chapter 17, Figure 17-4) and grow poorly on conventional media.
L. micdadei and some other Legionella species may stain weakly acid-fast. Early in
the infection, sputum Gram stain from patients with Legionella pneumonia contains
few or no polymorphonuclear leukocytes. The sensitivity of cultures of respiratory
specimens is as low as 10%, despite use of appropriate media. Culture diagnosis of
L. pneumophila infection often requires invasive procedures because at least 25% of
patients with Legionella infection do not produce sputum.
76
Rarely, Legionella has been recovered from blood, pleural fluid, and other extrapulmonary
sites.
The Legionella urinary antigen test is currently the most commonly used method of
diagnosis. It has a sensitivity of 60% to 80% and specificity greater than 95% for
L. pneumophila serogroup 1, but the test is limited to this single species and serogroup.
76
The sensitivity of direct fluorescent antibody assay for sputum ranges from 33% to
68%, with specificity greater than 95%,
76
but its use is hindered by difficulty of obtaining sputum in some patients, the expertise
required for interpretation, and the requirement for specific antibodies to the multiplicity
of Legionella species and serogroups. Polymerase chain reaction–based assays for sputum
have greater than 80% sensitivity and greater than 90% specificity, and their availability
is likely to become more widespread.
76
Clinical Course
A clinical response to appropriate antibiotic therapy is usually observed within the
first 48 hours. In contrast, radiographic findings may temporarily continue to progress
despite observed clinical improvement and ultimately take months to resolve.
66
Acute renal failure and oliguria, often independent of shock and myoglobinuria, may
develop in approximately 10% of patients and dialysis may be required. Many patients
note lingering fatigue and weakness for months following Legionella pneumonia.
The mortality of community-acquired Legionella pneumonia is approximately 15%. Poor
clinical outcomes are associated with immunodeficiencies, comorbidities, delayed initiation
of appropriate therapy, and the need for ventilatory support or dialysis.
Treatment
Azithromycin and fluoroquinolones are superior to erythromycin or clarithromycin for
treatment of Legionella infections. Although never used alone, the addition of rifampin
is advised for patients who are severely ill or immunocompromised.
18
Antibiotics should be continued for 10 to 21 days in immunocompetent patients to decrease
the rate of relapse.
18
Anaerobic Bacteria
Epidemiology
Mixed aerobic and anaerobic infection is usually a complication of macroaspiration
of oropharyngeal contents. Rare causes include rupture of the esophagus and extension
of intra-abdominal abscesses. Underlying pulmonary conditions such as malignancy and
pulmonary infarction are present in 20% of patients who have an anaerobic lung infection.
Although acute complications of macroaspiration are largely due to a chemical injury
pneumonitis (Mendelson syndrome) and/or infection by pathogenic aerobes in the oral
flora, many of these episodes later result in the emergence of mixed aerobic and anaerobic
pneumonia.
Clinical Manifestations
Anaerobic infections present as four different syndromes: chemical pneumonitis, aspiration
pneumonia, anaerobic pleuropneumonia, or primary anaerobic empyema.
Chemical pneumonitis can precede anaerobic pneumonia, and is characterized by the
acute onset of hypoxemia, fever, cough (often dry), dyspnea, and pleuritic pain. The
foul sputum and hemoptysis characteristic of anaerobic lung abscess are absent at
this stage. The risk of infection is dependent on the nature of the inoculum; many
cases of aspiration pneumonitis are inflammatory alone and not infectious. Imaging
may demonstrate bronchopneumonic opacities, but usually not lobar consolidation, in
the aspiration-prone segments of the lung (e.g., posterior segment of the right upper
lobe and superior segment of the right lower lobe; see eFig. 33-3). ARDS is a common
complication of aspiration of low pH gastric fluid.
Aspiration pneumonia is indistinguishable from either CAP or HAP (eFig. 33-18), with
the exception that it is seen in patients with risk factors for macroaspiration. Rapid
development of pulmonary opacities over a short period of time may suggest the diagnosis
of aspiration pneumonia (Fig. 33-12
and eFig. 33-19). High concentrations of amylase or pepsinogen in BAL fluid are very
suggestive of this entity.
191
Localization of an opacity in a dependent lung segment has less discriminating value.
Figure 33-12
Aspiration pneumonitis: rapid interval development of pulmonary opacities.
A, Frontal chest radiograph performed for central venous catheter placement shows
a right subclavian central venous catheter without pneumothorax; the lungs are clear.
B, Repeat frontal chest radiograph obtained following an episode of altered level
of consciousness and vomiting only a few hours after A shows interval development
of extensive mid and lower lung consolidation. Such rapid development of extensive
pulmonary opacities in the context of mental status changes accompanied by vomiting
is characteristic of aspiration. The differential diagnosis of rapid interval appearance
of extensive pulmonary opacities also includes increased pressure edema, noncardiac
edema injury, and hemorrhage.
(Courtesy Michael Gotway, MD.)
Anaerobic pleuropneumonia is characterized by necrosis and suppuration of lung parenchyma.
Early in the course, imaging may demonstrate dense segmental opacification with multiple
small lucent areas of lung necrosis (<2 cm in diameter), usually without air-fluid
levels (eFig. 33-20). In the absence of appropriate treatment, these lesions may evolve
into a primary lung abscess (eFig. 33-21) and empyema. Patients commonly present with
fatigue, low-grade fever, weight loss, and productive cough for several weeks after
an episode of loss of consciousness. Approximately half describe putrid sputum, and
some may have hemoptysis. Patients appear chronically ill and toxic, with temperatures
up to 39° C. In some patients, a single lung abscess greater than 2 cm in diameter
is detected in a dependent lung segment on radiography (Fig. 33-13
). The abscess may be multilocular; occasionally, multiple abscesses are located in
different lung segments.
Figure 33-13
A single parenchymal cavity with an air-fluid level typifies an anaerobic lung abscess.
Most often, these lesions are located in the dependent, aspiration-prone lung segments
(superior segment of the right lower lobe and left lower lobe and posterior segments
of the upper lobes). This patient also has a small left empyema.
Primary anaerobic empyemas are usually due to S. milleri/intermedius (see eFig. 33-7)
rather than anaerobes.
149
However, anaerobes still play a significant role. In these cases, the pleural manifestations
may dominate, with less evidence of pneumonia. Anaerobic empyema can also be seen
in the absence of parenchymal lung infection when empyema develops in association
with esophageal rupture or from subphrenic or other intra-abdominal abscesses. More
information on pleural empyema is in Chapter 80.
Microbiologic Diagnosis
Gram stain of sputum or examination of a bronchoscopically obtained specimen from
a patient with anaerobic pneumonia reveals numerous polymorphonuclear leukocytes with
an abundance of intracellular and extracellular bacteria. Typically, a mixture of
Gram stain reactions and morphologies are seen, including pale-staining gram-negative
rods with tapered ends (suggestive of Fusobacterium nucleatum), small, pale-staining
gram-negative coccobacilli, and chains of tiny gram-positive cocci.
Because the endogenous flora of the upper respiratory tract predominantly consists
of anaerobic bacteria, cultures of expectorated sputum are not appropriate for diagnosis
of anaerobic infections. With careful technique, recovery on average of 3.2 bacterial
isolates, of which 80% are anaerobes, is possible in a case of mixed aerobic/anaerobic
pneumonia or empyema. The most common anaerobes in pleuropulmonary infections include
F. nucleatum, Prevotella, Porphyromonas, Peptostreptococcus, and microaerophilic Streptococcus.
The major aerobic and facultative organisms recovered in conjunction with anaerobes
are Streptococcus species. Although S. aureus, various enteric gram-negative bacilli,
and Pseudomonas may also be isolated, their significance is often questionable. Molecular
techniques can often identify anaerobes in culture negative cases.
149
Clinical Course
Uncomplicated aspiration pneumonia generally responds promptly to appropriate antibiotics.
Fever resolves within a few days, and the chest radiograph normalizes within 3 weeks.
Fever resolves more slowly in anaerobic pleuropulmonary infection. Closure of abscess
cavities (see eFig. 33-21) and resorption of empyema collections may require months.
Fatality rates are low in adequately treated patients, except those with necrotizing
pneumonia, in which mortality approaches 20%.
149
Chronic lung abscess has been complicated by brain abscess, other metastatic abscess,
secondary amyloidosis, life-threatening hemoptysis, bronchopleural fistula or empyema
necessitans (rupture through the chest wall), but these complications are currently
rare.
Treatment
Emergence of β-lactamase–mediated resistance mandates that penicillin G and ampicillin
are no longer the drugs of choice for treatment of patients with serious anaerobic
pleuropulmonary infection. There is resistance not only among Bacteroides species
but also among Prevotella and some F. nucleatum strains. Empirical treatment for serious
anaerobic pleuropulmonary infection requires the use of a β-lactam/β-lactamase inhibitor
(e.g., ampicillin-sulbactam, ticarcillin-clavulanate, or piperacillin-tazobactam)
or clindamycin. Because of the frequent simultaneous presence of aerobes, metronidazole
monotherapy is not adequate for suspected anaerobic pneumonia. Occasional pulmonary
isolates are resistant to one or more of these agents. For example, Eikenella corrodens
is resistant to clindamycin. Carbapenem monotherapy is also effective but generally
provides unnecessarily broad coverage.
Ten days of total treatment is usually adequate for uncomplicated pneumonitis. Necrotizing
pneumonia, abscess, and empyema require prolonged parenteral therapy to achieve clinical
improvement, and extended courses of oral therapy, often requiring several months,
may be required for cure.
Drainage of empyema fluid is required. Surgical resection of anaerobic lung abscess
is almost never indicated. Bronchoscopy is useful for excluding an underlying malignancy
in patients without other risk factors (i.e., edentulous patients).
Less Common Causes of Pneumonia
A variety of pathogens are less common causes of pneumonia. These agents may be suspected
in the presence of unique risk factors or presentations, or may be diagnosed by results
of cultures.
Actinomycosis
A variety of species within the two genera of the Actinomycetaceae family (Actinomyces
and Propionibacterium), which are normally harmless commensals in the oropharynx,
can cause subacute to chronic pulmonary infections that are virtually indistinguishable.
Pulmonary actinomycosis follows aspiration of oropharyngeal material. Periodontitis
and other dental disease increase the risk of cervicofacial invasion and of pneumonia.
Most patients are 30 to 60 years old; men outnumber women by a ratio of 4:1.
Patients with actinomycosis appear chronically ill but not toxic. Constitutional symptoms,
including fatigue, weight loss, and low-grade fever, may be present for weeks to months
before diagnosis and often mimic the presentation of chronic fungal infection, tuberculosis,
or malignancy. Fever may be absent. Most patients gradually develop productive cough
and pleuritic chest pain, but hemoptysis and putrid sputum are unusual. Cervicofacial
involvement is rarely observed in patients with thoracic involvement.
The imaging finding classic for actinomycosis is direct extension of a cavity or mass
through an interlobar fissure. More commonly, changes are confined to a single lobe
with one or more small cavitary lesions (eFig. 33-22). In advanced cases, the findings
may be more distinctive, with penetration through the chest wall and/or destruction
of adjacent bone tissue (eFig. 33-23).
Members of the Actinomyces and Propionibacterium genera are gram-positive, diphtheroidal
or filamentous, branching bacilli. Most strains grow best in anaerobic conditions,
although some also grow aerobically. In patients with a cutaneous chest wall sinus,
the best means of establishing a diagnosis of actinomycosis is by detection of “sulfur
granules” that, when crushed and stained, form a characteristic pattern of gram-positive,
branching filaments (eFig. 33-24). The organism usually can be recovered from culture
of this material, provided anaerobic conditions are maintained for the specimen. Diagnosis
of an actinomycotic parenchymal lesion is more difficult. Sulfur granules are rarely
present in sputum, and recovery of the organism in sputum cultures is unreliable because
the organism may colonize without invading any mucosal surface. Definitive diagnosis
depends on demonstrating the characteristic histopathology and culture from a sterile
body fluid or tissue biopsy. Other organisms are commonly identified, including Haemophilus
(Actinobacillus) actinomycetemcomitans and Prevotella, in addition to the Actinomyces
or Propionibacterium.
Complications of pulmonary actinomycosis relate to its ability to invade across anatomic
barriers. Pleural empyema, cutaneous thoracic sinuses, mediastinitis, pericarditis,
and vertebral osteomyelitis are not infrequent. Metastatic infection, including brain,
skin, and bone, is more commonly seen with pulmonary actinomycosis than with other
variants (e.g., cervicofacial disease) but is still unusual. With adequate therapy,
death from actinomycosis is rare.
Prolonged antibiotic treatment is the key to curing actinomycosis. Actinomyces are
universally susceptible to penicillin G, which should be given in intravenous doses
of 12 to 20 million units daily for 4 to 6 weeks, followed by at least 6 months of
oral penicillin V or ampicillin. Multiple other drugs have also been successfully
used; prolonged therapy is essential. With polymicrobial infection, the presence of
the other organisms may require modification of therapy. If β-lactamase–producing
anaerobes are present, treatment choices as described for anaerobic pneumonia are
recommended. On occasion, clindamycin fails because of concomitant infection by H.
actinomycetemcomitans. Rarely, surgical resection is required for cure.
Chlamydophila psittaci (Formerly Chlamydia psittaci)—Psittacosis
Exposure to birds is the classic risk factor for psittacosis. Multiple species harbor
the organism, but most cases have been acquired from canaries, parakeets, cockatiels,
parrots, and pigeons. Although infected birds are typically ill, there can be asymptomatic
fecal carriage. C. psittaci can be detected in blood, tissues, feathers, and feces
of infected birds. Human acquisition is typically via inhalation of contaminated bird
excreta. Although approximately 50% of cases are reported in owners of infected pet
birds, there may be sporadic cases and occasional outbreaks without a history of known
bird exposure. History of exposure is more likely with more severe disease.
192
The symptoms of psittacosis may develop abruptly, with high fever and chills, or they
may evolve slowly. Headache, arthralgia, and painful myalgia (especially in the head
and neck) are prominent features. A severe cough develops that may be either dry and
hacking or productive of mucoid sputum. Chest pain and dyspnea are present with extensive
pulmonary involvement. Temperatures are 38° C to 40° C and are frequently accompanied
by relative bradycardia. Splenomegaly or occasionally a pale macular rash (Horder
spots) can be seen. Hematologic and blood chemistry findings are nonspecific, except
occasionally for findings consistent with granulomatous hepatitis.
C. psittaci is an obligate intracellular parasite that does not stain by the Gram
method but can be seen as large intracytoplasmic inclusions in infected cells when
stained with Giemsa stain. Cultivation of the organism, which requires tissue culture,
poses a threat to laboratory personnel and should be performed only in specialized
facilities. Nucleic acid testing offers a rapid alternative method for diagnosis,
with higher sensitivity than cultures.
193
In the absence of available nucleic acid testing, diagnosis of psittacosis can be
made by demonstrating a fourfold rise in complement-fixing antibodies in paired acute
and convalescent serum. A single titer of 16 or greater can be considered presumptive
evidence of infection in a patient with a compatible illness. The antibody can cross-react
with C. burnetii or Brucella.
Treatment with doxycycline is recommended, but the clinical response may be slow.
Because of the risk of relapse, therapy should be given for a minimum of 2 weeks after
fever has resolved. Chloramphenicol, erythromycin, azithromycin, and moxifloxacin
also have in vitro activity, but clinical experience with use of these drugs to treat
C. psittaci is limited. The case-fatality rate is about 1% with antimicrobial therapy.
Unusual complications include respiratory failure, encephalitis, hepatitis, disseminated
intravascular coagulation, renal failure, and endocarditis.
Coxiella burnetii—Q Fever
Worldwide, Q fever is a particular problem in farming communities in Europe, North
America, and Australia. C. burnetii asymptomatically infects a wide variety of domestic
and wild animals, as well as ticks. Transmission to humans is primarily via exposure
to the urine, feces, placenta, or unpasteurized milk of an infected animal: cows,
sheep, and goats are most common. Outbreaks have happened in tanneries, dairies, and
wool-rendering plants, among laboratory personnel, and in household members exposed
to an infected cat or dog during parturition.194, 195
Following an incubation period of 2 to 4 weeks, an atypical pneumonia syndrome develops
in 10% to 20% of infected persons.
194
High temperature (>40° C), relative bradycardia, conjunctivitis, hepatosplenomegaly,
and chest crackles may be detected; a rash is typically absent.
195
C. burnetii is a small, obligate intracellular bacterium that cannot be cultured on
standard media or visualized with the Gram stain. Because of the high infectivity
of the organism, cultures should be attempted only by experienced personnel in Biosafety
Level-3 laboratories. At present, the diagnosis usually relies on a fourfold rise
in antibody titer from acute to convalescent serum samples. Nucleic acid testing is
likely to provide a more rapid diagnosis, which would be useful in guiding treatment
decisions.
Although patients may be acutely ill on presentation, the disease is rarely fatal
and generally runs its course in 1 to 2 weeks.
194
Some patients, particularly older adults, have a very prolonged illness. The most
concerning aspect of Q fever is the potential for chronic vascular complications including
endocarditis, vascular graft infections, and infected aortic aneurysms. Acute Q fever
pneumonia during pregnancy is often associated with fetal loss.
Tetracyclines, especially doxycycline, are first-line therapy for Q fever. Quinolones
have excellent in vitro activity and may be advantageous in the treatment of meningoencephalitis.
195
Nocardiosis
Nocardia asteroides is the etiologic agent in more than 80% of pulmonary or disseminated
cases of nocardiosis, although several other species (e.g., Nocardia brasiliensis)
have also been associated with human infection. The organisms are widespread in nature,
primarily in soil. The respiratory tract, skin, and gastrointestinal tract are portals
of infection. Dysfunction of cell-mediated immunity and, to a much lesser extent,
immunoglobulin defects predispose to infection. Thus, the infection rate is increased
in patients who have lymphoma or leukemia, Cushing disease, or AIDS, or who are receiving
immunosuppressive medications. The most recent cases have been reported in lung, heart,
or stem-cell transplant recipients. Persons with pulmonary alveolar proteinosis are
also at increased risk. Nonetheless, approximately half of the patients in whom nocardiosis
develops have no known underlying medical disorder.
Although nocardiosis and actinomycosis are clinically similar infections of the lower
respiratory tract, nocardiosis can be distinguished by less proclivity for sinus tract
formation and a greater tendency for hematogenous dissemination in both healthy and
impaired hosts. Dissemination may involve almost every organ system, but the central
nervous system and skin are most common.
196
Many patients with pulmonary nocardiosis have low-grade fever, fatigue, weight loss,
productive cough, and pleuritic chest pain for weeks before seeking medical attention.
However, some immunosuppressed patients present with acute, fulminant pneumonia. Physical
examination is nonspecific unless sites of dissemination are obvious. Neurologic signs
of a mass lesion may be present. Cutaneous dissemination appears as multiple subcutaneous
abscesses with or without sinus tracts. Imaging commonly demonstrates localized bronchopneumonia
or lobar consolidation (eFig. 33-25), but there may also be solitary, multiple (eFig.
33-26), or miliary nodules, and abscesses (eFig. 33-27). Pleural effusion develops
in up to one third of cases.
Nocardia species are gram-positive bacilli that appear as beaded, branching filaments.
Unlike the anaerobic Actinomycetaceae, Nocardia requires aerobic growth conditions
and is usually weakly acid-fast when stained by the modified Ziehl-Neelsen method
(eFig. 33-28). Nocardia can be cultivated on conventional blood agar or Sabouraud
medium but growth may not be apparent for 3 to 21 days. Although an occasional colonizer
of the upper respiratory tract, recovery of Nocardia from a culture of sputum or invasively
obtained material is highly suggestive of the diagnosis.
Mortality approaches 50% in those with central nervous system lesions but is less
than 10% in those with only pulmonary disease.
196
Because of in vitro synergy, TMP-SMX has become the standard treatment.
196
In case of a sulfa allergy or a resistant organism, minocycline, amikacin, cefotaxime,
imipenem, or linezolid may be useful, but choices should always be guided by the results
of susceptibility testing.
196
Prolonged therapy is needed to prevent relapse. Adequate drainage or excision of abscesses
and empyema is a crucial adjunct to antimicrobial therapy.
Melioidosis (Burkholderia pseudomallei)
In endemic areas such as Southeast Asia and northern Australia, melioidosis may be
the most common cause of severe CAP.
197
B. pseudomallei is found in soil, vegetation, and water throughout tropical regions
between latitudes 20 degrees N and 20 degrees S.48, 198 Acquisition of the organism
is through cutaneous inoculation or inhalation in patients with regular contact with
water and soil.
48
Risk factors for disease include diabetes, alcoholism, and renal disease. Typhoons
or episodic heavy rain may increase the risk of acute fulminant pneumonia; more than
75% of cases happen during the rainy season.
198
Melioidosis can produce either acute fulminant pneumonia or indolent, cavitary disease.
Clinical manifestations of acute melioidosis include high fever, prostration, dyspnea,
pleuritic chest pain, purulent sputum, and hemoptysis. Concomitant bacteremia is common.
197
The chest radiograph typically shows diffuse miliary nodules, which may expand and
cavitate. Subacute or chronic B. pseudomallei pneumonia is milder and often manifests
after a period of latency. Patients may be entirely asymptomatic (i.e., abnormal radiograph
only), or present with an illness clinically and radiographically indistinguishable
from tuberculosis.
B. pseudomallei is an aerobic gram-negative bacillus that grows readily on routine
culture media. Despite improvements in recognition and treatment, melioidosis is still
associated with high morbidity and mortality.
197
B. pseudomallei is not sensitive to the usual CAP antibiotics but is usually susceptible
to carbapenems, ceftazidime, and TMP-SMX. Optimal treatment for disseminated or life-threatening
melioidosis requires initial intensive therapy with a carbapenem or ceftazidime followed
by 3 months of TMP-SMX.48, 197, 199
Rhodococcus equi
Rhodococcus equi may cause lung abscess and pneumonia. Most cases are seen in the
setting of impaired cell-mediated immunity (e.g., high doses of corticosteroids, HIV
infection, solid organ transplantation)
200
and in persons with a history of animal exposure. Illness develops subacutely, mimicking
mycobacterial or fungal infection. Chest radiographs often show upper lobe nodules
that gradually cavitate.
The organism is an intracellular gram-positive bacillus. It may stain weakly acid-fast
but is much smaller than mycobacteria. The most effective regimens appear to be prolonged
courses of vancomycin or erythromycin. Addition of rifampin may be useful.
Pulmonary Anthrax (Bacillus anthracis) (see Chapter 40)
Although B. anthracis is detected in many agricultural regions, anthrax is a rare
infection in the developed world. Spores, the transmissible agent of infection, reside
in soil, water, and vegetation and primarily infect large herbivorous animals (e.g.,
cows, sheep, and horses). Humans are infected by spores via contact with contaminated
animals or animal products (e.g., animal hides and wools).
33
B. anthracis is a proven agent of bioterrorism.201, 202, 203
The manifestations of anthrax are cutaneous, gastrointestinal, and inhalational (woolsorter's
disease); inhalational anthrax is the most severe. Disease results from germination
of B. anthracis spores in the lungs or draining lymph nodes, followed by growth of
the vegetative forms of the bacteria and production of edema toxin and lethal toxin.
Clinical illness begins insidiously with fever, malaise, nonproductive cough, and
precordial pain. This stage is followed by rapid pulmonary deterioration with dyspnea,
stridor, chest pain, tachypnea, cyanosis, nausea, vomiting, and drenching night sweats.
Diffuse edema of the neck and anterior chest may be evident, due to the action of
edema toxin. Meningitis is a common complication.
Radiographically, the lung parenchyma is initially clear. A widened mediastinum and
bilateral pleural effusions are clues to inhalational anthrax. Mediastinal widening
is seen in 100% of inhalational anthrax cases,
204
although a chest CT scan may be required to define these characteristics.
51
Later findings include vascular engorgement and lung parenchymal opacities.
B. anthracis is a large, facultative, gram-positive rod that forms spores. The organism
grows readily on routine culture media and can be rapidly recovered from cultures
of blood, sputum, and pleural fluid. In advanced disease, the organism may be demonstrated
by Gram stain of peripheral blood.
51
B. anthracis can be detected in nasal swabs of persons exposed to anthrax spores:
the predictive value of this test for diagnosing clinical disease is ill-defined.
51
Treatment recommendations for inhalational anthrax may be affected by resistance and
the potential need to treat mass casualties. Current recommendations for inhalational
anthrax call for initial treatment with ciprofloxacin plus one or two additional antibiotics
with in vitro activity, such as clindamycin, vancomycin, imipenem, meropenem, chloramphenicol,
penicillin, ampicillin, rifampin, and clarithromycin.
205
If the isolate is susceptible, therapy can be changed from the fluoroquinolone to
high-dose penicillin G or doxycycline. Intravenous therapy may be converted to oral
therapy once the patient's condition stabilizes. Since pulmonary and systemic anthrax
are associated with high mortality rates, therapy with an FDA-approved humanized monoclonal
antibody (Raxibacumab) to anthrax lethal toxin is recommended as an adjunct to antimicrobial
therapy.
51a
Treatment for 60 days is recommended, to eliminate spores that could be the source
of relapse. Although the reported mortality rate has been as high as 90%, 6 of 11
patients with inhalational anthrax survived during the 2001 anthrax attacks in the
United States.
51
Tularemia (Francisella tularensis) (see Chapter 40)
Although F. tularensis has been recovered from numerous insects and species of wild
or domestic mammals throughout the temperate zones of the Northern Hemisphere, fewer
than 200 cases of tularemia per year are reported in the United States.
52
Humans acquire infection following direct contact with tissues of an infected animal
(as when skinning or eating an infected animal), through the bite of an infected tick
or deerfly, or by inhalation of contaminated aerosols.47, 52, 206 Persons engaged
in landscaping or agricultural activities that generate aerosols in endemic areas
are at particular risk for development of pneumonic tularaemia.
47
Because of the efficiency of aerosol transmission, F. tularensis is regarded as a
potential agent of bioterrorism.
52
Pneumonia develops from inhalation of contaminated aerosols or as a complication of
bacteremia. Clinical manifestations typically begin abruptly with fever, chills, malaise,
and headache. Shortly thereafter, dyspnea, cough, and chest pain may develop.
52
Chest radiographs are usually normal at the onset (3 to 5 days following aerosol exposure)
but ultimately show diffuse bronchopneumonia, often with hilar adenopathy.
52
Pleural effusion is common and may be seen without parenchymal involvement.
52
F. tularensis is a fastidious, pleomorphic, gram-negative bacillus rarely visualized
on Gram stain of sputum and requires specially enriched media for optimal recovery
by culture. Because of the hazardous nature of the organism, culture is best undertaken
by reference laboratories. The organism can also be rapidly identified in tissues,
secretions, and exudates by use of immunohistochemical techniques.
52
Retrospective diagnosis can be accomplished by demonstrating a fourfold rise in agglutinating
titers. A single titer of 160 or greater is compatible with either past or current
infection.
Mortality can be as high as 60% if pneumonic tularemia is not suspected and treated
appropriately. Although gentamicin has been used successfully, streptomycin remains
the preferred therapy.
52
Ciprofloxacin is an acceptable alternative agent; doxycycline and chloramphenicol
are associated with higher relapse rates and require a longer duration of therapy.
52
Ceftriaxone is unsatisfactory despite in vitro activity. After a known aerosol exposure
to F. tularensis, prophylaxis with doxycycline or ciprofloxacin for 14 days is recommended.
52
Plague (Yersinia pestis) (see Chapter 40)
Plague is typically associated with ground squirrels, rabbits, prairie dogs, rats,
and other small ground animals. Rodent fleas are responsible for transmission of the
organism between animal hosts. Humans become infected when bitten by an infected rodent
flea, by handling an infected animal carcass, or by inhaling an aerosol from a human
or animal with pulmonary involvement. In the United States, most cases of plague are
in rural New Mexico, Arizona, and California.
46
Because of the disease severity and potential for aerosol transmission, Y. pestis
is also regarded as a potential bioterrorism weapon.
207
Three clinical forms of infection exist: pneumonic, bubonic, and septicemic. Although
the pneumonic form presents as a primary pneumonia, the lung may also be involved
in bubonic and septicemic infections. Plague pneumonia may develop 2 to 7 days after
the initial exposure. Early in the course of the illness, patients experience fever
and toxicity, followed by chest pain, productive cough, dyspnea, and hemoptysis. The
presence of hemoptysis can cause confusion with the hantavirus pulmonary syndrome,
whose geographic distribution overlaps with plague in the United States. If pulmonary
disease complicates bubonic plague, painful adenopathy is also noted. In the septicemic
form, the patient may show only signs of septic shock. Chest radiographs in cases
of pneumonic plague commonly reveal bilateral lower lobe alveolar opacities, but there
may also be nodules, adenopathy, and pleural effusions.
Y. pestis is a short, nonmotile, gram-negative rod. Most patients with pneumonic plague
have positive blood cultures. In addition, the organism can be recovered from sputum
and lymph node aspirates by routine bacteriologic techniques. Fluorescent antibody
staining of sputum and tissues facilitates the rapid diagnosis of plague but is available
only in specialized laboratories.
Because of the potential for person-to-person transmission, all patients with plague
pneumonia should be isolated. Recommended treatment consists of gentamicin or doxycycline.207,
208 Alternative treatments include fluoroquinolones, streptomycin, or chloramphenicol.
For all regimens, the duration of treatment is a minimum of 10 days.
Moraxella catarrhalis
M. catarrhalis causes pneumonia, acute exacerbations of COPD, otitis media, and maxillary
sinusitis.
209
Pneumonia typically is seen in patients with underlying COPD, although alcoholism,
malnutrition, increased age, congestive heart failure, and malignancy are also risks.
209
Because M. catarrhalis is part of the normal upper respiratory tract flora, only adequately
screened sputum samples provide useful diagnostic information. A purulent specimen
that contains many intracellular gram-negative diplococci and yields heavy growth
of M. catarrhalis is highly suggestive of true pneumonia. Blood cultures are rarely
positive.
209
The mortality of M. catarrhalis is approximately 10%, primarily due to exacerbations
of severe underlying pulmonary disease.
209
Effective agents include TMP-SMX, cephalosporin, macrolide, tetracycline, quinolone,
or β-lactam/β-lactamase inhibitor combination. Virtually all isolates are resistant
to penicillin and ampicillin because of β-lactamase production.
Neisseria meningitidis
N. meningitidis pneumonia is often a surprising culture diagnosis because clinical
manifestations of meningococcal pneumonia resemble those of pneumococcal pneumonia.
The estimated incidence of sporadic primary meningococcal pneumonia is 0.4 cases per
100,000 adults per year; pneumonia also complicates 5% to 15% of invasive meningococcal
infections.
210
Asymptomatic carriage rates vary according to the season and are increased under conditions
of crowding.
210
The organism is transmitted from person-to-person largely through droplet aerosols.
Nosocomial clusters of meningococcal pneumonia are well described.
N. meningitidis is a gram-negative diplococcus; its appearance in sputum is similar
to that of Moraxella and Acinetobacter. Rates of isolation of the organism from blood,
cerebrospinal fluid, and pleural fluid from patients with meningococcal pneumonia
are highly variable.
Aqueous penicillin G for 10 days, in daily doses of 4 to 6 million units, is adequate
therapy for isolated pneumonia. Coexistence of septicemia or meningitis warrants increasing
the dose to 18 to 24 million units per day. Isolates with decreased susceptibility
to penicillin are not yet a significant problem in the United States, but have been
reported in Europe and Africa.
211
Because meningococci can be transmitted from patients with pneumonia to susceptible
contacts, respiratory droplet isolation should be implemented during the initial days
of treatment. Prophylaxis with ceftriaxone, ciprofloxacin, or rifampin is advised
for household and other intimate contacts of the patient, including health care providers
who have been exposed to respiratory secretions.
Pasteurella multocida
Pasteurella multocida is part of the normal oral flora of many domestic and wild mammals.
Although skin and soft tissue infections following a cat or dog bite are the more
common manifestations of human infection, sporadic cases of pneumonia, lung abscess,
and empyema are seen in patients with chronic respiratory diseases, including COPD,
carcinoma, and bronchiectasis. Most patients recall prior exposure to animals.
Pasteurella pneumonia is indistinguishable from other etiologies of CAP, although
empyema may be more frequent. The organism is a small, gram-negative coccobacillus
indistinguishable from other gram-negative rods by Gram stain. Identification of the
organism by culture of sputum, blood, and pleural fluid is easily accomplished.
The treatment of choice for P. multocida pneumonia is penicillin G, 4 to 12 million
units daily for 10 to 14 days. Tetracycline, amoxicillin-clavulanate, second- and
third-generation cephalosporins, TMP-SMX, fluoroquinolones, and chloramphenicol are
also active. P. multocida is resistant to clindamycin and macrolides.
Nonresponding Pneumonia/Treatment Failure
Two different clinical patterns of treatment failure in pneumonia have been described
212
: progressive pneumonia with clinical deterioration including respiratory failure
or septic shock; and nonresponding pneumonia, in which clinical improvement is not
achieved (fever and clinical symptoms persist). In those treated as outpatients or
inpatients, evaluation for response should be undertaken after 72 hours of antibiotic
treatment, as this represents the median time required to achieve clinical improvement.
212
In addition to clinical evaluation, reduction of procalcitonin (PCT) levels after
3 to 4 days of treatment correlates with clinical responses.
213
Levels of certain biomarkers, mainly PCT and C-reactive protein, have also been found
useful for predicting inadequate response. Initial higher levels of PCT or C-reactive
protein represent a risk factor for inadequate response (odds ratio, 2.6),
213
whereas low levels are associated with responses to therapy. A recently described
biomarker, MR-proadrenomedullin, has shown a greater association with severity assessment,
and levels greater than 1.8 were associated with subsequent deterioration and ICU
admission.
214
The causes of nonresponding pneumonia are classified as infectious, noninfectious,
and of unknown origin.
212
eTable 33-5 lists common infectious and noninfectious causes.
eTable 33-5
Causes of Nonresponding Pneumonia
INFECTIOUS
Resistant microorganisms
Community-acquired pneumonia (e.g., Streptococcus pneumoniae, Staphylococcus aureus
Nosocomial pneumonia (e.g., Acinetobacter, methicillin-resistant Staphylococcus aureus,
Pseudomonas aeruginosa)
Uncommon microorganisms (e.g., Mycobacterium tuberculosis, Nocardia spp., fungi, Pneumocystis
jirovecii)
Complications of pneumonia
Empyema
Abscess or necrotizing pneumonia
Metastatic infection
NONINFECTIOUS
Neoplasms
Pulmonary hemorrhage
Pulmonary embolism
Sarcoidosis
Eosinophilic pneumonia
Pulmonary edema
Acute respiratory distress syndrome
Organizing pneumonia
Drug-induced pulmonary disease
Pulmonary vasculitis
Infectious Causes
In patients hospitalized for CAP, specific infections are responsible for 40% of nonresponding
cases. The most frequent microorganisms found are S. pneumoniae, Legionella, P. aeruginosa,
and S. aureus.
Patients with CAP, HAP, or VAP may fail to respond because of resistance to the empirical
antibiotic regimen selected. P. aeruginosa, which is not covered by empirical therapy
for CAP, causes about 10% of cases of nonresponding CAP.
212
Up to 50% of episodes of nonresponding VAP are caused by multiresistant microorganisms;
the most frequent causes are MRSA, P. aeruginosa, carbapenemase-producing Klebsiella,
and Acinetobacter species.
215
More unusual microorganisms in nonresponding CAP
212
include Mycobacteria, Nocardia species, anaerobes, fungi, Pneumocystis jirovecii,
and other organisms requiring antibiotics other than those recommended for CAP or
HAP (eFig. 33-29). Investigation of the etiology of some of these microorganisms requires
intensified microbiologic diagnostic testing as well as exhaustive review to search
for risk factors, including epidemiology (travel, professional, leisure, or animal
exposures), personal habits, and environmental factors.
Local or metastatic infectious complications also contribute to treatment failure.
Empyema (see eFig. 33-7) is one of the most frequent complications in pneumonia and
is thus a cause of nonresponse that must be evaluated with thoracentesis when a pleural
effusion is present. Other causes of treatment failure are abscess formation (see
eFig. 33-4) and necrotizing pneumonia (see eFigs. 33-20 and 33-21). Metastatic infections
such as endocarditis, arthritis, pericarditis, meningitis, or peritonitis can contribute
to treatment failure and are more common in bacteremic pneumonia. In approximately
30% of the cases, no specific cause for lack of response can be identified despite
adequate antibiotic treatment. This may be due to the presence of comorbidities or
to an exaggerated or diminished inflammatory response.
215a
Noninfectious Causes
Noninfectious diseases with acute involvement of the pulmonary parenchyma may simulate
pneumonia. These include pulmonary infarction, pulmonary hemorrhage, organizing pneumonia,
eosinophilic pneumonia, hypersensitivity pneumonitis, drug-induced lung disease, and
neoplasms. Alveolar cell lung cancer (eFig. 33-30 and Video 33-2
) may be particularly difficult to distinguish radiographically from pyogenic pneumonia.
The frequency of noninfectious etiologies has been reported to be 22% in CAP
212
and 19% in nosocomial pneumonia.
215
eTable 33-5 summarizes infectious and noninfectious causes of nonresponding pneumonia.
Diagnostic Evaluation
The diagnostic approach to treatment failure requires a complete reevaluation of the
history, physical examination, and laboratory studies including factors that may be
related to delayed response.212, 216 Reconsideration of the initial diagnosis is also
an important component of the diagnostic approach. Important epidemiologic clues may
suggest unusual microorganisms along with unexpected resistance to antimicrobials,
or underlying immunodeficiency such as HIV infection.
Microbiologic Studies
The microbiologic investigation of treatment failures requires comprehensive reexamination
of initial microbiologic results, together with obtaining new samples for culture
and other assays (eTable 33-6). Invasive techniques (i.e., bronchoscopy) for microbiologic
samples and local evaluation of airways are recommended if they are not contraindicated.
Both protected sheath brush and BAL sampling should be done during the same procedure
for bacterial cultures, direct fluorescent antibody staining, and nucleic acid testing.
Although culture results may be altered by the prior administration of antibiotics,
the sensitivity of brush or BAL cultures approaches 40% in nonresponding CAP. In patients
undergoing mechanical ventilation, the tracheal aspirate can provide diagnostic information.
Gram stain of cytocentrifuged BAL fluid can rapidly identify intracellular microorganisms
88
and may guide decisions regarding changes in antimicrobial therapy. Comprehensive
microbiologic studies should also be performed on samples from nonrespiratory sites
(eTable 33-7). When present, pleural fluid should be obtained for culture, direct
fluorescent antibody, and nucleic acid testing for likely pathogens. The role of transbronchial
biopsy is not established, and its indication depends on the possible alternative
diagnosis suspected.
eTable 33-6
Recommended Microbiologic Evaluation in Patients with Nonresolving Pneumonia
BLOOD CULTURES (TWO SETS)
URINE
Antigen test for detection of Legionella pneumophila
SPUTUM
Gram stain, Giemsa stain, immunofluorescence stains for Legionella; normal and modified
Ziehl-Neelsen stain for Mycobacterium spp. and Nocardia spp.
Cultures for conventional bacteria, Legionella, mycobacteria, and fungi
BRONCHOSCOPY SPECIMENS (USING PSB OR BAL)
*
Gram stain, Giemsa stain, immunofluorescence stains for Legionella and Pneumocystis
jirovecii; normal and modified Ziehl-Neelsen stain for Mycobacteria spp. and Nocardia
spp.
Cultures for aerobic and anaerobic bacteria, Legionella, mycobacteria, and fungi
PLEURAL FLUID
Gram stain, Giemsa stain, immunofluorescence stains for Legionella; normal and modified
Ziehl-Neelsen stain for Mycobacteria spp. and Nocardia spp.
Cultures for aerobic and anaerobic bacteria, Legionella, mycobacteria, and fungi
BAL, bronchoalveolar lavage; PSB, protected specimen brush.
*
Quantitative criteria for the interpretation of PSB and BAL specimens are described
in the text.
eTable 33-7
Possible Diseases Depending on Differential Cell Count in Bronchoalveolar Lavage Fluid
PREDOMINANCE OF POLYMORPHONUCLEAR LEUKOCYTES
Bacterial infection
Organizing pneumonia
PREDOMINANCE OF LYMPHOCYTES
Tuberculosis
Hypersensitivity pneumonitis
Sarcoidosis
Fibrosis
HEMOSIDERIN-LADEN MACROPHAGES
Alveolar hemorrhage
EOSINOPHILS
Pulmonary eosinophilia
Fungal infection
Pneumocystis jirovecii
Systemic diseases
Drug-induced disease
Imaging Studies
Chest radiographs may demonstrate complications such as pleural effusion, cavitation,
or new opacities. Chest CT scans provide a more detailed study of the parenchyma,
interstitium, pleura, and mediastinum, potentially suggesting specific microorganisms
(see eFig. 33-29) or alternative diagnoses. In a patient with applicable risk factors,
the appearance of nodular images with the halo sign (i.e., a nodule surrounded by
a halo of ground-glass attenuation, especially near the pleura) on CT scan is suggestive
of pulmonary aspergillosis (see Chapter 91 and eFigs. 91-8A and 91-10) or mucormycosis
(see Chapters 38, 91, and 95Chapter 38Chapter 91Chapter 95 and eFig. 91-9).217, 218
Nodules of similar appearance have also been described in cytomegalovirus infection
(see Chapter 91 and eFig. 91-2), granulomatosis with polyangiitis (formerly Wegener
granulomatosis), Kaposi sarcoma, and metastases with necrosis and/or hemorrhage. Ground-glass
opacities consistent with interstitial pneumonia suggest P. jirovecii pneumonia. Nodules
or multiple masses with or without cavitation are compatible with Nocardia species,
M. tuberculosis, or Q fever. Diffuse or mixed interstitial and alveolar opacities
may be due to viral infections or M. pneumoniae. Other imaging studies, such as chest
CT pulmonary angiography should be considered to evaluate the possibility of pulmonary
emboli.
Therapeutic Management
Correction of Host Abnormalities
Defects related to the host's immune system may impede recovery from pneumonia. Immunodeficiency
may arise as a complication of cancer chemotherapy, immunosuppressive agents, or corticosteroid
use; or it may result from a congenital (e.g., agammaglobulinemia) or acquired (e.g.,
HIV infection) immune defect. Many of these immune deficiencies are not remediable;
however, drug-related immunosuppression may be improved by discontinuing the offending
agent or reducing the dose. Although reduction of immunosuppression may promote recovery
from the active infection, it can also be complicated by enhanced inflammation due
to immune reconstitution.219, 220
Granulocytopenia (absolute granulocyte count less than 500 cells/mm3) has been associated
with fulminant, antibiotic-unresponsive pneumonia, and administration of granulocyte
colony-stimulating factor (G-CSF) or granulocyte-macrophage colony-stimulating factor
(GM-CSF) is effective in increasing the number of circulating neutrophils. Despite
this effect on neutrophils, routine administration of G-CSF or GM-CSF has not been
found to improve survival from infections.
221
Because pneumonia is the infection most frequently associated with a poor clinical
outcome in profoundly neutropenic patients, the use of G-CSF or GM-CSF in these patients
may be justified, even though a benefit has not been demonstrated.
222
Corticosteroid treatment has been investigated because of its suppressant effect on
inflammatory responses; studies have yielded discordant findings. A recent meta-analysis
found evidence for a positive effect on survival in severe cases of CAP.
223
In contrast, a recent randomized trial showed no benefit, although the number of patients
with severe CAP may have been insufficient to reveal a difference in this select group.
224
Antimicrobial Adjustment
The optimum therapeutic approach to nonresolving pneumonia requires close monitoring,
transfer to a higher level of care, and optimization of the antibiotic regimen, including
dosing.
212
The optimal time to make these changes is not defined, although it has been suggested
that one should wait until 72 hours after the initiation of treatment except in the
presence of severe clinical deterioration or dramatic progression as determined by
chest radiograph. Before initiating a change in antibiotics, new samples should be
obtained for microbiologic studies.
In nonresponding CAP, strong consideration should be given to extending the antibacterial
spectrum to ensure coverage of resistant S. pneumoniae, P. aeruginosa, S. aureus,
and anaerobes. Such broad-spectrum therapy should be undertaken after all abscesses
or empyemas have been drained, the results of all previous cultures are reviewed and,
whenever possible, vigorous new efforts have been made to identify the responsible
microorganisms. The specific antimicrobial regimen chosen depends on patient risk
factors, disease severity, and the local epidemiology of antimicrobial resistance.
In community-acquired MRSA, antimicrobial treatments may include linezolid or clindamycin
plus vancomycin, depending on results of susceptibility testing.21, 163
In nonresponding nosocomial pneumonia, combinations of up to three antibiotics may
be necessary to cover P. aeruginosa, MRSA, and the endemic flora of each hospital,
such as Acinetobacter species or other microorganisms.
215
The increasing spread of virulent carbapenemase-producing K. pneumoniae also necessitates
vigilance for these organisms and consideration of combinations of polymyxin B or
E, tigecycline, and/or ampicillin-sulbactam.
225
Occasionally, empirical coverage against Aspergillus species should be considered
(i.e., severe COPD, significant immunosuppressive therapy, corticosteroid treatments),
especially if supported by clinical, radiologic,
217
or laboratory data. The recommended approach is to cover empirically all likely causal
microorganisms while awaiting the results of repeated respiratory samples and then
adjust and deescalate antibiotics accordingly.
Lung Abscess
Lung abscesses are pus-containing necrotic lesions of the lung parenchyma that result
from aspiration of bacteria-laden secretions and show an air-fluid level (see Fig.
33-13). Lung abscesses are distinct from, and may follow, necrotizing pneumonia, in
which multiple small cavities develop in contiguous areas of the lung.226, 227 Lung
abscesses must be distinguished from septic pulmonary emboli, which are often multiple
and bilateral, involve the lower lobes (see Fig. 33-6), and are secondary to an endovascular
infection.
Unlike most other respiratory infections that are caused by single pathogens, lung
abscesses are caused by mixed populations of bacteria. The most common components
of the mixed bacterial populations in lung abscesses are anaerobic bacteria (principally
Peptostreptococcus species (now termed Finegoldia magna), F. nucleatum, and Prevotella
melaninogenica (formerly Bacteroides melaninogenicus). Microaerophilic streptococci
and viridans streptococci are also frequently isolated and can contribute to treatment
failure if appropriate antibiotics are not included.
228
Lung abscess may also be associated with pyogenic bacteria, mycobacteria, fungi, and
parasites such as Paragonimus, Entamoeba, and Echinococcus (see Chapter 39). Secondary
lung abscesses develop from congenital lung abnormalities, obstructing neoplasms,
foreign bodies, and bronchiectasis. Lung abscess may also complicate pulmonary infarction,
primary lung cancer (central carcinoma with necrosis), metastatic malignancies, and
the necrotic conglomerate lesions of silicosis and coal miners' pneumoconiosis. Lesions
in diseases such as granulomatosis with polyangiitis (formerly termed Wegener granulomatosis)
and rheumatoid arthritis with rheumatoid nodules may also mimic lung abscess.
The clinical manifestations of lung abscesses are distinct from those of CAP, because
they are usually prolonged in time (2 weeks to 3 months or more) and include fever,
night sweats, cough with foul-smelling sputum, fatigue, weight loss, and sometimes
hemoptysis.
The typical appearance of a lung abscess on a chest radiograph is a thick-walled cavity
with an air-fluid level (see Fig. 33-13 and eFigure 33-4, eFigure 33-13, eFigure 33-15).
A contrast-enhanced CT is occasionally necessary to differentiate lung abscess from
other conditions, and bronchoscopy may be needed to distinguish lung abscess from
endobronchial carcinoma.
Antibiotics with activity against anaerobic and aerobic bacteria and that are unaffected
by the β-lactamases produced by anaerobes are the mainstay of treatment for lung abscesses.
228
Clindamycin has been widely used and is superior to penicillin alone, undoubtedly
because of the increasing prevalence of β-lactamase production by the anaerobes that
cause lung abscesses. More recently, β-lactam/β-lactamase inhibitor combinations (amoxicillin-clavulanate
or ampicillin-sulbactam) have been found to provide cure rates indistinguishable from
those with clindamycin; moxifloxacin and carbapenems have also been used successfully.
228
Metronidazole alone is not recommended, because it lacks sufficient activity against
microaerophilic streptococci and viridans streptococci that are often part of the
mixed microbial flora in lung abscesses. If metronidazole is used, penicillin should
be added to cover streptococci. The optimal duration of antibiotic treatment has not
been determined, although treatment for 6 to 8 weeks is commonly employed.
Failure to respond to antibiotics within 7 to 10 days warrants investigation for alternative
diagnoses or complications. Antibiotic treatment may fail if the patient has immunodeficiency,
if the cavity is large (>8 cm), or if the abscess is due to pyogenic bacteria such
as P. aeruginosa or S. aureus. CT-guided percutaneous transthoracic tube drainage
229
or endoscopic drainage
230
are alternatives to surgical resection; the reported success rates with both of these
procedures are high, although no prospective controlled trials have been reported.
Complications of CT-guided tube drainage include pneumothorax, pyopneumothorax, and
bronchopleural fistula. After drainage, patients show clinical improvement usually
in 48 hours. Persistent fever can also be seen if there is a secondary pleural empyema
that requires drainage.
Prevention of Pneumonia
Vaccines
Prevention of pneumonia may be achieved by administering the influenza and pneumococcal
vaccines. Recommendations for administration of influenza
231
and pneumococcal
232
vaccines are presented in eTable 33-8 and eTable 33-9, respectively.
eTable 33-8
Recommendations for Administration of Influenza Vaccine*
Inactivated vaccine: All persons aged 6 months and older including pregnant women
Live attenuated vaccine†: Healthy, nonpregnant women aged 2 to 49 years without high-risk
medical conditions
*
Avoid giving vaccine to patients with anaphylactic allergy to eggs or to other influenza
vaccine components. The optimal period for vaccination is October to November. However,
it is acceptable to provide vaccine from September to early March.
†
Health care personnel who care for severe immunocompromised persons should receive
inactivated rather than live vaccine.
Modified from Recommended Immunization schedule for adults aged 19 years and older.
MMWR 62:Suppl, 2013.
eTable 33-9
Recommendations for PPSV23 and PCV13 by Risk Group for Adults 19 Years and Older*
Risk Group
PCV13 Recommended
PPSV23 Recommended
PPSV23 Revaccination 5 Years after First Dose
Immunocompetent
Cerebrospinal fluid leak
Cochlear implant
Chronic heart diseases†
Chronic lung diseases‡
Diabetes mellitus
Chronic liver diseases
Cerebrospinal fluid leak
Cochlear implant
Alcohol
Smoking
Asplenia
Sickle cell disease/ hemoglobinopathy
Congenital or acquired asplenia
Sickle cell disease/ hemoglobinopathy
Congenital or acquired asplenia
Sickle cell disease/ hemoglobinopathy
Congenital or acquired asplenia
Immunocompromised
HIV
Congenital or acquired immunodeficiency
Chronic renal failure
Leukemia/lymphoma
Generalized malignancy
Solid organ transplant
Multiple myeloma
Iatrogenic immunosuppression§
HIV
Congenital or acquired immunodeficiency
Chronic renal failure
Leukemia/lymphoma
Generalized malignancy
Solid organ transplant
Multiple myeloma
Iatrogenic immunosuppression
HIV
Congenital or acquired immunodeficiency
Chronic renal failure
Leukemia/lymphoma
Generalized malignancy
Solid organ transplant
Multiple myeloma
Iatrogenic immunosuppression
*
All adults aged 65 years and older should receive PVC13 and PPSV23, with the sequence
and interval depending on previous history of vaccination with pneumococcal vaccine.
†
Including congestive heart failure and cardiomyopathies.
‡
COPD, emphysema, and asthma.
§
Including long-term systemic corticosteroids and radiation therapy.
Modified from Centers for Disease Control and Prevention: Tomczyk S, Bennett NM, Stoecker
C, et al: Use of 13-valent pneumococcal conjugate vaccine and 23-valent pneumococcal
polysaccharide vaccine among adults aged ≥ 65 years: recommendations of the Advisory
Committee on Immunization Practices (ACIP). MMWR Morb Mortal Wkly Rep 63(37):822–825,
2014.
Inactivated influenza vaccination is recommended annually for all persons aged 6 months
and older, including pregnant women. For those averse to injections, a live attenuated
influenza vaccine can be given by intranasal administration to healthy persons 5 to
49 years old. The live attenuated vaccine must be avoided in pregnancy, in high-risk
persons with chronic underlying diseases or immunodeficiencies, and in health care
staff taking care of immunosuppressed patients; it is not approved for use in those
older than 49 years. While annual influenza vaccination is widely recommended, the
immunogenicity and efficacy of the currently available vaccine is lower in individuals
older than 65 years of age, and breakthrough infections are frequent.
232
Two pneumococcal vaccines are currently available. The purified polysaccharide vaccine
(PPSV23) contains capsular antigens isolated from 23 of the most prevalent capsule
types and is immunogenic in adults, although antibody levels decrease to prevaccination
levels after 4 to 7 years. The pneumococcal conjugate vaccine (PCV13) contains the
polysaccharide antigens from 13 of the most prevalent capsule types, conjugated to
a nontoxic mutant of diphtheria toxin protein, which generates T-cell help and long
lived memory B cells specific for the pneumococcal antigens. PPSV23 should be administered
to all individuals 65 years of age and older, as well as those 19 to 64 years of age
with chronic conditions that increase the risk of invasive pneumococcal infection
(e.g., diabetes mellitus, chronic lung, heart, or liver disease; cigarette smoking
or alcoholism). Patients aged 19 years and older with immunodeficiencies or other
conditions that impose an especially high risk of invasive pneumococcal infection
(asplenia, HIV or other congenital or acquired immunodeficiencies, myeloma, lymphoma,
leukemia, chronic renal failure) should receive an initial dose of PCV13 followed
8 weeks or longer later by PPSV23. eTable 33-9 lists the conditions and indications
for which administration of each of the pneumococcal vaccines is currently recommended.
233
In 2014, the updated ACIP recommendations are that both PCV13 and PPSV23 should be
administered in series to all adults 65 years of age and older. A dose of PCV13 should
be received first followed by a dose of PPSV23 6 to 12 months later. Individuals previously
vaccinated with PPSV23 should be given a dose of PCV13 after approximately 1 year.234,
235
Smoking Cessation
Not only is smoking a risk factor for pneumococcal disease, quitting smoking reduces
the risk.
236
The IDSA/ATS recommend smoking cessation counseling as well as pneumococcal vaccination
for smokers who are hospitalized with pneumonia.
18
Key Points
▪
All patients with suspected pneumonia should have a chest radiograph. Gram stains
of sputum and cultures of blood, sputum, and other sites should be obtained in hospitalized
patients before treatment. S. pneumoniae and L. pneumophila urinary antigens can make
an etiologic diagnosis with reasonable sensitivity and specificity.
▪
Aspiration is the cause of infection with S. pneumoniae, H. influenzae, gram-negative
bacilli, and other organisms, whereas aerosolization is the route of infection with
intracellular bacteria such as M. pneumoniae, Chlamydophila species, and C. burnetii.
Aside from inhalational pneumonia due to Legionella or contaminated medical aerosols,
aspiration is the cause of hospital-acquired pneumonia, especially in intubated patients.
▪
Nucleic acid amplification tests should be used increasingly to diagnose viruses and
fastidious bacteria, M. pneumoniae, C. pneumoniae, L. pneumophila, and B. pertussis
because culture procedures are too insensitive and too slow to be relevant therapeutically.
▪
In older and immunocompromised patients, the signs and symptoms of pneumonia 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. Older patients with pneumonia who present with altered mental
status without fever often have a delay in receiving antibiotics; this delay can increase
mortality.
▪
The treatment for pneumonia should be pathogen-directed, but definitive identification
of the patient's causal pathogen may be difficult. Therefore, the setting in which
the patient resides (e.g., community, hospital, nursing home), the severity of the
disease, the age of the patient, the presence of comorbidities and immunosuppression,
previous antimicrobial therapy, and specific clinical and radiologic manifestations
of the illness are used to select initial empirical antimicrobial therapy.
▪
If the etiologic agent has been identified, the 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.
Complete reference list available at ExpertConsult.
eFigure Image Gallery
eFigure 33-1
Lobar pneumonia due to pneumococcus.
Frontal chest radiograph shows homogeneous increased opacity conforming to the shape
of the right upper lobe, extending to the pleural surfaces, associated with air bronchograms
(arrows). These findings are typical of air space consolidation, and the pattern is
consistent with lobar pneumonia, commonly seen with pneumococcal or Klebsiella pulmonary
infections.
(Courtesy Michael Gotway, MD.)
eFigure 33-2
Atypical pneumonia due to adenovirus.
Frontal chest radiograph in a pediatric patient shows multifocal, bilateral central
peribronchial thickening, typical of an infiltrative process involving the pulmonary
interstitium, such as viral infection.
(Courtesy Michael Gotway, MD.)
eFigure 33-3
Aspiration pneumonia.
A, Frontal chest radiograph shows right lower lobe consolidation and volume loss;
note shift of trachea and cardiomediastinal structures toward the right. Trace right
pleural effusion is present. B–E, Axial chest CT displayed in lung windows shows right
lower lobe consolidation associated with small centrilobular nodules (arrowheads)
consistent with bronchopneumonia and bronchiolitis. This pattern is consistent with
aspiration pneumonia, particularly when seen in dependent lung regions, but is not
completely specific for aspiration; community-acquired or health care–acquired bronchopneumonia
may appear similar. However, what is specific for aspiration in this circumstance
is the frank aspiration of orally administered contrast (E,
single arrow, oral contrast in right lower lobe bronchus; D and E,
double arrows, oral contrast extending into right lower lobe pulmonary parenchyma),
which flows directly into the affected regions of lung.
(Courtesy Michael Gotway, MD.)
eFigure 33-4
Lung abscess.
A, Frontal chest radiograph in a patient with cough and purulent sputum shows a thick-walled
cavity with an irregular internal lining and air-fluid level in the left apex. B–E,
Axial chest CT displayed in soft tissue windows shows a rounded area of low attenuation
(arrows) in the left upper lobe, surrounded by consolidation consistent with a pulmonary
abscess. The internal low attenuation is fluid density, and an air-fluid level is
present, typical of pulmonary abscess. Reactive prevascular lymph node enlargement
is also evident.
(Courtesy Michael Gotway, MD.)
eFigure 33-5
Percutaneous transthoracic sampling of a pulmonary abscess.
A and B, Axial chest CT shows placement of a needle into a left apical cavity (same
patient as in eFig. 33-4). Purulent fluid was recovered, with microbiologic analysis
disclosing polymicrobial infection. The lesion resolved with antibiotic therapy.
(Courtesy Michael Gotway, MD.)
eFigure 33-6
Pneumococcal bronchopneumonia.
A, Frontal chest radiograph shows patchy bronchovascular thickening (arrows) in the
left lower lobe; trace blunting of the left costophrenic angle is present. B, Axial
chest CT 2 days following A shows nodular lingular consolidation (arrow) and numerous
small centrilobular nodules (arrowheads) consistent with bronchopneumonia. This bronchopneumonia
pattern contrasts with the lobar pneumonia pattern (see Fig. 33-1 and eFig. 33-1).
Both imaging patterns may be seen with pneumococcal pneumonia.
(Courtesy Michael Gotway, MD.)
eFigure 33-7
Streptococcus intermedius pneumonia and empyema.
A, Frontal chest radiograph shows right lung consolidation and volume loss. Some increased
opacity adjacent to the chest wall suggests pleural disease but the findings are nonspecific.
B–E, Axial chest CT displayed in an intermediate window to highlight the lung parenchyma
and soft tissue features simultaneously, obtained shortly after A, shows a rounded
gas collection containing fluid along the right chest wall consistent with empyema
and bronchopleural fistula. S. intermedius was recovered following right thoracostomy
tube placement.
(Courtesy Michael Gotway, MD.)
eFigure 33-8
Haemophilus influenzae pneumonia: bronchiolitis.
A, Frontal chest radiograph shows several nonspecific small nodular opacities bilaterally
(arrowheads). B, Axial chest CT through the lung bases shows numerous small centrilobular
nodules (arrowheads), some with branching configurations (arrows), the latter consistent
with “tree-in-bud” opacity, representing infectious bronchiolitis. The appearance
of small centrilobular nodules with branching configurations is not specific for Haemophilus
influenzae pneumonia and can be seen with other bacteria and occasionally with fungi
or even viruses.
(Courtesy Michael Gotway, MD.)
eFigure 33-9
Mycoplasma pneumoniae pneumonia: multilobar pneumonia.
A, Frontal chest radiograph shows right lower lobe consolidation (arrow) associated
with several small nodular opacities (arrowheads), the latter consistent with “acinar”
or “air space” nodules. B, Axial chest CT through the lower lungs displayed in lung
windows shows extensive bilateral consolidation (arrows) associated with small nodules
(arrowheads), varying from 3 to 4 mm to 1 cm in size.
(Courtesy Michael Gotway, MD.)
eFigure 33-10
Mycoplasma pneumoniae pneumonia: unilateral bronchopneumonia.
Frontal (A) and lateral (B) chest radiographs in a patient with Mycoplasma pneumoniae
pneumonia show patchy right lower lobe consolidation (arrows) consistent with bronchopneumonia,
but nonspecific with regard to the specific microbiologic etiology.
(Courtesy Michael Gotway, MD.)
eFigure 33-11
Methicillin-resistant Staphylococcus aureus pneumonia.
A, Frontal chest radiograph in a patient subsequently proven to have methicillin-resistant
Staphylococcus aureus (MRSA) pneumonia shows left lung consolidation (arrows) with
internal lucency consistent with necrosis and cavitation. B, Axial chest CT displayed
in lung windows shows left lower lobe consolidation with internal lucency (arrows)
consistent with a necrotic pneumonia. The patient recovered following antibiotic therapy.
(Courtesy Michael Gotway, MD.)
eFigure 33-12
Klebsiella pneumoniae bronchopneumonia.
A, Frontal chest radiograph shows patchy right lower lobe opacity (arrows). B–E, Axial
chest CT through the lower lobes displayed in lung windows shows patchy nodular opacities
(arrows) consistent with bronchopneumonia but not specific for a microbial etiology.
(Courtesy Michael Gotway, MD.)
eFigure 33-13
Klebsiella pneumoniae lung abscess.
A, Frontal chest radiograph shows a subpleural right apical cavity (arrows) with an
air-fluid level consistent with a pulmonary abscess. Axial chest CT displayed in soft
tissue (B) and lung (C) windows shows a nonspecific cavity (arrows) consistent with
a pulmonary abscess but not specific for a specific microbiologic etiology.
(Courtesy Michael Gotway, MD.)
eFigure 33-14
Pseudomonas aeruginosa bronchopneumonia.
A–C, Axial chest CT through the lower lobes displayed in lung windows shows nodular
consolidation (A and C,
arrows) and numerous small centrilobular nodules with branching morphologies consistent
with “tree-in-bud” opacities (arrowheads).
(Courtesy Michael Gotway, MD.)
eFigure 33-15
Pseudomonas aeruginosa cavitary pneumonia.
Frontal chest radiograph in a patient with P. aeruginosa pneumonia shows a large right
upper lobe thick-walled cavity (arrows).
(Courtesy Michael Gotway, MD.)
eFigure 33-16
Pseudomonas aeruginosa cavitary pneumonia.
Axial chest CT displayed in lung windows of a patient with P. aeruginosa pneumonia
shows several small, relatively thin-walled peripheral right upper lobe cavities (arrows).
(Courtesy Michael Gotway, MD.)
eFigure 33-17
Legionella pneumophila pneumonia: multilobar pneumonia.
Frontal chest radiograph in a patient with Legionella pneumonia and respiratory failure
shows left-greater-than-right multilobar consolidation.
(Courtesy Michael Gotway, MD.)
eFigure 33-18
Aspiration pneumonia: bronchopneumonia/bronchiolitis appearance at chest CT.
A and B, Axial chest CT through the lower lobes displayed in lung windows in a patient
with swallowing dysfunction shows numerous small centrilobular nodules, some with
branching morphologies (arrowheads), and peribronchial consolidation (arrows). The
imaging appearance is consistent with bronchopneumonia, but not specific for aspiration.
Note resemblance of this CT appearance with P. aeruginosa pneumonia (see eFig. 33-14),
Haemophilus influenzae pneumonia (see eFig. 33-8B), and pneumococcal bronchopneumonia
(see eFig. 33-6).
(Courtesy Michael Gotway, MD.)
eFigure 33-19
Aspiration bronchopneumonia: rapid appearance of new lung opacity at imaging and dependent
lung involvement.
Frontal chest radiograph performed at admission (A) shows clear lungs; several days
later, following a witnessed aspiration event, the radiograph (B) shows development
of multifocal peribronchial nodular foci (arrowheads). C, Lower thoracic images from
an abdominal CT scan several weeks before A and B shows only minimal basal atelectasis.
D and E, Axial chest CT through the lower lobes performed immediately following B
shows peribronchial consolidation (D,
arrows) and extensive lower lobe, dependent consolidation (E,
arrows). Note volume loss, evidenced by posterior displacement of the major fissures.
(Courtesy Michael Gotway, MD.)
eFigure 33-20
Anaerobic pneumonia.
A–D, Axial chest CT in a patient with polymicrobial anaerobic pneumonia shows multifocal
consolidation in the right middle lobe (A and B,
arrows) and bilateral lower lobes. The soft tissue window images show the right middle
lobe consolidation to be hypovascular; compare attenuation characteristics of the
right middle lobe opacity (arrows, B) with the appearance of the lower lobe consolidation
(arrowheads,
B). After several days, the poorly defined hypovascular right middle lobe consolidation
(B,
arrows,) evolved into discrete abscesses (D,
arrowheads).
(Courtesy Michael Gotway, MD.)
eFigure 33-21
Evolution of pulmonary aspiration into lung abscess.
A, Axial chest CT displayed in soft tissue windows performed shortly following a witnessed
aspiration event shows extensive bilateral lower lobe consolidation (arrows). B, Contrast-enhanced
chest CT performed several days following A shows developing necrosis and cavitation
(arrowheads) within the lower lobe consolidation. C and D, Repeat contrast-enhanced
chest CT performed over the ensuing week following A and B shows maturation of frank
bilateral lower lobe pulmonary abscesses (arrowheads); note well-defined, enhancing
walls surrounding these gas and fluid collections. E, Axial enhanced chest CT following
3 weeks of antibiotic therapy shows partial resolution of the bilateral lower lobe
pulmonary abscesses (arrowheads).
(Courtesy Michael Gotway, MD.)
eFigure 33-22
Actinomycosis: cavitary nodule.
A, Frontal chest radiograph shows right upper lobe consolidation and a poorly defined
nodular opacity (arrow). B, Frontal chest radiograph 2 weeks following A shows resolution
of the right upper lobe consolidation, now exposing a dominant cavitary right apical
nodule with internal opacity (arrow), and small surrounding nodules (arrowheads).
C and D, Axial chest CT displayed in lung windows performed within 1 day of the presenting
chest radiograph (A) shows the right apical opacity as a cavitary nodule with an internal
air-fluid level; surrounding ground-glass opacity and consolidation are present, as
seen on the chest radiograph (A). E and F, Chest CT displayed in lung windows performed
the same day as B shows the dominant right apical opacity with complex internal architecture
(arrows) and confirms small surrounding nodules. Biopsy of this lesion recovered Actinomyces
israelii.
(Courtesy Michael Gotway, MD.)
eFigure 33-23
Actinomycosis: chest wall involvement.
A, Frontal chest radiograph shows a right lower lung mass. This finding is nonspecific.
B, Rib detail radiograph shows subtle periosteal reaction (arrowheads) with erosion
of the inferior rib cortex (arrow) consistent with chest wall invasion. Biopsy of
the right lung mass recovered Actinomyces israelii.
(Courtesy Michael Gotway, MD.)
eFigure 33-24
Gram stain of an actinomycotic sulfur granule.
A, Original magnification ×100; B, original magnification ×400.
eFigure 33-25
Nocardia asteroides pulmonary infection: consolidation.
A, Axial chest CT shows extensive bilateral lower lobe consolidation and more anteriorly
located interstitial thickening and ground-glass opacity. The right lower lobe consolidation
was cavitary at a more inferior level. B, Axial chest CT in a different patient shows
bilateral lower lobe masslike opacities (arrows); biopsy of the left lower lobe lesion
recovered Nocardia asteroides.
(Courtesy Michael Gotway, MD.)
eFigure 33-26
Nocardia asteroides pulmonary infection: multiple nodules.
A and B, Axial chest CT in an immunosuppressed renal transplant recipient shows multiple
bilateral nodules, many of which are solid-appearing (arrowheads), due to N. asteroides.
C–E, Axial chest CT in another immunosuppressed renal transplant recipient shows ground-glass
opacity nodules (arrowheads), also shown to be due to N. asteroides.
(Courtesy Michael Gotway, MD.)
eFigure 33-27
Nocardia asteroides pulmonary infection: abscess.
A, Frontal chest radiograph shows a poorly defined opacity (arrows) in the subpleural
right upper lobe. B and C, Axial chest CT displayed in lung windows shows a subpleural
right upper lobe cavity (arrows) containing an air-fluid level. This lesion is nonspecific
in appearance and could be the result of a number of infections, but N. asteroides
was recovered at biopsy.
(Courtesy Michael Gotway, MD.)
eFigure 33-28
Modified acid-fast stain of sputum containing Nocardia asteroides shows filamentous
branching organisms.
eFigure 33-29
An infectious cause of “nonresponding” pneumonia: amebic pleuropulmonary infection.
A, Frontal chest radiograph in a 23-year-old man with fever and chest pain shows right
lower lobe consolidation and a small-to-moderate right pleural effusion, presumed
to represent pneumonia and parapneumonic effusion. B and C, Axial chest CT after the
patient failed to respond to therapy for community-acquired pneumonia was performed
to assess right pleural fluid drainage following thoracostomy tube placement (the
thoracostomy tube is visible posteriorly in B). Chest CT performed through the right
lower lung (B) shows consolidation with central low-attenuation (arrow), the latter
consistent with a pulmonary abscess or area of necrosis. Chest CT through the extreme
lung base and upper abdomen (C) shows a low attenuation focus (arrowhead) in the cranial
liver (L), also consistent with an abscess. The liver and lung lesions are in close
proximity to one another, suggesting that the liver lesion may have extended through
the diaphragm to produce the lung findings; such behavior is typical of an amebic
abscess. Further evaluation revealed that the patient recently immigrated to the United
States from Mexico, and stool analysis recovered Entamoeba histolytica trophozoites.
(Courtesy Michael Gotway, MD.)
eFigure 33-30
Noninfectious “nonresponding” pneumonia: invasive mucinous adenocarcinoma (formerly
referred to as mucinous bronchioloalveolar carcinoma).
A, Frontal chest radiograph in a patient with persistent shortness of breath shows
right lower lobe consolidation. The patient was treated with broad-spectrum antibiotics
for presumed community-acquired pneumonia. B, Repeat frontal chest radiograph 3 months
following A shows no change in the appearance of the right lower lobe opacity. C,
Axial chest CT through the right lung base shown in lung windows reveals relatively
nonspecific subpleural consolidation with air bronchograms and reticulation associated
with ground-glass opacity. D, Fused FDG-PET image shows the right lower lobe opacity
to be hypermetabolic. Bronchoscopic evaluation did not disclose a specific diagnosis
for the persistent right lower lobe opacity. Resection of the right lower lobe proved
invasive mucinous adenocarcinoma.
(Courtesy Michael Gotway, MD.)