# 10 - 131 Pneumonia

### 131 Pneumonia

Section 2	 Clinical Syndromes: 
Community-Acquired Infections
Lionel A. Mandell,

Michael S. Niederman

Pneumonia
DEFINITION
Pneumonia is an infection of the pulmonary parenchyma. Despite 
significant morbidity and mortality, it is often misdiagnosed, mis­
treated, and underestimated. Pneumonia has usually been classified as 
community-acquired (CAP), hospital-acquired (HAP), or ventilatorassociated (VAP). A fourth category, healthcare-associated pneumonia, 
should be discontinued because it did not reliably predict infection 
with resistant pathogens and was associated with increased use of 
broad-spectrum antibiotics. Rather than relying on a predefined subset 
of pneumonia cases, it is better to assess patients individually based 
on risk factors for infection with a resistant organism, such as certain 
comorbid illnesses, recent hospitalization, or recent antibiotic therapy.
Pneumonia caused by macroaspiration of oropharyngeal or gastric 
contents, usually referred to as aspiration pneumonia, is best thought 
of as a point on the continuum that includes CAP and HAP. Estimates 
suggest that aspiration pneumonia accounts for 5–15% of CAP cases, 
but reliable figures for HAP are unavailable. The airways or pulmonary 
parenchyma may be involved, and patients usually represent a clinical 
phenotype with risk factors for macroaspiration and involvement of 
characteristic anatomic pulmonary locations.
In this chapter, we will not be dealing with pneumonia in immuno­
compromised hosts.
PATHOPHYSIOLOGY
Pneumonia is the result of the proliferation of microbial pathogens 
in the alveoli and the host’s response to them. Until recently, it was 
thought that the lungs were sterile and that pneumonia resulted from 
the introduction of potential pathogens into this sterile environment. 
Typically, this introduction occurred through microaspiration of oro­
pharyngeal organisms into the lower respiratory tract. The overcoming 
of innate and adaptive immunity by such microorganisms could result 
in the clinical syndrome of pneumonia.
A complex and diverse community of bacteria in the lungs consti­
tutes the lung microbiota. Awareness of this microbiota has prompted 
a rethinking of how pneumonia develops. Mechanical factors, such as 
the hairs and turbinates of the nares, the branching tracheobronchial 
tree, mucociliary clearance, and gag and cough reflexes, play roles in 
host defense but are insufficient to effectively block bacterial access to 
the lower airways. In the absence of a sufficient barrier, microorgan­
isms may reach the lower respiratory tract by a variety of pathways, 
including inhalation, microaspiration, and direct mucosal dispersion.
The constitution of the lung microbiota is determined by three fac­
tors: microbial entry into the lungs, microbial elimination, and regional 
growth conditions for bacteria, such as pH, oxygen tension, and tem­
perature. The key question, however, is how a dynamic homeostasis 
among bacterial communities results in acute infection. Pneumonia 
therefore does not appear to be the result of the invasion of a sterile 
space by a particular microorganism but is more likely an emergent 
phenomenon dependent upon a number of mechanisms, including 
self-accelerating positive feedback loops.
A possible model for pneumonia is as follows. An inflamma­
tory event resulting in epithelial and/or endothelial injury results in 
the release of cytokines, chemokines, and catecholamines, some of 
which may selectively promote the growth of certain bacteria, such as 
Streptococcus pneumoniae and Pseudomonas aeruginosa. This cycle of 
inflammation, enhanced nutrient availability, and release of potential 

bacterial growth factors may result in a positive feedback loop that 
further accelerates inflammation and the growth of particular bacteria, 
which may then become dominant. In cases of CAP and HAP, the 
trigger may be a viral infection compounded by microaspiration of 
oropharyngeal organisms. In cases of true aspiration pneumonia, the 
trigger may possibly be the macroaspiration event itself.

Once triggered, innate and adaptive immune responses can help 
contain potential pathogens and prevent the development of pneumo­
nia. However, in the face of continuing inflammation (and especially if 
a positive feedback loop becomes sustainable), the process may proceed 
to a full-fledged pneumonia syndrome. Inflammatory mediators such 
as interleukin 6 and tumor necrosis factor result in fever, and chemo­
kines such as interleukin 8 and granulocyte colony-stimulating factor 
increase local neutrophil numbers. Mediators released by macrophages 
and neutrophils may create an alveolar capillary leak, resulting in 
impaired oxygenation, hypoxemia, and radiographic infiltrates. Bacte­
ria themselves may produce toxins that further amplify the inflamma­
tory response. Moreover, some bacterial pathogens appear to interfere 
with the hypoxic vasoconstriction that would normally occur with 
fluid-filled alveoli, possibly resulting in severe hypoxemia. Decreased 
compliance due to capillary leak, hypoxemia, increased respiratory 
drive, increased secretions, and occasionally infection-related bron­
chospasm all lead to worsening dyspnea. If severe enough, changes in 
lung mechanics secondary to reductions in lung volume, compliance, 
and intrapulmonary shunting of blood may cause respiratory failure.
PATHOLOGY
Classic pneumonia evolves through a series of stages. The initial stage 
is edema with a proteinaceous exudate and often bacteria in the alveoli. 
Next is a rapid transition to the red hepatization phase. Erythrocytes in 
this intraalveolar exudate give this stage its name. In the third phase, 
gray hepatization, erythrocytes have been lysed and degraded. The 
neutrophil is the predominant cell, fibrin deposition is abundant, and 
bacteria have disappeared. This phase corresponds with the successful 
containment of the infection and improvement in gas exchange. In the 
final phase, resolution, the macrophage reappears as the dominant cell 
in the alveolar space and the debris of neutrophils, bacteria and fibrin 
has been cleared, as has the inflammatory response.
CHAPTER 131
Pneumonia
This pattern has been described best for lobar pneumococcal pneu­
monia but may not apply to pneumonia of all etiologies. In VAP, respi­
ratory bronchiolitis may precede the development of a radiologically 
apparent infiltrate. A bronchopneumonia pattern is most common in 
nosocomial pneumonias, whereas a lobar pattern is more common in 
bacterial CAP. Despite the radiographic appearance, viral and Pneumo­
cystis pneumonias represent alveolar rather than interstitial processes.
COMMUNITY-ACQUIRED PNEUMONIA
■
■ETIOLOGY
Numerous microbes may cause CAP, including a variety of bacteria, 
viruses, fungi, and protozoa.
Newer viral pathogens include metapneumoviruses, the coronavi­
ruses responsible for severe acute respiratory syndrome (SARS) and 
Middle East respiratory syndrome (MERS), and the SARS-CoV-2 
coronavirus. First described in December 2019, SARS-CoV-2 and its 
associated clinical disease, COVID-19, reached pandemic proportions 
and are a cause of significant morbidity and mortality. The COVID-19 
pandemic has changed the etiologic profile of CAP, and the ultimate 
role that the SARS-CoV-2 virus will play as a cause of CAP remains to 
be seen. The virus and the disease are discussed in detail in Chap. 205.
Although most CAP cases are caused by relatively few pathogens, an 
accurate determination of their prevalence is difficult because labora­
tory testing methods are often insensitive and indirect (Table 131-1). 
Separation of potential agents into “typical” bacterial pathogens and 
“atypical” organisms may be helpful, although both types of pathogens 
can lead to similar clinical syndromes. The former group includes S. 
pneumoniae, Haemophilus influenzae, and, in selected patients, Staphylo­
coccus aureus and gram-negative bacilli such as Klebsiella pneumoniae and 
P. aeruginosa. The “atypical” organisms include Mycoplasma pneumoniae,

TABLE 131-1  Microbial Causes of Community-Acquired Pneumonia, 
by Site of Care
HOSPITALIZED PATIENTS
OUTPATIENTS
NON-ICU
ICU
Streptococcus 
pneumoniae
Mycoplasma pneumoniae 
Haemophilus influenzae
Chlamydia pneumoniae
Respiratory virusesa
S. pneumoniae
M. pneumoniae
C. pneumoniae
H. influenzae
Legionella spp.
Respiratory virusesa
S. pneumoniae
Staphylococcus aureus 
Legionella spp.
Gram-negative bacilli
H. influenzae
Respiratory virusesa
aInfluenza A and B viruses, SARS-CoV-2 and other coronaviruses, human 
metapneumovirus, adenoviruses, respiratory syncytial viruses, parainfluenza 
viruses.
Abbreviation: ICU, intensive care unit.
Chlamydia pneumoniae, and Legionella species as well as respiratory 
viruses such as influenza, adenoviruses, human metapneumoviruses, 
respiratory syncytial virus, and coronaviruses. With the increasing use 
of pneumococcal vaccine, the incidence of pneumococcal pneumonia 
is decreasing. M. pneumoniae plays more of a role in ambulatory cases, 
whereas Legionella tends to be associated with more serious cases and can 
be found in outbreaks, as well. C. pneumoniae now appears to account 
for <1% of CAP cases. Viruses are recognized as increasingly important 
in pneumonia, and polymerase chain reaction (PCR)–based testing indi­
cates their presence in the respiratory tract of 20–30% of healthy adults 
and in the same percentage of pneumonia patients, including those who 
are severely ill. The most common are influenza, parainfluenza, and 
respiratory syncytial viruses. Whether they are true etiologic pathogens, 
co-pathogens, or simply colonizers cannot always be determined. Atypi­
cal organisms cannot be cultured on standard media or seen on Gram 
stain, but their frequency and importance have significant implications 
for therapy. They are intrinsically resistant to all β-lactam antibiotics and 
require treatment with a macrolide, fluoroquinolone, or a tetracycline. 
In the 10–15% of CAP cases that are polymicrobial, the etiology usually 
includes a combination of typical and atypical pathogens.
PART 5
Infectious Diseases
Earlier literature suggested that aspiration pneumonia was caused 
primarily by anaerobes, with or without aerobic pathogens. A shift, 
however, has been noted recently: if aspiration pneumonia is acquired 
in a community or hospital setting, the likely pathogens are those 
usually associated with CAP or HAP. Anaerobes may still play a role, 
especially in patients with poor dentition, lung abscess, necrotizing 
pneumonia, or empyema.
S. aureus pneumonia is known to complicate influenza virus 
infection. However, methicillin-resistant S. aureus (MRSA) has been 
reported as a primary etiologic agent of CAP. Although cases caused 
by MRSA are relatively uncommon, clinicians must be aware of its 
potentially serious consequences, such as necrotizing pneumonia. Two 
factors have led to this problem: the spread of MRSA from the hospital 
setting to the community and the emergence of genetically distinct 
MRSA strains in the community associated with bacterial toxin pro­
duction. Community-associated MRSA (CA-MRSA) strains may infect 
healthy individuals who have had no association with health care.
Despite a careful history, physical examination, and radiographic 
studies, the causative pathogen is often difficult to predict with 
certainty, and in more than half of cases, a specific etiology is not 
determined. Nevertheless, epidemiologic and risk factors may suggest 
certain pathogens (Table 131-2).
■
■EPIDEMIOLOGY
It is estimated that 7 million or more CAP cases occur annually in the 
United States. The annual incidence in adults ranges from 16 to 23 
per 1000 population. The incidence of hospitalization is 650/100,000 
but rises dramatically to 2000/100,000 yearly in the elderly. Overall, 
approximately 30% of patients are hospitalized, resulting in 1.5 million 
admissions. Along with influenza, CAP is the eighth leading cause of 
death in the United States, resulting in >60,000 deaths annually. The 
mortality rate among outpatients is usually <5% but ranges from ~12 to 
40% among hospitalized patients. The exact rate depends on whether 

TABLE 131-2  Epidemiologic Factors Suggesting Possible Causes of 
Community-Acquired Pneumonia
FACTOR
POSSIBLE PATHOGEN(S)
Alcoholism
Streptococcus pneumoniae, oral anaerobes, 
Klebsiella pneumoniae, Acinetobacter spp., 
Mycobacterium tuberculosis
COPD and/or smoking
Haemophilus influenzae, Pseudomonas 
aeruginosa, Legionella spp., S. pneumoniae, 
Moraxella catarrhalis, Chlamydia pneumoniae
Structural lung disease 

(e.g., bronchiectasis)
P. aeruginosa, Burkholderia cepacia, 
Staphylococcus aureus
Dementia, stroke, decreased
level of consciousness
Oral anaerobes, gram-negative enteric bacteria
Lung abscess
CA-MRSA, oral anaerobes, endemic fungi,
M. tuberculosis, nontuberculous mycobacteria
Travel to Ohio or St. 
Lawrence river valley
Histoplasma capsulatum
Travel to southwestern
United States
Hantavirus, Coccidioides spp.
Travel to Southeast Asia
Burkholderia pseudomallei, avian influenza virus
Stay in hotel or on cruise
ship in previous 2 weeks
Legionella spp.
Local influenza activity
Influenza virus, S. pneumoniae, S. aureus
Exposure to infected 
humans
SARS-CoV-2
Exposure to birds
H. capsulatum, Chlamydia psittaci
Exposure to rabbits
Francisella tularensis
Exposure to sheep, goats,
parturient cats
Coxiella burnetii
Abbreviations: CA-MRSA, community-acquired methicillin-resistant Staphylococcus 
aureus; COPD, chronic obstructive pulmonary disease; SARS-CoV-2, severe acute 
respiratory syndrome coronavirus 2.
treatment takes place in or outside the intensive care unit (ICU). In the 
United States, CAP is the leading cause of death from infection among 
patients >65 years of age. Moreover, 18% of hospitalized CAP patients 
are readmitted within 1 month of discharge. The overall yearly CAP 
cost is estimated at $17 billion.
Risk factors for CAP in general and pneumococcal pneumonia in 
particular have implications for treatment. They include alcoholism, 
asthma, immunosuppression, institutionalization, and age >70 years. In 
the elderly, decreased cough and gag reflexes and reduced antibody and 
Toll-like receptor responses increase the likelihood of pneumonia. Risk 
factors for pneumococcal pneumonia include dementia, seizure disor­
ders, heart failure, cerebrovascular disease, alcoholism, tobacco smoking, 
chronic obstructive pulmonary disease (COPD), and HIV infection. 
CA-MRSA pneumonia is more likely in patients with skin coloniza­
tion or infection with CA-MRSA at other sites, and after viral infection. 
Enterobacteriaceae tend to infect patients recently hospitalized, given 
antibiotics, or who have comorbidities such as alcoholism, heart failure, 
or renal failure. P. aeruginosa is a particular problem in patients with 
severe structural lung disease (e.g., bronchiectasis, cystic fibrosis, or 
severe COPD). Risk factors for Legionella infection include diabetes, 
hematologic malignancy, cancer, severe renal disease, HIV infection, 
smoking, male gender, and a recent hotel stay or cruise ship trip.
■
■CLINICAL MANIFESTATIONS
The clinical presentation of pneumonia can vary from indolent to 
fulminant and from mild to fatal. Manifestations of worsening severity 
include both constitutional findings and those limited to the lung and 
associated structures. The patient is frequently febrile and/or tachy­
cardic and may experience chills and/or sweats. Cough may be non­
productive or productive of mucoid, purulent, or blood-tinged sputum. 
Gross hemoptysis is suggestive of necrotizing pneumonia (e.g., that 
due to CA-MRSA). Depending on severity, shortness of breath may be 
present, and pleural involvement may result in chest pain. Up to 20% of

patients may have gastrointestinal symptoms such as nausea, vomiting, 
or diarrhea. Other symptoms may include fatigue, headache, myalgias, 
and arthralgias.
Findings on physical examination vary with the degree of pulmo­
nary consolidation and the presence or absence of a significant pleural 
effusion. An increased respiratory rate and use of accessory muscles of 
respiration are common. Palpation may reveal increased or decreased 
tactile fremitus, and the percussion note can vary from dull to flat, 
reflecting underlying consolidated lung and pleural fluid, respectively. 
Crackles, bronchial breath sounds, and possibly a pleural friction rub 
may be heard. The clinical presentation may be less obvious in the 
elderly, who may initially display new-onset or worsening confusion, or 
worsening of a chronic illness, but few other manifestations. Severely 
ill patients may have septic shock and organ failure. In cases of CAP, 
symptoms can range from almost nonexistent to severe, and in those 
with aspiration pneumonia, chest radiographic findings are often in 
gravity-dependent parts of the lung.
■
■DIAGNOSIS
When confronted with possible CAP, the physician must ask two ques­
tions: Is this pneumonia, and, if so, what is the likely pathogen? The 
former question is answered by clinical and radiographic methods, 
whereas the latter requires laboratory techniques.
Clinical Diagnosis 
The differential diagnosis includes infectious 
and noninfectious entities, including acute bronchitis, exacerbations 
of chronic bronchitis, heart failure, and pulmonary embolism. The 
importance of a careful history cannot be overemphasized. The diag­
nosis of CAP requires a compatible history, such as cough, sputum pro­
duction, fever and dyspnea, and a new infiltrate on chest radiography.
Unfortunately, the sensitivity and specificity of physical examina­
tion findings are only 58% and 67%, respectively. Chest radiography is 
often unable to differentiate CAP from other conditions. Radiographic 
findings may suggest increased severity (e.g., cavitation or multilobar 
involvement) and occasionally suggest an etiologic diagnosis, such as 
pneumatoceles in S. aureus infection or an upper-lobe cavitating lesion 
in tuberculosis. Computed tomography (CT) may be of value in sus­
pected loculated effusion or cavitary cases or in postobstructive pneu­
monia caused by a tumor or foreign body. For outpatients, clinical and 
radiologic assessments are usually all that is required before treatment 
is started since most laboratory results are not available soon enough 
to influence initial management. In certain cases, the availability of 
rapid point-of-care outpatient tests can be important, such as for rapid 
diagnosis of influenza infection, and can prompt specific anti-influenza 
treatment and secondary prevention measures.
Etiologic Diagnosis 
The etiology of pneumonia usually cannot 
be determined solely on the basis of clinical or radiographic presenta­
tion. Data from >17,000 emergency department CAP cases showed an 
etiologic determination in only 7.6%. Except for CAP patients admitted 
to the ICU, no data exist showing that treatment directed at a specific 
pathogen is statistically superior to empirical therapy. The benefit of 
establishing a microbial etiology may be questioned, particularly in 
light of the cost of diagnostic testing. However, a number of reasons 
exist for attempting an etiologic diagnosis. Identification of a specific 
or unexpected pathogen allows focusing of the initial empirical regi­
men, with a consequent decrease in antibiotic selection pressure and 
the risk of resistance. Pathogens with important public safety implica­
tions, such as Mycobacterium tuberculosis, influenza, and SARS-CoV-2 
viruses, may be found. Finally, without susceptibility data, trends in 
resistance cannot be followed accurately, and appropriate empirical 
therapeutic regimens are harder to devise.
GRAM STAIN AND CULTURE OF SPUTUM  The main purpose of the 
sputum Gram stain is to ensure suitability of a specimen for culture. 
To be suitable, a sputum sample must have >25 neutrophils and <10 
squamous epithelial cells per low-power field. However, staining may 
also identify certain pathogens (e.g., S. pneumoniae, S. aureus, and 
gram-negative bacteria). The sensitivity and specificity of the sputum 
Gram stain and culture are highly variable. Even in cases of proven 

bacteremic pneumococcal pneumonia, the positive sputum cultures 
are ≤50%.

Many patients, particularly elderly individuals, may be unable to 
produce an appropriate sputum sample. Others may be taking antibiot­
ics that interfere with culture results. Inability to produce sputum can 
be caused by dehydration, whose correction may result in increased 
sputum production and a more obvious infiltrate on chest radiography. 
For patients admitted to the ICU and intubated, a deep-suction aspirate 
or bronchoalveolar lavage sample has a high yield on culture when sent 
to the laboratory as soon as possible. Since pathogens in severe and 
mild CAP may differ (Table 131-1), the greatest benefit of staining and 
culturing respiratory secretions is to alert the physician to unexpected 
and/or resistant pathogens and to permit appropriate modification of 
therapy. Other stains and cultures (e.g., for M. tuberculosis or fungi) 
may be useful as well. The sputum Gram stain and culture are recom­
mended only for hospitalized CAP patients, particularly those with 
severe cases or those with risks of MRSA or P. aeruginosa infection.
BLOOD CULTURES  The yield from blood cultures, even when samples 
are collected before antibiotic therapy, is disappointingly low. Only 
5–14% of cultures from hospitalized CAP patients are positive, and 
the most common pathogen is S. pneumoniae followed by S. aureus 
and P. aeruginosa. Since recommended empirical regimens all provide 
pneumococcal coverage, a blood culture positive for this pathogen has 
little, if any, effect on clinical outcome. However, susceptibility data 
may allow narrowing of antibiotic therapy in appropriate cases, and 
such data help to track microbial resistance patterns on a national basis. 
Because of the low yield and lack of significant impact on outcome, 
blood cultures are not considered de rigueur for all hospitalized CAP 
patients. Certain high-risk patients should have blood cultured, includ­
ing those with neutropenia secondary to pneumonia, asplenia, comple­
ment deficiencies, chronic liver disease, or severe CAP and those at risk 
of MRSA or P. aeruginosa infection.
CHAPTER 131
URINARY ANTIGEN TESTS  Two commercially available tests detect 
pneumococcal and Legionella urinary antigens. The Legionella pneu­
mophila test detects only serogroup 1, which accounts for most 
community-acquired cases of Legionnaires’ disease in the United States. 
Its sensitivity and specificity are 70% and 99%, respectively. The pneu­
mococcal urine antigen test also is quite sensitive and specific (70% and 
>90%, respectively). Although false-positive results can be obtained for 
pneumococcus-colonized children, the test is generally reliable. Both 
tests can detect antigen even after initiation of appropriate antibiotic 
therapy. Testing for urinary pneumococcal antigen can be reserved for 
severe cases; Legionella antigen can be sought in severe cases and when 
relevant epidemiologic factors are present.
Pneumonia
POLYMERASE CHAIN REACTION  PCR tests amplify a microorganism’s 
DNA or RNA, and multiplex PCR panels test for a number of viral and 
bacterial pathogens. These tests dramatically improve response times, 
compared to standard cultures, but the contamination of respiratory 
specimens by upper-airway flora may make semiquantitative or quan­
titative assays necessary for best results. PCR of nasopharyngeal swabs 
has become the standard for diagnosis of respiratory viral infection, 
including influenza and coronaviruses. PCR can also detect the nucleic 
acid of Legionella species, M. pneumoniae, C. pneumoniae, and myco­
bacteria. The cost-effectiveness of PCR testing, however, has not been 
definitively established.
SEROLOGY  A fourfold rise in specific IgM antibody titer between 
acute- and convalescent-phase serum samples is generally considered 
diagnostic of infection with a particular pathogen. Until recently, 
serologic tests were used to help identify atypical pathogens as well as 
selected unusual organisms such as Coxiella burnetii. However, these 
tests have fallen out of favor because of the delays in obtaining conva­
lescent phase results and difficulties with interpretation.
BIOMARKERS  Two of the most commonly used markers are C-reactive 
protein (CRP) and procalcitonin (PCT). Levels of these acute-phase 
reactants increase in the presence of an inflammatory response, par­
ticularly to bacterial pathogens. Nevertheless, PCT is insufficiently 
accurate for use in the diagnosis of bacterial CAP, and initial serum

PCT levels should not be used as a basis for withholding initial anti­
biotic treatment. CRP is considered even less sensitive than PCT for 
detecting bacterial pathogens. These tests should not be used alone but, 
in conjunction with findings from the history, physical examination, 
radiography, and laboratory tests, may facilitate antibiotic stewardship 
and appropriate management of seriously ill CAP patients.

TREATMENT
Community-Acquired Pneumonia 
SITE OF CARE
The decision to hospitalize a patient with CAP has considerable 
implications. The cost of inpatient management exceeds outpa­
tient treatment by a factor of 20, and hospitalization accounts for 
most CAP-related expenditures. However, late admission to the 
ICU is associated with increased mortality rates. The choice can 
be difficult: some patients can be managed at home, while others 
require hospitalization. Tools that objectively assess the risk of 
adverse outcomes, including severe illness and death, can help to 
minimize unnecessary hospitalizations. The two most frequently 
used are the Pneumonia Severity Index (PSI), a prognostic model 
that identifies patients at low risk of dying, and the CURB-65 
criteria, which yield a severity-of-illness score.
To determine the PSI, points are given for 20 variables, including 
age, coexisting illness, and abnormal physical and laboratory find­
ings. Based on the score, patients are assigned to one of five classes 
with these mortality rates: class 1, 0.1%; class 2, 0.6%; class 3, 2.8%; 
class 4, 8.2%; and class 5, 29.2%. Using the PSI results in lower 
admission rates for class 1 and 2 patients. Class 3 patients could ide­
ally be admitted to an observation unit pending further decisions.
PART 5
Infectious Diseases
The CURB-65 criteria include five variables: confusion (C); urea 
>7 mmol/L (U); respiratory rate ≥30/min (R); blood pressure—
systolic ≤90 mmHg or diastolic ≤60 mmHg (B); and age ≥65 years. 
Patients with a score of 0 (a 30-day mortality rate of 1.5%) can be 
treated as outpatients. With a score of 1 or 2, the patient should be 
hospitalized unless the score is entirely or in part attributable to an 
age of ≥65 years; in such cases, hospitalization may not be neces­
sary. Among patients with scores of ≥3, mortality rates are 22% 
overall; these patients may require ICU admission. The PSI score 
has greater efficacy and has been more robustly validated than the 
CURB-65 criteria but is more difficult to calculate.
In general, if a patient is unable to maintain oral intake, if 
compliance may be an issue when assessed on the basis of mental 
condition or living situation (e.g., cognitive impairment or home­
lessness), or if the patient’s O2 saturation on room air is <92%, 
hospitalization is necessary. If these considerations do not apply, 
clinical judgment in conjunction with a prediction rule should be 
used to determine the site of care.
Neither PSI nor CURB-65 is accurate in determining the need for 
ICU admission. Patients with septic shock requiring vasopressors or 
with acute respiratory failure requiring intubation and mechanical 
ventilation should be admitted directly to an ICU (Table 131-3), 
and those with three of the nine minor criteria listed in the latter 
table should be admitted to an ICU or a high-level monitoring unit. 
Mortality rates were higher among less ill patients who were admit­
ted to a medical floor but then deteriorated than among equally ill 
patients initially monitored in the ICU. 
ANTIBIOTIC RESISTANCE
Antimicrobial resistance is a significant problem that threatens 
to diminish our therapeutic armamentarium. Antibiotic misuse 
results in increased antibiotic selection pressure that can affect 
resistance locally and globally by clonal dissemination. For CAP, 
the main resistance issues currently involve S. pneumoniae and 
CA-MRSA. 
S. pneumoniae  In general, pneumococcal resistance to β-lactams 
is acquired by (1) direct DNA incorporation and remodeling of 
penicillin-binding proteins through contact with closely related 

TABLE 131-3  Criteria for Severe Community-Acquired Pneumonia
Minor criteria
  Respiratory rate ≥30 breaths/min
  PaO2/FiO2 ratio ≤250
  Multilobar infiltrates
  Confusion/disorientation
  Uremia (BUN level ≥20 mg/dL)
  Leukopenia (WBC count <4000 cells/μL)
  Thrombocytopenia (platelet count <100,000 cells/μL)
  Hypothermia (core temperature <36°C)
  Hypotension requiring aggressive fluid resuscitation
Major criteria
  Respiratory failure requiring invasive mechanical ventilation
  Septic shock requiring vasopressors
Abbreviations: BUN, blood urea nitrogen; PaO2/FiO2, arterial oxygen pressure/
fraction of inspired oxygen; WBC, white blood cell.
oral commensal bacteria (e.g., viridans group streptococci), (2) the 
process of natural transformation, or (3) mutation of certain genes.
Susceptibility to penicillins depends upon treatment with intra­
venous (IV) or oral agents.
For IV: Susceptible: minimum inhibitory concentration (MIC) 
≤2 µg/mL
  Intermediate: MIC >2 and ≤4 µg/mL
  Resistant: MIC ≥4 µg/mL
For oral: Susceptible: MIC ≤0.06 µg/mL
  Intermediate: MIC >0.06 and ≤1 µg/mL
  Resistant: MIC >1 µg/mL
For non–central nervous system pneumococcal infections, 
decreased susceptibility to penicillin is mitigated by usual doses. 
In the United States, only 0.6% of pneumococci are resistant to cef­
triaxone and cefotaxime. Risk factors for penicillin-resistant pneu­
mococcal infection include recent antimicrobial therapy, age of <2 
or >65 years, attendance at a day-care center, recent hospitalization, 
and HIV infection.
In contrast to penicillin resistance, macrolide resistance is increas­
ing in S. pneumoniae through several mechanisms. Target-site modi­
fication caused by ribosomal methylation in 23S rRNA encoded by 
the ermB gene results in high-level resistance (MIC, ≥64 μg/mL) to 
macrolides, lincosamides, and streptogramin B–type antibiotics. The 
efflux mechanism encoded by the mef gene (M phenotype) is usually 
associated with low-level resistance (MIC, usually <16 µg/mL). These 
two mechanisms account for ~40% and ~60%, respectively, of resis­
tant pneumococcal isolates in the United States. High-level resistance 
to macrolides is more common in Europe, whereas lower-level resis­
tance predominates in North America. The prevalence of macrolideresistant S. pneumoniae exceeds 25% in some countries; in Canada, 
it is ~22%, and in the United States approximately 40%. Much of this 
resistance is high-level, and treatment failures may result. In these 
situations, a macrolide should not be used as empirical monotherapy. 
In the United States and Canada, 87.5% of pneumococci are suscep­
tible to doxycycline.
The rate of pneumococcal resistance to fluoroquinolones (e.g., 
levofloxacin, moxifloxacin, and gemifloxacin) is usually <2%. 
Changes can occur in one or both target sites (topoisomerases II 
and IV) and are attributable to mutations in the gyrA and parC 
genes, respectively. An efflux pump may also play a role in pneu­
mococcal resistance to fluoroquinolones.
Isolates resistant to drugs from three or more antimicrobial 
classes with different mechanisms of action are considered multi­
drug-resistant (MDR) strains. The propensity for an association of 
pneumococcal resistance to penicillin with reduced susceptibility 
to other drugs, e.g. macrolides, tetracyclines, and trimethoprimsulfamethoxazole, is of concern. In the United States, 58.9% of

penicillin-resistant pneumococcal blood isolates are also resistant 
to macrolides.
The most important risk factor for antibiotic-resistant pneumo­
coccal infection is use of a specific antibiotic within the previous 
3 months. A history of prior antibiotic treatment is a critical factor 
in avoiding the use of an inappropriate antibiotic. 
CA-MRSA  CAP due to MRSA may be caused by the classic hospi­
tal-acquired strains or by genotypically and phenotypically distinct 
community-acquired strains. Most infections with the former are 
acquired either directly or indirectly during contact with the health 
care environment. However, in some hospitals, CA-MRSA strains 
are displacing the classic hospital-acquired strains, suggesting that 
the newer community-acquired strains may be more robust.
Methicillin resistance in S. aureus is determined by the mecA 
gene, which encodes for resistance to all β-lactam drugs At least 
five staphylococcal chromosomal cassette mec (SCCmec) types 
have been described. The typical hospital-acquired strain usu­
ally has a type II or III SCCmec element, whereas CA-MRSA 
has type IV. CA-MRSA isolates tend to be less resistant than 
the older hospital-acquired strains and are often susceptible to 
trimethoprim-sulfamethoxazole, clindamycin, and tetracycline in 
addition to vancomycin and linezolid. CA-MRSA strains also carry 
genes for superantigens such as enterotoxins B and C and PantonValentine leukocidin; the latter is a membrane-tropic toxin that can 
create cytolytic pores in neutrophils, monocytes, and macrophages. 
Risk factors for MRSA include colonization or prior infection and 
MRSA as suggested by gram-positive cocci in clusters on sputum 
Gram stain. Other factors that may raise suspicion of MRSA infec­
tion include recent antibiotics, hospitalization, influenza, cavitary 
or necrotizing pneumonia, or empyema. 
M. pneumoniae  Macrolide-resistant M. pneumoniae has been 
reported in a number of countries, including Germany (3%), Japan 
(30%), China (95%), and France and the United States (5–13%). 
Mycoplasma resistance to macrolides is increasing as a result of 
binding-site mutation in domain V of 23S rRNA. 
Gram-Negative Bacilli  A detailed discussion of resistance among 
gram-negative bacilli is beyond the scope of this chapter (see 
Chap. 166). Fluoroquinolone resistance among community isolates 
of Escherichia coli is increasing. Enterobacter species are typically 
resistant to cephalosporins, and the drugs of choice to treat these 
organisms are usually fluoroquinolones or carbapenems. Similarly, 
when infections due to bacteria producing extended-spectrum 
β-lactamases (ESBLs) are documented or suspected, a carbapenem 
should be considered. 
INITIAL ANTIBIOTIC MANAGEMENT
Since the etiology of CAP is rarely known at the outset of treatment, 
initial therapy is usually empirical and designed to cover the likeli­
est pathogens. In all cases, treatment should be initiated as expedi­
tiously as possible. CAP treatment guidelines in the United States 
from the American Thoracic Society (ATS) and the Infectious Dis­
eases Society of America (IDSA) consider the likely pathogens, risk 
of antimicrobial resistance, severity of illness, site of care, and risk 
of infection with specific bacteria such as MRSA and P. aeruginosa 
(Fig. 131-1, Tables 131-4 and 131-5). In the figure and the tables, 
the antibiotics are not listed in order of preference.
The approach to treatment of aspiration pneumonia is based 
on a number of factors, including site of acquisition (community 
vs hospital), normal or abnormal chest radiograph, and additional 
variables such as illness severity, state of dentition, and risk of 
infection with an MDR pathogen. Routine coverage of anaerobes 
is unnecessary unless dentition is poor or there is a lung abscess or 
necrotizing pneumonia.
Our approach to CAP treatment (Tables 131-4 and 131-5) is very 
similar to the CAP guidelines with the exceptions listed below. 
Outpatients  The exceptions to the CAP guidelines that we follow 
in treating patients are as follows:

Nonsevere
Severe
No risk
Risk
No risk
Risk
Recent 
hospitalization
and
antibiotics (PO or IV)
±
local validation*
Recent 
hospitalization
and
antibiotics (PO or IV)
±
local validation*
Prior 
respiratory
isolation
Prior 
respiratory
isolation
Add treatment
Add treatment
Obtain cultures†
Add treatment
FIGURE 131-1  Algorithm for assessment of inpatient risk of infection with 
methicillin-resistant Staphylococcus aureus (MRSA) or Pseudomonas aeruginosa. 
Underlying lung disease (e.g., bronchiectasis or very severe chronic obstructive 
pulmonary disease) are also risks for P. aeruginosa infection. *Local validation 
consists of information on local prevalence, resistance, and risk factors. †Can also 
use MRSA rapid nasal polymerase chain reaction (PCR) if available. IV, intravenous; 
PO, oral.
•	 We usually initiate coverage that includes atypical organisms as 
well as S. pneumoniae.
•	 Generally, we do not consider the risk of infection with P. aeruginosa 
CHAPTER 131
or MRSA particularly significant in outpatients.
•	 Prior antibiotic use should include both oral and parenteral agents.
Patients are stratified into two groups: those without comorbid­
ity or risk factors for antibiotic resistance and those with comor­
bidities (e.g., chronic heart, lung, liver, or kidney disease; diabetes; 
alcoholism; malignancy; or asplenia) with or without risk factors 
for resistance (Table 131-4). As a general rule, if patients have been 
treated with a drug from a particular class of antibiotics within the 
previous 3 months, drugs from a different class should be used to 
minimize resistance issues.
Pneumonia
For those without comorbidity or resistance risk factors, amox­
icillin alone or doxycycline is recommended in the guidelines. 
Monotherapy with amoxicillin is based on evidence of its efficacy 
in the treatment of hospitalized CAP patients. This recommenda­
tion is a change from the 2007 IDSA/ATS CAP guidelines. As a 
rule, however, we usually tend to initiate treatment that includes 
coverage for S. pneumoniae as well as the atypical pathogens 
(Table 131-4).
TABLE 131-4  Initial Treatment Strategies for Outpatients with 
Community-Acquired Pneumonia
STATUS
STANDARD REGIMEN
No comorbidities or risk 
factors for antibiotic 
resistancea
Combination therapy with amoxicillin (1 g tid) + 
either a macrolideb or doxycycline (100 mg bid)
or
Monotherapy with doxycycline (100 mg bid)
or
Monotherapy with a macrolideb,c
With comorbiditiesd ± 
risk factors for antibiotic 
resistancea
Combination therapy with
amoxicillin/clavulanatee or a cephalosporinf + 
either a macrolideb or doxycycline (100 mg bid)
or
Monotherapy with a respiratory fluoroquinoloneg
aAntibiotic treatment within the past 3 months or contact with the health care 
system. bAzithromycin (500 mg on day 1, then 250 mg/d for 4 days), clarithromycin 
(500 mg bid), or clarithromycin ER (1000 mg/d). cIf local prevalence of pneumococcal 
resistance is <25%. dIncluding chronic heart, lung, liver, or kidney disease; diabetes 
mellitus; alcoholism; malignancy; or asplenia. e500/125 mg tid or 875/125 mg bid. 
fCefpodoxime (200 mg bid) or cefuroxime (500 mg bid). gLevofloxacin (750 mg/d), 
moxifloxacin (400 mg/d), or gemifloxacin (320 mg/d).

TABLE 131-5  Initial Treatment for Inpatients with or without Risk 
Factors for Infection with MRSA or Pseudomonas aeruginosa
DISEASE SEVERITY, RISK STATUS
REGIMEN
Nonsevere
No risk factors
A β-lactama + a macrolideb
or
A respiratory fluoroquinolonec
Prior respiratory isolation
Add coverage for MRSAd or Pseudomonas 
aeruginosae
Recent hospitalization, antibiotic 
treatment, ± LVf
Add coverage for MRSAd or P. aeruginosae 
only if cultures are positive
Severe
No risk factors
A β-lactama + a macrolideb
or
A β-lactama + respiratory fluoroquinolonec
Prior respiratory isolation
Add coverage for MRSAd or P. aeruginosae
Recent hospitalization, antibiotic 
treatment ± LVf
Add coverage for MRSAd or P. aeruginosae
aAmpicillin-sulbactam (1.5–3 g q6h), ceftriaxone (1–2 g/d), cefotaxime (1–2 g 
q8h), ceftaroline (600 mg q12h), or ertapenem (1 g/d). bAzithromycin (500 mg/d) 
or clarithromycin (500 mg bid). cLevofloxacin (750 mg/d), moxifloxacin (400 mg/d), 
or gemifloxacin (320 mg/d). dVancomycin (15 mg/kg q12h, with adjustment based 
on serum levels) or linezolid (600 mg q12h). ePiperacillin-tazobactam (4.5 g q6h), 
cefepime (2 g q8h), ceftazidime (2 g q8h), imipenem (500 mg q6h), meropenem (1 g 
q8h), or aztreonam (2 g q8h). fObtain cultures. MRSA rapid nasal polymerase chain 
reaction can also be used if available.
Abbreviations: LV, local validation (local prevalence, resistance, risk factors); 
MRSA, methicillin-resistant Staphylococcus aureus.
PART 5
Infectious Diseases
Monotherapy with a macrolide is recommended in the guide­
lines only if there are contraindications to amoxicillin or doxy­
cycline and there is documented low risk of macrolide resistance 
(<25%). Otherwise, outpatient treatment is quite similar to the 
regimens recommended in the 2007 IDSA/ATS guidelines. Two 
relatively newer agents, lefamulin (a pleuromutilin) and omadacy­
cline (a tetracycline) are possible options for CAP patients unable to 
take β-lactams and/or wanting to avoid the fluoroquinolones. They 
are available in the United States but not in Canada. Treatment of 
influenza (Chap. 206) and COVID-19 (Chap. 205) is discussed in 
their own chapters. 
Inpatients  Our exceptions to the recommendations in the CAP 
guidelines are as follows:
•	 As a general rule, when initiating treatment for infection with 
P. aeruginosa, we use double coverage.
•	 The presence of all three risk factors is not required for drug 
resistance (recent hospitalization, recent oral or IV antibiotic 
treatment, ± local validation) (Fig. 131-1, Table 131-5).
The main considerations for determining initial empirical treat­
ment of hospitalized CAP patients are clinical severity and 
risk of infection with drug-resistant pathogens such as MRSA or 

P. aeruginosa. Hospitalization alone is not now considered a sig­
nificant risk factor for these pathogens. Hospitals should collect 
local data on MRSA and P. aeruginosa regarding prevalence, risk 
factors for infection, and antibiotic susceptibilities. Patients can be 
categorized as having nonsevere or severe CAP (Table 131-3), and 
those in each category may or may not have risk factors for MRSA 
or P. aeruginosa (Fig. 131-1). In scenarios involving these variables 
in hospitalized CAP patients, empirical treatment for either of these 
pathogens should be added to standard therapy in those previously 
colonized or infected with these pathogens, but not in the patient 
who is considered nonsevere and whose only risk factors are recent 
hospitalization and antibiotic treatment ± local validation data 
(Fig. 131-1). In this setting, if we begin treatment, we try to de-escalate 
if appropriate. In most patients, cultures should be performed but 
treatment usually withheld unless culture results or rapid nasal PCR 
results for MRSA are positive. 

Nonsevere, No Risk Factors 
For patients with nonsevere 
infection and no risk factors, treatment should consist of either a 
combination of a β-lactam and a macrolide or monotherapy with 
a respiratory fluoroquinolone (Table 131-5). In the event of con­
traindications to macrolides and fluoroquinolones, a β-lactam plus 
doxycycline may be used. Treatment with a β-lactam plus macrolide 
combination or a fluoroquinolone alone results in lower mortality 
than monotherapy with a β-lactam. 
Severe, No Risk Factors 
Patients with severe infection but 
no risk factors should receive combination therapy with either a 
β-lactam plus macrolide or a β-lactam and a respiratory fluoroqui­
nolone (Table 131-5). Observational studies suggest that combina­
tion therapy with a β-lactam plus macrolide may be preferable to a 
β-lactam plus fluoroquinolone. 
Nonsevere and Severe, with Risk Factors  To date, there are 
no prediction rules reliably identifying patients who should be started 
empirically on treatment for MRSA or P. aeruginosa. Current risk fac­
tors for infection with these pathogens are hierarchical. Prior isolation of 
these organisms, especially from the respiratory tract within the previous 
year, is a more robust risk factor than recent hospitalization and expo­
sure to parenteral antibiotics. For P. aeruginosa, underlying lung disease 
(e.g., bronchiectasis or very severe COPD) also is an important risk fac­
tor. If MRSA or P. aeruginosa has been isolated previously, appropriate 
empirical therapy should be started in both severe and nonsevere cases 

(Table 131-5). We prefer linezolid over vancomycin as first-line treat­
ment for MRSA because of its inhibition of bacterial exotoxin and 
better lung penetration. If the organism is not isolated from respiratory 
secretions or blood and/or the nasal or bronchoalveolar lavage PCR 
test for MRSA is negative and the patient is improving at 48 h, treat­
ment may be de-escalated to a standard regimen.
If, however, the risk factors are recent hospitalization and anti­
biotic use within the previous 3 months, appropriate samples 
should be obtained for culture, and, in severe cases only, extendedspectrum treatment for MRSA or P. aeruginosa should be initiated. 
Depending on the severity of infection, local data on P. aeruginosa 
resistance, and antibiotic use within the previous 90 days, single- or 
double-drug coverage should be used such as antipseudomonal 
β-lactam plus ciprofloxacin, levofloxacin, or aminoglycoside.
If two antipseudomonal agents are started, the drugs should be 
from different classes. Whenever possible, assessment for possible 
de-escalation of therapy is urged. If the patient’s illness is not severe, 
empirical extended treatment should be withheld until culture 
results are available.
Regardless of the site of care, CAP patients with proven influenza 
should be given anti-influenza treatment (e.g., oseltamivir) as well 
as appropriate antibacterial therapy. Physicians should be vigilant 
about possible superinfection with MRSA. If a viral pathogen such 
as influenza or SARS-CoV-2 is found and no bacterial pathogen 
is obvious, antibacterial treatment can be discontinued. However, 
in those with severe illness, the possibility of bacterial-viral coinfection should be considered.
Although hospitalized patients have traditionally received initial 
therapy by the IV route, some drugs, particularly the fluoroqui­
nolones, are very well absorbed and may be given orally from the 
outset to select patients. For those initially treated with IV agents, a 
switch to oral treatment is appropriate when the patient can ingest 
and absorb the drugs, is hemodynamically stable, and is showing 
clinical improvement. A 5-day course of treatment is usually suffi­
cient for uncomplicated CAP, but longer treatment may be required 
for patients who have not stabilized clinically and for those with 
bacteremia, metastatic infection, or infection with a more virulent 
pathogen such as P. aeruginosa or MRSA. There are some data to 
suggest that in select patients who are doing well and are clinically 
stable, treatment may be discontinued after 3 days. 
ADJUNCTIVE MEASURES
In addition to appropriate antimicrobial therapy, certain adjunctive 
measures should be used. Adequate hydration, oxygen therapy for

Pneumonia

CHAPTER 131
TABLE 131-6  Microbiologic Causes of Ventilator-Associated 
Pneumonia
NON-MDR PATHOGENS 
(CORE PATHOGENS)
MDR PATHOGENS
Streptococcus pneumoniae
Other Streptococcus spp.
Haemophilus influenzae
Methicillin-sensitive Staphylococcus 
aureus
Antibiotic-sensitive 
Enterobacteriaceae
  Escherichia coli
  Klebsiella pneumoniae
  Proteus spp.
  Enterobacter spp.
  Serratia marcescens
Pseudomonas aeruginosa
Methicillin-resistant S. aureus
Acinetobacter spp.
Antibiotic-resistant Enterobacteriaceae
  ESBL-positive strains
  Carbapenem-resistant strains
Legionella pneumophila
Burkholderia cepacia
Aspergillus spp.
Abbreviations: ESBL, extended-spectrum β-lactamase; MDR, multidrug-resistant.
hypoxemia, vasopressor treatment, and assisted ventilation when 
necessary are critical to successful treatment. Glucocorticoids may 
be beneficial in cases of severe CAP requiring invasive or noninva­
sive mechanical ventilation or with shock. Recent data show a mor­
tality benefit for corticosteroid therapy in those with severe CAP 
(ventilated and nonventilated), especially if there is a high level of 
systemic inflammation (CRP >15 mg/dL); therapy is usually con­
tinued for 8–14 days and given either by intermittent or continu­
ous infusion. Data support the use of dexamethasone plus a Janus 
kinase inhibitor or an interleukin 6 inhibitor in COVID-19 patients 
with rapidly increasing oxygen needs and systemic inflammation. 
FAILURE TO IMPROVE
Patients slow to respond to therapy should be reevaluated at about 
day 3 (or sooner if their condition is worsening), with several sce­
narios considered. A number of noninfectious conditions mimic 
pneumonia, including pulmonary edema, pulmonary embolism, 
lung carcinoma, radiation and hypersensitivity pneumonitis, and 
connective tissue disease involving the lungs. If the patient truly 
has CAP and empirical treatment is aimed at the likely expected 
pathogens, lack of response may be explained in a number of ways. 
The pathogen may be resistant to the drug, or a sequestered focus 
(e.g., lung abscess or empyema) may prevent antibiotic access to 
the pathogen. The patient may be getting the wrong drug or the 
correct drug at the wrong dose or frequency of administration. 
Another possibility is that CAP has been diagnosed correctly but an 
unexpected pathogen (e.g., CA-MRSA, M. tuberculosis, or a fungus) 
is the cause. Nosocomial superinfections—both pulmonary and 
extrapulmonary—are other possible explanations for a hospitalized 
patient’s failure to improve. In all cases of delayed response or wors­
ening condition, the patient must be carefully reassessed and appro­
priate studies initiated, possibly including CT or bronchoscopy. 
COMPLICATIONS
Complications of severe CAP include respiratory failure, shock and 
multiorgan failure, and exacerbation of comorbid illnesses. Three 
particularly noteworthy conditions are metastatic infection, lung 
abscess, and complicated pleural effusion. Metastatic infection 
(e.g., brain abscess or endocarditis) is unusual and requires a high 
degree of suspicion and a detailed workup for proper treatment. 
Lung abscess may occur in association with aspiration pneumonia 
or with infection caused by pathogens such as CA-MRSA, P. aeru­
ginosa, or (rarely) S. pneumoniae. A significant pleural effusion 
should be tapped for diagnostic and therapeutic purposes. If the 
fluid has a pH <7.2, a glucose level of <2.2 mmol/L, and a lactate 
dehydrogenase concentration of >1000 U/L or if bacteria are seen 
or cultured, drainage is needed.
Cardiovascular events with pneumonia, particularly in the 
elderly and usually in association with pneumococcal pneumonia 
and influenza, are increasingly recognized. These events, which 
may be acute or whose occurrence may extend to at least 1 year, 
include congestive heart failure, arrhythmia, myocardial infarction, 
or stroke and may be caused by a variety of mechanisms, including 
increased myocardial load and/or destabilization of atherosclerotic 
plaques by inflammation. 
FOLLOW-UP
Fever and leukocytosis usually resolve within 2–4 days in otherwise 
healthy CAP patients, but physical findings may persist longer. 
Chest radiographic abnormalities are slowest to resolve (4–12 weeks), 
with the speed of clearance depending on the patient’s age and 
underlying lung disease, and the etiologic pathogen. Patients may 
be discharged from hospital once their clinical condition, includ­
ing any comorbidity, is stable. The site of residence after discharge 
(nursing home, home with family, home alone) is an important 
consideration, particularly for elderly patients. For a hospitalized 
patient, we generally recommend a follow-up radiograph ~4–6 weeks 
later. If relapse or recurrence occurs, particularly in the same lung 
segment, the possibility of an underlying neoplasm or other local 
abnormalities (e.g., focal bronchiectasis) must be considered. For 
individuals managed as outpatients, routine follow-up chest radiog­
raphy is not necessary if they are nonsmokers, if they are otherwise 
well, and if symptoms resolved within 5–7 days.
■
■PROGNOSIS
The prognosis depends on the patient’s age, comorbidities, and site of 
treatment (inpatient or outpatient). Young patients without comorbid­
ity do well and usually recover fully after ~2 weeks. Older patients 
and those with comorbid conditions may take several weeks longer to 
recover fully. The overall mortality rate for the outpatient group is <5%. 
For patients requiring hospitalization, overall mortality ranges from 
12% to 40%, depending on the patient category and the processes of 
care, particularly the timely administration of appropriate antibiotics. 
Recent data, especially in older patients, show that the 1-year mortality 
following CAP exceeds the 30-day mortality.
■
■PREVENTION
The main preventive measure is vaccination. Recommendations of 
National Advisory Committees on Immunization Practices should be 
followed (Chap. 129).
VENTILATOR-ASSOCIATED PNEUMONIA
Research on hospital-acquired pneumonia has focused on VAP (onset 
≥48 h after mechanical ventilation). However, the same information 
and principles can also be applied to ventilated HAP and to nonICU HAP. Approximately 70% of HAP cases are acquired outside the 
ICU and 30% in the ICU; the fact that 35% of all HAP patients need 
mechanical ventilation defines ventilated HAP as a distinct entity. In 
nonintubated patients with HAP, an expectorated sputum sample is 
used for microbiologic diagnosis, but results are confounded by fre­
quent colonization by oral pathogens. Microbiologic information in 
VAP and ventilated HAP is obtained from direct access to deep lower 
respiratory tract samples, which provide reliable microbiologic data; 
however, these samples can also contain colonizing pathogens.
■
■ETIOLOGY
Potential etiologic agents of VAP include both MDR and non-MDR 
bacterial pathogens (Table 131-6). The non-MDR group of “core 
pathogens” is nearly identical to the pathogens found in severe CAP 
(Table 131-1); it is not surprising that such pathogens predominate 
if VAP develops in the first 5–7 days of the hospital stay. However, 
if patients have other risk factors (particularly prior antibiotic treat­
ment), MDR pathogens are a consideration, even early in the hospital 
course. The relative frequency of individual MDR pathogens can vary 
significantly from hospital to hospital and even between different criti­
cal care units within the same institution. Most hospitals have problems 
with P. aeruginosa and MRSA, but other MDR pathogens are often 
institution-specific. Less commonly, fungal and viral pathogens cause 
VAP, usually affecting severely immunocompromised patients. Rarely,

community-associated viruses cause mini-epidemics, usually when 
introduced by ill health care workers.

■
■EPIDEMIOLOGY
Pneumonia is a common complication among patients requiring 
mechanical ventilation. Prevalence estimates vary between 6 and 52 
cases per 100 patients, depending on the population studied. On any 
given day in the ICU, an average of 10% of patients will have pneumonia—
VAP in the overwhelming majority of cases. Although in recent years 
the frequency of this infection was declining as a result of effective 
prevention strategies, with the advent of COVID-19, there has been an 
increase in its frequency. The frequency of VAP changes with the dura­
tion of mechanical ventilation, with the highest hazard ratio in the first 
5 days and a plateau in additional cases (1% per day) after ~2 weeks. 
However, the cumulative rate among patients who remain ventilated 
for as long as 30 days is as high as 70%. These rates often do not reflect 
the recurrence of VAP in the same patient. Once a ventilated patient 
is transferred to a chronic-care facility or to home, the incidence of 
pneumonia drops significantly, especially in the absence of other risk 
factors for pneumonia. However, in chronic ventilator units, purulent 
tracheobronchitis becomes a significant issue, often interfering with 
efforts to wean patients off mechanical ventilation (Chap. 313).
Three factors are critical in the pathogenesis of VAP: colonization of 
the oropharynx with pathogenic microorganisms, aspiration of these 
organisms from the oropharynx into the lower respiratory tract, and 
compromise of normal host defense mechanisms. Most risk factors and 
their corresponding prevention strategies pertain to one of these three 
factors (Table 131-7).
The most important risk factor is the endotracheal tube, which 
bypasses the normal mechanical factors preventing aspiration. While 
the presence of an endotracheal tube may prevent large-volume aspi­
ration, microaspiration is actually exacerbated by secretions pooling 
above the cuff. The endotracheal tube and the concomitant need 
for suctioning can damage the tracheal mucosa, thereby facilitating 
tracheal colonization. In addition, pathogenic bacteria can form a 
glycocalyx biofilm on the tube’s surface that protects them from both 
antibiotics and host defenses. The bacteria can also be dislodged dur­
ing suctioning (done preferably with a closed catheter system) and 
can reinoculate the trachea, or tiny fragments of a glycocalyx can 
embolize to distal airways, carrying bacteria with them. The ventilator 
circuit tubing can harbor pathogenic organisms that can wash back to 
the patient if manipulated too often; thus, circuits are changed only 
when soiled and with each new patient. Heat moisture exchangers are 
changed every 5–7 days or if visibly soiled or malfunctioning.
PART 5
Infectious Diseases
In a high percentage of critically ill patients, the normal oropharyn­
geal flora is replaced by pathogenic microorganisms. The most impor­
tant risk factors are antibiotic selection pressure, cross-infection from 
other infected/colonized patients or contaminated equipment, severe 
systemic illness, and malnutrition. Of these factors, antibiotic exposure 
poses the greatest risk by far. Pathogens such as P. aeruginosa almost 
never cause infection in patients without prior exposure to antibiotics. 
The recent emphasis on hand hygiene has lowered the cross-infection 
rate.
Almost all intubated patients experience microaspiration and are 
at least transiently colonized with pathogenic bacteria. However, only 
around one-third of colonized patients develop VAP. Colony counts 
increase to high levels, sometimes days before the development of clini­
cal pneumonia; these increases suggest that the final step in VAP devel­
opment, independent of aspiration and oropharyngeal colonization, 
is the overwhelming of host defenses by a large bacterial inoculum. 
Severely ill patients with sepsis and trauma appear to enter a state of 
immunoparalysis several days after admission to the ICU—a time that 
corresponds to the greatest risk of developing VAP. The mechanism 
of this immunosuppression is not clear, although hyperglycemia and 
frequent transfusions adversely affect the immune response.
■
■CLINICAL MANIFESTATIONS
The clinical manifestations of HAP and VAP are nonspecific: fever, 
leukocytosis, increased respiratory secretions, and pulmonary 

TABLE 131-7  Pathogenic Mechanisms and Corresponding Prevention 
Strategies for Ventilator-Associated Pneumonia
PATHOGENIC MECHANISM
PREVENTION STRATEGY
Oropharyngeal colonization with 
pathogenic bacteria
 
  Elimination of normal flora, 
Avoidance of prolonged antibiotic 
courses; consider oral chlorhexidinea
overgrowth by pathogenic bacteria
  Large-volume oropharyngeal 
Short course of prophylactic antibiotics 
for comatose patients; short course of 
prophylactic inhaled aminoglycoside 
antibioticsb
aspiration around time of intubation
  Gastroesophageal reflux
Postpyloric enteral feeding with orally 
placed feeding tubea; avoidance of high 
gastric residuals, prokinetic agents
  Bacterial overgrowth of stomach
Avoidance of prophylactic agents 
that raise gastric pHa; selective 
decontamination of digestive tract with 
nonabsorbable antibioticsa
Cross-infection from other colonized 
patients
Hand washing, especially with alcoholbased hand rub; intensive infection 
control educationb; isolation; proper 
cleaning of reusable equipment
Large-volume aspiration
Ventilator circuit humidification
Endotracheal intubation; rapid-sequence 
intubation technique; avoidance of 
sedation; decompression of small-bowel 
obstruction
Change ventilator circuits only when 
soiled and with new patient; drain 
ventilator circuit condensate away 
from patient; replace heat moisture 
exchanger every 5–7 days or if soiled or 
malfunctioninga
Microaspiration around endotracheal 
tube
 
  Endotracheal intubation
Noninvasive ventilationb
  Prolonged duration of ventilation
Daily awakening from sedation,b 
weaning protocolsb
  Abnormal swallowing function
Early percutaneous tracheostomyb
  Secretions pooled above 
Head of bed elevatedb; continuous 
aspiration of subglottic secretions 
with specialized endotracheal tubeb; 
avoidance of reintubation; minimization 
of sedation and patient transport; 
prophylactic PEEPc of 5–8 cm
endotracheal tube
Altered lower respiratory host 
defenses
Tight glycemic controla; lowering of 
hemoglobin transfusion threshold
aStrategies with negative randomized trials or conflicting results. bStrategies 
demonstrated to be effective in at least one randomized controlled trial. cPositive 
end-expiratory pressure.
consolidation on physical examination, along with a new or changing 
radiographic infiltrate. The frequency of abnormal chest radiographs 
before the onset of pneumonia in intubated patients and the limitations 
of portable radiographic technique make interpretation of radiographs 
more difficult than in patients who are not intubated. Other clinical 
features may include tachypnea, tachycardia, worsening oxygenation, 
and increased minute ventilation. Serial changes in oxygenation may 
identify pneumonia earlier than other findings and may also be a 
means to monitor improvement with therapy.
■
■DIAGNOSIS
No single set of criteria is reliably diagnostic of pneumonia in a ven­
tilated patient. The inability to accurately identify such patients com­
promises efforts to prevent and treat VAP and even calls into question 
estimates of the impact of VAP on mortality rates.
Application of clinical criteria typical for CAP consistently results 
in overdiagnosis of VAP, largely because of (1) frequent tracheal colo­
nization with pathogenic bacteria in patients with endotracheal tubes, 
(2) multiple alternative causes of radiographic infiltrates in mechani­
cally ventilated patients, and (3) the high frequency of other sources

of fever in critically ill patients. The differential diagnosis of VAP 
includes atypical pulmonary edema, pulmonary contusion, alveolar 
hemorrhage, hypersensitivity pneumonitis, acute respiratory distress 
syndrome, and pulmonary infarction. Findings of fever and/or leu­
kocytosis may have alternative causes, including antibiotic-associated 
diarrhea, central line–associated infection, sinusitis, urinary tract 
infection, pancreatitis, and drug fever. Conditions mimicking pneumo­
nia are often documented in patients in whom VAP has been ruled out 
by accurate diagnostic techniques. Most of these alternative diagnoses 
do not require antibiotic treatment; require antibiotics different from 
those used to treat VAP (fungal or viral pneumonia); or require some 
additional intervention, such as surgical drainage or catheter removal, 
for optimal management.
This diagnostic dilemma has led to debate and controversy about 
whether a quantitative-culture approach as a means of eliminating 
false-positive clinical diagnoses is superior to a clinical approach 
enhanced by principles learned from quantitative-culture studies. The 
most recent IDSA/ATS guidelines for HAP/VAP give a weak recom­
mendation for a clinical approach based on semiquantitative cultures, 
with consideration of the availability of resources, cost, and the avail­
ability of expertise. The guidelines acknowledge that the use of a quan­
titative approach may result in less antibiotic use, which may be critical 
for antibiotic stewardship in the ICU. Therefore, the approach at each 
institution—or potentially for each patient—should be individualized 
and based on local colonization rates, local diagnostic expertise, and 
recent history of antibiotic therapy.
Quantitative-Culture Approach 
This method uses quantitative 
cultures of deep respiratory tract samples to distinguish colonization 
from true infection. The more distal in the respiratory tree the diagnos­
tic sampling, the more specific are the results and therefore the lower 
the threshold of growth necessary to diagnose pneumonia and exclude 
colonization. For example, an endotracheal aspirate yields proximal 
samples, and the diagnostic threshold is 106 cfu/mL. The protected 
specimen brush method, in contrast, collects distal samples and has a 
threshold of 103 cfu/mL. Conversely, sensitivity declines as more distal 
secretions are obtained, especially when they are collected blindly 
(i.e., by a technique other than bronchoscopy). Additional tests that 
may increase the diagnostic yield include Gram staining, differential 
cell counts, staining for intracellular organisms, and detection of local 
protein levels elevated in response to infection.
If the quantitative approach is used, therapy decisions should be 
linked to culture results (no antibiotics if below the diagnostic thresh­
old), with antibiotics withheld until results are available unless the 
patient is critically ill. Studies have documented less antibiotic use with 
this approach than with the clinical approach, but the results are less 
clear if antibiotic decisions are not directly linked to culture data. One 
common limitation of the quantitative approach is that the use of a new 
and effective antibiotic agent in the 24–48 h prior to sampling can lead 
to false-negative results. With antimicrobial-sensitive microorganisms, 
a single antibiotic dose can reduce colony counts below the diagnos­
tic threshold. After 3 days, the operating characteristics of the tests 
improve to the point at which they are equivalent to results obtained 
when no prior antibiotic therapy has been given. Conversely, colony 
counts above the diagnostic threshold during antibiotic therapy sug­
gest that the current antibiotics are ineffective. In addition, quantitative 
cultures may give results below the diagnostic threshold if samples are 
collected early in the course of infection or if sampling is delayed until 
after an effective host response has reduced bacterial counts. Ideally, a 
specimen should be obtained as soon as pneumonia is suspected and 
before antibiotic therapy is initiated or changed.
Clinical Approach 
The lack of specificity of a clinical diagnosis 
of VAP has hampered its utility, but this approach has been improved 
by the addition of microbiologic and other laboratory data. Tracheal 
aspirates generally yield at least twice as many potential pathogens as 
quantitative cultures, but the causative pathogen is almost always pres­
ent. The absence of bacteria in Gram-stained endotracheal aspirates 
makes pneumonia an unlikely cause of fever or pulmonary infiltrates. 
These findings, coupled with a heightened awareness of the alternative 

diagnoses possible in patients with suspected VAP, can prevent inap­
propriate antibiotic overtreatment. Furthermore, the absence of an 
MDR pathogen in tracheal aspirate cultures eliminates the need for 
MDR coverage, allowing de-escalation of empirical antibiotic therapy. 
Similarly, with newer and more sensitive molecular diagnostic meth­
ods, a suspected MDR pathogen can be eliminated as a therapy target 
if test results are negative. A clinical approach that focuses on careful 
antimicrobial use and de-escalation of therapy after culture results 
become available may have an impact on the avoidance of antimi­
crobial overuse and the consideration of alternative sites of infection 
similar to that of a quantitative-culture approach.

TREATMENT
Ventilator-Associated Pneumonia
Many studies have demonstrated higher mortality rates with the 
delay of initially appropriate empirical antibiotic therapy. The key to 
appropriate antibiotic management of VAP is an appreciation of the 
resistance patterns of the most likely pathogens in a given patient 
and consideration of local microbiology. 
ANTIBIOTIC RESISTANCE
Because of a higher risk of infection with MDR pathogens (Table 
131-6), VAP is treated with antibiotics different from those used 
for severe CAP. Antibiotic selection pressure leads to the frequent 
involvement of MDR pathogens by selecting either for drug-resistant 
isolates of common pathogens (e.g., MRSA and Enterobacteriaceae 
producing ESBLs or carbapenemases) or for intrinsically resistant 
pathogens (e.g., P. aeruginosa and Acinetobacter species). Frequent 
use of β-lactam drugs, especially cephalosporins, appears to be 
the major risk factor for infection with MRSA and ESBL-positive 
strains.
CHAPTER 131
P. aeruginosa can develop resistance to all routinely used anti­
biotics, and, even if initially sensitive, P. aeruginosa isolates may 
develop resistance during treatment. Either derepression of resis­
tance genes or selection of resistant clones within the large bacterial 
inoculum associated with most pneumonias may be the cause. 
Acinetobacter species, Stenotrophomonas maltophilia, and Burkholderia 
cepacia are intrinsically resistant to many of the empirical antibiotic 
regimens employed (see below). VAP caused by these pathogens 
typically emerges during treatment of other infections, and resis­
tance is always evident at initial diagnosis. 
EMPIRICAL THERAPY
Recommended options for empirical therapy are listed in Table 131-8. 
Treatment should be started once diagnostic specimens have been 
obtained. The major factors in the selection of agents are the pres­
ence of risk factors for MDR pathogens and the predicted risk of 
death (≤15% is considered low risk). Choices among the various 
options listed depend on local patterns of resistance and—a very 
important factor—the patient’s prior antibiotic exposure. Knowl­
edge of the local hospital’s—and even the specific ICU’s—anti­
biogram and the local incidence of specific MDR pathogens (e.g., 
MRSA) is critical in selecting appropriate empirical therapy.
Pneumonia
The majority of patients without risk factors for MDR infec­
tion can be treated with a single agent. In fact, mortality is lower 
with a single agent than with combination therapy for those with 
a low mortality risk. For these patients, monotherapy options 
listed in Table 131-8 are active against the core pathogens, as well 
as nonresistant P. aeruginosa. However, in selected settings, it may 
be possible to use a nonpseudomonal agent such as cefotaxime or 
moxifloxacin. Unfortunately, the proportion of patients with no 
MDR risk factors is <10% in some ICUs and is unknown for HAP 
patients. The major difference from CAP is the markedly lower 
incidence of atypical pathogens in VAP; the exception is Legionella, 
which can be a nosocomial pathogen, especially with local epidem­
ics due to breakdowns in the treatment of potable water in the hos­
pital. The standard recommendation for patients with risk factors 
for MDR infection and a high mortality risk is for three antibiotics:

TABLE 131-8  Empirical Antibiotic Treatment of Hospital-Acquired and 
Ventilator-Associated Pneumonia
NO RISK FACTORS 
FOR RESISTANT 
GRAM-NEGATIVE 
PATHOGEN
RISK FACTORS FOR RESISTANT GRAM-NEGATIVE 
PATHOGENa (CHOOSE ONE FROM EACH COLUMN)
Piperacillintazobactam (4.5 g 
IV q6h)
Cefepime (2 g IV q8h)
Levofloxacin (750 mg 
IV q24h)
Piperacillin-tazobactam 
(4.5 g IV q6h)
Cefepime (2 g IV q8h)
Ceftazidime (2 g IV q8h)
Imipenem (500 mg IV q6h)
Meropenem (1 g IV q8h)
Consider newer agentsc
Amikacin (15–20 mg/kg IV 
q24h)
Gentamicin (5–7 mg/kg IV 
q24h)
Tobramycin (5–7 mg/kg IV 
q24h)
Ciprofloxacin (400 mg IV q8h)
Levofloxacin (750 mg IV q24h)
Colistin (loading dose of 
5 mg/kg IV followed by 
maintenance doses of 2.5 mg 
× [1.5 × CrCl + 30] IV q12h)
Polymyxin B (2.5–3.0 mg/kg 
per day IV in 2 divided doses)
Risk Factors for MRSAb (Add to above)
Linezolid (600 mg IV q12h) or
Adjusted-dose vancomycin (trough level, 15–20 mg/dL)
aPrior antibiotic therapy, prior hospitalization, local antibiogram. bPrior antibiotic 
therapy, prior hospitalization, known MRSA colonization, chronic hemodialysis, 
local documented MRSA pneumonia rate >10% (or local rate unknown). cNewer 
agents can have activity against resistant P. aeruginosa (ceftazidime-avibactam, 
ceftolozane-tazobactam, imipenem-relebactam, plazomicin), carbapenem-resistant 
Enterobacteriaceae (ceftazidime-avibactam, imipenem-relebactam, meropenemvaborbactam), metallo-β-lactamase–producing Enterobacteriaceae (ceftazidimeavibactam, cefiderocol), Stenotrophomonas (cefiderocol), and Acinetobacter spp. 
(cefiderocol, sulbactam-durlobactam).
Abbreviations: CrCl, creatinine clearance rate; MRSA, methicillin-resistant 
Staphylococcus aureus.
PART 5
Infectious Diseases
two directed at P. aeruginosa and other resistant gram-negative 
organisms and one directed at MRSA. However, in the absence 
of septic shock, a single agent may be effective for these patients, 
provided there is a single agent that is likely to be effective against 
at least 90% of the gram-negative pathogens in that ICU. Empirical 
combination therapy enhances the likelihood of initially appropri­
ate therapy over that with monotherapy. A β-lactam agent provides 
the greatest coverage, yet even the broadest-spectrum agent—a 
carbapenem—still constitutes inappropriate initial therapy in up 
to 10–15% of cases at some centers. The emergence of carbapenem 
resistance at some institutions requires the addition of polymyx­
ins to the combination-therapy options. A number of emerging 
agents may modify our approach to therapy. New antipseudomonal 
agents include ceftazidime–avibactam, ceftolozane–tazobactam, 
imipenem–relebactam, and plazomicin. Therapy for carbapenemresistant Enterobacteriaceae can consist of ceftazidime–avibactam, 
imipenem–relebactam, or meropenem–vaborbactam, while Entero­
bacteriaceae that produce metallo-β-lactamases can be treated with 
ceftazidime–avibactam or cefiderocol. Acinetobacter spp. can be 
treated with cefiderocol (as part of a combination regimen) or with 
sulbactam-durlobactam, and Stenotrophomonas can be treated with 
cefiderocol. 
SPECIFIC TREATMENT
Once an etiologic diagnosis is made, broad-spectrum empirical 
therapy can be modified (de-escalated) to specifically address the 
known pathogen. For patients with MDR risk factors, antibiotic 
regimens can be reduced to a single agent in most cases. Only a 
minority of cases require a complete course with two or three drugs. 
A negative tracheal-aspirate culture or growth below the threshold 
for quantitative cultures of samples obtained before any antibiotic 
change strongly suggests that antibiotics should be discontinued 
or that an alternative diagnosis should be pursued. Identification 
of other confirmed or suspected sites of infection may require 
ongoing antibiotic therapy, but the spectrum of pathogens (and the 

corresponding antibiotic choices) may be different from those for 
VAP. A 7- or 8-day course of therapy is just as effective as a 2-week 
course and is associated with less frequent emergence of antibioticresistant strains. Exceptions include cases in which initial therapy is 
inappropriate or consists of second-line antibiotics and cases caused 
by some more resistant organisms, such as carbapenemase-producing 
Acinetobacter species. In these situations, serial measurements of 
procalcitonin may help guide duration of therapy.
A major controversy regarding specific therapy for VAP con­
cerns the need for ongoing combination treatment of Pseudomonas 
pneumonia. No randomized controlled trials have demonstrated a 
benefit of combination therapy with a β-lactam and an aminogly­
coside, nor have subgroup analyses in other trials found a survival 
benefit with such a regimen. Combination therapy may increase 
the likelihood of initially appropriate therapy and may have value 
in bacteremic infection with septic shock, but the benefit may last 
for only a few days. The unacceptably high rates of clinical failure 
and death despite combination therapy among patients with VAP 
caused by P. aeruginosa (see “Failure to Improve,” below) indicate 
that better regimens are needed, perhaps including aerosolized anti­
biotics. In most cases of Pseudomonas pneumonia, current guide­
lines recommend against continuing combination therapy after the 
isolate’s antimicrobial susceptibility is known. 
FAILURE TO IMPROVE
Treatment failure is not uncommon in VAP, especially that caused 
by MDR pathogens. VAP caused by MRSA is associated with a 40% 
clinical failure rate when treated with standard-dose vancomycin. 
One proposed but unproven solution is the use of high-dose indi­
vidualized treatment, although the risk of renal toxicity increases 
with this strategy. In addition, the MIC of MRSA to vancomycin 
has been increasing, and a high percentage of clinical failures 
occur when the MIC is in the upper range of sensitivity (i.e., 1.5–2 
μg/mL). Linezolid appears to be 15% more efficacious than even 
adjusted-dose vancomycin and is preferred in patients with renal 
insufficiency and those infected with high-MIC isolates of MRSA. 
VAP due to Pseudomonas has a 40–50% failure rate, no matter what 
the regimen. Therapy-related causes of clinical failure include not 
using the recommended combination regimen (Table 131-8) and 
inadequate antibiotic dosing. However, the emergence of β-lactam 
resistance during therapy is an important problem, especially in 
infection with Pseudomonas and Enterobacter species. Recurrent 
VAP caused by the same pathogen is possible because the biofilm 
on endotracheal tubes allows persistence and reintroduction of the 
microorganism. Studies of VAP caused by Pseudomonas show that 
approximately half of recurrent cases are caused by a new strain. 
Some studies have suggested that treatment failure may be less com­
mon with optimized β-lactam dosing and use of either prolonged or 
continuous infusion therapy.
Possible causes of treatment failure can be difficult to determine 
early in the therapeutic course and can include superinfection, the 
presence of extrapulmonary infection, as well as patient factors 
such as severe comorbid illness and immunosuppression. Serial 
quantitative cultures may clarify the microbiologic response, and 
recent data in ICU patients have shown a role for biomarkers, such 
as procalcitonin, to guide duration of therapy in conjunction with 
the patient’s initial response to treatment. 
COMPLICATIONS
Apart from death, the major complication of VAP is prolonga­
tion of mechanical ventilation, with corresponding increases in 
the duration of ICU and hospital stay. In most studies, the need 
for additional mechanical ventilation resulting from VAP justifies 
aggressive efforts at prevention.
In rare cases, necrotizing pneumonia (e.g., due to P. aeruginosa 
or S. aureus) can cause significant pulmonary hemorrhage or empy­
ema. More commonly, necrotizing infections result in the longterm complications of bronchiectasis and parenchymal scarring 
leading to recurrent pneumonia. Other long-term complications of

pneumonia can include need for prolonged oxygen therapy, a cata­
bolic state in a patient already nutritionally at risk, the necessity for 
ongoing rehabilitation, and—in the elderly—an inability to return 
to independent function and the need for nursing home placement. 
FOLLOW-UP
Clinical improvement, if it occurs, is usually evident within 48–72 h of 
the initiation of antimicrobial treatment, usually with an improve­
ment in oxygenation. Because findings on chest radiography often 
worsen initially during treatment, they are less helpful than clinical 
criteria as an indicator of response to therapy.
■
■PROGNOSIS
VAP is associated with crude mortality rates as high as 50–70%, but 
the real issue is attributable mortality. Many patients with VAP have 
underlying diseases that would result in death even if VAP did not 
occur. Attributable mortality exceeded 25% in one matched-cohort 
study, while more recent studies have suggested much lower rates 
(5–10%), although patients with VAP complicating COVID-19 have 
a higher attributable mortality than those with other forms of VAP. 
Some variability in VAP mortality rates is clearly related to the type 
of patient and ICU studied. VAP in trauma patients is not associated 
with attributable mortality, possibly because many of the patients were 
otherwise healthy before being injured. The causative pathogen also 
plays a major role. Generally, MDR pathogens are associated with 
significantly greater attributable mortality than non-MDR pathogens. 
Pneumonia caused by some pathogens (e.g., S. maltophilia) is simply a 
marker for a patient whose immune system is highly compromised and 
is therefore at high risk.
■
■PREVENTION (TABLE 131-7)
Because endotracheal intubation is a risk factor for VAP, the most impor­
tant preventive intervention is to avoid intubation or minimize its dura­
tion. Successful noninvasive ventilation avoids many of the problems 
associated with endotracheal tubes. Strategies that minimize the dura­
tion of ventilation through daily holding of sedation and formal weaning 
protocols have also been highly effective in preventing VAP.
Unfortunately, a tradeoff in risks is sometimes necessary. Aggressive 
attempts to extubate early may result in reintubation(s) and increase 
aspiration, posing a risk of VAP. Heavy continuous sedation increases 
VAP risk, but self-extubation because of insufficient sedation is also a 
risk. The tradeoffs also apply to antibiotic therapy. Short-course antibi­
otic prophylaxis can decrease the risk of early-onset VAP in comatose 
patients requiring intubation, and data suggest that antibiotics decrease 
VAP rates overall. Conversely, prolonged courses of antibiotics consis­
tently increase the risk of MDR VAP; pseudomonal VAP is rare among 
patients who have not recently received antibiotics. In one recent 
randomized trial, 3 days of daily inhaled aminoglycoside prophylaxis 
reduced the occurrence of VAP for the next 28 days, with no impact on 
mortality or antibiotic use.
Minimizing microaspiration around the endotracheal tube cuff 
also can prevent VAP. Simply elevating the head of the bed (at least 
30° above horizontal, but preferably 45°) and using specially modified 
endotracheal tubes that allow removal of the secretions pooled above 
the cuff can prevent microaspiration. The risk-to-benefit ratio of trans­
porting the patient outside the ICU for diagnostic tests or procedures 
should be carefully considered since VAP rates are increased among 
transported patients.
The role played by overgrowth of the normal bowel flora in the 
stomach—in the presence of elevated gastric pH—in the pathogen­
esis of VAP is questionable. Therefore, avoidance of agents that raise 
gastric pH may be relevant only in certain populations, such as liver 
transplant recipients and patients who have undergone other major 
intraabdominal procedures or who have bowel obstruction. MRSA and 
nonfermenters such as P. aeruginosa and Acinetobacter species are not 
normally part of the bowel flora but reside primarily in the nose and 
on the skin, respectively.
In outbreaks of VAP due to specific pathogens, the possibility of a 
breakdown in infection control measures (particularly contamination 

of reusable equipment) should be investigated. Even high rates of 
pathogens that are already common in a particular ICU may result 
from cross-infection. Education and reminders of the need for consis­
tent hand washing and other infection-control practices can minimize 
this risk.

HOSPITAL-ACQUIRED PNEUMONIA
While less well studied than VAP, HAP in nonintubated patients—both 
inside and outside the ICU—is similar to VAP. The main differences 
are the higher frequency of non-MDR pathogens and the generally 
better underlying host immunity in nonintubated patients. The lower 
frequency of MDR pathogens allows monotherapy in a larger propor­
tion of cases of HAP than of VAP. However, the bacteriology and 
outcome of ventilated HAP patients may be very similar to those of 
patients with VAP.
The only pathogens that may be more common in the non-VAP 
population are anaerobes because of a greater risk of macroaspira­
tion and the lower oxygen tensions in the lower respiratory tract of 
these patients. Anaerobes usually contribute only to polymicrobial 
pneumonias, and specific therapy targeting anaerobes probably is not 
needed since many of the recommended antibiotics are active against 
anaerobes.
Diagnosis is even more difficult for HAP in the nonintubated 
patient than for VAP. Lower respiratory tract samples appropriate for 
culture are considerably more difficult to obtain from nonintubated 
patients. Many of the underlying diseases that predispose a patient to 
HAP are also associated with an inability to cough adequately. Since 
blood cultures are infrequently positive (<15% of cases), the major­
ity of patients with HAP do not have culture data on which antibiotic 
modifications can be based, and de-escalation is less likely. Despite 
these difficulties, the better host defenses in non-ICU patients result in 
lower mortality rates than are documented for VAP and for ventilated 
HAP. In addition, the risk of antibiotic failure is lower in HAP.
CHAPTER 131
Pneumonia
GLOBAL IMPACT
From the available data, it is virtually impossible to accurately assess 
the impact of pneumonia from a global perspective. Any differences 
in incidence, disease burden, and costs across different age, ethnic, 
and racial groups are compounded by differences among countries in 
terms of etiologic pathogens, resistance rates, access to health-care and 
diagnostic facilities, and vaccine availability and use.
A standard approach with clearly defined outcome measures is 
needed before the impact of pneumonia can be accurately evaluated. 
However, simple extrapolation from U.S. data for CAP and HAP/
VAP shows that pneumonia has a significant impact on quality of life, 
morbidity, health costs, and mortality rates and that this impact has 
implications for patients and for society as a whole.
Acknowledgment
The authors gratefully acknowledge the contributions of Richard Wun­
derink, MD, to this chapter in a prior edition.
■
■FURTHER READING
Dequin PF et al: Hydrocortisone in severe community–acquired pneu­
monia. N Engl J Med 388:1931, 2023.
Dickson RP et al: Towards an ecology of the lung: New conceptual 
models of pulmonary microbiology and pneumonia pathogenesis. 
Lancet Respir Med 2:238, 2014.
File TM Jr: Community-acquired pneumonia. N Engl J Med 389:632, 2023.
Jain S et al: Community-acquired pneumonia requiring hospitaliza­
tion among U.S. adults. N Engl J Med 373:415, 2015.
Kalil AC et al: Management of adults with hospital-acquired and 
ventilator-associated pneumonia: 2016 clinical practice guidelines by 
the Infectious Diseases Society of America and the American Tho­
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Mandell LA, Niederman MS: Aspiration pneumonia. N Engl J Med 
380:651, 2019.
Mandell LA et al: Infectious Diseases Society of America/Ameri­
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