PNEUMONIA

DEFINITION
Pneumonia is an infection of the pulmonary parenchyma. Despite significant morbidity and mortality, it
is often misdiagnosed, mistreated, and
underestimated. Pneumonia has usually been classified as community-acquired (CAP), hospital-acquired
(HAP), or ventilator-associated
(VAP). A fourth category, health care–associated pneumonia (HCAP)
was introduced to encompass cases caused by multidrug-resistant
(MDR) pathogens typically associated with HAP and cases in unhospitalized individuals at risk of MDR
infection. Unfortunately, this category has not reliably predicted infection with resistant pathogens and
has been associated with increased use of broad-spectrum antibiotics, particularly those employed for
treatment of methicillin-resistant Staphylococcus aureus (MRSA) and antipseudomonal β-lactams.
Accordingly, use of the HCAP category should be discontinued. Rather than relying on a predefined
subset of pneumonia cases, it is better to assess patients individually on the basis of risk factors for
infection with a resistant organism. Risk factors for infection with MRSA and Pseudomonas aeruginosa
include prior isolation of the organism, particularly from the respiratory tract during the preceding year,
and/ or hospitalization and treatment with an antibiotic in the previous 90 days. 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.

PATHOPHYSIOLOGY
Pneumonia is the result of the proliferation of microbial pathogens at the alveolar level 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 oropharyngeal organisms into the lower respiratory tract.
Overcoming of innate and adaptive immunity by such microorganisms could result in the clinical
syndrome of pneumonia. Recent use of culture-independent techniques of microbial identification has
demonstrated a complex and diverse community of bacteria in the lungs that constitutes 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, all play a role in host defense but are insufficient to
effectively block bacterial access to the lower airways. In the absence of a sufficient barrier,
microorganisms 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 factors: microbial entry into the lungs, microbial elimination, and regional growth conditions for
bacteria, such as pH, oxygen tension, and temperature. 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 inflammatory 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 P. 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 simply be the
macroaspiration event itself. Once triggered, innate and adaptive immune responses can ideally help
contain potential pathogens and prevent the development of pneumonia. 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 chemokines 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. Moreover, some bacterial pathogens appear to interfere with the hypoxic
vasoconstriction that would normally occur with fluid-filled alveoli, and this interference may result in
severe hypoxemia. Decreased compliance due to capillary leak, hypoxemia, increased respiratory drive,
increased secretions, and occasionally infection-related bronchospasm 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. 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. In animal models, direct myocardial invasion by pneumococci may result in
scarring and impaired myocardial function and conductivity.

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 the intraalveolar exudate give this stage its name. In the third phase, gray hepatization,
no new erythrocytes are extravasating, and those already present 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, and bacteria and fibrin have been cleared, as has the inflammatory response.
This pattern has been described best for lobar pneumococcal pneumonia but may not apply to
pneumonia of all etiologies. In VAP, respiratory 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 Pneumocystis pneumonias represent alveolar rather than interstitial processes.

COMMUNITY-ACQUIRED PNEUMONIA

ETIOLOGY
The list of potential etiologic agents of CAP includes bacteria, fungi, viruses, and protozoa. Newer viral
pathogens include metapneumoviruses, the coronaviruses responsible for severe acute respiratory
syndrome (SARS) and Middle East respiratory syndrome (MERS), and the recently discovered coronavirus
that originated in Wuhan, China, and is designated SARS-CoV-2. First described in December 2019, SARS-
CoV-2 and its associated clinical disease, COVID-19, have reached pandemic proportions and are a cause
of significant morbidity and mortality. Although most CAP cases are caused by relatively few pathogens,
an accurate determination of their prevalence is difficult because laboratory testing methods are often
insensitive and indirect (Table 126-1). Separation of potential agents into “typical” bacterial pathogens
and “atypical” organisms may be helpful. The former group includes S. pneumoniae, Haemophilus
influenzae, and, in selected patients, S. aureus and gram-negative bacilli such as Klebsiella pneumoniae
and P. aeruginosa. The “atypical” organisms include Mycoplasma pneumoniae, Chlamydia pneumoniae,
and Legionella species as well as respiratory viruses such as influenza virus, adenoviruses, human
metapneumoviruses, respiratory syncytial virus, and coronaviruses. With the increasing use of
pneumococcal vaccine, the incidence of pneumococcal pneumonia is decreasing. Cases due to M.
pneumoniae and C. pneumoniae, however, appear to be increasing, especially among young adults.
Viruses are recognized as increasingly important in pneumonia, and polymerase chain reaction (PCR)–
based testing indicates 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. Atypical organisms cannot be cultured
on standard media or seen on Gram’s stain, but their frequency and importance have significant
implications for therapy. They are intrinsically resistant to all β-lactams and require treatment with a
macrolide, a 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. 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, 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 strains of MRSA in the community. 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.
CLINICAL MANIFESTATIONS
The clinical presentation of pneumonia can vary from indolent to fulminant and from mild to fatal in
severity. Manifestations of worsening severity include both constitutional findings and those limited to
the lung and associated structures. The patient is frequently febrile and/ or tachycardic and may
experience chills and/or sweats. Cough may be nonproductive 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, the patient may be able to speak in full sentences or may be short of
breath. With pleural involvement, the patient may experience pleuritic 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
pulmonary 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 but few other manifestations. Severely ill patients may
have septic shock and evidence of organ failure. In cases of CAP, symptoms can range from almost
nonexistent to severe, and chest radiographic findings are often in gravity-dependent parts of the lung.

DIAGNOSIS
When confronted with possible CAP, the physician must ask two questions: 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 diagnosis of CAP requires a compatible history, such as cough, sputum production, fever and
dyspnea, and a new infiltrate on chest radiography. Unfortunately, the sensitivity and specificity of
findings on physical examination are only 58% and 67%, respectively. Chest radiography is often
necessary to differentiate CAP from other conditions. Radiographic findings may suggest increased
severity (e.g., cavitation or multilobar involvement). Occasionally, radiographic results suggest an
etiologic diagnosis, such as pneumatoceles in S. aureus infection or an upper-lobe cavitating lesion in
tuberculosis. CT may be of value in suspected loculated effusion or cavitary cases or in postobstructive
pneumonia 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; for example, rapid diagnosis of influenza infection 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
presentation. Data from more than 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 to show 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 narrowing of the initial empirical regimen, with a consequent decrease in
antibiotic selection pressure and in the risk of resistance. Pathogens with important public safety
implications, such as Mycobacterium tuberculosis and influenza virus, may be found. Finally, without
susceptibility data, trends in resistance cannot be followed accurately, and appropriate empirical
therapeutic regimens are harder to devise.

GRAM’S STAIN AND CULTURE OF SPUTUM The main purpose of the sputum Gram’s 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’s stain and culture are highly variable. Even in cases of proven bacteremic
pneumococcal pneumonia, the yield of positive cultures from sputum is ≤50%. Many patients,
particularly elderly individuals, may be unable to produce an appropriate sputum sample. Others may be
taking antibiotics 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 126-1), 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’s stain and culture are recommended 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. 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. Because of the low
yield and the 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, including those with
neutropenia secondary to pneumonia, asplenia, complement deficiencies, chronic liver disease, or
severe CAP and those at risk of MRSA or P. aeruginosa infection.

URINARY ANTIGEN TESTS

Two commercially available tests detect pneumococcal and Legionella antigen in urine. The Legionella
pneumophila test detects only serogroup 1, which accounts for most community-acquired cases of
Legionnaires’ disease in the United States. The sensitivity and specificity of this antigen test are 70% and
99%, respectively. The pneumococcal 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 the initiation of
appropriate antibiotic therapy. Testing of urine for pneumococcal antigen can be reserved for severe
cases; Legionella antigen can be sought in severe cases and in situations where relevant epidemiologic
factors are present. 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, but the contamination of respiratory specimens by upper-airway flora may
make semiquantitative or quantitative assays necessary for best results. PCR of nasopharyngeal swabs
has become the standard for diagnosis of respiratory viral infection. PCR can also detect the nucleic acid
of Legionella species, M. pneumoniae, C. pneumoniae, and mycobacteria. 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 time required to obtain a final
result for the convalescent-phase sample and the difficulty of 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, particularly 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 antibiotic treatment. CRP
is considered even less sensitive than PCT for detecting bacterial pathogens. Thus 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 that of outpatient 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 hospital admissions. The two most frequently used rules 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 findings. On the basis of 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%. Use of the PSI results in lower admission rates for class 1 and class 2 patients. Class 3 patients
could ideally be admitted to an observation unit pending further decisions.
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 an age of ≥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 necessary. Among patients with scores of ≥3,
mortality rates are 22% overall; these patients may require ICU admission. The PSI has greater efficacy
than CURB-65 but is more difficult to calculate.
If a patient is unable to maintain oral intake, if compliance is thought to be an issue when
assessed on the basis of mental condition or living situation (e.g., cognitive impairment or
homelessness), 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 126-3), 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 are higher among less ill patients who were admitted 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 oral commensal bacteria
(e.g., viridans group streptococci), (2) the process of natural transformation, or (3) mutation of certain
genes. The S. pneumoniae minimal inhibitory concentration (MIC) breakpoint cutoffs for penicillin in
pneumonia are ≤2 μg/mL for susceptible, >2–4 μg/mL for intermediate, and ≥8 μg/mL for resistant. A
change in susceptibility thresholds dramatically decreased the proportion of pneumococcal isolates
considered nonsusceptible. For meningitis, MIC thresholds remain at the former lower levels.
Fortunately, resistance to penicillin appeared to plateau even before the change in MIC thresholds. Of
isolates in the United States, 65 years, attendance at a day-care center, recent hospitalization, and HIV
infection. In contrast to penicillin resistance, macrolide resistance is increasing in S. pneumoniae through
several mechanisms. Target-site modification 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, 1–32 μg/mL). These two mechanisms account for
~40% and ~60%, respectively, of resistant pneumococcal isolates in the United States. High-level
resistance to macrolides is more common in Europe, whereas lower-level resistance predominates in
North America. The prevalence of macrolide-resistant S. pneumoniae exceeds 25% in some countries; in
Canada the prevalence is ~22%, and in the United States it exceeds 30%. Much of this resistance is high
level, and failures of treatment may result in such cases. In these situations, a macrolide should not be
used as empirical monotherapy. Estimates of the prevalence of doxycycline resistance in the United
States are generally 20%. The rate of pneumococcal resistance to fluoroquinolones (e.g., ciprofloxacin,
moxifloxacin, and levofloxacin) is usually <2%. Changes can occur in one or both target sites
(topoisomerases II and IV); these changes are attributable to mutations in the gyrA and parC genes,
respectively. In addition, an efflux pump may play a role in pneumococcal resistance to fluoroquinolones.
Isolates resistant to drugs from three or more antimicrobial classes with different mechanisms of action
are considered MDR strains. The propensity for an association of pneumococcal resistance to penicillin
with reduced susceptibility to other drugs, such as macrolides, tetracyclines, and trimethoprim-
sulfamethoxazole, 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
pneumococcal 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 hospital-acquired strains or by genotypically and
phenotypically distinct community-acquired strains. Most infections with the former have been 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; this change suggests 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 usually 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. However, the most important
distinction is that CA-MRSA strains also carry genes for superantigens such as enterotoxins B and C and
Panton-Valentine leukocidin; the latter is a membrane-tropic toxin that can create cytolytic pores in
neutrophils, monocytes, and macrophages.

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. 161). Fluoroquinolone resistance among community isolates of Escherichia coli is increasing.
Enterobacter species are typically resistant to cephalosporins, and the drugs of choice for use against
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 likeliest pathogens. In all cases, treatment should be initiated as expeditiously
as possible. New CAP treatment guidelines in the United States have been presented in a joint statement
from the American Thoracic Society (ATS) and the Infectious Diseases Society of America (IDSA). These
guidelines 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. 126-1, Tables 126-4 and
126-5). In the figure and the tables, the antibiotics are not listed in order of preference. The approach to
treatment of aspiration pneumonia is based upon 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 the treatment of CAP (Tables 126-4 and 126-5) is very similar to that proposed in the new
CAP guidelines with the exceptions listed below.
Outpatients
The exceptions to the CAP guidelines that we follow
in treating patients are:
• 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 or MRSA particularly significant in
outpatients.
• Prior antibiotic use should include both oral and parenteral agents.
Patients are stratified into two groups: those without comorbidity or risk factors for antibiotic resistance
and those with comorbidities (e.g., chronic heart, lung, liver, or kidney disease; diabetes; alcoholism;
malignancy; or asplenia) with or without risk factors for resistance (Table 126-4). 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. For those without
comorbidity or resistance risk factors, amoxicillin alone or doxycycline is recommended in the recent
guidelines. Monotherapy with amoxicillin is based on evidence of its efficacy in the treatment of
hospitalized CAP patients. This recommendation is a change from that in 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 126-4). Monotherapy with a macrolide is
recommended in the new guidelines only if there are contraindications to amoxicillin or doxycycline and
there is documented low risk of macrolide resistance (<25%). Otherwise, the treatment of outpatients is
quite similar to the regimens recommended in the 2007 IDSA/ATS guidelines.

Inpatients
Our exceptions to the recommendations in the CAP guidelines are:
• 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. 126-1, Table 126-5).

The main considerations for determining initial empirical treatment of hospitalized CAP patients are
clinical severity and risk factors for infection with drug-resistant pathogens such as MRSA or P.
aeruginosa. Hospitalization alone is not now considered a significant risk factor for these pathogens.
Hospitals should collect local data on MRSA and P. aeruginosa with regard to prevalence, risk factors for
infection, and antibiotic susceptibilities. Patients can be categorized as having nonsevere or severe CAP
(Table 126-3), and those in each of these categories may or may not have risk factors for MRSA or P.
aeruginosa (Fig. 126-1). In the scenarios involving these variables in hospitalized CAP patients, empirical
treatment for either of these pathogens should be added to standard therapy unless a patient’s illness is
considered nonsevere and the risk factors are recent hospitalization and antibiotic treatment ± local
validation data (Fig. 126-1). Depending upon the patient, we may begin treatment in this situation and
then de-escalate it if appropriate. In such cases, cultures should be performed but treatment usually
withheld unless the culture results or the 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
126-5). In the event of contraindications to macrolides and fluoroquinolones, a β-lactam together with
doxycycline may be used. Treatment with a combination of a β-lactam and a macrolide 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 and a macrolide or a β-lactam and a respiratory fluoroquinolone (Table 126-5).

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 factors 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 exposure to parenteral antibiotics. For
HPIM21e_Part05_p941-p1796.indd 1014 20/01/22 6:35 PM 1015CHAPTER 126 Pneumonia P.
aeruginosa, underlying lung disease (e.g., bronchiectasis or very severe COPD) also is an important risk
factor. If MRSA or P. aeruginosa has been isolated previously, appropriate empirical therapy should be
started in both severe and nonsevere cases (Table 126-5). We prefer linezolid over vancomycin as first-
line treatment for MRSA because of its inhibition of bacterial exotoxin and its 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, treatment may be de-escalated
to a standard regimen. If, on the other hand, the risk factors are recent hospitalization and antibiotic use
within the previous 3 months, appropriate samples should be obtained for culture, and, in severe cases,
extended-spectrum treatment for MRSA or P. aeruginosa should be initiated. Depending upon 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. If two antipseudomonal agents are started, the
drugs should not be from the same class. 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 testing positive for
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. Although hospitalized
patients have traditionally received initial therapy by the IV route, some drugs, particularly the
fluoroquinolones, 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 sufficient 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.

ADJUNCTIVE MEASURES
In addition to appropriate antimicrobial therapy, certain adjunctive measures should be used. Adequate
hydration, oxygen therapy for hypoxemia, vasopressor treatment, and assisted ventilation when
necessary are critical to successful treatment. Routine use of glucocorticoids is not recommended for
CAP except in patients with refractory septic shock.

FAILURE TO IMPROVE
Patients slow to respond to therapy should be reevaluated at about day 3 (sooner if their condition is
worsening), with several scenarios 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 correct pathogen, lack of response may be explained in a number of ways. The
pathogen may be resistant to the drug selected, 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 worsening
condition, the patient must be carefully reassessed and appropriate 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.
aeruginosa, or (rarely) S. pneumoniae. A significant pleural effusion should be tapped for both diagnostic
and therapeutic purposes. If the fluid has a pH 1000 U/L or if bacteria are seen or cultured, drainage is
needed.

FOLLOW-UP
Fever and leukocytosis usually resolve within 2–4 days in otherwise healthy patients with CAP, 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.
Patients may be discharged from the hospital once their clinical condition, including 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 is documented,
particularly in the same lung segment, the possibility of an underlying neoplasm must be considered. For
individuals managed as outpatients, routine follow-up chest radiography is not necessary if they are
nonsmokers, if they are otherwise well, and if their 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 comorbidity 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 category of patient and the processes of care, particularly
the timely administration of appropriate antibiotics.

PREVENTION
The main preventive measure is vaccination. Recommendations of the Advisory Committee on
Immunization Practices should be followed for influenza and pneumococcal vaccines. A pneumococcal
polysaccharide vaccine (PPSV23) and a protein conjugate pneumococcal vaccine (PCV13). The former
contains capsular material from 23 pneumococcal serotypes; in the latter, capsular polysaccharide from
13 of the most common pneumococcal pathogens affecting children is linked to an immunogenic
protein. PCV13 produces T-cell–dependent antigens, resulting in long-term immunologic memory.
Administration of this vaccine to children has led to a decrease in the prevalence of antimicrobial-
resistant pneumococci and in the incidence of invasive pneumococcal disease among both children and
adults. However, vaccination can result in the replacement of vaccine with nonvaccine serotypes, as seen
with serotypes 19A and 35B following introduction of the original 7-valent conjugate vaccine. PCV13 is
also recommended for the elderly and for younger immunocompromised patients. Because of an
increased risk of pneumococcal infection, even among patients without obstructive lung disease,
smokers should be strongly encouraged to quit. The influenza vaccine is available in an inactivated or
recombinant form. During an influenza outbreak, unprotected patients at risk from complications should
be vaccinated immediately and given chemoprophylaxis with either oseltamivir or zanamivir for 2 weeks
—i.e., until vaccine-induced antibody levels are sufficiently high.
VENTILATOR-ASSOCIATED PNEUMONIA
Research on hospital-acquired pneumonia has focused on VAP. However, the same information and
principles can also be applied to ventilated HAP and to non-ICU HAP. Approximately 70% of HAP cases
are acquired outside the ICU and 30% in the ICU; the fact that 30% of all HAP patients need mechanical
ventilation defines ventilated HAP as a distinct entity. In non-intubated patients with HAP, an
expectorated sputum sample is used for microbiologic diagnosis, but results are confounded by frequent
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.

HOSPITAL-ACQUIRED PNEUMONIA
While less well studied than VAP, HAP in non-intubated 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 non-intubated patients. The lower frequency of MDR pathogens
allows monotherapy in a larger proportion 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 macroaspiration 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 non-intubated patient than for VAP. Lower
respiratory tract samples appropriate for culture are considerably more difficult to obtain from non-
intubated 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
majority 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.