The n e w e ng l a n d j o u r na l of m e dic i n e

review article

Dan L. Longo, M.D., Editor

Community-Acquired Pneumonia
Daniel M. Musher, M.D., and Anna R. Thorner, M.D.

L
ong recognized as a major cause of death, pneumonia has been From the Medical Care Line (Infectious
studied intensively since the late 1800s, the results of which led to many for- Disease Section), Michael E. DeBakey
Veterans Affairs Medical Center, and the
mative insights in modern microbiology.1,2 Despite this research and the de- Departments of Medicine and Molecular
velopment of antimicrobial agents, pneumonia remains a major cause of complica- Virology and Microbiology, Baylor Col-
tions and death. Community-acquired pneumonia (CAP) is a syndrome in which lege of Medicine — both in Houston
(D.M.M.); and the Division of Infectious
acute infection of the lungs develops in persons who have not been hospitalized re- Diseases, Brigham and Women’s Hospi-
cently and have not had regular exposure to the health care system. tal and Harvard Medical School, Boston
(A.R.T.). Address reprint requests to Dr.
Musher at the Infectious Disease Sec-
C ause tion, Michael E. DeBakey Veterans Affairs
Medical Center, Houston, TX 77030, or at
In the preantibiotic era, Streptococcus pneumoniae caused 95% of cases of pneumonia.1 dmusher@bcm.edu.

Although pneumococcus remains the most commonly identified cause of CAP, the N Engl J Med 2014;371:1619-28.
frequency with which it is implicated has declined,3 and it is now detected in only DOI: 10.1056/NEJMra1312885
Copyright © 2014 Massachusetts Medical Society.
about 10 to 15% of inpatient cases in the United States.4-7 Recognized factors con-
tributing to this decline include the widespread use of pneumococcal polysaccharide
vaccine in adults,8 the nearly universal administration of pneumococcal conjugate
vaccine in children,9 and decreased rates of cigarette smoking.10,11 In Europe and
other parts of the world where pneumococcal vaccines have been used less often
and smoking rates remain high, pneumococcus remains responsible for a higher
proportion of cases of CAP.12,13
Other bacteria that cause CAP include Haemophilus influenzae, Staphylococcus aureus,
Moraxella catarrhalis, Pseudomonas aeruginosa, and other gram-negative bacilli (Table 1).
Patients with chronic obstructive pulmonary disease (COPD) are at increased risk
for CAP caused by H. influenzae and Mor. catarrhalis.14 P. aeruginosa and other gram-
negative bacilli also cause CAP in persons who have COPD or bronchiectasis, es-
pecially in those taking glucocorticoids.15 There is a wide variation in the reported
incidence of CAP caused by Mycoplasma pneumoniae and Chlamydophila pneumoniae
(so-called atypical bacterial causes of CAP), depending in part on the diagnostic
techniques that are used.16,17 Newly available polymerase-chain-reaction (PCR)
techniques should help to clarify this point. Another type of bacterial pneumonia
caused by legionella species occurs in certain geographic locations and tends to
follow specific exposures. Mixed microaerophilic and anaerobic bacteria (so-called
oral flora) are often seen on Gram’s staining of sputum, and these organisms may
be responsible for cases in which no cause is found.
During influenza outbreaks, the circulating influenza virus becomes the prin-
cipal cause of CAP that is serious enough to require hospitalization, with secondary
bacterial infection as a major contributor.18-20 Respiratory syncytial virus, parainflu-
enza virus, human metapneumovirus, adenovirus, coronavirus, and rhinovirus are
commonly detected in patients with CAP, but it may be unclear to what extent
some of these organisms are causing the disease or have predisposed the patient
to secondary infection by bacterial pathogens.16,21-23 Other viruses that cause CAP
include the Middle East respiratory syndrome coronavirus (MERS-CoV), which re-
cently emerged in the Arabian Peninsula, and avian-origin influenza A (H7N9), which

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 The n e w e ng l a n d j o u r na l of m e dic i n e

Table 1. Infectious and Noninfectious Causes of a Syndrome Consistent with Community-Acquired Pneumonia (CAP) Leading to Hospital
Admission.*

Common Causes Less Common Causes Uncommon Causes

Infectious
Streptococcus pneumoniae, Pseudomonas aeruginosa or other Mycobacterium tuberculosis, nontuberculous mycobacteria, nocardia ­species,
Haemo­philus influenzae, gram-negative rods, Pneumo­ legionella species, Myco­­plasma pneumoniae,‡ Chlamydophila pneu­
Staph­ylococcus aureus, cystis jirovecii, Moraxella catar­ moniae,‡ Chlamydophila psittaci, Coxiella burnetii, Histoplasma capsula­
influenza virus, other rhalis, mixed microaerophilic tum, coccidioides species, Blastomyces dermatitidis, crypto­coccus and
­respiratory viruses† and anaerobic oral flora aspergillus species
Noninfectious
Pulmonary edema, lung Pulmonary infarction Cryptogenic organizing pneumonia, eosinophilic pneumonia, acute intersti-
­cancer, acute respiratory tial pneumonia, sarcoidosis, vasculitis (granulomatosis with polyangiitis),
distress syndrome pulmonary alveolar proteinosis, drug toxicity, radiation pneumonitis

* Causes of pneumonia vary according to the patient population, host immune status, and geographic region. No cause is determined in
about half of patients with CAP despite intense investigation. Normal flora, especially streptococci from the upper airways, may be responsible
for many of these cases.
† Routine use of the polymerase-chain-reaction (PCR) assay has substantially increased the detection of these agents, which include para­
influenza virus, respiratory syncytial virus, adenovirus, coronavirus, human metapneumovirus, and rhinovirus.
‡ The frequency of this organism in causing CAP is uncertain because serologic techniques have been unreliable. Currently available PCR assays
may provide reliable information in the future.

recently emerged in China; both of these newly are often present. However, some patients with
identified viruses have since spread elsewhere.24,25 pneumonia (especially those who are elderly) do
Nontuberculous mycobacteria and, in endemic not cough, produce sputum, or have an elevated
areas, fungi such as histoplasma and coccidioides white-cell count, and about 30% (including a
species cause subacute infections that are char- greater proportion of elderly patients) are afebrile
acterized by cough, fever, and new pulmonary in- at admission.3,5,28-30 New lung infiltrates may be
filtrates. Coxiella burnetii may cause acute pneumo- difficult to identify in patients with chronic lung
nia with cough, high fever, severe headache, and disease, in obese patients, and in those for whom
elevated aminotransferase levels. One cannot over- only portable chest radiography is available, or
emphasize the breadth of potential causes, infec- they may be present but are due to noninfectious
tious and noninfectious, of a syndrome consistent causes. In one study, 17% of patients who were
with CAP (Table 1). Most studies of the cause of hospitalized for CAP did not have an infection;
CAP have been performed at tertiary care hospi- pulmonary edema, lung cancer, and other mis-
tals, which may not be representative of the popu- cellaneous causes were responsible (Table 1).5 Al-
lation at large, although similar pathogens have though practitioners need to consider the diverse
been reported in studies of outpatients.26,27 Despite causes of a pneumonia-like syndrome before em-
the most conscientious efforts to determine the pirically prescribing antimicrobial therapy, such
cause, no cause is found in about half the patients conservatism must be balanced by the recogni-
who are hospitalized for CAP in the United States, tion that, for patients with CAP who are ill enough
indicating an important area for future investi- to require hospitalization, early initiation of anti-
gation.5,22,26 microbial therapy increases the likelihood of a
good outcome.14
A pproach t o Di agnosis
Technique s t o De ter mine C ause
The diagnosis of CAP is more challenging than it
might appear to be. The typical teaching is that In patients requiring hospitalization, clinicians
pneumonia is characterized by a newly recognized should make a conscientious effort to determine
lung infiltrate on chest imaging together with the causative organism. Such an effort enables the
fever, cough, sputum production, shortness of physician to direct treatment toward a specific
breath, physical findings of consolidation, and pathogen and facilitates a rational approach to
leukocytosis.14 Confusion and pleuritic chest pain changing therapy if a patient does not have a re-

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 Community-Acquired Pneumonia

sponse to empirical treatment or has an adverse disease.39 Performing sputum culture with the
drug reaction. Pathogen-directed therapy greatly use of selective media is necessary to detect other
fosters antibiotic stewardship, decreasing the cost legionella species.
of care and reducing the risk of complications PCR is a remarkably sensitive and specific tech-
such as Clostridium difficile infection. In hospitalized nique for identifying respiratory pathogens, espe-
patients with CAP, we favor obtaining Gram’s cially viruses. Commercially available PCR assays
staining and culture of sputum, blood cultures, can detect most important respiratory viruses as
testing for legionella and pneumococcal urinary well as Myc. pneumoniae and Chl. pneumoniae.40 For
antigens, and multiplex PCR assays for Myc. pneu- influenza, PCR is far more sensitive than rapid
moniae, Chl. pneumoniae, and respiratory viruses, antigen tests and has become the standard for
as well as other testing as indicated in patients diagnosis.41 On the basis of PCR, a respiratory
with specific risk factors or exposures. A low virus is identified in 20 to 40% of adults hospi-
serum procalcitonin concentration (<0.1 μg per talized for CAP.5,16,22,42 However, the interpreta-
liter) can help to support a decision to withhold tion of a positive test may be difficult, since re-
or discontinue antibiotics.31 spiratory viruses may either cause pneumonia
Microscopic examination of pulmonary secre- directly or predispose the patient to bacterial
tions may provide immediate information about pneumonia.5,22,43 Thus, positive results on PCR
possible causative organisms. Results on Gram’s do not exclude the possibility that bacterial pneu-
staining and culture of sputum are positive in monia is present. Nearly 20% of patients with
more than 80% of cases of pneumococcal pneu- CAP who have proven bacterial pneumonia are
monia when a good-quality specimen (>10 inflam- coinfected with a virus.5,22,43
matory cells per epithelial cell) can be obtained PCR detection of bacteria in respiratory sam-
before, or within 6 to 12 hours after, the initia- ples is also problematic. In most instances, bac-
tion of antibiotics. The yield diminishes with teria that cause pneumonia reach the lungs after
increasing time after antibiotics have been initi- colonizing the upper airways, so a positive PCR
ated and with decreasing quality of the sputum result may reflect colonization or infection.44 In
sample.32 Nebulization with hypertonic saline one study in Africa, quantitative PCR of naso-
(so-called induced sputum) may increase the like- pharyngeal swabs obtained from patients with
lihood of obtaining a valid sample. CAP, most of whom had the acquired immuno-
Blood cultures are positive in about 20 to 25% deficiency syndrome (AIDS), was positive in 82%
of inpatients with pneumococcal pneumonia33 but of patients who had pneumococcal pneumonia,
in fewer cases of pneumonia caused by H. influenzae with few false positive results.45 The generaliz-
or P. aeruginosa and only rarely in cases caused by ability of this method to patients without AIDS in
Mor. catarrhalis. In hematogenous Staph. aureus pneu- developed countries remains to be determined.
monia, blood cultures are nearly always positive,
but they are positive in only about 25% of cases T r e atmen t
in which inhalation or aspiration is responsible
for the CAP.34 Scoring of Disease Severity
Newer diagnostic techniques have become im- Scoring systems may predict the severity of dis-
portant in establishing the cause of CAP. Enzyme- ease and help determine whether a patient with
linked immunosorbent assay (ELISA) of urine CAP requires hospitalization or admission to an
samples detected pneumococcal cell-wall poly- intensive care unit (ICU).46,47 Validated instru-
saccharide in 77 to 88% of patients with bacte- ments include the Pneumonia Severity Index
remic pneumococcal pneumonia35-37 and in 64% (PSI) (Tables S1 and S2 in the Supplementary Ap-
with nonbacteremic pneumonia.35 The more sen- pendix, available with the full text of this article
sitive multiplex-capture assay for pneumococcal at NEJM.org),48 the CURB-65 score (a measure of
capsular polysaccharides is not yet available for confusion, blood urea nitrogen, respiratory rate,
clinical use in the United States but should in- and blood pressure in a patient ≥65 years of age),49
crease the yield.12 ELISA for legionella urinary and the guidelines of the Infectious Diseases So-
antigen is positive in about 74% of patients with ciety of America and the American Thoracic So-
pneumonia caused by Legionella pneumophila sero- ciety (IDSA/ATS).14,50 The decision to hospitalize
type 1,38 with increased sensitivity in more severe a patient ultimately depends on the physician’s

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 The n e w e ng l a n d j o u r na l of m e dic i n e

judgment, but all factors that are contained in dom and Sweden recommend amoxicillin or
these scoring systems should be considered. Be- penicillin as empirical therapy for CAP in outpa-
cause the PSI is so age-dependent, an elevated tients.53,54 Several factors favor the use of a beta-
score in a young adult should be regarded with lactam as empirical therapy for CAP in outpa-
alarm. tients. First, most clinicians do not know the
The SMART-COP score (evaluating systolic level of pneumococcal resistance in their com-
blood pressure, multilobar infiltrates, albumin, munities, and Str. pneumoniae is more susceptible
respiratory rate, tachycardia, confusion, oxygen, to penicillins than to macrolides or doxycycline.
and pH), which was designed to predict which Second, even though the prevalence of Str. pneu-
patients require ICU admission, was originally re- moniae as a cause of CAP has decreased, it seems
ported to be 92% sensitive, as compared with inappropriate to treat a patient with a macrolide
74% for the PSI and 39% for CURB-65.51 We or doxycycline to which 15 to 30% of strains of
have recently found that the PSI is more sensitive Str. pneumoniae are resistant.59 In some parts of the
than SMART-COP and much more sensitive than world, rates of pneumococcal resistance to macro­
CURB-65 for determining which patients will lides are far higher.60 Third, if a patient does not
need ICU admission.52 have a prompt response to a beta-lactam, a mac-
rolide or doxycycline can be substituted to treat a
Guidelines for Empirical Therapy possible atypical bacterial infection, such as that
Guidelines for empirical antimicrobial therapy caused by Myc. pneumoniae. In the United States,
for CAP have contributed to a greater uniformity because one third of H. influenzae isolates and a
of treatment,14,53,54 and their use in hospitalized majority of Mor. catarrhalis isolates produce beta-
patients has been associated with better out- lactamase, amoxicillin–clavulanate may be pref-
comes.55,56 Once the diagnosis of CAP is made, erable to amoxicillin or penicillin, especially in
antimicrobial therapy should be started as soon patients with underlying lung disease.
as possible and at the site where the diagnosis is For patients with CAP who require hospitaliza-
made.14 An initial target period of 4 hours from tion and in whom no cause of infection is im-
initial contact with the medical care system un- mediately apparent, IDSA/ATS guidelines recom-
til antibiotic administration was later changed mend empirical therapy with either a beta-lactam
to 6 hours, in part because the data on which the plus a macrolide or a quinolone alone.14 These
target period was based were regarded as low regimens have been studied extensively and gen-
quality55 and because the use of a target period erally produce a cure in about 90% of patients
resulted in overdiagnosis of CAP and inappropri- with CAP of mild or moderate severity.48,61,62
ate use of antimicrobial agents.57,58 In 2012, the For patients requiring ICU admission, the
target period was retired altogether and replaced guidelines recommend a minimum of a beta-lac-
by the recommendation that treatment be initi- tam plus either a macrolide or a quinolone.14
ated promptly and at the point of care where the Three scenarios merit special mention. First, when
diagnosis of pneumonia was first made. influenza is active in the community, patients
Outpatients with CAP are generally treated with CAP should be treated with oseltamivir even
empirically. A cause of infection is usually not if more than 48 hours have elapsed since the onset
sought because of the substantial cost of diag- of symptoms.63,64 If the likelihood of influenza
nostic testing. For outpatients without coexisting infection is high, treatment should be continued
illnesses or recent use of antimicrobial agents, even if the relatively insensitive rapid antigen
IDSA/ATS guidelines recommend the administra- detection test is negative; a negative result on PCR
tion of a macrolide (provided that <25% of pneu- for influenza virus probably allows for the discon-
mococci in the community have high-level mac- tinuation of anti-influenza therapy.65 Because
rolide resistance) or doxycycline. For outpatients of the high rate of bacterial superinfection,
with coexisting illnesses or recent use of antimi- ceftriaxone and vancomycin or linezolid (for
crobial agents, the guidelines recommend the use methicillin-resistant Staph. aureus [MRSA]) should
of levofloxacin or moxifloxacin alone or a beta- also be given unless a good-quality respiratory
lactam (e.g., amoxicillin–clavulanate) plus a mac- specimen shows no bacteria on Gram’s staining
rolide. and there is no other evidence of bacterial infec-
By contrast, guidelines from the United King- tion. Droplet and contact precautions should be

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 Community-Acquired Pneumonia

used when influenza is suspected. Second, in pa-

Table 2. Clinical Features Associated with Specific Causes of CAP.
tients at high risk for Staph. aureus pneumonia (e.g.,
those taking glucocorticoids or those with influ- Favoring typical bacterial or legionella pneumonia
enza), vancomycin or linezolid should be added to Hyperacute presentation
treat MRSA. Ceftaroline, which is active against Presentation with septic shock
Staph. aureus, including MRSA, as well as Str. Absence of upper respiratory symptoms
pneumoniae and H. inf luenzae, may eventually re-
Initial upper respiratory illness followed by acute deterioration (suggesting
place ceftriaxone plus vancomycin or linezolid as viral infection with bacterial superinfection)
anti-MRSA regimen, although it has not yet been
White-cell count, >15,000 or ≤6000 cells per cubic millimeter with increased
approved by the Food and Drug Administration for band forms
treating MRSA pneumonia. Third, when P. aerugi- Dense segmental or lobar consolidation
nosa is a consideration, as in patients with struc-
Procalcitonin level, ≥0.25 µg per liter
tural lung disease such as COPD or bronchiectasis
(especially if they are receiving treatment with Favoring atypical bacterial (mycoplasma or chlamydophila) pneumonia
glucocorticoids or other immunosuppressive Absence of factors that favor typical bacterial pneumonia
drugs), an antipseudomonal beta-lactam or car- Family cluster
bapenem should be given. IDSA/ATS guidelines Cough persisting >5 days without acute deterioration
recommend the use of two antipseudomonal drugs Absence of sputum production
because it is difficult to predict the susceptibility
Normal or minimally elevated white-cell count
pattern of pseudomonas species. Initial therapy
Procalcitonin level, ≤0.1 µg per liter
may be empirical, but antibiotics should be tailored
to the causative organism, which underlines the Favoring nonbacterial (viral) pneumonia
clear advantage of establishing the cause of in- Absence of factors that favor bacterial pneumonia
fection. Exposure to sick contacts
Upper respiratory symptoms at time of presentation
Empirical Therapy — Does One Size Fit All?
Patchy pulmonary infiltrates
The IDSA/ATS guidelines were written in an at-
Normal or minimally elevated white-cell count
tempt to develop a uniform set of recommenda-
Procalcitonin level, ≤0.1 µg per liter
tions that would provide appropriate antimicro-
bial therapy for the majority of patients with Favoring influenza pneumonia
CAP. Although individual causative organisms Absence of factors that favor typical bacterial pneumonia
cannot be determined with certainty on the basis Influenza active in the community
of findings at presentation, the medical literature Sudden onset of flulike syndrome
supports the concept that constellations of clini- Positive diagnostic test for influenza virus
cal findings may guide diagnosis and selection
of therapy (Table 2).66-70 Our approach to the selec-
tion of an appropriate antimicrobial regimen is sulbactam) plus a macrolide or with a quinolone
intended to balance the tension between a failure (levofloxacin or moxifloxacin).5,66-70 If risk factors
to treat, on the one hand, and overtreatment by raise concern for P. aeruginosa infection, we use
attempting to cover all possible causes, on the an antipseudomonal beta-lactam (e.g., cefepime
other. or piperacillin–tazobactam). In contrast to the
A patient whose constellation of findings in- IDSA/ATS guidelines (which recommend the use
cludes an acute onset of chills and fever, cough of two antipseudomonal agents), we typically give
with sputum production, pleuritic chest pain, a a second antipseudomonal agent only to patients
high or suppressed white-cell count with increased who are severely ill (Table 3). In patients who
band forms, a dense segmental or lobar consoli- have a milder version of this syndrome and who
dation, or a serum procalcitonin level of more than do not require hospital admission, amoxicillin–
0.25 μg per liter is likely to have typical bacte- clavulanate may be given in place of a parenteral
rial pneumonia, such as pneumococcal pneumo- beta-lactam. A quinolone should be used judi-
nia.5,66-70 Such patients should be hospitalized ciously and only in outpatients who have sub-
(if indicated on the basis of the PSI) and treated stantial coexisting illnesses or who have recently
with a beta-lactam (e.g., ceftriaxone or ampicillin– taken antibiotics from another class. In contrast

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 The n e w e ng l a n d j o u r na l of m e dic i n e

are unlikely to have bacterial pneumonia (Table 2).

Table 3. Empirical Treatment of CAP.
It might be best to treat their symptoms and ob-
Outpatient* serve them. If they have been started on antibac-
For syndromes suggesting typical bacterial pneumonia: amoxicillin–clavulanate terial agents for typical bacterial pneumonia, these
with the addition of azithromycin if legionella species are a consideration; drugs could be discontinued, especially if initial
levofloxacin or moxifloxacin may be used instead
studies for bacteria are negative.5,31 If influenza
For syndromes suggesting influenza pneumonia: oseltamivir with observation is active in the community and the syndrome is
for secondary bacterial infection
consistent (e.g., sudden onset, fever, cough, and
For syndromes suggesting viral pneumonia other than influenza: symptomatic
therapy
myalgias), oseltamivir should be given unless the
result on PCR is negative for influenza. Docu-
For syndromes suggesting mycoplasma or chlamydophila pneumonia:
azithromycin or doxycycline mentation of a noninfluenza respiratory virus by
means of PCR in such patients supports the
Inpatient†
choice of observation alone without antibiotics.
For initial empirical therapy: a beta-lactam (ceftriaxone, cefotaxime, or ceftaroline)
plus azithromycin; levofloxacin or moxifloxacin may be used instead
Myc. pneumoniae infection is more likely in young
adults who have low-grade fever and a nonpro-
If influenza is likely: oseltamivir‡
ductive cough for 5 or more days without acute
If influenza is complicated by secondary bacterial pneumonia: ceftriaxone or deterioration, especially if the illness developed in
cefotaxime plus either vancomycin or linezolid§ in addition to oseltamivir
a family cluster.68,70,71 Treatment for Myc. pneu-
If Staphylococcus aureus is likely: vancomycin or linezolid in addition to the
antibacterial regimen moniae infection with a macrolide seems appropri-
ate, particularly if testing for viruses is negative.
If pseudomonas pneumonia is likely: antipseudomonal beta-lactam
(piperacillin–tazobactam, cefepime, meropenem, or imipenem– When patients are hospitalized for CAP and
cilastatin)¶ plus azithromycin no causative organism is identified, most clini-
cians presume that a bacterial infection is re-
* The decision to treat pneumonia on an outpatient basis should be made after sponsible and treat with full courses of broad-
assessing the need for hospitalization and only if follow-up contact is planned.
The use of quinolones is typically reserved for outpatients with substantial spectrum antibacterial therapy.72 Some studies
­coexisting illnesses or recent use of antibiotics from another class. suggest that the use of biomarkers can distinguish
† Patients who are hospitalized for pneumonia are sufficiently likely to have a bacterial from nonbacterial pneumonia.31,73 In a
bacterial infection that antibacterial agents are nearly always prescribed unless
an alternative diagnosis is strongly suspected. In every hospitalized patient, meta-analysis of 14 randomized trials, procalci-
all reasonable efforts should be made to determine the causative organism, tonin guidance for antibiotic use was associated
and antimicrobial therapy should be directed toward identified organisms. with a reduction in antibiotic use without an in-
‡ In patients who are severely ill, intravenous zanamivir can be obtained after
approval of an emergency investigational new drug application. crease in either mortality or treatment failure.73
§ These regimens target the most likely causes of bacterial pneumonia second- Because of the substantial overlap in procalcito-
ary to influenza pneumonia, including Streptococcus pneumoniae, Haemophilus nin levels among individual patients, such testing
influenzae, Str. pyogenes, and Staph. aureus. Ceftaroline may be effective against
these bacterial pathogens, including methicillin-resistant Staph. aureus (MRSA), should be only one of several factors considered
but it is not yet approved by the Food and Drug Administration for MRSA in the decision to withhold antibiotics.5
pneumonia.
¶ A second antipseudomonal drug (ciprofloxacin or an aminoglycoside) can be
added in patients with severe CAP in whom P. aeruginosa is likely, because sus- Duration of Therapy
ceptibility is difficult to predict. Therapy can be narrowed to one agent with ac- Early in the antibiotic era, pneumonia was treated
tivity against gram-negative bacilli once susceptibility results are available. for about 5 days; some studies even showed that
a single dose of penicillin G procaine was cura-
to the IDSA/ATS guidelines, because of concern tive.74,75 The standard duration of treatment later
about pneumococcal resistance, we would not use evolved to 5 to 7 days.76,77 A meta-analysis of
doxycycline or azithromycin alone to treat outpa- studies comparing treatment durations of 7 days
tients in whom the syndrome suggests typical or less with durations of 8 days or more showed
bacterial infection. no differences in outcomes,78 and prospective
Patients with CAP who have none of the fac- studies have shown that 5 days of therapy are as
tors that favor bacterial infection and who have effective as 10 days79 and 3 days are as effective
known exposure to sick contacts, upper respira- as 8.80 Nevertheless, practitioners have gradually
tory symptoms at the time of presentation, patchy increased the duration of treatment for CAP to 10 to
pulmonary infiltrates, a normal or minimally el- 14 days.72,81 A responsible approach to balancing
evated white-cell count with a normal differential, antibiotic stewardship with concern about insuf-
and a procalcitonin level of 0.1 μg per liter or less ficient antibiotic therapy would be to limit treat-

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 Community-Acquired Pneumonia

ment to 5 to 7 days, especially in outpatients, or

Table 4. Reasons for a Lack of Response to Treatment
in inpatients who have a prompt response to of CAP.
therapy.14,77,82
Pneumonia that is caused by Staph. aureus or Correct organism but inappropriate antibiotic choice or dose
gram-negative bacilli tends to be destructive, and Resistance of organism to selected antibiotic
concern that small abscesses may be present has Wrong dose (e.g., in a patient who is morbidly obese or
led clinicians to use more prolonged therapy, has fluid overload)
depending on the presence or absence of coex- Antibiotics not administered
isting illnesses and the response to therapy. He- Correct organism and correct antibiotic but infection is
matogenous Staph. aureus pneumonia mandates loculated (e.g., most commonly empyema)
treatment for at least 4 weeks, but segmental or Obstruction (e.g., lung cancer, foreign body)
lobar pneumonia that is caused by this organism Incorrect identification of causative organism
may be treated for 2 weeks.83 Cavitating pneu- No identification of causative organism and empirical
monia and lung abscesses are usually treated for therapy directed toward wrong organism
several weeks; some experts continue treatment Noninfectious cause
until cavities have resolved. The lack of a response Drug-induced fever
to seemingly appropriate treatment in a patient
Presence of an unrecognized, concurrent infection
with CAP should lead to a complete reappraisal,
rather than simply to selection of alternative anti-
biotics (Table 4). with ventilator-associated pneumonia was stopped
early because no 28-day mortality benefit was
Immunomodulatory Drugs seen in those who received this drug.91
Macrolides inhibit important intracellular signal-
ing pathways and suppress production of tran- Noninfec t ious C ompl ic at ions
scription factors, such as nuclear factor κB and
activator protein 1, which, in turn, decrease the Influenza pneumonia92,93 and bacterial pneumo-
production of inflammatory cytokines and the ex- nia94-97 are each strongly associated with acute
pression of adhesion molecules.84 Many, but not cardiac events. In a veterans hospital, myocardial
all, retrospective studies have shown that the ad- infarction and new major arrhythmias (most com-
dition of a macrolide to a beta-lactam antibiotic monly, atrial fibrillation) were each seen in 7 to
to treat pneumococcal pneumonia or all-cause 10% of patients who were admitted for CAP, wors-
CAP reduces morbidity and mortality, presumably ening of heart failure occurred in nearly 20%,
by inhibiting the inflammatory response.85,86 and one or more of these complications occurred
Statins block the synthesis of 3-hydroxy- in 25% of patients.94,97 It is likely that myocardial
3-methylglutaryl coenzyme A (HMG-CoA) re- infarction occurs when pulmonary inflammation
ductase, inhibiting the synthesis of farnesyl py- releases cytokines that up-regulate inflammation
rophosphate and geranylgeranyl pyrophosphate in a vulnerable atherosclerotic plaque.96,98 The
(which are needed to activate G proteins), there- mechanism for atrial fibrillation is uncertain;
by dampening inflammatory responses.87 Obser- this arrhythmia usually resolves spontaneously
vational studies have shown better outcomes in within a few weeks. Heart failure probably re-
patients who were taking statins at the time of flects added stress on the heart together with de-
admission for pneumonia, even though such pa- creased oxygenation. These cardiac events are as-
tients tend to have a greater number of coexist- sociated with substantial increases in mortality.99
ing illnesses related to coronary artery disease.86
No data from randomized trials to examine these Ou t c ome s
effects of macrolides or statins in patients with
CAP are available. The potential benefit of mac- The 30-day rate of death in patients who are hos-
rolides must be balanced against the very small pitalized for CAP is approximately 10 to 12%
increase in sudden cardiac deaths observed in pa- (Tables S1 and S2 in the Supplementary Appen-
tients taking azithromycin.88 Other studies, how- dix).48,61,62 After discharge from the hospital,
ever, have shown conflicting results.89,90 A ran- about 18% of patients are readmitted within 30
domized trial of adjunctive simvastatin in patients days.100 Many patients, especially elderly ones,

n engl j med 371;17 nejm.org october 23, 2014 1625

 The n e w e ng l a n d j o u r na l of m e dic i n e

may take several months to return to their previ- will elucidate the frequency with which legionella,
ous state of health, and some never do.101,102 In chlamydophila, and mycoplasma species, along
those who survive for 30 days, mortality is sub- with other pathogens, cause CAP. It remains to
stantially increased at 1 year and, in the case of be determined whether the availability of sensi-
pneumococcal pneumonia, remains elevated for tive diagnostic tests such as PCR will increase
3 to 5 years,103,104 suggesting that development the use of targeted therapies and reduce depen-
of CAP serves as a marker for underlying condi- dence on empirical antibiotic therapy. Increasing
tions that limit lifespan. antibiotic resistance in bacteria may compound
the difficulty of selecting an effective regimen.
F u t ur e Dir ec t ions Randomized trials are needed to determine wheth-
er the antiinflammatory activity of macrolides or
Important unresolved problems remain with re- statins is beneficial in treating CAP.
spect to CAP. Despite the most diligent efforts,
No potential conflict of interest relevant to this article was
no causative organism is identified in half of pa- reported.
tients. It is unclear what proportion of these cases Disclosure forms provided by the authors are available with
are attributable to infection by so-called typical the full text of this article at NEJM.org.
We thank Drs. Thomas M. File and John G. Bartlett for their
or atypical bacterial pathogens, oral flora, virus- critical review of an earlier version of this manuscript and for
es, or other pathogens. The increased use of PCR their insightful comments.

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