Epidemiology, pathogenesis, and microbiology of community-

acquired pneumonia in adults

Author
Thomas J Marrie, MD
Section Editor
John G Bartlett, MD
Deputy Editor
Anna R Thorner, MD
Last literature review version 18.3: septiembre 2010 | This topic last updated: abril 16, 2010
INTRODUCTION — Community-acquired pneumonia (CAP) is a common and potentially serious illness.
It is associated with considerable morbidity and mortality, particularly in elderly patients and those with
significant comorbidities [1]. (See "Prognosis of community-acquired pneumonia in adults".)

The epidemiology, pathogenesis, and microbiology of CAP will be reviewed here. A variety of other
important issues related to CAP are discussed separately. These include:

 The diagnostic approach to patients with CAP. (See "Diagnostic approach to community-acquired

pneumonia in adults".)
 The use of sputum cultures for the evaluation of bacterial pneumonia. (See "Sputum cultures for
the evaluation of bacterial pneumonia".)
 How one makes the decision to admit patients with CAP to the hospital. (See "Community-
acquired pneumonia in adults: Risk stratification and the decision to admit".)
 Treatment recommendations for CAP in patients treated in the outpatient setting.
(See "Treatment of community-acquired pneumonia in adults in the outpatient setting".)
 Treatment recommendations for CAP in patients requiring hospitalization. (See "Treatment of
community-acquired pneumonia in adults who require hospitalization".)
 The evidence for efficacy of different antibiotic medications in the empiric treatment of CAP and
issues related to drug resistance. (See"Antibiotic studies for the treatment of community-acquired
pneumonia in adults".)
 Pneumonia in special populations, such as aspiration pneumonia and immunocompromised
patients. (See "Aspiration pneumonia in adults" and"Common pulmonary infections in
immunocompromised patients".)

EPIDEMIOLOGY — The overall rate of CAP ranges from 8 to 15 per 1000 persons per year; the highest
rates are at the extremes of age. There is seasonal variation, with more cases occurring during the
winter months. The rates of pneumonia are higher for men than for women and for black persons
compared with Caucasians. The etiology of CAP, varies by geographic variation, however, Streptococcus
pneumoniae is the most common cause of pneumonia worldwide.

PATHOGENESIS — The lungs are constantly exposed to particulate material and microbes that are
present in the upper airways and, by microaspiration, enter the lower respiratory tract. Nevertheless,
the lower airways usually remain sterile because of the pulmonary defense mechanisms. These host
defenses can be categorized as innate (nonspecific) or acquired (specific). The development of CAP
indicates either a defect in host defenses, exposure to a particularly virulent microorganism, or an
overwhelming inoculum [2-4].

Although microaspiration is the most common mechanism through which pathogens reach the lung,
hematogenous spread from a distant infected site, direct spread from a contiguous focus, and
macroaspiration are other mechanisms.

Bacterial virulence factors — Some microorganisms have developed specific mechanisms to overcome

pulmonary host defenses and establish infection [2-4]. Examples include:
  Chlamydophila pneumoniae produces a ciliostatic factor
 Mycoplasma pneumoniae can shear off cilia
 Influenza virus markedly reduces tracheal mucus velocity within hours of onset of infection and
for up to 12 weeks postinfection.
 Streptococcus pneumoniae and Neisseria meningitidis produce proteases that can split secretory
IgA. In addition, the pneumococcus produces other virulence factors including: the capsule that
inhibits phagocytosis, pneumolysin, a thiol-activated cytolysin that interacts with cholesterol in
host cell membranes, neuraminidase, and hyaluronidase.
 Mycobacterium spp, Nocardia spp, and Legionella spp, are resistant to the microbicidal activity of
phagocytes.

Predisposing host conditions — In addition to microbial virulence factors, diseases and conditions in
the host may lead to impairment of pulmonary defense and increased risk of CAP (table 1). These
conditions include [5]:

 Alterations in the level of consciousness, which predispose to both macroaspiration of stomach

contents (due to stroke, seizures, drug intoxication, anesthesia, and alcohol abuse) and to
microaspiration of upper airway secretions during sleep
 Smoking tobacco
 Alcohol consumption
 Hypoxemia
 Acidosis
 Toxic inhalations
 Pulmonary edema
 Uremia
 Malnutrition
 Administration of immunosuppressive agents (solid organ or stem cell transplant recipients, or
patients receiving chemotherapy)
 Mechanical obstruction of a bronchus
 Being elderly, there is a marked increase in the rate of pneumonia in persons ≥65 years
 Cystic fibrosis
 Bronchiectasis
 Chronic obstructive pulmonary disease (COPD)
 Previous episode of pneumonia or chronic bronchitis
 Immotile cilia syndrome
 Kartagener's syndrome (ciliary dysfunction, situs inversus, sinusitis, bronchiectasis)
 Young's syndrome (azoospermia, sinusitis, pneumonia)

Drugs — Several studies have suggested an increased incidence of nosocomial pneumonia when the
gastric pH is increased by the use of H2 blockers or antacids. This issue is now being addressed in
patients with community-acquired pneumonia. Two studies have shown an increased risk of CAP among
patients taking gastric acid-suppressive therapy, including proton pump inhibitors (PPIs) and H2 blockers
[6,7]. However, a subsequent large case-control study found an increased risk of CAP only among
patients who started a PPI within the previous 30 days and particularly in those who initiated therapy
within the previous 48 hours [8]. The significance of this finding is uncertain since maximum acid-
blocking effect takes at least one week to develop. (See "Risk factors and prevention of hospital-
acquired, ventilator-associated, and healthcare-associated pneumonia in adults", section on 'Role of
gastric pH'.)

Several studies have shown an association between use of antipsychotic drugs and CAP, although the
mechanism remains unclear. In one case-control study, use of antipsychotic drugs was associated with
an almost 60 percent increase in the risk of pneumonia among elderly persons requiring hospitalization
[9]. In another case-control study, current use of atypical (odds ratio [OR] 2.61, 95% CI 1.48-4.61) or
typical (OR 1.76, 95% CI 1.22-2.53) antipsychotic use was associated with a dose-dependent increased
risk for CAP compared with past use [10]. Atypical antipsychotic use was also associated with an
increase in the risk of fatal CAP (OR 5.97, 95% CI 1.49-23.98).

MICROBIOLOGY — There are more than 100 microbes (bacteria, viruses, fungi, and parasites) that can
cause CAP. Most cases of pneumonia are caused by four or five microorganisms, but the distribution of
pathogens varies with the clinical setting.

The most common pathogens based upon the severity of illness as judged by the site of care (outpatient
versus inpatient versus intensive care unit [ICU]) are shown in the figures (figure 1A-C) [11-53].
Streptococcus pneumoniae is the most frequently isolated pathogen. Relative to other pathogens,
respiratory viruses, Mycoplasma pneumoniae, Legionella spp, Chlamydophila (formerly Chlamydia)
pneumoniae, and Haemophilus influenzae are also common. The "atypical" pathogens (M. pneumoniae,
Legionella spp, C. pneumoniae, C. psittaci) are not often identified in clinical practice, because there is
not a specific, rapid, or standardized test for their detection with the exception of L. pneumophila.

Influenza remains the most predominant viral cause of CAP in adults. Other recognized viral pathogens
include respiratory syncytial virus (RSV), parainfluenza virus and, less often, adenovirus,
metapneumovirus, varicella, and severe acute respiratory syndrome (SARS).

Staphylococcus aureus, Enterobacteriaceae, and Pseudomonas aeruginosa are pathogens in a selected

group of patients (eg, post-influenza, prior antimicrobial treatment, or pulmonary comorbidities) [54]. In
another specific group, patients admitted to the ICU with severe CAP, the predominant pathogens are S.
pneumoniae, enteric gram-negative bacilli, S. aureus, respiratory viruses, Legionella spp, and H.
influenzae (figure 1C).

The frequency of other etiologic agents, such as Mycobacterium tuberculosis, Chlamydophila psittaci
(psittacosis), Coxiella burnetii (Q fever), Francisella tularensis (tularemia), and endemic fungi
(histoplasmosis, coccidioidomycosis, histoplasmosis), vary with the epidemiologic setting.

Definitions — Bacteria are the most common cause of CAP and have traditionally been divided into two
groups: "typical" and "atypical" agents:

 "Typical" organisms include S. pneumoniae, Haemophilus influenzae, Staphylococcus aureus,

Group A streptococci, Moraxella catarrhalis, anaerobes, and aerobic gram-negative bacteria.
 "Atypical" refers to pneumonia caused by Legionella spp, Mycoplasma pneumoniae,
Chlamydophila (formerly Chlamydia) pneumoniae, and C. psittaci.

In the individual patient, there are no findings from history, physical examination, or routine laboratory
studies that allow the clinician to distinguish pneumonia caused by atypical from typical organisms.
Indeed, the term "atypical pneumonia" should no longer be used.

Microbiologic diagnosis — A microbiologic diagnosis is confirmed in about 60 percent of cases of CAP

in research studies and in only about 20 percent of cases in everyday practice. When considering the
etiology of CAP it is useful to categorize patients into those who can be treated on an ambulatory basis,
those who require hospitalization, and those who require admission to an intensive care unit. The rank
order of the most common causes of pneumonia vary according to the severity of illness as illustrated in
the following studies:

 In a prospective study of 507 patients treated in an ambulatory setting in Canada, the most
commonly identified microorganisms were M. pneumoniae (15 percent), C. pneumoniae (12
percent), S. pneumoniae (6 percent), and H. influenzae (5 percent) [11]. Despite considerable
effort, an etiologic diagnosis could not be determined in 50 percent of cases.
  In a prospective report of 326 cases of CAP requiring hospitalization in Japan, the most common
microorganisms identified were S. pneumoniae (23 percent), H. influenzae (7 percent), and M.
pneumoniae (5 percent) [55]. An etiologic pathogen was identified in 61 percent of cases. In
contrast to studies from Western countries, Legionella infection was encountered in only two of
the Japanese patients.
 In a series of 185 patients with CAP requiring intensive care unit admission in the United
Kingdom, the most commonly identified microorganisms were S. pneumoniae (22 percent),
Legionella spp (18 percent), viruses (10 percent), S. aureus (9 percent), and H. influenzae (4
percent) [56]. An etiologic agent was identified in 68 percent of cases.

The distribution of pathogens appears to be different in patients with CAP requiring intensive care
unit admission in Europe (outside of the United Kingdom) [56]. There was a lower frequency of
Legionella and a higher frequency of gram-negative enteric bacilli infections. The most commonly
identified microorganisms were S. pneumoniae (22 percent), gram-negative bacilli (9 percent), S.
aureus (7 percent), C. pneumoniae (7 percent), Legionella spp (6 percent), and H. influenzae (5
percent).
 A prospective study of 148 patients with CAP presenting in septic shock in the United States
found the most commonly identified microorganisms were S. pneumoniae (19 percent), S. aureus
(18 percent), gram-negative bacilli (18 percent; Klebsiella pneumoniae [11 percent] and
Pseudomonas aeruginosa [7 percent]), and H. influenzae (14 percent) [57].

Epidemiologic clues — There are a few clinical clues that must be taken into account when considering
the etiology of CAP (table 1):

 Know the local epidemiology and the patient's travel history (eg, endemic fungi such as
Histoplasma, Coccidioides, Blastomyces, and Paracoccidioides spp; Hantavirus)
 Elicit history of specific exposures (eg, Histoplasma spp and bat or bird droppings, Chlamydophila
psittaci and birds)
 Be aware of national and international outbreaks (eg, influenza or severe acute respiratory
syndrome [SARS])
 Never forget Mycobacterium tuberculosis
 Pneumocystis jirovecii (formerly P. carinii) is often forgotten as a cause of CAP now that highly
active antiretroviral therapy has resulted in a decrease in the number of cases of PCP in HIV-
infected patients
 Methicillin-resistant Staphylococcus aureus is an increasingly recognized cause of severe,
occasionally necrotizing CAP

Bacteria — Bacteria are the most common cause of CAP. The true incidence of these infections is
uncertain because of the difficulty in distinguishing colonizing organisms from pathogens.

S. pneumoniae — S. pneumoniae is the most common cause of CAP. Many studies have isolated the
organism in only 5 to 18 percent of cases. However, the rate of isolation increases when more invasive
methods are used for obtaining specimens, such as transtracheal aspiration, which eliminates
contaminating oropharyngeal flora. It is currently believed that many culture-negative cases are caused
by pneumococcus. The data supporting this conclusion are presented separately. (See "Pneumococcal
pneumonia in adults", section on 'Epidemiology'.)

H. influenzae — Non-typeable H. influenzae is an important cause of pneumonia in elderly adults and in

patients with underlying pulmonary disease such as cystic fibrosis and COPD. The clinical features are
indistinguishable from CAP caused by other organisms. (See "Microbiology, epidemiology and treatment
of Haemophilus influenzae".)
M. pneumoniae — Mycoplasma pneumoniae is one of the most common causes of atypical pneumonia
in series from the United States and other parts of the world, accounting for up to 15 percent of cases of
pneumonia treated in an ambulatory setting [11]. M. pneumoniae is transmitted from person-to-person
by infected respiratory droplets during close contact. Infection rates are highest in school-aged children,
military recruits, and college students. (See "Mycoplasma pneumoniae infection in adults".)

Chlamydophila (Chlamydia) pneumoniae — C. pneumoniae is thought to account for 5 to 10 percent

of cases of CAP. The infection is most common in those aged 65 to 79 years. Unlike other respiratory
infections, which have peak rates in the winter months, C. pneumoniae infection does not vary
significantly by season. Pneumonia and bronchitis are the most common respiratory infections
associated with C. pneumoniae. (See"Pneumonia caused by Chlamydophila (Chlamydia) species in
adults".)

Legionella — Legionella accounts for 2 to 9 percent of cases of CAP. Legionella can occur as a sporadic
infection or cause outbreaks. Travel associated legionellosis is becoming more common. In most
instances Legionella is transmitted to humans by inhalation of aerosols containing the bacteria.
Outbreaks have been associated with exposure to a variety of aerosol-producing devices, including
showers, a grocery store mist machine, cooling towers, whirlpool spas, and decorative fountains.
(See "Epidemiology and pathogenesis of Legionella infection".)

Gram-negative bacilli — Gram-negative bacilli, especially K. pneumoniae, Escherichia coli,

Enterobacter spp, Serratia spp, Proteus spp, P. aeruginosa, and Acinetobacter spp, are uncommon
causes of CAP except in patients with severe pneumonia requiring admission to an intensive care unit
where, as a group, they are among the most commonly isolated organisms after S. pneumoniae (figure
1C) [58,59]. (See "Treatment of community-acquired pneumonia in adults who require hospitalization",
section on 'Common pathogens'.)

 Klebsiella pneumonia — K. pneumoniae must be considered as a cause of severe CAP in patients

who have significant underlying disease such as COPD, diabetes, and alcohol abuse. In a study of
112 immunocompetent patients with severe CAP, multivariate analysis found K. pneumoniae was
an independent risk factor for mortality [59]. (See "Overview of Klebsiella pneumoniae infection",
section on 'Community-acquired pneumonia'.)
 Pseudomonas aeruginosa — Risk factors for community-acquired P. aeruginosa pneumonia
include bronchiectasis (eg, due to cystic fibrosis) and the use of repeated antibiotic courses or
prolonged glucocorticoids in patients with other structural lung abnormalities such as COPD and
pulmonary fibrosis [1,54,60]. Immunocompromise (eg, neutropenia, HIV infection, solid organ or
hematopoietic stem cell transplantation) and previous hospitalization are other risk factors for
Pseudomonas pneumonia. (See "Pseudomonas aeruginosa pneumonia".)
 Acinetobacter spp — Acinetobacter spp are well-recognized as pathogens causing nosocomial
pneumonia. In addition, A. baumannii is emerging as a cause of severe CAP with high mortality.
Multidrug resistance is an increasing problem with Acinetobacter infection. (See"Clinical
manifestations of Acinetobacter infection", section on 'Pneumonia' and "General principles of the
treatment and prevention of Acinetobacter infection".)
 Moraxella catarrhalis — Moraxella is a gram-negative diplococcus that can cause lower respiratory
tract infections in adults with chronic obstructive pulmonary disease and in immunocompromised
persons. In a review of 58 patients with M. catarrhalis bacteremia, 70 percent had predisposing
factors such as neutropenia, malignancy, or COPD either alone or in combination [61]. Many
patients with this infection are malnourished. Not infrequently it is a copathogen [62].

S. aureus — S. aureus pneumonia that is community-acquired is usually seen in elderly adults and in
younger patients who are recovering from influenza (postinfluenza pneumonia). However, the
pneumococcus remains the most frequent pathogen in this setting. (See "Clinical manifestations and
diagnosis of seasonal influenza in adults", section on 'Secondary bacterial pneumonia'.)
Community-associated methicillin-resistant S. aureus (CA-MRSA) is often associated with severe
necrotizing pneumonia [63-69]. The tendency to necrotizing pneumonia may be mediated by Panton-
Valentine leukocidin (PVL), which is typically present in CA-MRSA strains [63-68,70,71]. This was
illustrated in a study that compared the clinical features of 16 patients with PVL-positive S. aureus
pneumonia to 36 cases of PVL-negative S. aureus pneumonia [63]. Hemoptysis was significantly
associated with pneumonia in patients with PVL-positive strains compared with those with PVL-negative
strains (38 versus 3 percent). (See "Epidemiology of methicillin-resistant Staphylococcus aureus
infection in adults", section on 'CA-MRSA infection'.)

The role of PVL was more directly demonstrated in a mouse model of acute pneumonia that included
PVL-negative and PVL-positive CA-MRSA strains, as well as purified PVL; PVL alone was sufficient to
cause necrotizing pneumonia [72]. PVL induced global changes in the transcriptional levels of genes
encoding multiple staphylococcal proteins, including the lung inflammatory factor staphylococcal protein
A.

CA-MRSA pneumonia may be associated with influenza infection [66-68,73]. During the 2003 to 2004
influenza season, 17 cases of S. aureus CAP were reported to the Centers for Disease Control and
Prevention from nine states; 15 cases were CA-MRSA [67]. All isolates had community-associated
genetic characteristics; 12 of 13 available S. aureus isolates had the Panton-Valentine leukocidin gene.
Influenza virus infection was also documented in 12 (71 percent) of cases. All patients were hospitalized
and death occurred in five (29 percent); four of the deaths were in patients with MRSA infection.
Another outbreak of 10 cases of severe CA-MRSA pneumonia occurred in association with influenza
during the 2006-2007 influenza season [68]. Six of the patients died.

Group A streptococcus — Group A streptococcus (GAS, S. pyogenes) can cause a fulminant

pneumonia with early empyema formation even in young, immunocompetent hosts. In a prospective
surveillance study for invasive GAS infection, pneumonia accounted for 11 percent of cases with a
mortality rate of 38 percent compared with 26 percent for necrotizing fasciitis and 12 percent for the
entire cohort of invasive disease [74].

The largest outbreak of GAS pneumonia in the United States occurred in 2002 among military recruits at
the recruiting depot in San Diego [75,76]. Twenty-seven percent of 127 cases of pneumonia were
definitely or probably due to GAS and another 17 percent were coinfected with GAS and another
pathogen [75,76]. The epidemic occurred despite prophylaxis against GAS, but was ended after the
administration of additional prophylaxis [76].

Anaerobes — Anaerobic organisms may be the cause of aspiration pneumonia and lung abscess.
However, their role in CAP is not clear since detection in routine sputum cultures is not possible. Some
studies using transtracheal and bronchoscopic aspirates with quantitative cultures suggest that
anaerobes may account for 20 to 30 percent of pneumonias [77]. (See "Aspiration pneumonia in
adults".)

Neisseria meningitidis — N. meningitidis is an uncommon cause of CAP. Meningococcal pneumonia

has no distinguishing clinical features compared with other causes of CAP. However, pneumonia due to
N. meningitidis should be reported to the health department and prophylaxis given as for meningitis or
septicemia. (See "Clinical manifestations of meningococcal infection".)

Mycobacterium tuberculosis — M. tuberculosis is an important cause of CAP in developing countries

and in some regions of the United States [78,79]. Missed diagnosis is common as illustrated in report
from Baltimore in which 16 of 33 patients (48 percent) with culture-confirmed pulmonary TB were
initially treated for presumed CAP [79]. (See "Clinical manifestations of pulmonary tuberculosis".)

Other bacteria — Other bacteria that can cause CAP include Francisella tularensis (tularemia) and
Coxiella burnetii (Q fever). These microorganisms are described below. (See 'Community-acquired
pneumonia and bioterrorism agents' below.)
Viruses — Viruses are estimated to be the cause of CAP in 10 to 31 percent of cases in adults [5,56,80-
82]. In contrast, in children less than five years of age, viruses are the most common cause of
pneumonia. However, studies focusing on viral pathogens causing CAP are rare.

The frequency of specific viral pathogens varies with the diagnostic study used for detection. In a
prospective study of 105 adults with infiltrates on chest radiographs that had respiratory and
blood/serum samples evaluated by conventional microbiologic techniques and multiplex real-time PCR,
respiratory viral infections were detected in 15 (14 percent) and 59 (56 percent) by conventional
methods and PCR, respectively [83]. The most common viral pathogens identified by either method
were:

 Rhinovirus (18 cases)

 Coronavirus (14 cases)
 Influenza (14 cases)
 Parainfluenza (8 cases)

In 30 of 32 patients in whom rhinovirus or coronavirus were implicated, another pathogen was

identified. The clear conclusion is that in most instances, rhinovirus or coronavirus are probably not
causing the pneumonia, but impairing upper airway defenses so that pathogens can establish
themselves in the lower respiratory tract.

In a subsequent study that used PCR, other viruses identified in a substantial percentage of adults
hospitalized with CAP included human metapneumovirus and respiratory syncytial virus [82].

A randomized controlled trial in 107 hospitalized patients in the Netherlands with CAP also found that
real-time PCR increased the diagnostic yield compared to conventional diagnostic procedures (43
compared to 21 percent) with 26 viral etiologies identified by PCR compared to only 16 by conventional
methods [84].

The results of these studies confirm that viruses are commonly found in the nasopharynx of adults with
CAP. However, it is not clear whether these viruses are the sole agents causing CAP or whether they
participate in the pathogenesis of CAP by impairing host defenses.

Influenza virus — Influenza A or B viruses cause an acute respiratory illness that occurs in outbreaks
and epidemics worldwide, mainly in the winter season. Influenza viruses can cause pneumonia, although
they are far more likely to cause upper respiratory tract infection and to predispose to secondary
pulmonary infection by bacteria. (See "Clinical manifestations and diagnosis of seasonal influenza in
adults".)

Primary influenza pneumonia occurs when influenza virus infection directly involves the lung, typically
producing a severe pneumonia. Influenza pneumonia occurs most frequently in certain groups of
patients with underlying chronic illnesses who are classified as "high risk" for this infection. These high
risk groups include patients with heart or lung disease, diabetes mellitus, renal disease,
hemoglobinopathy, or immunosuppression; residents of nursing homes or chronic care facilities; and
otherwise healthy individuals over age 65.

Parainfluenza virus — Parainfluenza viruses are important respiratory pathogens in

immunocompromised adults, causing potentially life-threatening lower respiratory tract infections.
(See "Parainfluenza viruses in adults".)

Respiratory syncytial virus — Respiratory syncytial virus (RSV) causes acute respiratory tract illness
in persons of all ages. Traditionally a viral pathogen of children, RSV can cause CAP in elderly adults.
(See "Respiratory syncytial virus infection: Clinical features and diagnosis".)

Adenovirus — Adenoviral pneumonia was first described among military recruits in whom it causes an
"atypical pneumonia". The usual symptoms are fever, malaise, and cough (often with substernal
discomfort). Increased peribronchial markings with patchy alveolar infiltrates are found on chest
radiography. Pneumonia occasionally results in fatalities. (See "Epidemiology and clinical manifestations
of adenovirus infection".)

Human metapneumovirus — Human metapneumovirus (HMPV) was first described in 2001 in the

Netherlands. HMPV can cause upper and lower respiratory tract infection in patients of all age groups,
but symptomatic disease most often occurs in the young children or older adults. It is an emerging
pathogen as a cause of CAP in adults. (See "Human metapneumovirus infections".)

Severe acute respiratory syndrome (SARS) — In November 2002, an outbreak of severe acute
respiratory infection started in Guangdong Province in southern China and spread worldwide affecting
more than 8,000 persons. SARS was due to a novel coronavirus that jumped the species barrier from
civet cats to man. The case fatality rate of the 2003 Hong Kong outbreak was 11 percent, but higher
mortality was seen in elderly adults (≥60 years of age) and pregnant women. (See "Severe acute
respiratory syndrome (SARS)".)

Other coronaviruses — Human coronaviruses were first described in association with respiratory

infections in 1935, but were ignored until the advent of SARS. HCoV-229E and HCoV-OC43 caused upper
and lower respiratory tract infections prior to the SARS outbreaks. Since that time, human
coronaviruses, HCoV-NL63 and CoV-HKU1 have been identified as additional etiologic agents in CAP.

HCoV-NL63 was recovered from 19/525 (3.6 percent) of respiratory specimens collected from
laboratories across Canada in 2001 and 2002 [85], primarily causing infections of the upper respiratory
tract. In contrast, CoV-HKU1 accounted for 2.4 percent (10/418) of community-acquired pneumonia in
Hong Kong [86]. (See "Coronaviruses".)

Hantavirus — In May 1993, an outbreak of severe respiratory illness, caused by a previously unknown
virus, hantavirus, occurred in the southwestern United States. The illness was preceded by prodromal
flu-like symptoms followed by noncardiogenic pulmonary edema. The virus accounting for the initial
cases, Sin Nombre virus, is spread to humans from infected mice. Subsequently other hantaviruses have
been found to cause hantavirus pulmonary syndrome and the disease has been described in other parts
of the United States, western Canada, and South America. It is important to recognize that Hantavirus
does not cause pneumonia but instead causes an acute respiratory distress syndrome (ARDS)-like
picture, due to the host response to this virus. (See "Epidemiology and diagnosis of hantavirus
infections" and "Hantavirus cardiopulmonary syndrome".)

Avian influenza — The first association of avian influenza H5N1 with clinical respiratory disease
occurred in Hong Kong in 1997, when 18 human cases occurred during a poultry outbreak of highly
pathogenic H5N1 influenza in live-bird markets. The clinical features of avian influenza are variable,
being determined in part by the strain. In the 1997 outbreak, 58 percent of patients had pneumonia.
The World Health Organization and the Centers for Disease Control and Prevention consider avian
influence a potential source for the next global influenza pandemic. (See"Epidemiology, transmission,
and pathogenesis of avian influenza".)

Varicella — Varicella pneumonia is the most frequent complication of varicella infection in normal

healthy adults with a reported incidence of about one in 400 cases. The case fatality rate is between 10
and 30 percent. (See "Clinical features of varicella-zoster virus infection: Chickenpox".)

Fungi — Fungal infection is an unusual cause of CAP in the immunocompetent patient. Fungal infection
is more common in the immunocompromised patient, particularly those with neutropenia, on chronic
immunosuppressive therapy (eg, organ transplant recipients), and those infected with HIV. Fungal
infections can be endemic to particular geographic areas; as a result, the specific epidemiology of some
fungal infections is important as diagnostic clues.

A retrospective study examined the microbiologic etiology of 94 cases of community-acquired pulmonary

fungal infection hospitalized in Taiwan [87]. The criteria for diagnosis were a lung lesion on chest
radiographs and either the presence or isolation of fungi from a tissue biopsy, pleural effusion, or blood.
The most frequently isolated fungi were Aspergillus species (56 percent), followed by Cryptococcus
species (31 percent) and Candida species (4 percent).

Cryptococcus spp — Cryptococcus organisms are found in the soil throughout the world and a
significant percent of the population has most likely been exposed to these organisms. Primary infections
occur in both immunocompetent and immunocompromised persons. In immunocompetent individuals,
primary infections are most commonly asymptomatic and usually discovered as an incidental finding on
chest radiograph. In contrast, cryptococcal pneumonia in immunocompromised patients is usually
symptomatic with the most common signs and symptoms being cough, fever, and dyspnea.
(See "Microbiology and epidemiology of cryptococcal infection" and "Cryptococcal infection outside the
central nervous system".)

Histoplasma capsulatum — Histoplasma capsulatum is found worldwide; within the United States,

infection is most common in the Midwestern states located in the Ohio and Mississippi River valleys. H.
capsulatum proliferates best in soil contaminated with bird or bat droppings. Fewer than five percent of
exposed individuals develop symptomatic disease after a low level exposure. However, the majority of
patients develop symptomatic infection following more extensive exposure, as occurs with activities that
disturb heavily contaminated soil or areas with large amounts of bird or bat droppings.

Symptomatic patients with acute histoplasmosis generally present with a flu-like illness with pulmonary
complaints and radiographic abnormalities, including bronchopneumonia or signs of interstitial
pneumonitis. (See "Pathogenesis and clinical features of pulmonary histoplasmosis".)

Coccidioides spp — Coccidioidomycosis is the infection caused by the dimorphic fungi of the genus
Coccidioides (C. immitis and C. posadasii). These fungi are endemic to certain lower deserts of the
western hemisphere including southern Arizona, central California, southwestern New Mexico, and west
Texas in the United States. They are also found in parts of Mexico, Central, and South America.
(See "Primary coccidioidal infection", section on 'Epidemiology' and "Primary coccidioidal infection",
section on 'Microbiology'.)

A prospective observational study of 55 adults with CAP in Arizona found serologic evidence for
Coccidioidomycosis (valley fever) as the etiologic agent in 16 (29 percent) patients [88]. This study
suggests that valley fever is a common cause of CAP after exposure in a disease-endemic region and
that patients exposed in these regions that develop CAP should undergo laboratory evaluation for this
organism.

The most common presenting symptoms of primary coccidioidal infection are chest pain, cough, and
fever. Although initial infections usually have a respiratory component, chest radiographs are
unremarkable in up to one half of all patients. Common radiographic abnormalities include unilateral
infiltrate and ipsilateral hilar adenopathy. (See "Primary coccidioidal infection".)

Other fungi — Other fungi that can cause CAP include Aspergillus spp and Pneumocystis jirovecii
(formerly P. carinii). Infection with these fungi occurs primarily in the setting of immunosuppression.
Pulmonary aspergillosis is particularly associated with severe neutropenia, while P. jirovecii is particularly
associated with HIV infection. (See "Clinical features and diagnosis of invasive aspergillosis" and "Clinical
presentation and diagnosis of Pneumocystis carinii (P. jirovecii) infection in HIV-infected
patients" and "Epidemiology, clinical manifestations, and diagnosis of Pneumocystis carinii (P. jirovecii)
pneumonia in non-HIV-infected patients".)

Mixed infections — The role of more than one causative microorganism in CAP is difficult to establish.
A prospective study of 1511 consecutive hospitalized patients examined the incidence of mixed
respiratory pathogens in patients with CAP [89]. Microbiologic evaluation included sputum and blood
cultures (and pleural fluid, transbronchial aspirates, protected specimen brush, and bronchial alveolar
lavage when available), paired serologies (for influenza, parainfluenza, respiratory syncytial, and
adenoviruses and C. pneumoniae, M. pneumoniae, L. pneumophila, and C. burnetii), and urine antigen
(for S. pneumoniae and L. pneumophila). Of 610 patients in whom an etiology was identified, 82 (13
percent) had more than one microorganism. S. pneumoniae was identified in 44 of 82 mixed infections
(54 percent).

The clinical importance of mixed infections on outcome is difficult to assess, although there is a
suggestion that patients with mixed infections have a more severe illness as illustrated in a prospective
study of 493 patients with CAP in whom an extensive microbiologic workup was performed [90].
Compared with patients with monomicrobial pneumonia, patients with mixed pneumonia were more
likely to have complications of the pneumonia (39.3 versus 18.6 percent); however, they were also more
likely to have an underlying comorbid illness (64 versus 45 percent).

Community-acquired pneumonia and bioterrorism agents — Biological agents that may be used

for bioterrorism and can present as a CAP syndrome include Bacillus anthracis (inhalational anthrax),
Yersinia pestis (pneumonic plague), Francisella tularensis (tularemia), Coxiella burnetii (Q fever),
Legionella spp, Influenza virus, and hantavirus (table 2) [91]. (See "Identifying and managing casualties
of biological terrorism".)

Bacillus anthracis (anthrax) — On October 2, 2001, a 63 year old male from Florida became the first
case of inhalational anthrax in the United States since 1968 and was the first due to an act of biological
terrorism. Anthrax was deliberately spread through the postal system by sending letters with a powder
containing Bacillus anthracis, a gram-positive bacillus that forms spores. Two of the 22 persons infected
in the postal attack developed inhalational anthrax. (See "Microbiology, pathogenesis, and epidemiology
of anthrax".)

Inhalational anthrax is the deadliest form of the disease. The incubation period following exposure is one
to six days. The classic chest radiograph findings are mediastinal widening with pleural effusions. A
World Health Organization expert committee estimated that if 50 kg of anthrax was released over an
urban population of 5 million there would be 250,000 casualties; 100,000 of who would be expected to
die without treatment [92]. (See "Clinical manifestations and diagnosis of anthrax".)

Yersinia pestis (plague) — Biological weapons programs in the United States and the Soviet Union
following World War II developed techniques for aerosolizing Yersinia pestis, the agent of plague. The
hypothetical intentional release of aerosolized plague would cause widespread illness; the case fatality
rate for primary pneumonic plague is close to 100 percent if treatment is not initiated within 24 hours.

The time to onset of symptoms following exposure is two to three days. The most common chest
radiograph findings are bilateral infiltrates, often with pleural effusions. (See "Clinical manifestations,
diagnosis, and treatment of plague (Yersinia pestis infection)".)

Francisella tularensis (tularemia) — Tularemia is caused by the gram-negative bacilli, Francisella

tularensis. During the 1950s and 1960s both the United States and the Soviet Union biological weapons
program developed aerosolized F. tularensis. It has been estimated that dispersal of 50 kg of virulent F.
tularensis over a metropolitan area with 5 million people would result in 250,000 incapacitating
casualties including 19,000 deaths [93].

Tularemia has a longer incubation period than either inhalational anthrax or plague. The classic chest
radiographic findings are bilateral infiltrates with hilar adenopathy. (See "Clinical manifestations,
diagnosis, and treatment of tularemia".)

Coxiella burnetii (Q fever) — Coxiella burnetii is the etiologic agent of Q fever, and a Centers for
Disease Control (CDC) category B biological agent. As a biological warfare agent, C. burnetii can be
easily dispersed as an aerosol with a high infectivity rate and pneumonia as the major manifestation.
(See "Clinical features, diagnosis, treatment, and prevention of Q fever".)
Epidemiologic conditions and/or risk factors related to specific
pathogens in community-acquired pneumonia

Condition Commonly encountered pathogen(s)

Alcoholism Streptococcus pneumoniae, oral anaerobes, Klebsiella pneumoniae,
Acinetobacter species, Mycobacterium tuberculosis

COPD and/or smoking Haemophilus influenzae, Pseudomonas aeruginosa, Legionella species, S. pneumoniae,

Moraxella catarrhalis, Chlamydophila pneumoniae

Aspiration Gram-negative enteric pathogens, oral anaerobes

Lung abscess CA-MRSA, oral anaerobes, endemic fungal pneumonia, M. tuberculosis, atypical
mycobacteria

Exposure to bat or bird Histoplasma capsulatum

droppings

Exposure to birds Chlamydophila psittaci (if poultry: avian influenza)

Exposure to rabbits Francisella tularensis

Exposure to farm animals Coxiella burnetti (Q fever)

or parturient cats

HIV infection (early) S. pneumoniae, H. influenzae, M. tuberculosis

HIV infection (late) The pathogens listed for early infection plus Pneumocystis jirovecii, Cryptococcus,
Histoplasma, Aspergillus, atypical mycobacteria (especially Mycobacterium kansasii), P.
aeruginosa, H. influenzae

Hotel or cruise ship stay Legionella species

in previous 2 weeks

Travel to or residence in Coccidioides species, Hantavirus

southwestern United
States

Travel to or residence in Burkholderia pseudomallei, avian influenza, SARS

Southeast and East Asia

Influenza active in Influenza, S. pneumoniae, Staphylococcus aureus, H. influenzae

community

Cough >2 weeks with Bordetella pertussis

whoop or posttussive
vomiting

Structural lung disease Pseudomonas aeruginosa, Burkholderia cepacia, S. aureus

(eg, bronchiectasis)

Injection drug use S. aureus, anaerobes, M. tuberculosis, S. pneumoniae

 Endobronchial obstruction Anaerobes, S. pneumoniae, H. influenzae, S. aureus

In context of bioterrorism Bacillus anthracis (anthrax), Yersinia pestis (plague), Francisella tularensis (tularemia)

CA-MRSA: community-acquired methicillin-resistant Staphylococcus aureus; COPD: chronic obstructive

pulmonary disease; SARS: severe acute respiratory syndrome. Reproduced with permission from:
Mandell, LA, Wunderink, RG, Anzueto, A, et al. Infectious Diseases Society of America/American
Thoracic Society consensus guidelines on the management of community-acquired pneumonia in adults.
Clin Infect Dis 2007; 44:S27. Copyright ©2007 University of Chicago Press.

Treatment of community-acquired pneumonia in adults in the

outpatient setting
Author
Thomas M File, Jr, MD
Section Editor
John G Bartlett, MD
Deputy Editor
Anna R Thorner, MD
Last literature review version 18.3: septiembre 2010 | This topic last updated: septiembre 29,
2010
INTRODUCTION — Community-acquired pneumonia (CAP) is defined as an acute infection of the
pulmonary parenchyma in a patient who has acquired the infection in the community, as distinguished
from hospital-acquired (nosocomial) pneumonia. A third category of pneumonia, designated "healthcare-
associated pneumonia," is acquired in other healthcare facilities such as nursing homes, dialysis centers,
and outpatient clinics.

CAP is a common and potentially serious illness. It is associated with considerable morbidity and
mortality, particularly in elderly patients and those with significant comorbidities [1,2]. (See "Prognosis
of community-acquired pneumonia in adults".)

The treatment of CAP in adults in the outpatient setting will be reviewed here. A variety of other
important issues related to CAP are discussed separately. These include:

 The diagnostic approach to patients with CAP. (See "Diagnostic approach to community-acquired

pneumonia in adults".)
 How one makes the decision to admit patients with CAP to the hospital. (See "Community-
acquired pneumonia in adults: Risk stratification and the decision to admit".)
 Treatment recommendations for CAP in patients requiring hospitalization. (See "Treatment of
community-acquired pneumonia in adults who require hospitalization".)
 Treatment recommendations for patients with healthcare-associated pneumonia. (See "Treatment
of hospital-acquired, ventilator-associated, and healthcare-associated pneumonia in adults".)
 The evidence for efficacy of different antibiotic medications in the empiric treatment of CAP and
issues related to drug resistance. (See"Antibiotic studies for the treatment of community-acquired
pneumonia in adults".)
 The epidemiology and microbiology of CAP. (See "Epidemiology, pathogenesis, and microbiology
of community-acquired pneumonia in adults".)
 Pneumonia in special populations, such as aspiration pneumonia and immunocompromised
patients. (See "Aspiration pneumonia in adults" and"Common pulmonary infections in
immunocompromised patients".)
INDICATIONS FOR HOSPITALIZATION — Determination of whether a patient with CAP can be safely
treated as an outpatient or requires hospitalization is essential before selecting an antibiotic regimen.
Severity of illness is the most critical factor in making this determination, but other factors should also
be taken into account. These include ability to maintain oral intake, likelihood of compliance, history of
substance abuse, cognitive impairment, living situation, and patient functional status. These issues with
appropriate references are discussed in detail elsewhere. (See "Community-acquired pneumonia in
adults: Risk stratification and the decision to admit".)

Summarized briefly, prediction rules have been developed to assist in the decision of site of care for
CAP. The two most commonly used prediction rules are the Pneumonia Severity Index (PSI) and CURB-
65. The PSI is better studied and validated, but requires a more complicated assessment.

CURB-65 uses five prognostic variables:

 Confusion (based upon a specific mental test or disorientation to person, place, or time)
 Urea (blood urea nitrogen in the United States) >7 mmol/L (20 mg/dL)
 Respiratory rate >30 breaths/minute
 Blood pressure [BP] (systolic <90 mmHg or diastolic <60 mmHg)
 Age >65 years

The authors of the original CURB-65 report suggested that patients with a CURB-65 score of 0 to 1, who
comprised 45 percent of the original cohort and 61 percent of the later cohort, were at low risk and
could probably be treated as outpatients; those with a score of 2 should be admitted to the hospital, and
those with a score of 3 or more should be assessed for ICU care, particularly if the score was 4 or 5.

A simplified version (CRB-65), which does not require testing for blood urea nitrogen, may be
appropriate for decision-making in primary care practitioners' offices. With either version, admission to
the hospital is recommended if one or more points are present.

Clinical judgment should be used for all patients, incorporating the prediction rule scores as a component
of the decision for hospitalization or intensive care unit admission, but not as an absolute determinant
[3].

PRINCIPLES OF ANTIMICROBIAL THERAPY — CAP can be caused by a variety of pathogens, with

bacteria being the most common identifiable cause (figure 1A-C) [2,4,5]. The choice of initial therapy is
complicated by the emergence of antibiotic resistance among Streptococcus pneumoniae, the most
common bacterium responsible for CAP. (See "Epidemiology, pathogenesis, and microbiology of
community-acquired pneumonia in adults", section on 'Microbiology' and "Antibiotic studies for the
treatment of community-acquired pneumonia in adults", section on 'Drug resistance and choice of
therapy'.)

Empiric therapy — Antibiotic therapy is typically begun on an empiric basis, since the causative
organism is not identified in an appreciable proportion of cases of CAP treated in the outpatient setting
(figure 1A) [2,6]. In addition, the clinical features and chest radiographic findings are not sufficiently
specific to determine etiology and influence treatment decisions. The sputum Gram stain can be useful
for directing the choice of initial therapy if performed on a good quality sample and interpreted by skilled
examiners using appropriate criteria [2]. (See "Diagnostic approach to community-acquired pneumonia
in adults", section on 'Sputum'.)

The 2007 Infectious Diseases Society of America/American Thoracic Society (IDSA/ATS) guidelines on
the management of community-acquired pneumonia suggest that routine tests to identify an etiology for
CAP are optional for patients who do not require hospitalization [2]. This recommendation is based in
part upon the low rate of failure of empiric therapy in patients with CAP treated in the outpatient setting.
The efficacy of empiric therapy was illustrated in a study of over 700 ambulatory patients treated for
CAP in one of six emergency departments seen from November 2000 through April 2001, in which
empiric antibiotics (a macrolide or fluoroquinolone in >88 percent) were almost universally effective,
with only 2.2 percent requiring hospitalization within three weeks of initial emergency department visit
[7].

In contrast, testing for a microbial diagnosis is important in clinical or epidemiologic settings suggesting
possible infection with an organism that requires treatment different from standard empiric regimens.
These include Legionella species, Mycobacterium tuberculosis, influenza A and B or avian influenza,
community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA), or agents of bioterrorism
[2]. (See "Diagnostic approach to community-acquired pneumonia in adults" and "Sputum cultures for
the evaluation of bacterial pneumonia", section on 'Community-acquired pneumonia'.)

The selection of antimicrobial regimens for empiric therapy is based upon a number of factors, including:

 The most likely pathogen(s). (See 'Common pathogens' below.)

 Clinical trials proving efficacy. (See "Antibiotic studies for the treatment of community-acquired
pneumonia in adults".)
 Risk factors for antimicrobial resistance. The choice of empiric therapy must take into account the
emergence of antibiotic resistance among Streptococcus pneumoniae, one of the most common
bacteria responsible for CAP. (See 'Risk factors for drug resistance' below.)
 Medical comorbidities that may influence the likelihood of a specific pathogen and may be a risk
factor for treatment failure.

Additional factors that may affect the choice of antimicrobial regimen include the potential for inducing
antimicrobial resistance, pharmacokinetic and pharmacodynamic properties, safety profile, and cost [8].

Common pathogens — Although a variety of bacterial pathogens can cause CAP, a limited number are
responsible for the majority of cases. (See"Epidemiology, pathogenesis, and microbiology of community-
acquired pneumonia in adults", section on 'Microbiology'.)

With respect to patients treated in the outpatient setting, the most frequently isolated pathogens are
Streptococcus pneumoniae, Mycoplasma pneumoniae, Chlamydophila pneumoniae, and respiratory
viruses (eg, influenza, parainfluenza, respiratory syncytial virus) (figure 1A). Legionella pneumoniae and
Haemophilus influenzae are less common. The "atypical" pathogens are not often identified in clinical
practice because there are not specific, rapid, or standardized tests for their detection, with the
exception of L. pneumophila. (See "Clinical manifestations and diagnosis of Legionella infection".)

Patients with CAP due to Staphylococcus aureus, Enterobacteriaceae, and Pseudomonas aeruginosa are
typically sicker and require admission to the hospital. (See "Treatment of community-acquired
pneumonia in adults who require hospitalization", section on 'Common pathogens'.)

Risk factors for drug resistance — Risk factors for and other issues related to drug resistance in
patients with CAP are discussed in detail elsewhere. (See "Antibiotic studies for the treatment of
community-acquired pneumonia in adults", section on 'Drug resistance and choice of therapy'.)

Summarized briefly, risk factors for drug-resistant S. pneumoniae in adults include:

 Age >65 years

 Beta-lactam, macrolide, or fluoroquinolone therapy within the past three to six months
 Alcoholism
 Medical comorbidities
 Immunosuppressive illness or therapy
 Exposure to a child in a day care center

Recent therapy or a repeated course of therapy with beta-lactams, macrolides, or fluoroquinolones is a

risk factor for pneumococcal resistance to the same class of antibiotic.
The impact of discordant drug therapy, which refers to treatment of an infection with an antimicrobial
agent to which the causative organism has demonstrated in vitro resistance, appears to vary with
antibiotic class and possibly with specific agents within a class. Most studies have been performed in
patients with S. pneumoniae infection and suggest that current levels of beta-lactam resistance
generally do not cause treatment failure when appropriate agents
(eg, amoxicillin, ceftriaxone, cefotaxime) and doses are used. Of the beta-lactams, cefuroxime is a
possible exception. In addition, there appears to be an increased risk of macrolide failure in patients with
macrolide-resistant S. pneumoniae. (See"Antibiotic studies for the treatment of community-acquired
pneumonia in adults", section on 'Outcomes with discordant drug therapy'.)

GUIDELINES — A number of medical societies have issued guidelines for the treatment of CAP
[2,9,10]. The antibiotic regimens advocated by a collaboration between the Infectious Disease Society of
America and the American Thoracic Society (IDSA/ATS) in 2007 [2], and guidelines from the British
Thoracic Society (BTS) in 2009 [9] are summarized in tables 1 and 2, respectively (table 1 and table 2).
Both guidelines note problems with the emergence of drug-resistant S. pneumoniae (DRSP).

The following discussion will review antibiotic therapy in ambulatory patients with CAP. Guideline
recommendations for therapy of patients with CAP treated in the inpatient setting are presented
separately. (See "Treatment of community-acquired pneumonia in adults who require hospitalization".)

 The regimens chosen by the IDSA/ATS guidelines mainly rely on macrolides (with or without a
beta-lactam) or newer fluoroquinolones for outpatient therapy (table 1) [2]. The guidelines
promote the use of macrolides to provide coverage for both S. pneumoniae and atypical
pathogens (particularly, M. pneumoniae and C. pneumoniae), which account for the majority of
cases of CAP in ambulatory patients (figure 1A). In studies from different regions of the world,
atypical pathogens account for 20 to 30 percent of cases of CAP [11].
 The BTS guidelines tend to select older antibiotics than those recommended in North America
(table 2) [9].

North American approach — The macrolides, which are effective against the atypical pathogens, are
recommended in the absence of significant risk factors for macrolide-resistant S. pneumoniae.
Experience in North America, suggests that macrolide-resistant S. pneumoniae is less significant for
patients without comorbidities or risk factors compared to patients with risk factors [8,12,13]. Recent
use of macrolide antibiotics is considered a risk factor for resistant S pneumoniae; thus, monotherapy
with a macrolide is not recommended for persons who received a macrolide antibiotic in the preceding
three months. (See "Resistance of Streptococcus pneumoniae to the macrolides, azalides, lincosamines,
and ketolides".)

BTS approach — In the 2009 British Thoracic Society guidelines, the preferred drug for outpatient
management is amoxicillin (500 mg orally three times daily), with doxycycline or clarithromycin as
alternatives, including for those with penicillin allergy (table 2) [9].

The rationale is that amoxicillin at these doses is effective against most strains of S. pneumoniae with
decreased susceptibility to penicillin. Most of the macrolide-resistant S. pneumoniae in Europe is erm-
mediated high-level resistance. As a result, the macrolides are not optimal first-line empiric agents.
(See "Antibiotic studies for the treatment of community-acquired pneumonia in adults", section on
'Macrolide resistance' and"Resistance of Streptococcus pneumoniae to the macrolides, azalides,
lincosamines, and ketolides".)

Coverage of atypical pathogens — The BTS approach places less significance than the North
American approach on the need to treat the atypical pathogens empirically in ambulatory patients. Initial
empiric therapy that covers M. pneumoniae is considered unnecessary, since the pathogen exhibits
epidemic periodicity every four to five years and largely affects younger persons.
Although the clinical course of M. pneumoniae or C. pneumoniae infection is often self-limited, these
pathogens can cause severe CAP. As a result, it has been argued that appropriate treatment for even
mild CAP due to Mycoplasma reduces both morbidity and the duration of symptoms [14].
(See "Mycoplasma pneumoniae infection in adults".)

The efficacy of empiric coverage of atypical pathogens was evaluated in a 2005 meta-analysis that
evaluated 18 randomized trials of over 6700 patients with mild to moderate CAP who were assigned to
treatment with either a beta-lactam or an antibiotic active against atypical pathogens [15]. There was no
overall advantage to covering atypical pathogens in terms of the rate of failure to achieve clinical cure or
improvement (relative risk 0.97, 95% CI 0.87-1.07) but, in a subgroup analysis, there was a
significantly lower failure rate for Legionella infection with such a regimen (relative risk 0.40, 95% CI
0.19-0.85). These trials were not designed to compare the time to response with the different regimens.

TREATMENT REGIMENS — Treatment regimens for outpatients with CAP are based upon studies of the
effectiveness of antibiotics, the severity of illness, the presence of comorbid conditions, and the
prevalence of risk factors for drug resistant S. pneumoniae (DRSP). (See "Antibiotic studies for the
treatment of community-acquired pneumonia in adults".)

We suggest the following approach to empiric antimicrobial therapy. Pathogen-specific therapy is

discussed separately. (See "Pneumococcal pneumonia in adults" and "Mycoplasma pneumoniae infection
in adults" and "Pneumonia caused by Chlamydophila (Chlamydia) species in adults" and"Treatment and
prevention of Legionella infection" and "Pseudomonas aeruginosa pneumonia".)

No comorbidities or recent antibiotic use — For uncomplicated pneumonia in patients who do not

require hospitalization, have no significant comorbidities and/or use of antibiotics within the last three
months, and where there is not a high prevalence of macrolide-resistant strains, we recommend any one
of the following oral regimens:

 Azithromycin (500 mg on day one followed by four days of 250 mg a day); 500 mg a day for
three days, or 2 g single dose (microsphere formulation) are acceptable alternative regimens
 Clarithromycin XL (two 500 mg tablets once daily) for five days or until afebrile for 48 to 72 hours
 Doxycycline (100 mg twice a day) for 7 to 10 days

There is concern that widespread use of fluoroquinolones in outpatients will promote the development of
fluoroquinolone-resistance among respiratory pathogens (as well as other colonizing pathogens) and
may lead to an increased incidence of C. difficile colitis [16]. In addition, empiric use of fluoroquinolones
should not be used for patients at risk for Mycobacterium tuberculosis without an appropriate
assessment for tuberculosis infection. The administration of a fluoroquinolone in patients with
tuberculosis has been associated with a delay in diagnosis, increase in resistance, and poor outcomes.
(See "Antibiotic studies for the treatment of community-acquired pneumonia in adults", section on
'Fluoroquinolone resistance' and "Epidemiology, microbiology, and pathophysiology of Clostridium
difficile infection in adults", section on 'Antibiotics'.)

Because of these concerns, the use of fluoroquinolones is discouraged in ambulatory patients with CAP
without comorbid conditions or recent antimicrobial use, unless it is known that there is a high
prevalence of high-level macrolide-resistant S. pneumoniae in the local community. When such
resistance is present, the regimen for patients with comorbidities or recent antibiotic use described in
the next section can be followed. (See"Antibiotic studies for the treatment of community-acquired
pneumonia in adults", section on 'Macrolide resistance'.)

Despite these recommendations, fluoroquinolones continue to be given, often inappropriately, for CAP.
In one report of 768 ambulatory patients with CAP seen in an emergency department in 2000 and 2001,
245 (32 percent) were treated with levofloxacin; one-half of these patients did not meet the criteria for
appropriate fluoroquinolone therapy [7].
Telithromycin is NOT recommended as a first-line empiric regimen because of concerns about toxicity.
(See "Azithromycin, clarithromycin, and telithromycin", section on 'Summary warning about
telithromycin'.)

Although erythromycin is the least expensive macrolide, we rarely use this drug for three reasons:
multiple daily doses over several days are required; compliance is limited by gastrointestinal side effects,
as well as dosing; and there is a risk of sudden cardiac death due to QT interval prolongation,
particularly when other drugs metabolized by CYP3A4 are taken concurrently [17]. The drugs noted
above are as effective, more convenient to use, and less toxic. (See "Acquired long QT syndrome".)

Comorbidities or recent antibiotic use — The presence of significant comorbidities (ie, chronic

obstructive pulmonary disease [COPD], liver or renal disease, cancer, diabetes, chronic heart disease,
alcoholism, asplenia, or immunosuppression), and/or use of antibiotics within the prior three months,
increases the risk of infection with more resistant pathogens. We recommend one of the following oral
regimens for such patients:

 A respiratory fluoroquinolone (gemifloxacin 320 mg daily, levofloxacin 750 mg daily,

or moxifloxacin 400 mg daily) for a minimum of five days. (See 'Treatment duration and
response' below.)
 Combination therapy with a beta-lactam effective against S. pneumoniae (high-dose amoxicillin,
1 g three times daily or amoxicillin-clavulanate 2 g twice daily or cefpodoxime 200 mg twice daily
or cefuroxime 500 mg twice daily) PLUS either a macrolide (azithromycin 500 mg on day one
followed by four days of 250 mg a day or clarithromycin 250 mg twice daily or clarithromycin XL
1000 mg once daily) ordoxycycline (100 mg twice daily). Treatment should be continued for a
minimum of five days. (See 'Treatment duration and response' below.)

These regimens are also appropriate where there is a high prevalence of "high-level" macrolide-resistant
S. pneumoniae, even in the absence of comorbidity or recent antimicrobial use. When choosing between
fluoroquinolones, in vitro studies of moxifloxacin and gemifloxacin show more activity against penicillin-
resistant pneumococci strains than levofloxacin; the clinical significance of these findings is not yet clear
[18].

Gemifloxacin causes a rash in 2.8 percent of patients overall, but a higher rate (14 percent) in women
under 40 years of age who received the drug for seven or more days. The rash is generally mild, occurs
after the fifth day of therapy, and resolves with discontinuation of the agent. The rash is not associated
with phototoxicity or hypersensitivity and does not preclude the use of other fluoroquinolones in the
future, although repeated courses of gemifloxacin should be avoided in such patients.
(See "Gemifloxacin: Drug information".)

Telithromycin should be reserved as an option for patients at risk for drug-resistant pneumococcal

infection in whom alternative agents are not appropriate. However, it should NOT be prescribed in
patients with known liver disease. (See "Azithromycin, clarithromycin, and telithromycin", section on
'Summary warning about telithromycin'.)

Pathogen-directed therapy — Once the etiology of CAP has been identified using reliable
microbiologic methods, antimicrobial therapy should be directed at that pathogen (table 3) [2].

Treatment duration and response — With respect to treatment duration, we generally agree with the
2007 IDSA/ATS guidelines [2]. Ambulatory patients with CAP should be treated for a minimum of five
days; because of the prolonged half-life of azithromycin, a shorter duration of drug administration may
be indicated for this agent.

Support for this recommendation comes from a meta-analysis of 15 randomized controlled trials of
almost 2800 patients with mild to moderate CAP, which found comparable clinical outcomes with less
than seven days compared to more than seven days of antimicrobial therapy [19]. Antibiotic therapy
should not be stopped until the patient is afebrile for 48 to 72 hours and is clinically stable.
(See "Antibiotic studies for the treatment of community-acquired pneumonia in adults", section on
'Duration of therapy'.)

Most patients with CAP begin to improve soon after the initiation of appropriate antibiotic therapy as
evidenced by resolution of symptoms, physical findings, and laboratory signs of active infection (table
4). However, some symptoms often persist as the patient convalesces [20-22]. This was illustrated in a
study of sequential interviews in 134 ambulatory patients with CAP [20]. The median time to resolution
ranged from three days for fever to 14 days for both cough and fatigue. At least one symptom (eg,
cough, fatigue, dyspnea) was still present at 28 days in one-third of patients. In another report, 76
percent had at least one symptom at 30 days, most commonly fatigue, compared to 45 percent by
history in the one month prior to the onset of CAP [22].

These symptoms are usually not sufficient to interfere with work as illustrated in a review of 399
ambulatory patients with CAP in which the median time of return to work was six days even though one-
third had at least one persistent symptom at 14 days [21]. (See "Prognosis of community-acquired
pneumonia in adults", section on 'Mortality and symptom resolution'.)

Persistence of such symptoms is not an indication to extend the course of antibiotic therapy as long as
the patient has demonstrated some clinical response to treatment [2].

Follow-up chest radiograph — Chest x-ray findings usually clear more slowly than clinical
manifestations (see "Treatment of community-acquired pneumonia in adults who require
hospitalization", section on 'Radiographic response'). Routine chest x-rays for follow-up of CAP patients
who are responding clinically are unnecessary. Some authorities recommend a follow-up chest x-ray at 7
to 12 weeks after treatment for selected patients who are over age 40 years or are smokers, to
document resolution of the pneumonia and exclude underlying diseases, such as malignancy [23].

The nonresponding patient — General issues relating to nonresolving pneumonia are discussed in

detail separately. (See "Nonresolving pneumonia".)

Among patients with CAP, nonresponse is primarily seen in those who require hospitalization, occurring
in 6 to 15 percent of such patients. The incidence of treatment failure is not well defined in ambulatory
patients with CAP because population-based studies would be required [2]. (See"Treatment of
community-acquired pneumonia in adults who require hospitalization", section on 'The nonresponding
patient'.)

VACCINATION — Patients with CAP should be appropriately vaccinated for influenza and pneumococcal
infection. Screening for influenza vaccination status is warranted during influenza season (eg, from
October through March in the northern hemisphere) in all patients. Screening for pneumococcal
vaccination status is warranted in patients age 65 or older or with other indications for
vaccination. Vaccination can be performed during outpatient treatment. (See "Seasonal influenza
vaccination in adults" and "Pneumococcal vaccination in adults".)

SMOKING CESSATION — Smoking cessation should be a goal for patients with CAP who smoke
[2]. (See "Management of smoking cessation in adults".)

INFORMATION FOR PATIENTS — Educational materials on this topic are available for patients.
(See "Patient information: Pneumonia in adults".) We encourage you to print or e-mail this topic review,
or to refer patients to our public web site, www.uptodate.com/patients, which includes this and other
topics.

SUMMARY AND RECOMMENDATIONS

 Outpatient treatment
1. Previously healthy and no use of antimicrobials within the previous 3 months:

A macrolide (azithromycin, clarithromycin, or erythromycin)

OR
Doxycyline*

2. Presence of comorbidities such as chronic heart, lung, liver or renal disease; diabetes mellitus; alcoholism;
malignancies; asplenia; immunosuppressing conditions or use of immunosuppressing drugs; or use of
antimicrobials within the previous 3 months (in which case an alternative from a different class should be
selected):

A respiratory fluoroquinolone (moxifloxacin, gemifloxacin, or levofloxacin [750 mg])

OR
A beta-lactam (first-line agents: high-dose amoxicillin, amoxicillin-clavulanate; alternative agents: ceftriaxone,
cefpodoxime, or cefuroxime) PLUS a macrolide (azithromycin, clarithromycin, or erythromycin)*

3. In regions with a high rate (>25 percent) of infection with high-level (MIC ≥16 µg/mL) macrolide-
resistant Streptococcus pneumoniae, consider use of alternative agents listed in (2) above.

Inpatients, non-ICU treatment

A respiratory fluoroquinolone (moxifloxacin, gemifloxacin, or levofloxacin [750 mg])
OR
An antipneumococcal beta-lactam (preferred agents: cefotaxime, ceftriaxone, or ampicillin-sulbactam; ertapenem
for selected patients) PLUS a macrolide (azithromycin, clarithromycin, or erythromycin)*

Inpatients, ICU treatment

An antipneumococcal beta-lactam (cefotaxime, ceftriaxone, or ampicillin-sulbactam) PLUS azithromycin
OR
An antipneumococcal beta-lactam (cefotaxime, ceftriaxone, or ampicillin-sulbactam) PLUS a respiratory
fluoroquinolone (moxifloxacin, gemifloxacin, or levofloxacin [750 mg])
OR
For penicillin-allergic patients, a respiratory fluoroquinolone (moxifloxacin, gemifloxacin, or levofloxacin [750
mg]) PLUS aztreonam

Special concerns
If Pseudomonas is a consideration:

An antipneumococcal, antipseudomonal beta-lactam (piperacillin-tazobactam, cefepime, imipenem, or

meropenem) PLUS either ciprofloxacin or levofloxacin (750 mg)
OR
The above beta-lactam PLUS an aminoglycoside PLUS azithromycin
OR
The above beta-lactam PLUS an aminoglycoside PLUS a respiratory fluoroquinolone (moxifloxacin, gemifloxacin, or
levofloxacin [750 mg]); for penicillin-allergic patients, substitute aztreonam for above beta-lactam

If CA-MRSA is a consideration:

Add vancomycin or linezolid

This table provides the 2007 recommendations of the Infectious Diseases Society of America and the
American Thoracic Society (IDSA/ATS) for reference purposes. Please see the UpToDate text for information about
choosing between the different guidelines and about the preferred doses and durations of the individual
antibiotics. CA-MRSA: community-acquired methicillin-resistentStaphylococcus aureus; ICU: intensive care unit.
* Doxycycline may be used as an alternative to a macrolide, but there is stronger evidence to support the use of a
macrolide than doxycycline for CAP. Modified with permission from: Mandell, LA, Wunderink, RG, Anzueto, A, et al.
Infectious Diseases Society of America/American Thoracic Society consensus guidelines on the management of
community-acquired pneumonia in adults. Clin Infect Dis 2007; 44 Suppl 2:S27. Copyright © 2007 University of
Chicago Press.