Download an overview of community-acquired respiratory tract infections

REVIEW
AN OVERVIEW OF COMMUNITY-ACQUIRED
RESPIRATORY TRACT INFECTIONS
—
Charles W. Stratton, MD*
ABSTRACT
Community-acquired respiratory tract infections
continue to be among the most common and
important infections seen by practicing clinicians.
These infections not surprisingly have some common aspects in regards to the microbes involved as
well as their pathogenesis and typically involve the
sinuses, the airways, and the lungs. Acute respiratory tract infections can be caused by a wide variety of microorganisms including viruses. This
variety of respiratory pathogens is, in part, why the
diagnosis and therapy of these infections remains a
problem. The lack of rapid, accurate, and reliable
methods for diagnosis makes it difficult to direct
antimicrobial therapy at a specific pathogen. Thus,
empirical therapy with broad-spectrum antimicrobial agents often is relied upon due to the absence
of Gram’s stain and culture results. As viruses can
cause many of these community-acquired respiratory tract infections, overuse of empirical antimicrobial therapy frequently occurs. Empirical antimicrobial therapy is not only ineffective against
viral respiratory tract infections, but overuse of such
therapy can lead to microbial resistance. Indeed,
resistance has occurred with many of the bacterial
pathogens causing community-acquired respiratory tract infections. Yet, effective antimicrobial therapy of respiratory tract infections caused by
bacterial pathogens is important in preventing hos*Associate Professor of Medicine and Pathology,
Vanderbilt University School of Medicine, Nashville,
Tennessee.
Address correspondence to: Charles W. Stratton, MD, The
Vanderbilt Clinic, Room 4525-TVC, 21st & Edgehill Road,
Nashville, TN 37232. E-mail: [email protected].
†Organisms in the Chlamydia order were grouped by
DNA homology, which resulted in 2 distinct families of
chlamydial organisms, the Chlamydophila and Chlamydia
families.
212
pitalization or decreasing length of hospitalization.
As a rule, acute respiratory tract infections caused
by viruses are self-limited and should not be treated. A notable and recent exception is influenza,
which has become relatively easy to diagnose and
treat. This overview will focus primarily on community-acquired respiratory tract infections that are
caused by those pathogens, including the influenza
virus, which can be treated. Community-acquired
respiratory tract infections that are caused by such
pathogens include acute bacterial sinusitis, influenza, Chlamydophila pneumoniae respiratory tract
syndrome, acute exacerbations of chronic bronchitis, and community-acquired pneumonia.
(Adv Stud Pharm. 2005;2(6):212-218)
C
ommunity-acquired respiratory tract infections continue to be among the most common and important infections seen by
practitioners. These infections typically
involve the sinuses, the airways, and the lungs and can
be caused by a wide variety of microorganisms including viruses. As a rule, acute respiratory tract infections
caused by viruses are self-limited and should not be
treated. A notable and recent exception is influenza,
which has become relatively easy to diagnose and to
treat. This overview will focus primarily on community-acquired respiratory tract infections that are caused
by those pathogens, including the influenza virus,
which can be treated. Community-acquired respiratory tract infections that are caused by such pathogens
include acute bacterial sinusitis, influenza,
Chlamydophila (Chlamydia)† pneumoniae respiratory
tract syndrome, acute exacerbations of chronic bronchitis, and community-acquired pneumonia.
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EPIDEMIOLOGY OF COMMUNITY-ACQUIRED
RESPIRATORY TRACT INFECTIONS
Community-acquired respiratory tract infections are
the most common, and potentially most severe, of
infections treated by clinicians.1,2 Risk factors for community-acquired respiratory tract infections include:
extremes of age (young and elderly), smoking, alcoholism, immunosuppression, and comorbid conditions
such as congestive heart disease and chronic obstructive
pulmonary disease (COPD). Respiratory tract infections are the most common reason for office visits in the
United States. There are approximately 112 million
office visits per year for these respiratory tract infections,
which is over twice that for the second most common
reason, essential hypertension at 48 million office visits
per year.3 A seasonal increase in the incidence of community-acquired respiratory tract infections is recognized with cold and rainy seasons being associated with
increased respiratory tract infections due to crowding.
For example, when viruses such as influenza and respiratory syncytial virus are circulating in the community,
an increase in invasive pneumococcal disease has been
documented.4 Although community-acquired respiratory tract infections are common and seasonal, the epidemiology of these infections can be confusing. This is
because some acute respiratory tract infections such as
influenza can be easily transmitted from one person to
another. Accordingly, respiratory tract infections such as
influenza have a known seasonal occurrence and may
occur in epidemics.1,2 Other respiratory tract infections
such as acute exacerbations of chronic bronchitis are
related to colonization of the airways and thus involve
the patient’s own flora. Yet other community-acquired
respiratory tract infections may be multifactorial, perhaps beginning with a viral respiratory tract infection
and then complicated by aspiration/colonization of the
person’s own oral flora, which finally results in bacterial
tracheobronchitis/pneumonia.5 It is actually easier to
first consider the pathogenesis of community-acquired
respiratory tract infections and then examine in more
detail the epidemiological aspects of each of the common types of respiratory tract infections.
PATHOGENESIS OF COMMUNITY-ACQUIRED
RESPIRATORY TRACT INFECTIONS
The pathogenesis of community-acquired respiratory tract infections is similar to and usually begins with
impairment of the mucociliary defense mechanism.6
Such impairment may be due to an acute viral infection
Advanced Studies in Pharmacy
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of the respiratory tract, but is also a chronic problem in
persons who smoke tobacco or are exposed to secondhand tobacco smoke. The impairment of the mucociliary defense mechanism is due to damage/death of the
ciliated epithelial cells lining the sinuses and airways.
This is particularly a problem with infection of the respiratory tract caused by the influenza virus7 because
influenza per se causes damage/death of cells lining the
sinuses and airways. Interestingly, infection of these ciliated cells by another recently defined respiratory tract
pathogen, C pneumoniae, also interferes with the
mucociliary defense mechanism by paralyzing the cilia.8
The paralysis of cilia accounts for the persistent cough
seen in the characteristic tracheobronchitis caused by
this atypical pathogen. The dominant respiratory tract
pathogens seen in bacterial infections following impairment of the mucociliary defense mechanism are
Streptococcus pneumoniae, Haemophilus influenzae, and
atypical pathogens such as Mycoplasma pneumoniae,
Legionella species, and C pneumoniae. Some of these
pathogens such as S pneumoniae and H influenzae are
present in the normal flora of the upper respiratory tract
and may cause infection after aspiration. Others, such as
C pneumoniae, are initially acquired from droplet nuclei
containing elementary bodies that have been aerosolized
by the coughing of an infected person, but then can
cause a low-grade chronic respiratory tract infection in
which exacerbations can be triggered by viral infections.
Legionella species are acquired from an external source
such as dust, air conditioner mist, drinking water/aspiration, or showers. It is these multiple pathways for respiratory tract infections that make their epidemiology
somewhat confusing.
INFLUENZA
Influenza continues to be an important community-acquired respiratory disease and remains in the top
10 causes of death in the United States each year.9
This means that even in nonepidemic years, more that
20 000 Americans die annually from influenza.
Influenza is an RNA virus with affinity only for cells of
the respiratory tract.10 There are 2 important types of
influenza virus, influenza A and B, with influenza A
being more active in its antigenic drift and the only
influenza type that undergoes antigenic shift.11
The diagnosis of acute influenza has for the most
part been a clinical one, based in part on the knowledge
that influenza is present in the local area.12 Generally,
the acute onset of fever, chills, cough, malaise, and
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severe myalgias are clinical findings that identify
patients with influenza-like illness but are not particularly useful for confirming or excluding the diagnosis of
influenza. These clinical findings are, however, sufficient to warrant the use of commercially available rapid
assays for the identification of type A and B influenza
viruses.13 There are a number of these assays available;
they vary in complexity, specificity, sensitivity, test
time, specimen analyzed, and cost. In general, these
rapid influenza tests are more than 70% sensitive and
90% specific for influenza antigens.14 The results of
these rapid influenza tests are quite useful in guiding
treatment decisions and are changing the practice pattern of clinicians who care for patients with influenza.
Treatment of acute influenza may be symptomatic
or specific. Antiviral pharmacotherapy has been shown
to reduce the duration of disease, decrease viral shedding, relieve symptoms during disease, and enhance
defervescence.15 The first antiviral agents, amantadine
and rimantadine, were effective only against influenza
A. Moreover, these agents can have neurological and
gastrointestinal side effects, and resistant strains of
influenza virus rapidly occur. However, with the
advent of the neuraminidase inhibitors, zanamivir and
oseltamivir, antiviral therapy effective against both
influenza A and B is now available.16 These neuraminidase inhibitors have minimal side effects and far fewer
problems with the development of resistant strains as
infectivity of resistant strains is usually compromised.
It must be remembered that antiviral therapy with any
of these agents is effective only when initiated within
48 hours of the onset of symptoms.
C PNEUMONIAE RESPIRATORY TRACT SYNDROME
C pneumoniae is a recently recognized species of
Chlamydia17 and is now known as a significant cause of
both upper and lower respiratory tract infections.18 The
C pneumoniae respiratory tract syndrome is specifically
covered in this overview because it is a relatively new
syndrome and may be unappreciated by many physicians and pharmacists. C pneumoniae infection has been
described in otolaryngeal diseases such as pharyngitis,
tonsillitis, laryngitis, sinusitis, and otitis media with an
incidence ranging from 5% to 20%.18,19 Involvement of
C pneumoniae in these upper respiratory tract infections, particularly laryngitis in an adult, may herald
lower respiratory tract infection, with upper respiratory
tract symptoms fading as a persistent cough ensues.18,20
Lower respiratory tract infection with C pneumoniae is
214
characterized by a persistent cough that may initially
mimic pertussis.18,20-23 The duration of this cough is usually greater than 2 weeks and may be as long as 3
months. Although low-grade fever may be present initially, these patients are generally afebrile by the time
they seek medical assistance. The white blood count is
usually not elevated in patients infected with C pneumoniae. An important difference between the persistent
cough caused by C pneumoniae tracheobronchitits and
that seen with pertussis is that within a week or two, the
chlamydial cough becomes productive of grayish-green
bronchial plugs in the morning only.
Lower respiratory tract infections caused by C
pneumoniae may involve an acute tracheobronchitis
accompanied by laryngitis and sinusitis, chronic
bronchitis, or community-acquired pneumonia.
Although the name C pneumoniae suggests its role as
a cause of community-acquired pneumonia, where
studies have demonstrated that it accounts for 6% to
20% of these pneumonias, it is more likely to cause
acute tracheobronchitis or chronic bronchitis than
pneumonitis.18,20 Indeed, chronic infection by C pneumoniae has been found to be common in chronic
bronchitis.18,24 This chronic infection may contribute
to the pathogenesis of chronic bronchitis, with
cilostasis8 and chronic inflammation. Over time, this
chronic chlamydial infection of the bronchi may contribute to the development of both small airway disease and emphysema. In fact, chronic C pneumoniae
infection is now a recognized risk factor for the development of COPD.25 In addition to its role in chronic
bronchitis and COPD, C pneumoniae has also been
associated with both child-onset and adult-onset asthma.26,27 The exact role(s) of C pneumoniae infection in
asthma is currently being determined. It is known
that acute respiratory tract infections, including those
caused by C pneumoniae, cause exacerbations of asthma in children.28 Chronic C pneumoniae infection also
may play a role in asthma by contributing to the
chronic inflammatory derangements of the airways
and could even play a role in new-onset asthma.29
Clearly, chronic C pneumoniae infection may lead to
an increase in the severity of asthma; prolonged
antichlamydial therapy appears to result in an
improvement in asthma control.30
ACUTE EXACERBATIONS OF CHRONIC BRONCHITIS
Acute exacerbations of chronic bronchitis are
important because the incidence of chronic bronchitis
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is rising, especially in persons aged 18 to 44 years and
in the elderly.31 Chronic bronchitis comprises 90% of
all cases of COPD.32 The major risk factors for COPD
are smoking tobacco; a family history of obstructive
lung disease; exposure to tobacco smoke and atmospheric, domestic, and occupational pollutants; and
recurrent respiratory tract infections, particularly with
C pneumoniae 25 and during infancy. COPD accounts
for more than 14 million office visits to family physicians and 500 000 hospital admissions annually.33
COPD is the fourth leading cause of death in the
United States and the second most important cause of
work disability. Patients with COPD and chronic
bronchitis are prone to acute exacerbations, which frequently are caused by bacterial pathogens; antimicrobial therapy of these acute exacerbations appears
warranted.34,35 The most common bacterial pathogens
are H influenzae and S pneumoniae with C pneumoniae becoming increasingly recognized as both a common and important pathogen in COPD and chronic
bronchitis.24,25 Infection with S pneumoniae and other
gram-positive cocci tend to cause a less severe bronchitis than infection with Enterobacteriaceae and
Pseudomonas.36,37 Nontypeable H influenzae is an
important pathogen in chronic bronchitis that can be
difficult to eradicate due to its intracellular location38;
therefore, the ability of an antimicrobial agent to penetrate human cells is an important factor in treating
this microorganism.
COMMUNITY-ACQUIRED PNEUMONIA
Community-acquired pneumonia remains an
important therapeutic problem in medical practice.6,39,40 In the United States, approximately 4 million
cases of pneumonia are reported annually. Including
influenza, pneumonia is the sixth leading cause of
death in the United States. The mortality rate for community-acquired pneumonia continues to be approximately 14%. It is the possibility of communityacquired pneumonia that causes concern when a
patient presents with a community-acquired respiratory tract infection.41 Even a relatively benign viral respiratory tract infection can lead to a secondary bacterial
pneumonia.7,42 This consideration is, in part, what the
clinician uses to determine whether antibiotics should
be given to a patient with a community-acquired respiratory tract infection. The annual direct and indirect
costs of community-acquired pneumonia total $23
billion. Although the influenza virus can cause
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community-acquired pneumonia, S pneumoniae,
H influenzae, and the atypical pathogens M pneumoniae, Legionella species, and C pneumoniae cause the
majority of these infections. Empirical antimicrobial
therapy should cover each of these bacterial
pathogens,41 including resistant strains.43
ACUTE BACTERIAL SINUSITIS
Acute bacterial sinusitis is a major problem today
with approximately 31 million cases of acute and chronic sinusitis being reported annually in the United
States.44-46 The annual direct and indirect costs of acute
bacterial sinusitis in the United States are more than
$3.4 billion. The diagnosis of acute bacterial sinusitis
can be difficult and involves localized maxillary facial
pain, poor response to decongestants, history of purulent nasal secretions/discharge, and abnormal transillumination result. Antimicrobial therapy of acute bacterial
sinusitis is important because the complications of these
sinus infections include chronic sinusitis; orbital complications, especially in children; and intracranial complications such as meningitis, epidural abscess, subdural
empyema, venous sinus thrombosis, and cerebral
abscess.47 Acute bacterial sinusitis is the fifth most common diagnosis for which antimicrobial agents are prescribed. The dominant bacterial pathogens in acute
bacterial sinusitis are S pneumoniae and H influenzae.
MANAGEMENT OF COMMUNITY-ACQUIRED
RESPIRATORY TRACT INFECTIONS
There are important factors to consider with the
therapeutic options for bacterial community-acquired
respiratory tract infections. The choice of initial antimicrobial therapy is usually empirical because of the serious
nature of many of these respiratory tract infections.48 If
purulent nasal discharge or purulent expectorated sputum specimens are available, a Gram’s stain is often quite
useful in guiding the initial choice of antimicrobial
agents.49 Often a precise microbiological diagnosis is difficult, if not impossible, because the specialized and
invasive procedures needed to obtain a specimen are out
of proportion to the course of infection in the normal
host. Even when specimens from the sinuses, airways, or
lungs can be collected, the differentiation of infection
from colonization or contamination is a problem.49-53
Moreover, mixed infections occur frequently.54 In mixed
infections, one of the pathogens (eg, C pneumoniae) may
be difficult to detect with normal microbiological diagnostic procedures. A number of newly identified respi-
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ratory tract pathogens such as C pneumoniae17 and
Simkania55 are difficult to detect and are still being
assessed in terms of their pathogenic potential. Finally,
resistance of the most common bacterial pathogens has
emerged and is increasing.56,57 This was first seen in H
influenzae and more recently in S pneumoniae.58
Clinical management of respiratory tract infections
has been complicated over the past decade by the emergence and spread of resistance in S pneumoniae to betalactam agents and to macrolides both worldwide and in
the United States.59 Three-year data from the Prospective
Resistant Organism Tracking and Epidemiology for the
Ketolide Telithromycin-United States (PROTEKT US)
longitudinal surveillance study initiated in 2000 have
recently been published.60 The latest results from PROTEKT US showed that the prevalence of pneumococcal
penicillin nonsusceptibility in the United States is either
remaining the same or decreasing slightly. Overall pneumococcal macrolide (erythromycin) resistance rates have
been at approximately 30% over 2000 to 2003, a level
which is consistently higher than penicillin resistance.60
Importantly, the proportion of S pneumoniae isolated
demonstrating multidrug resistance has been static over
2000 to 2003, and has an overall prevalence of approximately 31%.60 Multidrug-resistant S pneumoniae will
most likely make the treatment of community-acquired
respiratory tract infections more difficult.
Given the broad spectrum of respiratory tract
pathogens and the problem of resistance, it becomes
very clear that currently there are few, if any, ideal
antimicrobial agents for respiratory tract infections.
The characteristics of the ideal antimicrobial agent for
community-acquired respiratory tract infections are
listed in the Table. Clearly, the ideal antibiotic should
Table. Characteristics of the Ideal Antibiotic for
Community-Acquired Respiratory Tract Infections
• Activity against broad spectrum of pathogens causing respiratory tract infections, but not against enteric bacteria occurring
in other parts of the body
have excellent activity against a targeted spectrum of
respiratory tract infections with a low potential for the
development of resistance. Ideally, the agent should
not have significant activity against enteric bacteria
occurring in other parts of the body as such activity
may lead to increased resistance in these enteric bacteria. The model agent should have a high clinical success rate with empirical therapy. A favorable safety
profile is also important for the ideal antimicrobial.
Ideal therapy should have convenient dosing and oral
as well as intravenous dosing should be available.
Finally, a short treatment duration would be useful to
address compliance issues.
CONCLUSIONS
Older classes of antimicrobial agents such as betalactam agents, macrolides, azolides, and fluoroquinolones all have members that have proven useful
for the therapy of bacterial respiratory tract infections.
Unfortunately, the emergence of newer pathogens as
well as the emergence of resistance has lowered the
clinical efficacy of these older agents.61,62 Newer classes
of antimicrobial agents may provide additional agents
that will prove useful for respiratory tract infections.
These include the streptogramin class with quinupristin/dalfopristin, the oxazolidinone class with
linezolid, and the ketolide class with telithromycin.
Some of these newer classes such as the streptogramin
class and oxazolidinone class are directed primarily
against resistant gram-positive bacteria and should
prove useful for respiratory tract infections caused by
multidrug-resistant S pneumoniae. The ketolide class
has the broadest spectrum of the newer classes of
antimicrobial agents and is active against the important
respiratory pathogens, including multidrug-resistant
pneumococci.63 Moreover, ketolides such as
telithromycin are bactericidal as well as chlamydiacidal.
Such bactericidal activity is important for eradication
as well as decreasing resistance.64 Time will tell how useful these agents will be for the therapy of communityacquired respiratory tract infections.
• Low potential for resistance
• Empirical therapy associated with high clinical success rate
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• Convenient dosing schedule (including both oral and intravenous formulations)
• Short treatment duration
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