Executive Summary
Improving the care of adult patients with community-acquired pneumonia (CAP) has been
the focus of many different organizations, and several have developed guidelines for
management of CAP. Two of the most widely referenced are those of the Infectious Diseases
Society of America (IDSA) and the American Thoracic Society (ATS). In response to
confusion regarding differences between their respective guidelines, the IDSA and
the ATS convened a joint committee to develop a unified CAP guideline document.
The guidelines are intended primarily for use by emergency medicine physicians, hospitalists,
and primary care practitioners; however, the extensive literature evaluation suggests
that they are also an appropriate starting point for consultation by specialists.
Substantial overlap exists among the patients whom these guidelines address and those
discussed in the recently published guidelines for health care-associated pneumonia
(HCAP). Pneumonia in nonambulatory residents of nursing homes and other long-term
care facilities epidemiologically mirrors hospital-acquired pneumonia and should be
treated according to the HCAP guidelines. However, certain other patients whose conditions
are included in the designation of HCAP are better served by management in accordance
with CAP guidelines with concern for specific pathogens. Implementation of Guideline
Recommendations.
1. Locally adapted guidelines should be implemented to improve process of care variables
and relevant clinical outcomes. (Strong recommendation; level I evidence.)
Enthusiasm for developing these guidelines derives, in large part, from evidence that
previous CAP guidelines have led to improvement in clinically relevant outcomes. Consistently
beneficial effects in clinically relevant parameters (listed in table 3) followed
the introduction of a comprehensive protocol (including a combination of components
from table 2) that increased compliance with published guidelines. The first recommendation,
therefore, is that CAP management guidelines be locally adapted and implemented.
Documented benefits.
2. CAP guidelines should address a comprehensive set of elements in the process of
care rather than a single element in isolation. (Strong recommendation; level III
evidence.)
3. Development of local CAP guidelines should be directed toward improvement in specific
and clinically relevant outcomes. (Moderate recommendation; level III evidence.)
Site-of-Care Decisions
Almost all of the major decisions regarding management of CAP, including diagnostic
and treatment issues, revolve around the initial assessment of severity. Site-of-care
decisions (e.g., hospital vs. outpatient, intensive care unit [ICU] vs. general ward)
are important areas for improvement in CAP management.
Hospital admission decision
4. Severity-of-illness scores, such as the CURB-65 criteria (confusion, uremia, respiratory
rate, low blood pressure, age 65 years or greater), or prognostic models, such as
the Pneumonia Severity Index (PSI), can be used to identify patients with CAP who
may be candidates for outpatient treatment. (Strong recommendation; level I evidence.)
5. Objective criteria or scores should always be supplemented with physician determination
of subjective factors, including the ability to safely and reliably take oral medication
and the availability of outpatient support resources. (Strong recommendation; level
II evidence.)
6. For patients with CURB-65 scores ⩾2, more-intensive treatment—that is, hospitalization
or, where appropriate and available, intensive in-home health care services—is usually
warranted. (Moderate recommendation; level III evidence.)
Physicians often admit patients to the hospital who could be well managed as outpatients
and who would generally prefer to be treated as outpatients. Objective scores, such
as the CURB-65 score or the PSI, can assist in identifying patients who may be appropriate
for outpatient care, but the use of such scores must be tempered by the physician's
determination of additional critical factors, including the ability to safely and
reliably take oral medication and the availability of outpatient support resources.
ICU admission decision.
7. Direct admission to an ICU is required for patients with septic shock requiring
vasopressors or with acute respiratory failure requiring intubation and mechanical
ventilation. (Strong recommendation; level II evidence.)
8. Direct admission to an ICU or high-level monitoring unit is recommended for patients
with 3 of the minor criteria for severe CAP listed in table 4. (Moderate recommendation;
level II evidence.)
In some studies, a significant percentage of patients with CAP are transferred to
the ICU in the first 24–48 h after hospitalization. Mortality and morbidity among
these patients appears to be greater than those among patients admitted directly to
the ICU. Conversely, ICU resources are often overstretched in many institutions, and
the admission of patients with CAP who would not directly benefit from ICU care is
also problematic. Unfortunately, none of the published criteria for severe CAP adequately
distinguishes these patients from those for whom ICU admission is necessary. In the
present set of guidelines, a new set of criteria has been developed on the basis of
data on individual risks, although the previous ATS criteria format is retained. In
addition to the 2 major criteria (need for mechanical ventilation and septic shock),
an expanded set of minor criteria (respiratory rate, >30 breaths/min; arterial oxygen
pressure/fraction of inspired oxygen (PaO2/FiO2) ratio, <250; multilobar infiltrates;
confusion; blood urea nitrogen level, >20 mg/dL; leukopenia resulting from infection;
thrombocytopenia; hypothermia; or hypotension requiring aggressive fluid resuscitation)
is proposed (table 4). The presence of at least 3 of these criteria suggests the need
for ICU care but will require prospective validation.
Diagnostic Testing
9. In addition to a constellation of suggestive clinical features, a demonstrable
infiltrate by chest radiograph or other imaging technique, with or without supporting
microbiological data, is required for the diagnosis of pneumonia. (Moderate recommendation;
level III evidence.)
Recommended diagnostic tests for etiology
10. Patients with CAP should be investigated for specific pathogens that would significantly
alter standard (empirical) management decisions, when the presence of such pathogens
is suspected on the basis of clinical and epidemiologic clues. (Strong recommendation;
level II evidence.)
Recommendations for diagnostic testing remain controversial. The overall low yield
and infrequent positive impact on clinical care argue against the routine use of common
tests, such as blood and sputum cultures. Conversely, these cultures may have a major
impact on the care of an individual patient and are important for epidemiologic reasons,
including the antibiotic susceptibility patterns used to develop treatment guidelines.
A list of clinical indications for more extensive diagnostic testing (table 5) was,
therefore, developed, primarily on the basis of 2 criteria: (1) when the result is
likely to change individual antibiotic management and (2) when the test is likely
to have the highest yield.
11. Routine diagnostic tests to identify an etiologic diagnosis are optional for outpatients
with CAP. (Moderate recommendation; level III evidence.)
12. Pretreatment blood samples for culture and an expectorated sputum sample for stain
and culture (in patients with a productive cough) should be obtained from hospitalized
patients with the clinical indications listed in table 5 but are optional for patients
without these conditions. (Moderate recommendation; level I evidence.)
13. Pretreatment Gram stain and culture of expectorated sputum should be performed
only if a good-quality specimen can be obtained and quality performance measures for
collection, transport, and processing of samples can be met. (Moderate recommendation;
level II evidence.)
14. Patients with severe CAP, as defined above, should at least have blood samples
drawn for culture, urinary antigen tests for Legionella pneumophila and Streptococcus
pneumoniae performed, and expectorated sputum samples collected for culture. For intubated
patients, an endotracheal aspirate sample should be obtained. (Moderate recommendation;
level II evidence.)
The most clear-cut indication for extensive diagnostic testing is in the critically
ill CAP patient. Such patients should at least have blood drawn for culture and an
endotracheal aspirate obtained if they are intubated; consideration should be given
to more extensive testing, including urinary antigen tests for L. pneumophila and
S. pneumoniae and Gram stain and culture of expectorated sputum in nonintubated patients.
For inpatients without the clinical indications listed in table 5, diagnostic testing
is optional (but should not be considered wrong).
Antibiotic Treatment
Empirical antimicrobial therapy.Empirical antibiotic recommendations (table 7) have
not changed significantly from those in previous guidelines. Increasing evidence has
strengthened the recommendation for combination empirical therapy for severe CAP.
Only 1 recently released antibiotic has been added to the recommendations: ertapenem,
as an acceptable β-lactam alternative for hospitalized patients with risk factors
for infection with gram-negative pathogens other than Pseudomonas aeruginosa. At present,
the committee is awaiting further evaluation of the safety of telithromycin by the
US Food and Drug Administration before making its final recommendation regarding this
drug. Recommendations are generally for a class of antibiotics rather than for a specific
drug, unless outcome data clearly favor one drug. Because overall efficacy remains
good for many classes of agents, the more potent drugs are given preference because
of their benefit in decreasing the risk of selection for antibiotic resistance.
Outpatient treatment
15. Previously healthy and no risk factors for drug-resistant S. pneumoniae (DRSP)
infection:
A macrolide (azithromycin, clarithromycin, or erythromycin) (strong recommendation;
level I evidence)
Doxycycline (weak recommendation; level III evidence)
16. Presence of comorbidities, such as chronic heart, lung, liver, or renal disease;
diabetes mellitus; alcoholism; malignancies; asplenia; immunosuppressing conditions
or use of immunosuppressing drugs; use of antimicrobials within the previous 3 months
(in which case an alternative from a different class should be selected); or other
risks for DRSP infection:
A. A respiratory fluoroquinolone (moxifloxacin, gemifloxacin, or levofloxacin [750
mg]) (strong recommendation; level I evidence) B. A. β-lactam plus a macrolide (strong
recommendation; level I evidence) (High-dose amoxicillin [e.g., 1 g 3 times daily]
or amoxicillin-clavulanate [2 g 2 times daily] is preferred; alternatives include
ceftriaxone, cefpodoxime, and cefuroxime [500 mg 2 times daily]; doxycycline [level
II evidence] is an alternative to the macrolide.)
17. In regions with a high rate (>25%) of infection with high-level (MIC, ⩾16 µg/mL)
macrolide-resistant S. pneumoniae, consider the use of alternative agents listed above
in recommendation 16 for any patient, including those without comorbidities. (Moderate
recommendation; level III evidence.)
Inpatient, non-ICU treatment
18. A respiratory fluoroquinolone (strong recommendation; level I evidence)
19. β-lactam plus a macrolide (strong recommendation; level I evidence) (Preferred
β-lactam agents include cefotaxime, ceftriaxone, and ampicillin; ertapenem for selected
patients; with doxycycline [level III evidence] as an alternative to the macrolide.
A respiratory fluoroquinolone should be used for penicillin-allergic patients.)
Increasing resistance rates have suggested that empirical therapy with a macrolide
alone can be used only for the treatment of carefully selected hospitalized patients
with nonsevere disease and without risk factors for infection with drug-resistant
pathogens. However, such monotherapy cannot be routinely recommended. Inpatient, ICU
treatment
20. β-lactam (cefotaxime, ceftriaxone, or ampicillin-sulbactam) plus either azithromycin
(level II evidence) or a fluoroquinolone (level I evidence) (strong recommendation)
(For penicillin-allergic patients, a respiratory fluoroquinolone and aztreonam are
recommended.)
21. For Pseudomonas infection, use an antipneumococcal, antipseudomonal β-lactam (piperacillin-tazobactam,
cefepime, imipenem, or meropenem) plus either ciprofloxacin or levofloxacin (750-mg
dose) or the above β-lactam plus an aminoglycoside and azithromycin or the above β-lactam
plus an aminoglycoside and an antipneumococcal fluoroquinolone (for penicillin-allergic
patients, substitute aztreonam for the above β-lactam).
(Moderate recommendation; level III evidence.)
22. For community-acquired methicillin-resistant Staphylococcus aureus infection,
add vancomycin or linezolid. (Moderate recommendation; level III evidence.)
Infections with the overwhelming majority of CAP pathogens will be adequately treated
by use of the recommended empirical regimens. The emergence of methicillin-resistant
S. aureus as a CAP pathogen and the small but significant incidence of CAP due to
P. aeruginosa are the exceptions. These pathogens occur in specific epidemiologic
patterns and/or with certain clinical presentations, for which empirical antibiotic
coverage may be warranted. However, diagnostic tests are likely to be of high yield
for these pathogens, allowing early discontinuation of empirical treatment if results
are negative. The risk factors are included in the table 5 recommendations for indications
for increased diagnostic testing.Pathogens suspected on the basis of epidemiologic
considerations.
Risk factors for other uncommon etiologies of CAP are listed in table 8, and recommendations
for treatment are included in table 9.
Pathogen-directed therapy.
23. Once the etiology of CAP has been identified on the basis of reliable microbiological
methods, antimicrobial therapy should be directed at that pathogen. (Moderate recommendation;
level III evidence.)
24. Early treatment (within 48 h of the onset of symptoms) with oseltamivir or zanamivir
is recommended for influenza A. (Strong recommendation; level I evidence.)
25. Use of oseltamivir and zanamivir is not recommended for patients with uncomplicated
influenza with symptoms for >48 h (level I evidence), but these drugs may be used
to reduce viral shedding in hospitalized patients or for influenza pneumonia. (Moderate
recommendation; level III evidence.)
Pandemic influenza
26. Patients with an illness compatible with influenza and with known exposure to
poultry in areas with previous H5N1 infection should be tested for H5N1 infection.
(Moderate recommendation; level III evidence.)
27. In patients with suspected H5N1 infection, droplet precautions and careful routine
infection control measures should be used until an H5N1 infection is ruled out. (Moderate
recommendation; level III evidence.)
28. Patients with suspected H5N1 infection should be treated with oseltamivir (level
II evidence) and antibacterial agents targeting S. pneumoniae and S. aureus, the most
common causes of secondary bacterial pneumonia in patients with influenza (level III
evidence). (Moderate recommendation.)
Time to first antibiotic dose.
29. For patients admitted through the emergency department (ED), the first antibiotic
dose should be administered while still in the ED. (Moderate recommendation; level
III evidence.)
Rather than designating a specific window in which to initiate treatment, the committee
felt that hospitalized patients with CAP should receive the first antibiotic dose
in the ED. Switch from intravenous to oral therapy.
30. Patients should be switched from intravenous to oral therapy when they are hemodynamically
stable and improving clinically, are able to ingest medications, and have a normally
functioning gastrointestinal tract. (Strong recommendation; level II evidence.)
31. Patients should be discharged as soon as they are clinically stable, have no other
active medical problems, and have a safe environment for continued care. Inpatient
observation while receiving oral therapy is not necessary. (Moderate recommendation;
level II evidence.)
Duration of antibiotic therapy.
32. Patients with CAP should be treated for a minimum of 5 days (level I evidence),
should be afebrile for 48–72 h, and should have no more than 1 CAP-associated sign
of clinical instability (table 10) before discontinuation of therapy (level II evidence).
(Moderate recommendation.)
33. A longer duration of therapy may be needed if initial therapy was not active against
the identified pathogen or if it was complicated by extrapulmonary infection, such
as meningitis or endocarditis. (Weak recommendation; level III evidence.)
Other Treatment Considerations
34. Patients with CAP who have persistent septic shock despite adequate fluid resuscitation
should be considered for treatment with drotrecogin alfa activated within 24 h of
admission. (Weak recommendation; level II evidence.)
35. Hypotensive, fluid-resuscitated patients with severe CAP should be screened for
occult adrenal insufficiency. (Moderate recommendation; level II evidence.)
36. Patients with hypoxemia or respiratory distress should receive a cautious trial
of noninvasive ventilation unless they require immediate intubation because of severe
hypoxemia (PaO2/FiO2 ratio, <150) and bilateral alveolar infiltrates. (Moderate recommendation;
level I evidence.)
37. Low-tidal-volume ventilation (6 cm3/kg of ideal body weight) should be used for
patients undergoing ventilation who have diffuse bilateral pneumonia or acute respiratory
distress syndrome. (Strong recommendation; level I evidence.)
Management of Nonresponding Pneumonia Definitions and classification.
38. The use of a systematic classification of possible causes of failure to respond,
based on time of onset and type of failure (table 11), is recommended. (Moderate recommendation;
level II evidence.)
As many as 15% of patients with CAP may not respond appropriately to initial antibiotic
therapy. A systematic approach to these patients (table 11) will help to determine
the cause. Because determination of the cause of failure is more accurate if the original
microbiological etiology is known, risk factors for nonresponse or deterioration (table
12) figure prominently in the list of situations in which more aggressive and/or extensive
initial diagnostic testing is warranted (table 5).
Prevention (see table 13)
39. All persons ⩾50 years of age, others at risk for influenza complications, household
contacts of high-risk persons, and health care workers should receive inactivated
influenza vaccine as recommended by the Advisory Committee on Immunization Practices,
Centers for Disease Control and Prevention. (Strong recommendation; level I evidence.)
40. The intranasally administered live attenuated vaccine is an alternative vaccine
formulation for some persons 5–49 years of age without chronic underlying diseases,
including immunodeficiency, asthma, or chronic medical conditions. (Strong recommendation;
level I evidence.)
41. Health care workers in inpatient and outpatient settings and long-term care facilities
should receive annual influenza immunization. (Strong recommendation; level I evidence.)
42. Pneumococcal polysaccharide vaccine is recommended for persons ⩾65 years of age
and for those with selected high-risk concurrent diseases, according to current Advisory
Committee on Immunization Practices guidelines. (Strong recommendation; level II evidence.)
43. Vaccination status should be assessed at the time of hospital admission for all
patients, especially those with medical illnesses. (Moderate recommendation; level
III evidence.)
44. Vaccination may be performed either at hospital discharge or during outpatient
treatment. (Moderate recommendation; level III evidence.)
45. Influenza vaccine should be offered to persons at hospital discharge or during
outpatient treatment during the fall and winter. (Strong recommendation; level III
evidence.)
46. Smoking cessation should be a goal for persons hospitalized with CAP who smoke.
(Moderate recommendation; level III evidence.)
47. Smokers who will not quit should also be vaccinated for both pneumococcus and
influenza. (Weak recommendation; level III evidence.)
48. Cases of pneumonia that are of public health concern should be reported immediately
to the state or local health department. (Strong recommendation; level III evidence.)
49. Respiratory hygiene measures, including the use of hand hygiene and masks or tissues
for patients with cough, should be used in outpatient settings and EDs as a means
to reduce the spread of respiratory infections. (Strong recommendation; level III
evidence.)
Introduction
Improving the care of patients with community-acquired pneumonia (CAP) has been the
focus of many different organizations. Such efforts at improvement in care are warranted,
because CAP, together with influenza, remains the seventh leading cause of death in
the United States [1]. According to one estimate, 915,900 episodes of CAP occur in
adults ⩾65 years of age each year in the United States [2]. Despite advances in antimicrobial
therapy, rates of mortality due to pneumonia have not decreased significantly since
penicillin became routinely available [3].
Groups interested in approaches to the management of CAP include professional societies,
such as the American Thoracic Society (ATS) and the Infectious Diseases Society of
America (IDSA); government agencies or their contract agents, such as the Center for
Medicare and Medicaid Services and the Department of Veterans Affairs; and voluntary
accrediting agencies, such as the Joint Commission on Accreditation of Healthcare
Organizations. In addition, external review groups and consumer groups have chosen
CAP outcomes as major quality indicators. Such interest has resulted in numerous guidelines
for the management of CAP [4]. Some of these guidelines represent truly different
perspectives, including differences in health care systems, in the availability of
diagnostic tools or therapeutic agents, or in either the etiology or the antibiotic
susceptibility of common causative microorganisms. The most widely referenced guidelines
in the United States have been those published by the ATS [5, 6] and the IDSA [7–9].
Differences, both real and imagined, between the ATS and IDSA guidelines have led
to confusion for individual physicians, as well as for other groups who use these
published guidelines rather than promulgating their own. In response to this concern,
the IDSA and the ATS convened a joint committee to develop a unified CAP guideline
document. This document represents a consensus of members of both societies, and both
governing councils have approved the statement.Purpose and scope.The purpose of this
document is to update clinicians with regard to important advances and controversies
in the management of patients with CAP. The committee chose not to address CAP occurring
in immunocompromised patients, including solid organ, bone marrow, or stem cell transplant
recipients; patients receiving cancer chemotherapy or long-term (>30 days) high-dose
corticosteroid treatment; and patients with congenital or acquired immunodeficiency
or those infected with HIV who have CD4 cell counts <350 cells/mm3, although many
of these patients may be infected with the same microorganisms. Pneumonia in children
(⩽18 years of age) is also not addressed.
Substantial overlap exists among the patients these guidelines address and those discussed
in the recently published guidelines for health care-associated pneumonia (HCAP) [10].
Two issues are pertinent: (1) an increased risk of infection with drug-resistant isolates
of usual CAP pathogens, such as Streptococcus pneumoniae, and (2) an increased risk
of infection with less common, usually hospital-associated pathogens, such as Pseudomonas
and Acinetobacter species and methicillin-resistant Staphylococcus aureus (MRSA).
Pneumonia in nonambulatory residents of nursing homes and other long-term care facilities
epidemiologically mirrors hospital-acquired pneumonia and should be treated according
to the HCAP guidelines. However, certain other patients whose conditions are included
under the designation of HCAP are better served by management in accordance with CAP
guidelines with concern for specific pathogens. For example, long-term dialysis alone
is a risk for MRSA infection but does not necessarily predispose patients to infection
with other HCAP pathogens, such as Pseudomonas aeruginosa or Acinetobacter species.
On the other hand, certain patients with chronic obstructive pulmonary disease (COPD)
are at greater risk for infection with Pseudomonas species but not MRSA. These issues
will be discussed in specific sections below.
The committee started with the premise that mortality due to CAP can be decreased.
We, therefore, have placed the greatest emphasis on aspects of the guidelines that
have been associated with decreases in mortality. For this reason, the document focuses
mainly on management and minimizes discussions of such factors as pathophysiology,
pathogenesis, mechanisms of antibiotic resistance, and virulence factors.
The committee recognizes that the majority of patients with CAP are cared for by primary
care, hospitalist, and emergency medicine physicians [11], and these guidelines are,
therefore, directed primarily at them. The committee consisted of infectious diseases,
pulmonary, and critical care physicians with interest and expertise in pulmonary infections.
The expertise of the committee and the extensive literature evaluation suggest that
these guidelines are also an appropriate starting point for consultation by these
types of physicians.
Although much of the literature cited originates in Europe, these guidelines are oriented
toward the United States and Canada. Although the guidelines are generally applicable
to other parts of the world, local antibiotic resistance patterns, drug availability,
and variations in health care systems suggest that modification of these guidelines
is prudent for local use.Methodology.The process of guideline development started
with the selection of committee cochairs by the presidents of the IDSA [12] and ATS
[13], in consultation with other leaders in the respective societies. The committee
cochairs were charged with selection of the rest of the committee. The IDSA members
were those involved in the development of previous IDSA CAP guidelines [9], whereas
ATS members were chosen in consultation with the leadership of the Mycobacteria Tuberculosis
and Pulmonary Infection Assembly, with input from the chairs of the Clinical Pulmonary
and Critical Care assemblies. Committee members were chosen to represent differing
expertise and viewpoints on the various topics. One acknowledged weakness of this
document is the lack of representation by primary care, hospitalist, and emergency
medicine physicians.
The cochairs generated a general outline of the topics to be covered that was then
circulated to committee members for input. A conference phone call was used to review
topics and to discuss evidence grading and the general aims and expectations of the
document. The topics were divided, and committee members were assigned by the cochairs
and charged with presentation of their topic at an initial face-to-face meeting, as
well as with development of a preliminary document dealing with their topic. Controversial
topics were assigned to 2 committee members, 1 from each society.
An initial face-to-face meeting of a majority of committee members involved presentations
of the most controversial topics, including admission decisions, diagnostic strategies,
and antibiotic therapy. Prolonged discussions followed each presentation, with consensus
regarding the major issues achieved before moving to the next topic. With input from
the rest of the committee, each presenter and committee member assigned to the less
controversial topics prepared an initial draft of their section, including grading
of the evidence. Iterative drafts of the statement were developed and distributed
by e-mail for critique, followed by multiple revisions by the primary authors. A second
face-to-face meeting was also held for discussion of the less controversial areas
and further critique of the initial drafts. Once general agreement on the separate
topics was obtained, the cochairs incorporated the separate documents into a single
statement, with substantial editing for style and consistency. The document was then
redistributed to committee members to review and update with new information from
the literature up to June 2006. Recommended changes were reviewed by all committee
members by e-mail and/or conference phone call and were incorporated into the final
document by the cochairs.
This document was then submitted to the societies for approval. Each society independently
selected reviewers, and changes recommended by the reviewers were discussed by the
committee and incorporated into the final document. The guideline was then submitted
to the IDSA Governing Council and the ATS Board of Directors for final approval.Grading
of guideline recommendations.Initially, the committee decided to grade only the strength
of the evidence, using a 3-tier scale (table 1) used in a recent guideline from both
societies [10]. In response to reviewers' comments and the maturation of the field
of guideline development [14], a separate grading of the strength of the recommendations
was added to the final draft. More extensive and validated criteria, such as GRADE
[14], were impractical for use at this stage. The 3-tier scale similar to that used
in other IDSA guideline documents [12] and familiar to many of the committee members
was therefore chosen.
The strength of each recommendation was graded as “strong,” “moderate,” or “weak.”
Each committee member independently graded each recommendation on the basis of not
only the evidence but also expert interpretation and clinical applicability. The final
grading of each recommendation was a composite of the individual committee members'
grades. For the final document, a strong recommendation required ⩾6 (of 12) of the
members to consider it to be strong and the majority of the others to grade it as
moderate.
The implication of a strong recommendation is that most patients should receive that
intervention. Significant variability in the management of patients with CAP is well
documented. Some who use guidelines suggest that this variability itself is undesirable.
Industrial models suggesting that variability per se is undesirable may not always
be relevant to medicine [15]. Such models do not account for substantial variability
among patients, nor do they account for variable end points, such as limitation of
care in patients with end-stage underlying diseases who present with CAP. For this
reason, the committee members feel strongly that 100% compliance with guidelines is
not the desired goal. However, the rationale for variation from a strongly recommended
guideline should be apparent from the medical record.
Conversely, moderate or weak recommendations suggest that, even if a majority would
follow the recommended management, many practitioners may not. Deviation from guidelines
may occur for a variety of reasons [16, 17]. One document cannot cover all of the
variable settings, unique hosts, or epidemiologic patterns that may dictate alternative
management strategies, and physician judgment should always supersede guidelines.
This is borne out by the finding that deviation from guidelines is greatest in the
treatment of patients with CAP admitted to the ICU [18]. In addition, few of the recommendations
have level I evidence to support them, and most are, therefore, legitimate topics
for future research. Subsequent publication of studies documenting that care that
deviates from guidelines results in better outcomes will stimulate revision of the
guidelines. The committee anticipates that this will occur, and, for this reason,
both the ATS and IDSA leaderships have committed to the revision of these guidelines
on a regular basis.
We recognize that these guidelines may be used as a measure of quality of care for
hospitals and individual practitioners. Although these guidelines are evidence based,
the committee strongly urges that deviations from them not necessarily be considered
substandard care, unless they are accompanied by evidence for worse outcomes in a
studied population.
Implementation of Guideline Recommendations
Locally adapted guidelines should be implemented to improve process of care variables
and relevant clinical outcomes. (Strong recommendation; level I evidence.)
Enthusiasm for developing this set of CAP guidelines derives, in large part, from
evidence that previous CAP guidelines have led to improvement in clinically relevant
outcomes [17, 19–21]. Protocol design varies among studies, and the preferable randomized,
parallel group design has been used in only a small minority. Confirmatory studies
that use randomized, parallel groups with precisely defined treatments are still needed,
but a consistent pattern of benefit is found in the other types of level I studies.Documented
benefits.Published protocols have varied in primary focus and comprehensiveness, and
the corresponding benefits vary from one study to another. However, the most impressive
aspect of this literature is the consistently beneficial effect seen in some clinically
relevant parameter after the introduction of a protocol that increases compliance
with published guidelines.
A decrease in mortality with the introduction of guideline-based protocols was found
in several studies [19, 21]. A 5-year study of 28,700 patients with pneumonia who
were admitted during implementation of a pneumonia guideline demonstrated that the
crude 30-day mortality rate was 3.2% lower with the guideline (adjusted OR, 0.69;
95% CI, 0.49–0.97) [19], compared with that among patients treated concurrently by
nonaffiliated physicians. After implemention of a practice guideline at one Spanish
hospital [21], the survival rate at 30 days was higher (OR, 2.14; 95% CI, 1.23–3.72)
than at baseline and in comparison with 4 other hospitals without overt protocols.
Lower mortality was seen in other studies, although the differences were not statistically
significant [22, 23]. Studies that documented lower mortality emphasized increasing
the number of patients receiving guideline-recommended antibiotics, confirming results
of the multivariate analysis of a retrospective review [24].
When the focus of a guideline was hospitalization, the number of less ill patients
admitted to the hospital was consistently found to be lower. Using admission decision
support, a prospective study of >1700 emergency department (ED) visits in 19 hospitals
randomized between pathway and “conventional” management found that admission rates
among low-risk patients at pathway hospitals decreased (from 49% to 31% of patients
in Pneumonia Severity Index [PSI] classes I–III; P < .01) without differences in patient
satisfaction scores or rate of readmission [20]. Calculating the PSI score and assigning
the risk class, providing oral clarithromycin, and home nursing follow-up significantly
(P = .01) decreased the number of low-mortality-risk admissions [25]. However, patient
satisfaction among outpatients was lower after implementation of this guideline, despite
survey data that suggested most patients would prefer outpatient treatment [26]. Of
patients discharged from the ED, 9% required hospitalization within 30 days, although
another study showed lower readmission rates with the use of a protocol [23]. Admission
decision support derived from the 1993 ATS guideline [5] recommendations, combined
with outpatient antibiotic recommendations, reduced the CAP hospitalization rate from
13.6% to 6.4% [23], and admission rates for other diagnoses were unchanged. Not surprisingly,
the resultant overall cost of care decreased by half (P = .01).
Protocols using guidelines to decrease the duration of hospitalization have also been
successful. Guideline implementation in 31 Connecticut hospitals decreased the mean
length of hospital stay (LOS) from 7 to 5 days (P < .001) [27]. An ED-based protocol
decreased the mean LOS from 9.7 to 6.4 days (P < .0001), with the benefits of guideline
implementation maintained 3 years after the initial study [22]. A 7-site trial, randomized
by physician group, of guideline alone versus the same guideline with a multifaceted
implementation strategy found that addition of an implementation strategy was associated
with decreased duration of intravenous antibiotic therapy and LOS, although neither
decrease was statistically significant [28]. Several other studies used guidelines
to significantly shorten the LOS, by an average of >1.5 days [20, 21].
Markers of process of care can also change with the use of a protocol. The time to
first antibiotic dose has been effectively decreased with CAP protocols [22, 27, 29].
A randomized, parallel group study introduced a pneumonia guideline in 20 of 36 small
Oklahoma hospitals [29], with the identical protocol implemented in the remaining
hospitals in a second phase. Serial measurement of key process measures showed significant
improvement in time to first antibiotic dose and other variables, first in the initial
20 hospitals and later in the remaining 16 hospitals. Implementing a guideline in
the ED halved the time to initial antibiotic dose [22].
2. CAP guidelines should address a comprehensive set of elements in the process of
care rather than a single element in isolation. (Strong recommendation; level III
evidence.)
Common to all of the studies documented above, a comprehensive protocol was developed
and implemented, rather than one addressing a single aspect of CAP care. No study
has documented that simply changing 1 metric, such as time to first antibiotic dose,
is associated with a decrease in mortality. Elements important in CAP guidelines are
listed in table 2. Of these, rapid and appropriate empirical antibiotic therapy is
consistently associated with improved outcome. We have also included elements of good
care for general medical inpatients, such as early mobilization [30] and prophylaxis
against thromboembolic disease [31]. Although local guidelines need not include all
elements, a logical constellation of elements should be addressed.
3. Development of local CAP guidelines should be directed toward improvement in specific
and clinically relevant outcomes. (Moderate recommendation; level III evidence.)
In instituting CAP protocol guidelines, the outcomes most relevant to the individual
center or medical system should be addressed first. Unless a desire to change clinically
relevant outcomes exists, adherence to guidelines will be low, and institutional resources
committed to implement the guideline are likely to be insufficient. Guidelines for
the treatment of pneumonia must use approaches that differ from current practice and
must be successfully implemented before process of care and outcomes can change. For
example, Rhew et al. [32] designed a guideline to decrease LOS that was unlikely to
change care, because the recommended median LOS was longer than the existing LOS for
CAP at the study hospitals. The difficulty in implementing guidelines and changing
physician behavior has also been documented [28, 33].
Clinically relevant outcome parameters should be evaluated to measure the effect of
the local guideline. Outcome parameters that can be used to measure the effect of
implementation of a CAP guideline within an organization are listed in table 3. Just
as it is important not to focus on one aspect of care, studying more than one outcome
is also important. Improvements in one area may be offset by worsening in a related
area; for example, decreasing admission of low-acuity patients might increase the
number of return visits to the ED or hospital readmissions [25].
Site-of-Care Decisions
Almost all of the major decisions regarding management of CAP, including diagnostic
and treatment issues, revolve around the initial assessment of severity. We have,
therefore, organized the guidelines to address this issue first.Hospital admission
decision.The initial management decision after diagnosis is to determine the site
of care—outpatient, hospitalization in a medical ward, or admission to an ICU. The
decision to admit the patient is the most costly issue in the management of CAP, because
the cost of inpatient care for pneumonia is up to 25 times greater than that of outpatient
care [34] and consumes the majority of the estimated $8.4–$10 billion spent yearly
on treatment.
Other reasons for avoiding unnecessary admissions are that patients at low risk for
death who are treated in the outpatient setting are able to resume normal activity
sooner than those who are hospitalized, and 80% are reported to prefer outpatient
therapy [26, 35]. Hospitalization also increases the risk of thromboembolic events
and superinfection by more-virulent or resistant hospital bacteria [36].
4. Severity-of-illness scores, such as the CURB-65 criteria (confusion, uremia, respiratory
rate, low blood pressure, age 65 years or greater), or prognostic models, such as
the PSI, can be used to identify patients with CAP who may be candidates for outpatient
treatment. (Strong recommendation; level I evidence.)
Significant variation in admission rates among hospitals and among individual physicians
is well documented. Physicians often overestimate severity and hospitalize a significant
number of patients at low risk for death [20, 37, 38]. Because of these issues, interest
in objective site-of-care criteria has led to attempts by a number of groups to develop
such criteria [39–48]. The relative merits and limitations of various proposed criteria
have been carefully evaluated [49]. The 2 most interesting are the PSI [42] and the
British Thoracic Society (BTS) criteria [39, 45].
The PSI is based on derivation and validation cohorts of 14,199 and 38,039 hospitalized
patients with CAP, respectively, plus an additional 2287 combined inpatients and outpatients
[42]. The PSI stratifies patients into 5 mortality risk classes, and its ability to
predict mortality has been confirmed in multiple subsequent studies. On the basis
of associated mortality rates, it has been suggested that risk class I and II patients
should be treated as outpatients, risk class III patients should be treated in an
observation unit or with a short hospitalization, and risk class IV and V patients
should be treated as inpatients [42].
Yealy et al. [50] conducted a cluster-randomized trial of low-, moderate-, and high-intensity
processes of guideline implementation in 32 EDs in the United States. Their guideline
used the PSI for admission decision support and included recommendations for antibiotic
therapy, timing of first antibiotic dose, measurement of oxygen saturation, and blood
cultures for admitted patients. EDs with moderate- to high-intensity guideline implementation
demonstrated more outpatient treatment of low-risk patients and higher compliance
with antibiotic recommendations. No differences were found in mortality rate, rate
of hospitalization, median time to return to work or usual activities, or patient
satisfaction. This study differs from those reporting a mortality rate difference
[19, 21] in that many hospitalized patients with pneumonia were not included. In addition,
EDs with low-intensity guideline implementation formed the comparison group, rather
than EDs practicing nonguideline, usual pneumonia care.
The BTS original criteria of 1987 have subsequently been modified [39, 51]. In the
initial study, risk of death was increased 21-fold if a patient, at the time of admission,
had at least 2 of the following 3 conditions: tachypnea, diastolic hypotension, and
an elevated blood urea nitrogen (BUN) level. These criteria appear to function well
except among patients with underlying renal insufficiency and among elderly patients
[52, 53].
The most recent modification of the BTS criteria includes 5 easily measurable factors
[45]. Multivariate analysis of 1068 patients identified the following factors as indicators
of increased mortality: confusion (based on a specific mental test or disorientation
to person, place, or time), BUN level >7 mmol/L (20 mg/dL), respiratory rate ⩾30 breaths/min,
low blood pressure (systolic, <90 mm Hg; or diastolic, ⩽60 mm Hg), and age ⩾65 years;
this gave rise to the acronym CURB-65. In the derivation and validation cohorts, the
30-day mortality among patients with 0, 1, or 2 factors was 0.7%, 2.1%, and 9.2%,
respectively. Mortality was higher when 3, 4, or 5 factors were present and was reported
as 14.5%, 40%, and 57%, respectively. The authors suggested that patients with a CURB-65
score of 0–1 be treated as outpatients, that those with a score of 2 be admitted to
the wards, and that patients with a score of ⩾3 often required ICU care. A simplified
version (CRB-65), which does not require testing for BUN level, may be appropriate
for decision making in a primary care practitioner's office [54].
The use of objective admission criteria clearly can decrease the number of patients
hospitalized with CAP [20, 23, 25, 55]. Whether the PSI or the CURB-65 score is superior
is unclear, because no randomized trials of alternative admission criteria exist.
When compared in the same population, the PSI classified a slightly larger percentage
of patients with CAP in the low-risk categories, compared with the CURB or CURB-65
criteria, while remaining associated with a similar low mortality rate among patients
categorized as low risk [56]. Several factors are important in this comparison. The
PSI includes 20 different variables and, therefore, relies on the availability of
scoring sheets, limiting its practicality in a busy ED [55]. In contrast, the CURB-65
criteria are easily remembered. However, CURB-65 has not been as extensively studied
as the PSI, especially with prospective validation in other patient populations (e.g.,
the indigent inner-city population), and has not been specifically studied as a means
of reducing hospital admission rates. In EDs with sufficient decision support resources
(either human or computerized), the benefit of greater experience with the PSI score
may favor its use for screening patients who may be candidates for outpatient management
[50, 57–59].
5. Objective criteria or scores should always be supplemented with physician determination
of subjective factors, including the ability to safely and reliably take oral medication
and the availability of outpatient support resources. (Strong recommendation; level
II evidence.)
Studies show that certain patients with low PSI or CURB-65 scores [20, 60, 61] require
hospital admission, even to the ICU [49, 62, 63]. Both scores depend on certain assumptions.
One is that the main rationale for admission of a patient with CAP is risk of death.
This assumption is clearly not valid in all cases. Another is that the laboratory
and vital signs used for scoring are stable over time rather than indicative of transient
abnormalities. This is also not true in all cases. Therefore, dynamic assessment over
several hours of observation may be more accurate than a score derived at a single
point in time. Although advantageous to making decisions regarding hospital admission,
sole reliance on a score for the hospital admission decision is unsafe.
Reasons for the admission of low-mortality-risk patients fall into 4 categories: (1)
complications of the pneumonia itself, (2) exacerbation of underlying diseases(s),
(3) inability to reliably take oral medications or receive outpatient care, and/or
(4) multiple risk factors falling just above or below thresholds for the score [62].
Use of the PSI score in clinical trials has demonstrated some of its limitations,
which may be equally applicable to other scoring techniques. A modification of the
original PSI score was needed when it was applied to the admission decision. An arterial
saturation of <90% or an arterial oxygen pressure (PaO2) of <60 mm Hg as a complication
of the pneumonia, was added as a sole indicator for admission for patients in risk
classes I–III as an added “margin of safety” in one trial [42]. In addition to patients
who required hospital admission because of hypoxemia, a subsequent study identified
patients in low PSI risk classes (I–III) who needed hospital admission because of
shock, decompensated coexisting illnesses, pleural effusion, inability to maintain
oral intake, social problems (the patient was dependent or no caregiver was available),
and lack of response to previous adequate empirical antibiotic therapy [64]. Of 178
patients in low PSI risk classes who were treated as inpatients, 106 (60%) presented
with at least 1 of these factors. Other medical or psychosocial needs requiring hospital
care include intractable vomiting, injection drug abuse, severe psychiatric illness,
homelessness, poor overall functional status [65], and cognitive dysfunction [61,
66].
The PSI score is based on a history of diseases that increase risk of death, whereas
the CURB-65 score does not directly address underlying disease. However, pneumonia
may exacerbate an underlying disease, such as obstructive lung disease, congestive
heart failure, or diabetes mellitus, which, by themselves, may require hospital admission
[60, 67]. Atlas et al. [25] were able to reduce hospital admissions among patients
in PSI risk classes I–III from 58% in a retrospective control group to 43% in a PSI-based
intervention group. Ten of 94 patients in the latter group (compared with 0 patients
in the control population) were subsequently admitted, several for reasons unrelated
to their pneumonia. Also, the presence of rare illnesses, such as neuromuscular or
sickle cell disease, may require hospitalization but not affect the PSI score.
The necessary reliance on dichotomous predictor variables (abnormal vs. normal) in
most criteria and the heavy reliance on age as a surrogate in the PSI score may oversimplify
their use for admission decisions. For example, a previously healthy 25-year-old patient
with severe hypotension and tachycardia and no additional pertinent prognostic factors
would be placed in risk class II, whereas a 70-year-old man with a history of localized
prostate cancer diagnosed 10 months earlier and no other problems would be placed
in risk class IV [42]. Finally, patient satisfaction was lower among patients treated
outside the hospital in one study with a PSI-based intervention group [25], suggesting
that the savings resulting from use of the PSI may be overestimated and that physicians
should consider additional factors not measured by the PSI.
6. For patients with CURB-65 scores ⩾2, more-intensive treatment—that is, hospitalization
or, where appropriate and available, intensive in-home health care services—is usually
warranted. (Moderate recommendation; level III evidence.)
Although the PSI and CURB-65 criteria are valuable aids in avoiding inappropriate
admissions of low-mortality-risk patients, another important role of these criteria
may be to help identify patients at high risk who would benefit from hospitalization.
The committee preferred the CURB-65 criteria because of ease of use and because they
were designed to measure illness severity more than the likelihood of mortality. Patients
with a CURB-65 score ⩾2 are not only at increased risk of death but also are likely
to have clinically important physiologic derangements requiring active intervention.
These patients should usually be considered for hospitalization or for aggressive
in-home care, where available. In a cohort of ∼3000 patients, the mortality with a
CURB-65 score of 0 was only 1.2%, whereas 3–4 points were associated with 31% mortality
[45].
Because the PSI score is not based as directly on severity of illness as are the CURB-65
criteria, a threshold for patients who would require hospital admission or intensive
outpatient treatment is harder to define. The higher the score, the greater the need
for hospitalization. However, even a patient who meets criteria for risk class V on
the basis of very old age and multiple stable chronic illnesses may be successfully
managed as an outpatient [23].ICU admission decision.
7. Direct admission to an ICU is required for patients with septic shock requiring
vasopressors or with acute respiratory failure requiring intubation and mechanical
ventilation. (Strong recommendation; level II evidence.)
8. Direct admission to an ICU or high-level monitoring unit is recommended for patients
with 3 of the minor criteria for severe CAP listed in table 4. (Moderate recommendation;
level II evidence.)
The second-level admission decision is whether to place the patient in the ICU or
a high-level monitoring unit rather than on a general medical floor. Approximately
10% of hospitalized patients with CAP require ICU admission [68–70], but the indications
vary strikingly among patients, physicians, hospitals, and different health care systems.
Some of the variability among institutions results from the availability of high-level
monitoring or intermediate care units appropriate for patients at increased risk of
complications. Because respiratory failure is the major reason for delayed transfer
to the ICU, simple cardiac monitoring units would not meet the criteria for a high-level
monitoring unit for patients with severe CAP. One of the most important determinants
of the need for ICU care is the presence of chronic comorbid conditions [68–72]. However,
approximately one-third of patients with severe CAP were previously healthy [73].
The rationale for specifically defining severe CAP is 4-fold:
Appropriate placement of patients optimizes use of limited ICU resources.
Transfer to the ICU for delayed respiratory failure or delayed onset of septic shock
is associated with increased mortality [74]. Although low-acuity ICU admissions do
occur, the major concern is initial admission to the general medical unit, with subsequent
transfer to the ICU. As many as 45% of patients with CAP who ultimately require ICU
admission were initially admitted to a non-ICU setting [75]. Many delayed transfers
to the ICU represent rapidly progressive pneumonia that is not obvious on admission.
However, some have subtle findings, including those included in the minor criteria
in table 4, which might warrant direct admission to the ICU.
The distribution of microbial etiologies differs from that of CAP in general [76–79],
with significant implications for diagnostic testing and empirical antibiotic choices.
Avoidance of inappropriate antibiotic therapy has also been associated with lower
mortality [80, 81].
Patients with CAP appropriate for immunomodulatory treatment must be identified. The
systemic inflammatory response/severe sepsis criteria typically used for generic sepsis
trials may not be adequate when applied specifically to severe CAP [82]. For example,
patients with unilateral lobar pneumonia may have hypoxemia severe enough to meet
criteria for acute lung injury but not have a systemic response.
Several criteria have been proposed to define severe CAP. Most case series have defined
it simply as CAP that necessitates ICU admission. Objective criteria to identify patients
for ICU admission include the initial ATS definition of severe CAP [5] and its subsequent
modification [6, 82], the CURB criteria [39, 45], and PSI severity class V (or IV
and V) [42]. However, none of these criteria has been prospectively validated for
the ICU admission decision. Recently, these criteria were retrospectively evaluated
in a cohort of patients with CAP admitted to the ICU [63]. All were found to be both
overly sensitive and nonspecific in comparison with the original clinical decision
to admit to the ICU. Revisions of the criteria or alternative criteria were, therefore,
recommended.
For the revised criteria, the structure of the modified ATS criteria for severe CAP
was retained [6]. The 2 major criteria—mechanical ventilation with endotracheal intubation
and septic shock requiring vasopressors—are absolute indications for admission to
an ICU.
In contrast, the need for ICU admission is less straightforward for patients who do
not meet the major criteria. On the basis of the published operating characteristics
of the criteria, no single set of minor criteria is adequate to define severe CAP.
Both the ATS minor criteria [75] and the CURB criteria [45] have validity when predicting
which patients will be at increased risk of death. Therefore, the ATS minor criteria
and the CURB variables were included in the new proposed minor criteria (table 4).
Age, by itself, was not felt to be an appropriate factor for the ICU admission decision,
but the remainder of the CURB-65 criteria [45] were retained as minor criteria (with
the exception of hypotension requiring vasopressors as a major criterion). Rather
than the complex criteria for confusion in the original CURB studies, the definition
of confusion should be new-onset disorientation to person, place, or time.
Three additional minor criteria were added. Leukopenia (white blood cell count, <4000
cells/mm3) resulting from CAP has consistently been associated with excess mortality,
as well as with an increased risk of complications such as acute respiratory distress
syndrome (ARDS) [77, 79, 83–87]. In addition, leukopenia is seen not only in bacteremic
pneumococcal disease but also in gram-negative CAP [88, 89]. When leukopenia occurs
in patients with a history of alcohol abuse, the adverse manifestations of septic
shock and ARDS may be delayed or masked. Therefore, these patients were thought to
benefit from ICU monitoring. The coagulation system is often activated in CAP, and
development of thrombocytopenia (platelet count, <100,000 cells/mm3) is also associated
with a worse prognosis [86, 90–92]. Nonexposure hypothermia (core temperature, <36°C)
also carries an ominous prognosis in CAP [83, 93]. The committee felt that there was
sufficient justification for including these additional factors as minor criteria.
Other factors associated with increased mortality due to CAP were also considered,
including acute alcohol ingestion and delirium tremens [79, 85, 94], hypoglycemia
and hyperglycemia, occult metabolic acidosis or elevated lactate levels [91], and
hyponatremia [95]. However, many of these criteria overlap with those selected. Future
studies validating the proposed criteria should record these factors as well, to determine
whether addition or substitution improves the predictive value of our proposed criteria.
With the addition of more minor criteria, the threshold for ICU admission was felt
to be the presence of at least 3 minor criteria, based on the mortality association
with the CURB criteria. Selecting 2 criteria appears to be too nonspecific, as is
demonstrated by the initial ATS criteria [5]. Whether each of the criteria is of equal
weight is also not clear. Therefore, prospective validation of this set of criteria
is clearly needed.
Diagnostic Testing
9. In addition to a constellation of suggestive clinical features, a demonstrable
infiltrate by chest radiograph or other imaging technique, with or without supporting
microbiological data, is required for the diagnosis of pneumonia. (Moderate recommendation;
level III evidence.)
The diagnosis of CAP is based on the presence of select clinical features (e.g., cough,
fever, sputum production, and pleuritic chest pain) and is supported by imaging of
the lung, usually by chest radiography. Physical examination to detect rales or bronchial
breath sounds is an important component of the evaluation but is less sensitive and
specific than chest radiographs [96]. Both clinical features and physical exam findings
may be lacking or altered in elderly patients. All patients should be screened by
pulse oximetry, which may suggest both the presence of pneumonia in patients without
obvious signs of pneumonia and unsuspected hypoxemia in patients with diagnosed pneumonia
[42, 97, 98].
A chest radiograph is required for the routine evaluation of patients who are likely
to have pneumonia, to establish the diagnosis and to aid in differentiating CAP from
other common causes of cough and fever, such as acute bronchitis. Chest radiographs
are sometimes useful for suggesting the etiologic agent, prognosis, alternative diagnoses,
and associated conditions. Rarely, the admission chest radiograph is clear, but the
patient's toxic appearance suggests more than bronchitis. CT scans may be more sensitive,
but the clinical significance of these findings when findings of radiography are negative
is unclear [99]. For patients who are hospitalized for suspected pneumonia but who
have negative chest radiography findings, it may be reasonable to treat their condition
presumptively with antibiotics and repeat the imaging in 24–48 h.
Microbiological studies may support the diagnosis of pneumonia due to an infectious
agent, but routine tests are frequently falsely negative and are often nonspecific.
A history of recent travel or endemic exposure, if routinely sought, may identify
specific potential etiologies that would otherwise be unexpected as a cause of CAP
(see table 8) [100].
Recommended Diagnostic Tests for Etiology
10. Patients with CAP should be investigated for specific pathogens that would significantly
alter standard (empirical) management decisions, when the presence of such pathogens
is suspected on the basis of clinical and epidemiologic clues. (Strong recommendation;
level II evidence.)
The need for diagnostic testing to determine the etiology of CAP can be justified
from several perspectives. The primary reason for such testing is if results will
change the antibiotic management for an individual patient. The spectrum of antibiotic
therapy can be broadened, narrowed, or completely altered on the basis of diagnostic
testing. The alteration in therapy that is potentially most beneficial to the individual
is an escalation or switch of the usual empirical regimen because of unusual pathogens
(e.g., endemic fungi or Mycobacterium tuberculosis) or antibiotic resistance issues.
Broad empirical coverage, such as that recommended in these guidelines, would not
provide the optimal treatment for certain infections, such as psittacosis or tularemia.
Increased mortality [80] and increased risk of clinical failure [81, 101] are more
common with inappropriate antibiotic therapy. Management of initial antibiotic failure
is greatly facilitated by an etiologic diagnosis at admission. De-escalation or narrowing
of antibiotic therapy on the basis of diagnostic testing is less likely to decrease
an individual's risk of death but may decrease cost, drug adverse effects, and antibiotic
resistance pressure.
Some etiologic diagnoses have important epidemiologic implications, such as documentation
of severe acute respiratory syndrome (SARS), influenza, legionnaires disease, or agents
of bioterrorism. Diagnostic testing for these infections may affect not only the individual
but also many other people. Although pneumonia etiologies that should be reported
to public health officials vary by state, in general, most states' health regulations
require reporting of legionnaires disease, SARS, psittacosis, avian influenza (H5N1),
and possible agents of bioterrorism (plague, tularemia, and anthrax). In addition,
specific diagnostic testing and reporting are important for pneumonia cases of any
etiology thought to be part of a cluster or caused by pathogens not endemic to the
area.
There are also societal reasons for encouraging diagnostic testing. The antibiotic
recommendations in the present guidelines are based on culture results and sensitivity
patterns from patients with positive etiologic diagnoses [102]. Without the accumulated
information available from these culture results, trends in antibiotic resistance
are more difficult to track, and empirical antibiotic recommendations are less likely
to be accurate.
The main downside of extensive diagnostic testing of all patients with CAP is cost,
which is driven by the poor quality of most sputum microbiological samples and the
low yield of positive culture results in many groups of patients with CAP. A clear
need for improved diagnostic testing in CAP, most likely using molecular methodology
rather than culture, has been recognized by the National Institutes of Health [103].
The cost-benefit ratio is even worse when antibiotic therapy is not streamlined when
possible [104, 105] or when inappropriate escalation occurs [95]. In clinical practice,
narrowing of antibiotic therapy is, unfortunately, unusual, but the committee strongly
recommends this as best medical practice. The possibility of polymicrobial CAP and
the potential benefit of combination therapy for bacteremic pneumococcal pneumonia
have complicated the decision to narrow antibiotic therapy. Delays in starting antibiotic
therapy that result from the need to obtain specimens, complications of invasive diagnostic
procedures, and unneeded antibiotic changes and additional testing for false-positive
tests are also important considerations.
The general recommendation of the committee is to strongly encourage diagnostic testing
whenever the result is likely to change individual antibiotic management. For other
patients with CAP, the recommendations for diagnostic testing focus on patients in
whom the diagnostic yield is thought to be greatest. These 2 priorities often overlap.
Recommendations for patients in whom routine diagnostic testing is indicated for the
above reasons are listed in table 5. Because of the emphasis on clinical relevance,
a variety of diagnostic tests that may be accurate but the results of which are not
available in a time window to allow clinical decisions are neither recommended nor
discussed.
11. Routine diagnostic tests to identify an etiologic diagnosis are optional for outpatients
with CAP. (Moderate recommendation; level III evidence.)
Retrospective studies of outpatient CAP management usually show that diagnostic tests
to define an etiologic pathogen are infrequently performed, yet most patients do well
with empirical antibiotic treatment [42, 106]. Exceptions to this general rule may
apply to some pathogens important for epidemiologic reasons or management decisions.
The availability of rapid point-of-care diagnostic tests, specific treatment and chemoprevention,
and epidemiologic importance make influenza testing the most logical. Influenza is
often suspected on the basis of typical symptoms during the proper season in the presence
of an epidemic. However, respiratory syncytial virus (RSV) can cause a similar syndrome
and often occurs in the same clinical scenario [107]. Rapid diagnostic tests may be
indicated when the diagnosis is uncertain and when distinguishing influenza A from
influenza B is important for therapeutic decisions.
Other infections that are important to verify with diagnostic studies because of epidemiologic
implications or because they require unique therapeutic intervention are SARS and
avian (H5N1) influenza, disease caused by agents of bioterrorism, Legionella infection,
community-acquired MRSA (CA-MRSA) infection, M. tuberculosis infection, or endemic
fungal infection. Attempts to establish an etiologic diagnosis are also appropriate
in selected cases associated with outbreaks, specific risk factors, or atypical presentations.
12. Pretreatment blood samples for culture and an expectorated sputum sample for stain
and culture (in patients with a productive cough) should be obtained from hospitalized
patients with the clinical indications listed in table 5 but are optional for patients
without these conditions. (Moderate recommendation; level I evidence.)
13. Pretreatment Gram stain and culture of expectorated sputum should be performed
only if a good-quality specimen can be obtained and quality performance measures for
collection, transport, and processing of samples can be met. (Moderate recommendation;
level II evidence.)
14. Patients with severe CAP, as defined above, should at least have blood samples
drawn for culture, urinary antigen tests for Legionella pneumophila and S. pneumoniae
performed, and expectorated sputum samples collected for culture. For intubated patients,
an endotracheal aspirate sample should be obtained. (Moderate recommendation; level
II evidence.)
The only randomized controlled trial of diagnostic strategy in CAP has demonstrated
no statistically significant differences in mortality rate or LOS between patients
receiving pathogen-directed therapy and patients receiving empirical therapy [108].
However, pathogen-directed therapy was associated with lower mortality among the small
number of patients admitted to the ICU. The study was performed in a country with
a low incidence of antibiotic resistance, which may limit its applicability to areas
with higher levels of resistance. Adverse effects were significantly more common in
the empirical therapy group but may have been unique to the specific antibiotic choice
(erythromycin).
The lack of benefit overall in this trial should not be interpreted as a lack of benefit
for an individual patient. Therefore, performing diagnostic tests is never incorrect
or a breach of the standard of care. However, information from cohort and observational
studies may be used to define patient groups in which the diagnostic yield is increased.
Patient groups in which routine diagnostic testing is indicated and the recommended
tests are listed in table 5.Blood cultures.Pretreatment blood cultures yielded positive
results for a probable pathogen in 5%–14% in large series of nonselected patients
hospitalized with CAP [104, 105, 109–111]. The yield of blood cultures is, therefore,
relatively low (although it is similar to yields in other serious infections), and,
when management decisions are analyzed, the impact of positive blood cultures is minor
[104, 105]. The most common blood culture isolate in all CAP studies is S. pneumoniae.
Because this bacterial organism is always considered to be the most likely pathogen,
positive blood culture results have not clearly led to better outcomes or improvements
in antibiotic selection [105, 112]. False-positive blood culture results are associated
with prolonged hospital stay, possibly related to changes in management based on preliminary
results showing gram-positive cocci, which eventually prove to be coagulase-negative
staphylococci [95, 109]. In addition, false-positive blood culture results have led
to significantly more vancomycin use [95].
For these reasons, blood cultures are optional for all hospitalized patients with
CAP but should be performed selectively (table 5). The yield for positive blood culture
results is halved by prior antibiotic therapy [95]. Therefore, when performed, samples
for blood culture should be obtained before antibiotic administration. However, when
multiple risk factors for bacteremia are present, blood culture results after initiation
of antibiotic therapy are still positive in up to 15% of cases [95] and are, therefore,
still warranted in these cases, despite the lower yield.
The strongest indication for blood cultures is severe CAP. Patients with severe CAP
are more likely to be infected with pathogens other than S. pneumoniae, including
S. aureus, P. aeruginosa, and other gram-negative bacilli [77–80, 95, 113, 114]. Many
of the factors predictive of positive blood culture results [95] overlap with risk
factors for severe CAP (table 4). Therefore, blood cultures are recommended for all
patients with severe CAP because of the higher yield, the greater possibility of the
presence of pathogens not covered by the usual empirical antibiotic therapy, and the
increased potential to affect antibiotic management.
Blood cultures are also indicated when patients have a host defect in the ability
to clear bacteremia—for example, as a result of asplenia or complement deficiencies.
Patients with chronic liver disease also are more likely to have bacteremia with CAP
[95]. Leukopenia is also associated with a high incidence of bacteremia [79, 95].Respiratory
tract specimen Gram stain and culture.The yield of sputum bacterial cultures is variable
and strongly influenced by the quality of the entire process, including specimen collection,
transport, rapid processing, satisfactory use of cytologic criteria, absence of prior
antibiotic therapy, and skill in interpretation. The yield of S. pneumoniae, for example,
is only 40%–50% from sputum cultures from patients with bacteremic pneumococcal pneumonia
in studies performed a few decades ago [115, 116]. A more recent study of 100 cases
of bacteremic pneumococcal pneumonia found that sputum specimens were not submitted
in 31% of cases and were judged as inadequate in another 16% of cases [117]. When
patients receiving antibiotics for >24 h were excluded, Gram stain showed pneumococci
in 63% of sputum specimens, and culture results were positive in 86%. For patients
who had received no antibiotics, the Gram stain was read as being consistent with
pneumococci in 80% of cases, and sputum culture results were positive in 93%.
Although there are favorable reports of the utility of Gram stain [118], a meta-analysis
showed a low yield, considering the number of patients with adequate specimens and
definitive results [119]. Recent data show that an adequate specimen with a predominant
morphotype on Gram stain was found in only 14% of 1669 hospitalized patients with
CAP [120]. Higher PSI scores did not predict higher yield. However, a positive Gram
stain was highly predictive of a subsequent positive culture result.
The benefit of a sputum Gram stain is, therefore, 2-fold. First, it broadens initial
empirical coverage for less common etiologies, such as infection with S. aureus or
gram-negative organisms. This indication is probably the most important, because it
will lead to less inappropriate antibiotic therapy. Second, it can validate the subsequent
sputum culture results.
Forty percent or more of patients are unable to produce any sputum or to produce sputum
in a timely manner [108, 120]. The yield of cultures is substantially higher with
endotracheal aspirates, bronchoscopic sampling, or transthoracic needle aspirates
[120–126], although specimens obtained after initiation of antibiotic therapy are
unreliable and must be interpreted carefully [120, 127, 128]. Interpretation is improved
with quantitative cultures of respiratory secretions from any source (sputum, tracheal
aspirations, and bronchoscopic aspirations) or by interpretation based on semiquantitative
culture results [122, 123, 129]. Because of the significant influence on diagnostic
yield and cost effectiveness, careful attention to the details of specimen handling
and processing are critical if sputum cultures are obtained.
Because the best specimens are collected and processed before antibiotics are given,
the time to consider obtaining expectorated sputum specimens from patients with factors
listed in table 5 is before initiation of antibiotic therapy. Once again, the best
indication for more extensive respiratory tract cultures is severe CAP. Gram stain
and culture of endotracheal aspirates from intubated patients with CAP produce different
results than expectorated sputum from non-ICU patients [76, 120]. Many of the pathogens
in the broader microbiological spectrum of severe CAP are unaffected by a single dose
of antibiotics, unlike S. pneumoniae. In addition, an endotracheal aspirate does not
require patient cooperation, is clearly a lower respiratory tract sample, and is less
likely to be contaminated by oropharyngeal colonizers. Nosocomial tracheal colonization
is not an issue if the sample is obtained soon after intubation. Therefore, culture
and Gram stain of endotracheal aspirates are recommended for patients intubated for
severe CAP. In addition to routine cultures, a specific request for culture of respiratory
secretions on buffered charcoal yeast extract agar to isolate Legionella species may
be useful in this subset of patients with severe CAP in areas where Legionella is
endemic, as well as in patients with a recent travel history [130].
The fact that a respiratory tract culture result is negative does not mean that it
has no value. Failure to detect S. aureus or gram-negative bacilli in good-quality
specimens is strong evidence against the presence of these pathogens. Growth inhibition
by antibiotics is lower with these pathogens than with S. pneumoniae, but specimens
obtained after initiation of antibiotic therapy are harder to interpret, with the
possibility of colonization. Necrotizing or cavitary pneumonia is a risk for CA-MRSA
infection, and sputum samples should be obtained in all cases. Negative Gram stain
and culture results should be adequate to withhold or stop treatment for MRSA infection.
Severe COPD and alcoholism are major risk factors for infection with P. aeruginosa
and other gram-negative pathogens [131]. Once again, Gram stain and culture of an
adequate sputum specimen are usually adequate to exclude the need for empirical coverage
of these pathogens.
A sputum culture in patients with suspected legionnaires disease is important, because
the identification of Legionella species implies the possibility of an environmental
source to which other susceptible individuals may be exposed. Localized community
outbreaks of legionnaires disease might be recognized by clinicians or local health
departments because ⩾2 patients might be admitted to the same hospital. However, outbreaks
of legionnaires disease associated with hotels or cruise ships [132–134] are rarely
detected by individual clinicians, because travelers typically disperse from the source
of infection before developing symptoms. Therefore, a travel history should be actively
sought from patients with CAP, and Legionella testing should be performed for those
who have traveled in the 2 weeks before the onset of symptoms. Urinary antigen tests
may be adequate to diagnose and treat an individual, but efforts to obtain a sputum
specimen for culture are still indicated to facilitate epidemiologic tracking. The
availability of a culture isolate of Legionella dramatically improves the likelihood
that an environmental source of Legionella can be identified and remediated [135–137].
The yield of sputum culture is increased to 43%–57% when associated with a positive
urinary antigen test result [138, 139].
Attempts to obtain a sample for sputum culture from a patient with a positive pneumococcal
urinary antigen test result may be indicated for similar reasons. Patients with a
productive cough and positive urinary antigen test results have positive sputum culture
results in as many as 40%–80% of cases [140–143]. In these cases, not only can sensitivity
testing confirm the appropriate choice for the individual patient, but important data
regarding local community antibiotic resistance rates can also be acquired.Other cultures.Patients
with pleural effusions >5 cm in height on a lateral upright chest radiograph [111]
should undergo thoracentesis to yield material for Gram stain and culture for aerobic
and anaerobic bacteria. The yield with pleural fluid cultures is low, but the impact
on management decisions is substantial, in terms of both antibiotic choice and the
need for drainage.
Nonbronchoscopic bronchoalveolar lavage (BAL) in the ED has been studied in a small,
randomized trial of intubated patients with CAP [144]. A high percentage (87%) of
nonbronchoscopic BAL culture results were positive, even in some patients who had
already received their first dose of antibiotics. Unfortunately, tracheal aspirates
were obtained from only a third of patients in the control group, but they all were
culture positive. Therefore, it is unclear that endotracheal aspirates are inferior
to nonbronchoscopic BAL. The use of bronchoscopic BAL, protected specimen brushing,
or transthoracic lung aspiration has not been prospectively studied for initial management
of patients with CAP [123]. The best indications are for immunocompromised patients
with CAP or for patients with CAP in whom therapy failed [101, 145].Antigen tests.Urinary
antigen tests are commercially available and have been cleared by the US Food and
Drug Administration (FDA) for detection of S. pneumoniae and L. pneumophila serogroup
1 [138, 140, 146–149]. Urinary antigen testing appears to have a higher diagnostic
yield in patients with more severe illness [139, 140].
For pneumococcal pneumonia, the principal advantages of antigen tests are rapidity
(∼15 min), simplicity, reasonable specificity in adults, and the ability to detect
pneumococcal pneumonia after antibiotic therapy has been started. Studies in adults
show a sensitivity of 50%–80% and a specificity of >90% [146, 149, 150]. This is an
attractive test for detecting pneumococcal pneumonia when samples for culture cannot
be obtained in a timely fashion or when antibiotic therapy has already been initiated.
Serial specimens from patients with known bacteremia were still positive for pneumococcal
urinary antigen in 83% of cases after 3 days of therapy [147]. Comparisons with Gram
stain show that these 2 rapidly available tests often do not overlap, with only 28%
concordance (25 of 88) among patients when results of either test were positive [140].
Only ∼50% of Binax pneumococcal urinary antigen-positive patients can be diagnosed
by conventional methods [140, 150]. Disadvantages include cost (approximately $30
per specimen), although this is offset by increased diagnosis-related group-based
reimbursement for coding for pneumococcal pneumonia, and the lack of an organism for
in vitro susceptibility tests. False-positive results have been seen in children with
chronic respiratory diseases who are colonized with S. pneumoniae [151] and in patients
with an episode of CAP within the previous 3 months [152], but they do not appear
to be a significant problem in colonized patients with COPD [140, 152].
For Legionella, several urinary antigen assays are available, but all detect only
L. pneumophila serogroup 1. Although this particular serogroup accounts for 80%–95%
of community-acquired cases of legionnaires disease [138, 153] in many areas of North
America, other species and serogroups predominate in specific locales [154, 155].
Prior studies of culture-proven legionnaires disease indicate a sensitivity of 70%–90%
and a specificity of nearly 99% for detection of L. pneumophila serogroup 1. The urine
is positive for antigen on day 1 of illness and continues to be positive for weeks
[138, 150].
The major issue with urinary bacterial antigen detection is whether the tests allow
narrowing of empirical antibiotic therapy to a single specific agent. The recommended
empirical antibiotic regimens will cover both of these microorganisms. Results of
a small observational study suggest that therapy with a macrolide alone is adequate
for hospitalized patients with CAP who test positive for L. pneumophila urinary antigen
[156]. Further research is needed in this area.
In contrast, rapid antigen detection tests for influenza, which can also provide an
etiologic diagnosis within 15–30 min, can lead to consideration of antiviral therapy.
Test performance varies according to the test used, sample type, duration of illness,
and patient age. Most show a sensitivity of 50%–70% in adults and a specificity approaching
100% [157–159]. Advantages include the high specificity, the ability of some assays
to distinguish between influenza A and B, the rapidity with which the results can
be obtained, the possibly reduced use of antibacterial agents, and the utility of
establishing this diagnosis for epidemiologic purposes, especially in hospitalized
patients who may require infection control precautions. Disadvantages include cost
(approximately $30 per specimen), high rates of false-negative test results, false-positive
assays with adenovirus infections, and the fact that the sensitivity is not superior
to physician judgment among patients with typical symptoms during an influenza epidemic
[157, 158, 160].
Direct fluorescent antibody tests are available for influenza and RSV and require
∼2 h. For influenza virus, the sensitivity is better than with the point-of-care tests
(85%–95%). They will detect animal subtypes such as H5N1 and, thus, may be preferred
for hospitalized patients [161, 162]. For RSV, direct fluorescent antibody tests are
so insensitive (sensitivity, 20%–30%) in adults that they are rarely of value [163].Acute-phase
serologic testing.The standard for diagnosis of infection with most atypical pathogens,
including Chlamydophila pneumoniae, Mycoplasma pneumoniae, and Legionella species
other than L. pneumophila, relies on acute- and convalescent-phase serologic testing.
Most studies use a microimmunofluorescence serologic test, but this test shows poor
reproducibility [164]. Management of patients on the basis of a single acute-phase
titer is unreliable [165], and initial antibiotic therapy will be completed before
the earliest time point to check a convalescent-phase specimen.PCR.A new PCR test
(BD ProbeTec ET Legionella pneumophila; Becton Dickinson) that will detect all serotypes
of L. pneumophila in sputum is now cleared by the FDA, but extensive published clinical
experience is lacking. Most PCR reagents for other respiratory pathogens (except Mycobacterium
species) are “home grown,” with requirements for use based on compliance with NCCLS
criteria for analytical validity [166]. Despite the increasing use of these tests
for atypical pathogens [167, 168], a 2001 review by the Centers for Disease Control
and Prevention (CDC) of diagnostic assays for detection of C. pneumoniae indicated
that, of the 18 PCR reagents, only 4 satisfied the criteria for a validated test [166].
The diagnostic criteria defined in this review are particularly important for use
in prospective studies of CAP, because most prior reports used liberal criteria, which
resulted in exaggerated rates. For SARS, several PCR assays have been developed, but
these tests are inadequate because of high rates of false-negative assays in early
stages of infection [169, 170].
Antibiotic Treatment
A major goal of therapy is eradication of the infecting organism, with resultant resolution
of clinical disease. As such, antimicrobials are a mainstay of treatment. Appropriate
drug selection is dependent on the causative pathogen and its antibiotic susceptibility.
Acute pneumonia may be caused by a wide variety of pathogens (table 6). However, until
more accurate and rapid diagnostic methods are available, the initial treatment for
most patients will remain empirical. Recommendations for therapy (table 7) apply to
most cases; however, physicians should consider specific risk factors for each patient
(table 8). A syndromic approach to therapy (under the assumption that an etiology
correlates with the presenting clinical manifestations) is not specific enough to
reliably predict the etiology of CAP [172–174]. Even if a microbial etiology is identified,
debate continues with regard to pathogen-specific treatment, because recent studies
suggest coinfection by atypical pathogens (such as C. pneumoniae, Legionella species,
and viruses) and more traditional bacteria [120, 175]. However, the importance of
treating multiple infecting organisms has not been firmly established.
The majority of antibiotics released in the past several decades have an FDA indication
for CAP, making the choice of antibiotics potentially overwhelming. Selection of antimicrobial
regimens for empirical therapy is based on prediction of the most likely pathogen(s)
and knowledge of local susceptibility patterns. Recommendations are generally for
a class of antibiotics rather than a specific drug, unless outcome data clearly favor
one drug. Because overall efficacy remains good for many classes of agents, the more
potent drugs are given preference because of their benefit in decreasing the risk
of selection for antibiotic resistance. Other factors for consideration of specific
antimicrobials include pharmacokinetics/pharmacodynamics, compliance, safety, and
cost.
Likely Pathogens in CAP
Although CAP may be caused by a myriad of pathogens, a limited number of agents are
responsible for most cases. The emergence of newly recognized pathogens, such as the
novel SARS-associated coronavirus [170], continually increases the challenge for appropriate
management.
Table 6 lists the most common causes of CAP, in decreasing order of frequency of occurrence
and stratified for severity of illness as judged by site of care (ambulatory vs. hospitalized).
S. pneumoniae is the most frequently isolated pathogen. Other bacterial causes include
nontypeable Haemophilus influenzae and Moraxella catarrhalis, generally in patients
who have underlying bronchopulmonary disease, and S. aureus, especially during an
influenza outbreak. Risks for infection with Enterobacteriaceae species and P. aeruginosa
as etiologies for CAP are chronic oral steroid administration or severe underlying
bronchopulmonary disease, alcoholism, and frequent antibiotic therapy [79, 131], whereas
recent hospitalization would define cases as HCAP. Less common causes of pneumonia
include, but are by no means limited to, Streptococcus pyogenes, Neisseria meningitidis,
Pasteurella multocida, and H. influenzae type b.
The “atypical” organisms, so called because they are not detectable on Gram stain
or cultivatable on standard bacteriologic media, include M. pneumoniae, C. pneumoniae,
Legionella species, and respiratory viruses. With the exception of Legionella species,
these microorganisms are common causes of pneumonia, especially among outpatients.
However, these pathogens are not often identified in clinical practice because, with
a few exceptions, such as L. pneumophila and influenza virus, no specific, rapid,
or standardized tests for their detection exist. Although influenza remains the predominant
viral cause of CAP in adults, other commonly recognized viruses include RSV [107],
adenovirus, and parainfluenza virus, as well as less common viruses, including human
metapneumovirus, herpes simplex virus, varicella-zoster virus, SARS-associated coronavirus,
and measles virus. In a recent study of immunocompetent adult patients admitted to
the hospital with CAP, 18% had evidence of a viral etiology, and, in 9%, a respiratory
virus was the only pathogen identified [176]. Studies that include outpatients find
viral pneumonia rates as high as 36% [167]. The frequency of other etiologic agents—for
example, M. tuberculosis, Chlamydophila psittaci (psittacosis), Coxiella burnetii
(Q fever), Francisella tularensis (tularemia), Bordetella pertussis (whooping cough),
and endemic fungi (Histoplasma capsulatum, Coccidioides immitis, Cryptococcus neoformans,
and Blastomyces hominis)—is largely determined by the epidemiologic setting (table
8) but rarely exceeds 2%–3% total [113, 177]. The exception may be endemic fungi in
the appropriate geographic distribution [100].
The need for specific anaerobic coverage for CAP is generally overestimated. Anaerobic
bacteria cannot be detected by diagnostic techniques in current use. Anaerobic coverage
is clearly indicated only in the classic aspiration pleuropulmonary syndrome in patients
with a history of loss of consciousness as a result of alcohol/drug overdose or after
seizures in patients with concomitant gingival disease or esophogeal motility disorders.
Antibiotic trials have not demonstrated a need to specifically treat these organisms
in the majority of CAP cases. Small-volume aspiration at the time of intubation should
be adequately handled by standard empirical severe CAP treatment [178] and by the
high oxygen tension provided by mechanical ventilation.
Antibiotic Resistance Issues
Resistance to commonly used antibiotics for CAP presents another major consideration
in choosing empirical therapy. Resistance patterns clearly vary by geography. Local
antibiotic prescribing patterns are a likely explanation [179–181]. However, clonal
spread of resistant strains is well documented. Therefore, antibiotic recommendations
must be modified on the basis of local susceptibility patterns. The most reliable
source is state/provincial or municipal health department regional data, if available.
Local hospital antibiograms are generally the most accessible source of data but may
suffer from small numbers of isolates.Drug-resistant S. pneumoniae (DRSP).The emergence
of drug-resistant pneumococcal isolates is well documented. The incidence of resistance
appears to have stabilized somewhat in the past few years. Resistance to penicillin
and cephalosporins may even be decreasing, whereas macrolide resistance continues
to increase [179, 182]. However, the clinical relevance of DRSP for pneumonia is uncertain,
and few well-controlled studies have examined the impact of in vitro resistance on
clinical outcomes of CAP. Published studies are limited by small sample sizes, biases
inherent in observational design, and the relative infrequency of isolates exhibiting
high-level resistance [183–185]. Current levels of β-lactam resistance do not generally
result in CAP treatment failures when appropriate agents (i.e., amoxicillin, ceftriaxone,
or cefotaxime) and doses are used, even in the presence of bacteremia [112, 186].
The available data suggest that the clinically relevant level of penicillin resistance
is a MIC of at least 4 mg/L [3]. One report suggested that, if cefuroxime is used
to treat pneumococcal bacteremia when the organism is resistant in vitro, the outcome
is worse than with other therapies [112]. Other discordant therapies, including penicillin,
did not have an impact on mortality. Data exist suggesting that resistance to macrolides
[187–189] and older fluoroquinolones (ciprofloxacin and levofloxacin) [180, 190, 191]
results in clinical failure. To date, no failures have been reported for the newer
fluoroquinolones (moxifloxacin and gemifloxacin).
Risk factors for infection with β-lactam-resistant S. pneumoniae include age <2 years
or >65 years, β-lactam therapy within the previous 3 months, alcoholism, medical comorbidities,
immunosuppressive illness or therapy, and exposure to a child in a day care center
[112, 192–194]. Although the relative predictive value of these risk factors is unclear,
recent treatment with antimicrobials is likely the most significant. Recent therapy
or repeated courses of therapy with β-lactams, macrolides, or fluoroquinolones are
risk factors for pneumococcal resistance to the same class of antibiotic [181, 193,
195, 196]. One study found that use of either a β-lactam or macrolide within the previous
6 months predicted an increased likelihood that, if pneumococcal bacteremia is present,
the organism would be penicillin resistant [196]. Other studies have shown that repeated
use of fluoroquinolones predicts an increased risk of infection with fluoroquinolone-resistant
pneumococci [195, 197]. Whether this risk applies equally to all fluoroquinolones
or is more of a concern for less active antipneumococcal agents (levofloxacin and
ciprofloxacin) than for more active agents (moxifloxacin and gemifloxacin) is uncertain
[190, 197, 198].
Recommendations for the use of highly active agents in patients at risk for infection
with DRSP is, therefore, based only in part on efficacy considerations; it is also
based on a desire to prevent more resistance from emerging by employing the most potent
regimen possible. Although increasing the doses of certain agents (penicillins, cephalosporins,
levofloxacin) may lead to adequate outcomes in the majority of cases, switching to
more potent agents may lead to stabilization or even an overall decrease in resistance
rates [179, 180].CA-MRSA.Recently, an increasing incidence of pneumonia due to CA-MRSA
has been observed [199, 200]. CA-MRSA appears in 2 patterns: the typical hospital-acquired
strain [80] and, recently, strains that are epidemiologically, genotypically, and
phenotypically distinct from hospital-acquired strains [201, 202]. Many of the former
may represent HCAP, because these earlier studies did not differentiate this group
from typical CAP. The latter are resistant to fewer antimicrobials than are hospital-acquired
MRSA strains and often contain a novel type IV SCCmec gene. In addition, most contain
the gene for Panton-Valentine leukocidin [200, 202], a toxin associated with clinical
features of necrotizing pneumonia, shock, and respiratory failure, as well as formation
of abscesses and empyemas. The large majority of cases published to date have been
skin infections in children. In a large study of CA-MRSA in 3 communities, 2% of CA-MRSA
infections were pneumonia [203]. However, pneumonia in both adults [204] and children
has been reported, often associated with preceding influenza. This strain should also
be suspected in patients who present with cavitary infiltrates without risk factors
for anaerobic aspiration pneumonia (gingivitis and a risk for loss of consciousness,
such as seizures or alcohol abuse, or esophogeal motility disorders). Diagnosis is
usually straightforward, with high yields from sputum and blood cultures in this characteristic
clinical scenario. CA-MRSA CAP remains rare in most communities but is expected to
be an emerging problem in CAP treatment.
Empirical Antimicrobial Therapy
Outpatient treatment.The following regimens are recommended for outpatient treatment
on the basis of the listed clinical risks.
15. Previously healthy and no risk factors for DRSP infection:
A. A macrolide (azithromycin, clarithromycin, or erythromycin) (strong recommendation;
level I evidence)
Doxycycline (weak recommendation; level III evidence)
16. Presence of comorbidities, such as chronic heart, lung, liver, or renal disease;
diabetes mellitus; alcoholism; malignancies; asplenia; immunosuppressing conditions
or use of immunosuppressing drugs; use of antimicrobials within the previous 3 months
(in which case an alternative from a different class should be selected); or other
risks for DRSP infection:
A. A respiratory fluoroquinolone (moxifloxacin, gemifloxacin, or levofloxacin [750
mg]) (strong recommendation; level I evidence)
β-lactam plus a macrolide (strong recommendation; level I evidence) (High-dose amoxicillin
[e.g., 1 g 3 times daily] or amoxicillin-clavulanate [2 g 2 times daily] is preferred;
alternatives include ceftriaxone, cefpodoxime, and cefuroxime [500 mg 2 times daily];
doxycycline [level II evidence] is an alternative to the macrolide.)
17. In regions with a high rate (>25%) of infection with high-level (MIC, ⩾16 µg/mL)
macrolide-resistant S. pneumoniae, consider the use of alternative agents listed above
in recommendation 16 for any patient, including those without comorbidities. (Moderate
recommendation; level III evidence.)
The most common pathogens identified from recent studies of mild (ambulatory) CAP
were S. pneumoniae, M. pneumoniae, C. pneumoniae, and H. influenzae [177, 205]. Mycoplasma
infection was most common among patients <50 years of age without significant comorbid
conditions or abnormal vital signs, whereas S. pneumoniae was the most common pathogen
among older patients and among those with significant underlying disease. Hemophilus
infection was found in 5%—mostly in patients with comorbidities. The importance of
therapy for Mycoplasma infection and Chlamydophila infection in mild CAP has been
the subject of debate, because many infections are self-limiting [206, 207]. Nevertheless,
studies from the 1960s of children indicate that treatment of mild M. pneumoniae CAP
reduces the morbidity of pneumonia and shortens the duration of symptoms [208]. The
evidence to support specific treatment of these microorganisms in adults is lacking.
Macrolides have long been commonly prescribed for treatment of outpatients with CAP
in the United States, because of their activity against S. pneumoniae and the atypical
pathogens. This class includes the erythromycin-type agents (including dirithromycin),
clarithromycin, and the azalide azithromycin. Although the least expensive, erythromycin
is not often used now, because of gastrointestinal intolerance and lack of activity
against H. influenzae. Because of H. influenzae, azithromycin is preferred for outpatients
with comorbidities such as COPD.
Numerous randomized clinical trials have documented the efficacy of clarithromycin
and azithromycin as monotherapy for outpatient CAP, although several studies have
demonstrated that clinical failure can occur with a resistant isolate. When such patients
were hospitalized and treated with a β-lactam and a macrolide, however, all survived
and generally recovered without significant complications [188, 189]. Most of these
patients had risk factors for which therapy with a macrolide alone is not recommended
in the present guidelines. Thus, for patients with a significant risk of DRSP infection,
monotherapy with a macrolide is not recommended. Doxycycline is included as a cost-effective
alternative on the basis of in vitro data indicating effectiveness equivalent to that
of erythromycin for pneumococcal isolates.
The use of fluoroquinolones to treat ambulatory patients with CAP without comorbid
conditions, risk factors for DRSP, or recent antimicrobial use is discouraged because
of concern that widespread use may lead to the development of fluoroquinolone resistance
[185]. However, the fraction of total fluoroquinolone use specifically for CAP is
extremely small and unlikely to lead to increased resistance by itself. More concerning
is a recent study suggesting that many outpatients given a fluoroquinolone may not
have even required an antibiotic, that the dose and duration of treatment were often
incorrect, and that another agent often should have been used as first-line therapy.
This usage pattern may promote the rapid development of resistance to fluoroquinolones
[209].
Comorbidities or recent antimicrobial therapy increase the likelihood of infection
with DRSP and enteric gram-negative bacteria. For such patients, recommended empirical
therapeutic options include (1) a respiratory fluoroquinolone (moxifloxacin, gemifloxacin,
or levofloxacin [750 mg daily]) or (2) combination therapy with a β-lactam effective
against S. pneumoniae plus a macrolide (doxycycline as an alternative). On the basis
of present pharmacodynamic principles, high-dose amoxicillin (amoxicillin [1 g 3 times
daily] or amoxicillin-clavulanate [2 g 2 times daily]) should target >93% of S. pneumoniae
and is the preferred β-lactam. Ceftriaxone is an alternative to high-dose amoxicillin
when parenteral therapy is feasible. Selected oral cephalosporins (cefpodoxime and
cefuroxime) can be used as alternatives [210], but these are less active in vitro
than high-dose amoxicillin or ceftriaxone. Agents in the same class as the patient
had been receiving previously should not be used to treat patients with recent antibiotic
exposure.
Telithromycin is the first of the ketolide antibiotics, derived from the macrolide
family, and is active against S. pneumoniae that is resistant to other antimicrobials
commonly used for CAP (including penicillin, macrolides, and fluoroquinolones). Several
CAP trials suggest that telithromycin is equivalent to comparators (including amoxicillin,
clarithromycin, and trovafloxacin) [211–214]. There have also been recent postmarketing
reports of life-threatening hepatotoxicity [215]. At present, the committee is awaiting
further evaluation of the safety of this drug by the FDA before making its final recommendation.Inpatient,
non-ICU treatment.The following regimens are recommended for hospital ward treatment.
18. A respiratory fluoroquinolone (strong recommendation; level I evidence)
19. β-lactam plus a macrolide (strong recommendation; level I evidence) (Preferred
β-lactam agents include cefotaxime, ceftriaxone, and ampicillin; ertapenem for selected
patients; with doxycycline [level III evidence] as an alternative to the macrolide.
A respiratory fluoroquinolone should be used for penicillin-allergic patients.)
The recommendations of combination treatment with a β-lactam plus a macrolide or monotherapy
with a fluoroquinolone were based on retrospective studies demonstrating a significant
reduction in mortality compared with that associated with administration of a cephalosporin
alone [216–219]. Multiple prospective randomized trials have demonstrated that either
regimen results in high cure rates. The major discriminating factor between the 2
regimens is the patient's prior antibiotic exposure (within the past 3 months).
Preferred β-lactams are those effective against S. pneumoniae and other common, nonatypical
pathogens without being overly broad spectrum. In January 2002, the Clinical Laboratory
Standards Institute (formerly the NCCLS) increased the MIC breakpoints for cefotaxime
and ceftriaxone for nonmeningeal S. pneumoniae infections. These new breakpoints acknowledge
that nonmeningeal infections caused by strains formerly considered to be intermediately
susceptible, or even resistant, can be treated successfully with usual doses of these
β-lactams [112, 186, 220].
Two randomized, double-blind studies showed ertapenem to be equivalent to ceftriaxone
[221, 222]. It also has excellent activity against anaerobic organisms, DRSP, and
most Enterobacteriaceae species (including extended-spectrum β-lactamase producers,
but not P. aeruginosa). Ertapenem may be useful in treating patients with risks for
infection with these pathogens and for patients who have recently received antibiotic
therapy. However, clinical experience with this agent is limited. Other “antipneumococcal,
antipseudomonal” β-lactam agents are appropriate when resistant pathogens, such as
Pseudomonas, are likely to be present. Doxycycline can be used as an alternative to
a macrolide on the basis of scant data for treatment of Legionella infections [171,
223, 224].
Two randomized, double-blind studies of adults hospitalized for CAP have demonstrated
that parenteral azithromycin alone was as effective, with improved tolerability, as
intravenous cefuroxime, with or without intravenous erythromycin [225, 226]. In another
study, mortality and readmission rates were similar, but the mean LOS was shorter
among patients receiving azithromycin alone than among those receiving other guideline-recommended
therapy [227]. None of the 10 patients with erythromycin-resistant S. pneumoniae infections
died or was transferred to the ICU, including 6 who received azithromycin alone. Another
study showed that those receiving a macrolide alone had the lowest 30-day mortality
but were the least ill [219]. Such patients were younger and were more likely to be
in lower-risk groups.
These studies suggest that therapy with azithromycin alone can be considered for carefully
selected patients with CAP with nonsevere disease (patients admitted primarily for
reasons other than CAP) and no risk factors for infection with DRSP or gram-negative
pathogens. However, the emergence of high rates of macrolide resistance in many areas
of the country suggests that this therapy cannot be routinely recommended. Initial
therapy should be given intravenously for most admitted patients, but some without
risk factors for severe pneumonia could receive oral therapy, especially with highly
bioavailable agents such as fluoroquinolones. When an intravenous β-lactam is combined
with coverage for atypical pathogens, oral therapy with a macrolide or doxycycline
is appropriate for selected patients without severe pneumonia risk factors [228].Inpatient,
ICU treatment.The following regimen is the minimal recommended treatment for patients
admitted to the ICU.
20. β-lactam (cefotaxime, ceftriaxone, or ampicillin-sulbactam) plus either azithromycin
(level II evidence) or a fluoroquinolone (level I evidence) (strong recommendation)
(For penicillin-allergic patients, a respiratory fluoroquinolone and aztreonam are
recommended.)
A single randomized controlled trial of treatment for severe CAP is available. Patients
with shock were excluded; however, among the patients with mechanical ventilation,
treatment with a fluoroquinolone alone resulted in a trend toward inferior outcome
[229]. Because septic shock and mechanical ventilation are the clearest reasons for
ICU admission, the majority of ICU patients would still require combination therapy.
ICU patients are routinely excluded from other trials; therefore, recommendations
are extrapolated from nonsevere cases, in conjunction with case series and retrospective
analyses of cohorts with severe CAP.
For all patients admitted to the ICU, coverage for S. pneumoniae and Legionella species
should be ensured [78, 230] by using a potent antipneumococcal β-lactam and either
a macrolide or a fluoroquinolone. Therapy with a respiratory fluoroquinolone alone
is not established for severe CAP [229], and, if the patient has concomitant pneumococcal
meningitis, the efficacy of fluoroquinolone monotherapy is uncertain. In addition,
2 prospective observational studies [231, 232] and 3 retrospective analyses [233–235]
have found that combination therapy for bacteremic pneumococcal pneumonia is associated
with lower mortality than monotherapy. The mechanism of this benefit is unclear but
was principally found in the patients with the most severe illness and has not been
demonstrated in nonbacteremic pneumococcal CAP studies. Therefore, combination empirical
therapy is recommended for at least 48 h or until results of diagnostic tests are
known.
In critically ill patients with CAP, a large number of microorganisms other than S.
pneumoniae and Legionella species must be considered. A review of 9 studies that included
890 patients with CAP who were admitted to the ICU demonstrates that the most common
pathogens in the ICU population were (in descending order of frequency) S. pneumoniae,
Legionella species, H. influenzae, Enterobacteriaceae species, S. aureus, and Pseudomonas
species [171]. The atypical pathogens responsible for severe CAP may vary over time
but can account collectively for ⩾20% of severe pneumonia episodes. The dominant atypical
pathogen in severe CAP is Legionella [230], but some diagnostic bias probably accounts
for this finding [78].
The recommended standard empirical regimen should routinely cover the 3 most common
pathogens that cause severe CAP, all of the atypical pathogens, and most of the relevant
Enterobacteriaceae species. Treatment of MRSA or P. aeruginosa infection is the main
reason to modify the standard empirical regimen. The following are additions or modifications
to the basic empirical regimen recommended above if these pathogens are suspected.
21. For Pseudomonas infection, use an antipneumococcal, antipseudomonal β-lactam (piperacillin-tazobactam,
cefepime, imipenem, or meropenem) plus either ciprofloxacin or levofloxacin (750-mg
dose) or the above β-lactam plus an aminoglycoside and azithromycin or the above β-lactam
plus an aminoglycoside and an antipneumococcal fluoroquinolone. (For penicillin-allergic
patients, substitute aztreonam for the above β-lactam.)
(Moderate recommendation; level III evidence.)
Pseudomonal CAP requires combination treatment to prevent inappropriate initial therapy,
just as Pseudomonas nosocomial pneumonia does [131]. Once susceptibilities are known,
treatment can be adjusted accordingly. Alternative regimens are provided for patients
who may have recently received an oral fluoroquinolone, in whom the aminoglycoside-containing
regimen would be preferred. A consistent Gram stain of tracheal aspirate, sputum,
or blood is the best indication for Pseudomonas coverage. Other, easier-to-treat gram-negative
microorganisms may ultimately be proven to be the causative pathogen, but empirical
coverage of Pseudomonas species until culture results are known is least likely to
be associated with inappropriate therapy. Other clinical risk factors for infection
with Pseudomonas species include structural lung diseases, such as bronchiectasis,
or repeated exacerbations of severe COPD leading to frequent steroid and/or antibiotic
use, as well as prior antibiotic therapy [131]. These patients do not necessarily
require ICU admission for CAP [236], so Pseudomonas infection remains a concern for
them even if they are only hospitalized on a general ward. The major risk factor for
infection with other serious gram-negative pathogens, such as Klebsiella pneumoniae
or Acinetobacter species, is chronic alcoholism.
22. For CA-MRSA infection, add vancomycin or linezolid. (Moderate recommendation;
level III evidence.)
The best indicator of S. aureus infection is the presence of gram-positive cocci in
clusters in a tracheal aspirate or in an adequate sputum sample. The same findings
on preliminary results of blood cultures are not as reliable, because of the significant
risk of contamination [95]. Clinical risk factors for S. aureus CAP include end-stage
renal disease, injection drug abuse, prior influenza, and prior antibiotic therapy
(especially with fluoroquinolones [237]).
For methicillin-sensitive S. aureus, the empirical combination therapy recommended
above, which includes a β-lactam and sometimes a respiratory fluoroquinolone, should
be adequate until susceptibility results are available and specific therapy with a
penicillinase-resistant semisynthetic penicillin or first-generation cephalosporin
can be initiated. Both also offer additional coverage for DRSP. Neither linezolid
[241] nor vancomycin [238] is an optimal drug for methicillin-sensitive S. aureus.
Although methicillin-resistant strains of S. aureus are still the minority, the excess
mortality associated with inappropriate antibiotic therapy [80] would suggest that
empirical coverage should be considered when CA-MRSA is a concern. The most effective
therapy has yet to be defined. The majority of CA-MRSA strains are more susceptible
in vitro to non-β-lactam antimicrobials, including trimethoprim-sulfamethoxazole (TMP-SMX)
and fluoroquinolones, than are hospital-acquired strains. Previous experience with
TMP-SMX in other types of severe infections (endocarditis and septic thrombophlebitis)
suggests that TMP-SMX is inferior to vancomycin [239]. Further experience and study
of the adequacy of TMP-SMX for CA-MRSA CAP is clearly needed. Vancomycin has never
been specifically studied for CAP, and linezolid has been found to be better than
ceftriaxone for bacteremic S. pneumoniae in a nonblinded study [240] and superior
to vancomycin in retrospective analysis of studies involving nosocomial MRSA pneumonia
[241]. Newer agents for MRSA have recently become available, and others are anticipated.
Of the presently available agents, daptomycin should not be used for CAP, and no data
on pneumonia are available for tigecycline.
A concern with CA-MRSA is necrotizing pneumonia associated with production of Panton-Valentine
leukocidin and other toxins. Vancomycin clearly does not decrease toxin production,
and the effect of TMP-SMX and fluoroquinolones on toxin production is unclear. Addition
of clindamycin or use of linezolid, both of which have been shown to affect toxin
production in a laboratory setting [242], may warrant their consideration for treatment
of these necrotizing pneumonias [204]. Unfortunately, the emergence of resistance
during therapy with clindamycin has been reported (especially in erythromycin-resistant
strains), and vancomycin would still be needed for bacterial killing.
Pathogens Suspected on the Basis of Epidemiologic Considerations
Clinicians should be aware of epidemiologic conditions and/or risk factors that may
suggest that alternative or specific additional antibiotics should be considered.
These conditions and specific pathogens, with preferred treatment, are listed in tables
8 and 9.
Pathogen-Directed Therapy
23. Once the etiology of CAP has been identified on the basis of reliable microbiological
methods, antimicrobial therapy should be directed at that pathogen. (Moderate recommendation;
level III evidence.)
Treatment options may be simplified (table 9) if the etiologic agent is established
or strongly suspected. Diagnostic procedures that identify a specific etiology within
24–72 h can still be useful for guiding continued therapy. This information is often
available at the time of consideration for a switch from parenteral to oral therapy
and may be used to direct specific oral antimicrobial choices. If, for example, an
appropriate culture reveals penicillin-susceptible S. pneumoniae, a narrow-spectrum
agent (such as penicillin or amoxicillin) may be used. This will, hopefully, reduce
the selective pressure for resistance.
The major issue with pathogen-specific therapy is management of bacteremic S. pneumoniae
CAP. The implications of the observational finding that dual therapy was associated
with reduced mortality in bacteremic pneumococcal pneumonia [231–235] are uncertain.
One explanation for the reduced mortality may be the presence of undiagnosed coinfection
with an atypical pathogen; although reported to occur in 18%–38% of CAP cases in some
studies [73, 175], much lower rates of undiagnosed coinfection are found in general
[171] and specifically in severe cases [78]. An alternative explanation is the immunomodulatory
effects of macrolides [244, 245]. It is important to note that these studies evaluated
the effects of initial empirical therapy before the results of blood cultures were
known and did not examine effects of pathogen-specific therapy after the results of
blood cultures were available. The benefit of combination therapy was also most pronounced
in the more severely ill patients [233, 234]. Therefore, discontinuation of combination
therapy after results of cultures are known is most likely safe in non-ICU patients.
24. Early treatment (within 48 h of onset of symptoms) with oseltamivir or zanamivir
is recommended for influenza A. (Strong recommendation; level I evidence.)
25. Use of oseltamivir and zanamivir is not recommended for patients with uncomplicated
influenza with symptoms for >48 h (level I evidence), but these drugs may be used
to reduce viral shedding in hospitalized patients or for influenza pneumonia. (Moderate
recommendation; level III evidence.)
Studies that demonstrate that treatment of influenza is effective only if instituted
within 48 h of the onset of symptoms have been performed only in uncomplicated cases
[246–249]. The impact of such treatment on patients who are hospitalized with influenza
pneumonia or a bacterial pneumonia complicating influenza is unclear. In hospitalized
adults with influenza, a minority of whom had radiographically documented pneumonia,
no obvious benefit was found in one retrospective study of amantadine treatment [250].
Treatment of antigen- or culture-positive patients with influenza with antivirals
in addition to antibiotics is warranted, even if the radiographic infiltrate is caused
by a subsequent bacterial superinfection. Because of the longer period of persistent
positivity after infection, the appropriate treatment for patients diagnosed with
only 1 of the rapid diagnostic tests is unclear. Because such patients often have
recoverable virus (median duration of 4 days) after hospitalization, antiviral treatment
seems reasonable from an infection-control standpoint alone.
Because of its broad influenza spectrum, low risk of resistance emergence, and lack
of bronchospasm risk, oseltamivir is an appropriate choice for hospitalized patients.
The neuraminidase inhibitors are effective against both influenza A and B viruses,
whereas the M2 inhibitors, amantadine, and rimantadine are active only against influenza
A [251]. In addition, viruses recently circulating in the United States and Canada
are often resistant to the M2 inhibitors on the basis of antiviral testing [252, 253].
Therefore, neither amantadine nor rimantadine should be used for treatment or chemoprophylaxis
of influenza A in the United States until susceptibility to these antiviral medications
has been reestablished among circulating influenza A viruses [249].
Early treatment of influenza in ambulatory adults with inhaled zanamivir or oral oseltamivir
appears to reduce the likelihood of lower respiratory tract complications [254–256].
The use of influenza antiviral medications appears to reduce the likelihood of respiratory
tract complications, as reflected by reduced usage rates of antibacterial agents in
ambulatory patients with influenza. Although clearly important in outpatient pneumonia,
this experience may also apply to patients hospitalized primarily for influenza.
Parenteral acyclovir is indicated for treatment of varicella-zoster virus infection
[257] or herpes simplex virus pneumonia. No antiviral treatment of proven value is
available for other viral pneumonias—that is, parainfluenza virus, RSV, adenovirus,
metapneumovirus, the SARS agent, or hantavirus. For all patients with viral pneumonias,
a high clinical suspicion of bacterial superinfection should be maintained.Pandemic
influenza.
26. Patients with an illness compatible with influenza and with known exposure to
poultry in areas with previous H5N1 infection should be tested for H5N1 infection.
(Moderate recommendation; level III evidence.)
27. In patients with suspected H5N1 infection, droplet precautions and careful routine
infection control measures should be used until an H5N1 infection is ruled out. (Moderate
recommendation; level III evidence.)
28. Patients with suspected H5N1 infection should be treated with oseltamivir (level
II evidence) and antibacterial agents targeting S. pneumoniae and S. aureus, the most
common causes of secondary bacterial pneumonia in patients with influenza (level III
evidence). (Moderate recommendation.)
Recent human infections caused by avian influenza A (H5N1) in Vietnam, Thailand, Cambodia,
China, Indonesia, Egypt, and Turkey raise the possibility of a pandemic in the near
future. The severity of H5N1 infection in humans distinguishes it from that caused
by routine seasonal influenza. Respiratory failure requiring hospitalization and intensive
care has been seen in the majority of the >140 recognized cases, and mortality is
∼50% [258, 259]. If a pandemic occurs, deaths will result from primary influenza pneumonia
with or without secondary bacterial pneumonia. This section highlights issues for
consideration, recognizing that treatment recommendations will likely change as the
pandemic progresses. More specific guidance can be found on the IDSA, ATS, CDC, and
WHO Web sites as the key features of the pandemic become clearer. Additional guidance
is available at http://www.pandemicflu.gov.
The WHO has delineated 6 phases of an influenza pandemic, defined by increasing levels
of risk and public health response [260]. During the current pandemic alert phase
(phase 3: cases of novel influenza infection without sustained person-to-person transmission),
testing should be focused on confirming all suspected cases in areas where H5N1 infection
has been documented in poultry and on detecting the arrival of the pandemic strain
in unaffected countries. Early clinical features of H5N1 infection include persistent
fever, cough, and respiratory difficulty progressing over 3–5 days, as well as lymphopenia
on admission to the hospital [258, 259, 261]. Exposure to sick and dying poultry in
an area with known or suspected H5N1 activity has been reported by most patients,
although the recognition of poultry outbreaks has sometimes followed the recognition
of human cases [261].
Rapid bedside tests to detect influenza A have been used as screening tools for avian
influenza in some settings. Throat swabs tested by RT-PCR have been the most sensitive
for confirming H5N1 infection to date, but nasopharyngeal swabs, washes, and aspirates;
BAL fluid; lung and other tissues; and stool have yielded positive results by RT-PCR
and viral culture with varying sensitivity. Convalescent-phase serum can be tested
by microneutralization for antibodies to H5 antigen in a small number of international
reference laboratories. Specimens from suspected cases of H5N1 infection should be
sent to public health laboratories with appropriate biocontainment facilities; the
case should be discussed with health department officials to arrange the transfer
of specimens and to initiate an epidemiologic evaluation. During later phases of an
ongoing pandemic, testing may be necessary for many more patients, so that appropriate
treatment and infection control decisions can be made, and to assist in defining the
extent of the pandemic. Recommendations for such testing will evolve on the basis
of the features of the pandemic, and guidance should be sought from the CDC and WHO
Web sites (http://www.cdc.gov and http://www.who.int).
Patients with confirmed or suspected H5N1 influenza should be treated with oseltamivir.
Most H5N1 isolates since 2004 have been susceptible to the neuraminidase inhibitors
oseltamivir and zanamivir and resistant to the adamantanes (amantidine and rimantidine)
[262, 263]. The current recommendation is for a 5-day course of treatment at the standard
dosage of 75 mg 2 times daily. In addition, droplet precautions should be used for
patients with suspected H5N1 influenza, and they should be placed in respiratory isolation
until that etiology is ruled out. Health care personnel should wear N-95 (or higher)
respirators during medical procedures that have a high likelihood of generating infectious
respiratory aerosols.
Bacterial superinfections, particularly pneumonia, are important complications of
influenza pneumonia. The bacterial etiologies of CAP after influenza infection have
included S. pneumoniae, S. aureus, H. influenzae, and group A streptococci. Legionella,
Chlamydophila, and Mycoplasma species are not important causes of secondary bacterial
pneumonia after influenza. Appropriate agents would therefore include cefotaxime,
ceftriaxone, and respiratory fluoroquinolones. Treatment with vancomycin, linezolid,
or other agents directed against CA-MRSA should be limited to patients with confirmed
infection or a compatible clinical presentation (shock and necrotizing pneumonia).
Because shortages of antibacterials and antivirals are anticipated during a pandemic,
the appropriate use of diagnostic tests will be even more important to help target
antibacterial therapy whenever possible, especially for patients admitted to the hospital.
Time to First Antibiotic Dose
29. For patients admitted through the ED, the first antibiotic dose should be administered
while still in the ED. (Moderate recommendation; level III evidence.)
Time to first antibiotic dose for CAP has recently received significant attention
from a quality-of-care perspective. This emphasis is based on 2 retrospective studies
of Medicare beneficiaries that demonstrated statistically significantly lower mortality
among patients who received early antibiotic therapy [109, 264]. The initial study
suggested a breakpoint of 8 h [264], whereas the subsequent analysis found that 4
h was associated with lower mortality [109]. Studies that document the time to first
antibiotic dose do not consistently demonstrate this difference, although none had
as large a patient population. Most importantly, prospective trials of care by protocol
have not demonstrated a survival benefit to increasing the percentage of patients
with CAP who receive antibiotics within the first 4–8 h [22, 65]. Early antibiotic
administration does not appear to shorten the time to clinical stability, either [265],
although time of first dose does appear to correlate with LOS [266, 267]. A problem
of internal consistency is also present, because, in both studies [109, 264], patients
who received antibiotics in the first 2 h after presentation actually did worse than
those who received antibiotics 2–4 h after presentation. For these and other reasons,
the committee did not feel that a specific time window for delivery of the first antibiotic
dose should be recommended. However, the committee does feel that therapy should be
administered as soon as possible after the diagnosis is considered likely.
Conversely, a delay in antibiotic therapy has adverse consequences in many infections.
For critically ill, hemodynamically unstable patients, early antibiotic therapy should
be encouraged, although no prospective data support this recommendation. Delay in
beginning antibiotic treatment during the transition from the ED is not uncommon.
Especially with the frequent use of once-daily antibiotics for CAP, timing and communication
issues may result in patients not receiving antibiotics for >8 h after hospital admission.
The committee felt that the best and most practical resolution to this issue was that
the initial dose be given in the ED [22].
Data from the Medicare database indicated that antibiotic treatment before hospital
admission was also associated with lower mortality [109]. Given that there are even
more concerns regarding timing of the first dose of antibiotic when the patient is
directly admitted to a busy inpatient unit, provision of the first dose in the physician's
office may be best if the recommended oral or intramuscular antibiotics are available
in the office.
Switch from Intravenous to Oral Therapy
30. Patients should be switched from intravenous to oral therapy when they are hemodynamically
stable and improving clinically, are able to ingest medications, and have a normally
functioning gastrointestinal tract. (Strong recommendation; level II evidence.)
31. Patients should be discharged as soon as they are clinically stable, have no other
active medical problems, and have a safe environment for continued care. Inpatient
observation while receiving oral therapy is not necessary. (Moderate recommendation;
level II evidence.)
With the use of a potent, highly bioavailable antibiotic, the ability to eat and drink
is the major consideration for switching from intravenous to oral antibiotic therapy
for non-ICU patients. Initially, Ramirez et al. [268] defined a set of criteria for
an early switch from intravenous to oral therapy (table 10). In general, as many as
two-thirds of all patients have clinical improvement and meet criteria for a therapy
switch in the first 3 days, and most non-ICU patients meet these criteria by day 7.
Subsequent studies have suggested that even more liberal criteria are adequate for
the switch to oral therapy. An alternative approach is to change from intravenous
to oral therapy at a predetermined time, regardless of the clinical response [269].
One study population with nonsevere illness was randomized to receive either oral
therapy alone or intravenous therapy, with the switch occurring after 72 h without
fever. The study population with severe illness was randomized to receive either intravenous
therapy with a switch to oral therapy after 2 days or a full 10-day course of intravenous
antibiotics. Time to resolution of symptoms for the patients with nonsevere illness
was similar with either regimen. Among patients with more severe illness, the rapid
switch to oral therapy had the same rate of treatment failure and the same time to
resolution of symptoms as prolonged intravenous therapy. The rapid-switch group required
fewer inpatient days (6 vs. 11), although this was likely partially a result of the
protocol, but the patients also had fewer adverse events.
The need to keep patients in the hospital once clinical stability is achieved has
been questioned, even though physicians commonly choose to observe patients receiving
oral therapy for ⩾1 day. Even in the presence of pneumococcal bacteremia, a switch
to oral therapy can be safely done once clinical stability is achieved and prolonged
intravenous therapy is not needed [270]. Such patients generally take longer (approximately
half a day) to become clinically stable than do nonbacteremic patients. The benefits
of in-hospital observation after a switch to oral therapy are limited and add to the
cost of care [32].
Discharge should be considered when the patient is a candidate for oral therapy and
when there is no need to treat any comorbid illness, no need for further diagnostic
testing, and no unmet social needs [32, 271, 272]. Although it is clear that clinically
stable patients can be safely switched to oral therapy and discharged, the need to
wait for all of the features of clinical stability to be present before a patient
is discharged is uncertain. For example, not all investigators have found it necessary
to have the white blood cell count improve. Using the definition for clinical stability
in table 10, Halm et al. [273] found that 19.1% of 680 patients were discharged from
the hospital with ⩾1 instability. Death or readmission occurred in 10.5% of patients
with no instability on discharge, in 13.7% of patients with 1 instability, and in
46.2% with ⩾2 instabilities. In general, patients in higher PSI classes take longer
to reach clinical stability than do patients in lower risk classes [274]. This finding
may reflect the fact that elderly patients with multiple comorbidities often recover
more slowly. Arrangements for appropriate follow-up care, including rehabilitation,
should therefore be initiated early for these patients.
In general, when switching to oral antibiotics, either the same agent as the intravenous
antibiotic or the same drug class should be used. Switching to a different class of
agents simply because of its high bioavailability (such as a fluoroquinolone) is probably
not necessary for a responding patient. For patients who received intravenous β-lactam-macrolide
combination therapy, a switch to a macrolide alone appears to be safe for those who
do not have DRSP or gram-negative enteric pathogens isolated [275].
Duration of Antibiotic Therapy
32. Patients with CAP should be treated for a minimum of 5 days (level I evidence),
should be afebrile for 48–72 h, and should have no more than 1 CAP-associated sign
of clinical instability (table 10) before discontinuation of therapy (level II evidence).
(Moderate recommendation.)
33. A longer duration of therapy may be needed if initial therapy was not active against
the identified pathogen or if it was complicated by extrapulmonary infection, such
as meningitis or endocarditis. (Weak recommendation; level III evidence.)
Most patients with CAP have been treated for 7–10 days or longer, but few well-controlled
studies have evaluated the optimal duration of therapy for patients with CAP, managed
in or out of the hospital. Available data on short-course treatment do not suggest
any difference in outcome with appropriate therapy in either inpatients or outpatients
[276]. Duration is also difficult to define in a uniform fashion, because some antibiotics
(such as azithromycin) are administered for a short time yet have a long half-life
at respiratory sites of infection.
In trials of antibiotic therapy for CAP, azithromycin has been used for 3–5 days as
oral therapy for outpatients, with some reports of single-dose therapy for patients
with atypical pathogen infections [276–278]. Results with azithromycin should not
be extrapolated to other drugs with significantly shorter half-lives. The ketolide
telithromycin has been used for 5–7 days to treat outpatients, including some with
pneumococcal bacteremia or PSI classes ⩾III [211]. In a recent study, high-dose (750
mg) levofloxacin therapy for 5 days was equally successful and resulted in more afebrile
patients by day 3 than did the 500-mg dose for 7–10 days (49.1% vs. 38.5%; P = .03)
[276]. On the basis of these studies, 5 days appears to be the minimal overall duration
of therapy documented to be effective in usual forms of CAP.
As is discussed above, most patients become clinically stable within 3–7 days, so
longer durations of therapy are rarely necessary. Patients with persistent clinical
instability are often readmitted to the hospital and may not be candidates for short-duration
therapy. Short-duration therapy may be suboptimal for patients with bacteremic S.
aureus pneumonia (because of the risk of associated endocarditis and deep-seated infection),
for those with meningitis or endocarditis complicating pneumonia, and for those infected
with other, less common pathogens (e.g., Burkholderia pseudomallei or endemic fungi).
An 8-day course of therapy for nosocomial P. aeruginosa pneumonia led to relapse more
commonly than did a 15-day course of therapy [279]. Whether the same results would
be applicable to CAP cases is unclear, but the presence of cavities or other signs
of tissue necrosis may warrant prolonged treatment. Studies of duration of therapy
have focused on patients receiving empirical treatment, and reliable data defining
treatment duration after an initially ineffective regimen are lacking.
Other Treatment Considerations
34. Patients with CAP who have persistent septic shock despite adequate fluid resuscitation
should be considered for treatment with drotrecogin alfa activated within 24 h of
admission. (Weak recommendation, level II evidence.)
Drotrecogin alfa activated is the first immunomodulatory therapy approved for severe
sepsis. In the United States, the FDA recommended the use of drotrecogin alfa activated
for patients at high risk of death. The high-risk criterion suggested by the FDA was
an Acute Physiologic and Chronic Health Assessment (APACHE) II score ⩾25, based on
a subgroup analysis of the overall study. However, the survival advantage (absolute
risk reduction, 9.8%) of drotrecogin alfa activated treatment of patients in the CAP
subgroup was equivalent to that in the subgroup with APACHE II scores ⩾25 [92, 280,
281]. The greatest reduction in the mortality rate was for S. pneumoniae infection
(relative risk, 0.56; 95% CI, 0.35–0.88) [282]. Subsequent data have suggested that
the benefit appears to be greatest when the treatment is given as early in the hospital
admission as possible. In the subgroup with severe CAP caused by a pathogen other
than S. pneumoniae and treated with appropriate antibiotics, there was no evidence
that drotrecogin alfa activated affected mortality.
Although the benefit of drotrecogin alfa activated is clearly greatest for patients
with CAP who have high APACHE II scores, this criterion alone may not be adequate
to select appropriate patients. An APACHE II score ⩾25 was selected by a subgroup
analysis of the entire study cohort and may not be similarly calibrated in a CAP-only
cohort. Two-organ failure, the criterion suggested for drotrecogin alfa activated
use by the European regulatory agency, did not influence the mortality benefit for
patients with CAP [92].
Therefore, in addition to patients with septic shock, other patients with severe CAP
could be considered for treatment with drotrecogin alfa activated. Those with sepsis-induced
leukopenia are at extremely high risk of death and ARDS and are, therefore, potential
candidates. Conversely, the benefit of drotrecogin alfa activated is not as clear
when respiratory failure is caused more by exacerbation of underlying lung disease
rather than by the pneumonia itself. Other minor criteria for severe CAP proposed
above are similar to organ failure criteria used in many sepsis trials. Consideration
of treatment with drotrecogin alfa activated is appropriate, but the strength of the
recommendation is only level II.
35. Hypotensive, fluid-resuscitated patients with severe CAP should be screened for
occult adrenal insufficiency. (Moderate recommendation; level II evidence.)
A large, multicenter trial has suggested that stress-dose (200–300 mg of hydrocortisone
per day or equivalent) steroid treatment improves outcomes of vasopressor-dependent
patients with septic shock who do not have an appropriate cortisol response to stimulation
[283]. Once again, patients with CAP made up a significant fraction of patients entered
into the trial. In addition, 3 small pilot studies have suggested that there is a
benefit to corticosteroid therapy even for patients with severe CAP who are not in
shock [284–286]. The small sample size and baseline differences between groups compromise
the conclusions. Although the criteria for steroid replacement therapy remain controversial,
the frequency of intermittent steroid treatment in patients at risk for severe CAP,
such as those with severe COPD, suggests that screening of patients with severe CAP
is appropriate with replacement if inadequate cortisol levels are documented. If corticosteroids
are used, close attention to tight glucose control is required [287].
36. Patients with hypoxemia or respiratory distress should receive a cautious trial
of noninvasive ventilation (NIV) unless they require immediate intubation because
of severe hypoxemia (arterial oxygen pressure/fraction of inspired oxygen [PaO2/FiO2]
ratio, <150) and bilateral alveolar infiltrates. (Moderate recommendation; level I
evidence.)
Patients who do not require immediate intubation but who have either hypoxemia or
respiratory distress should receive a trial of NIV [114, 288, 289]. Patients with
underlying COPD are most likely to benefit. Patients with CAP who were randomized
to receive NIV had a >25% absolute risk reduction for the need for intubation [114].
The use of NIV may also improve intermediate-term mortality. Inability to expectorate
may limit the use of NIV [290], but intermittent application of NIV may allow for
its use in patients with productive cough unless sputum production is excessive. Prompt
recognition of a failed NIV trial is critically important, because most studies demonstrate
worse outcomes for patients who require intubation after a prolonged NIV trial [288,
290]. Within the first 1–2 h of NIV, failure to improve respiratory rate and oxygenation
[114, 289, 290] or failure to decrease carbon dioxide partial pressure (pCO2) in patients
with initial hypercarbia [114] predicts NIV failure and warrants prompt intubation.
NIV provides no benefit for patients with ARDS [289], which may be nearly indistinguishable
from CAP among patients with bilateral alveolar infiltrates. Patients with CAP who
have severe hypoxemia (PaO2/FiO2 ratio, <150) are also poor candidates for NIV [290].
37. Low-tidal-volume ventilation (6 cm3/kg of ideal body weight) should be used for
patients undergoing ventilation who have diffuse bilateral pneumonia or ARDS. (Strong
recommendation; level I evidence.)
Distinguishing between diffuse bilateral pneumonia and ARDS is difficult, but it may
not be an important distinction. Results of the ARDSNet trial suggest that the use
of low-tidal-volume ventilation provides a survival advantage [291]. Pneumonia, principally
CAP, was the most common cause of ARDS in that trial, and the benefit of the low-tidal-volume
ventilatory strategy appeared to be equivalent in the population with pneumonia compared
with the entire cohort. The absolute risk reduction for mortality in the pneumonia
cohort was 11%, indicating that, in order to avoid 1 death, 9 patients must be treated
[292].
Other aspects of the management of severe sepsis and septic shock in patients with
CAP do not appear to be significantly different from those for patients with other
sources of infection. Recommendations for these aspects of care are reviewed elsewhere
[293].
Management of Nonresponding Pneumonia
Because of the limitations of diagnostic testing, the majority of CAP is still treated
empirically. Critical to empirical therapy is an understanding of the management of
patients who do not follow the normal response pattern.
Although difficult to define, nonresponse is not uncommon. Overall, 6%–15% of hospitalized
patients with CAP do not respond to the initial antibiotic treatment [81, 84, 101,
294]. The incidence of treatment failure among patients with CAP who are not hospitalized
is not well known, because population-based studies are required. Almirall et al.
[295] described an overall hospitalization rate of 60% in a population-based study,
but the rate of failure among the 30% of patients who initially presented to their
primary care physician was not provided. The frequency of prior antibiotic therapy
among Medicare patients admitted to the hospital with CAP is 24%–40% [95, 109], but
the percentage who received prior antibiotic therapy for the acute episode of pneumonia
itself versus other indications is unclear. For patients initially admitted to the
ICU, the risk of failure to respond is already high; as many as 40% will experience
deterioration even after initial stabilization in the ICU [101].
Mortality among nonresponding patients is increased several-fold in comparison with
that among responding patients [296]. Overall mortality rates as high as 49% have
been reported for an entire population of nonresponding hospitalized patients with
CAP [76, 84, 101], and the mortality rate reported in one study of early failure was
27% [81]. APACHE II score was not the only factor independently associated with mortality
in the nonresponding group, suggesting that the excess mortality may be due to factors
other than severity of illness at presentation [101].Definition and classification.
38. The use of a systematic classification of possible causes of failure to respond,
based on time of onset and type of failure (table 11), is recommended. (Moderate recommendation;
level II evidence.)
The term “nonresponding pneumonia” is used to define a situation in which an inadequate
clinical response is present despite antibiotic treatment. Lack of a clear-cut and
validated definition in the literature makes nonresponse difficult to study. Lack
of response also varies according to the site of treatment. Lack of response in outpatients
is very different from that in patients admitted to the ICU. The time of evaluation
is also important. Persistent fever after the first day of treatment differs significantly
from fever persisting (or recurring) at day 7 of treatment.
Table 11 provides a construct for evaluating nonresponse to antibiotic treatment of
CAP, based on several studies addressing this issue [76, 81, 84, 101]. Two patterns
of unacceptable response are seen in hospitalized patients [101]. The first is progressive
pneumonia or actual clinical deterioration, with acute respiratory failure requiring
ventilatory support and/or septic shock, usually occurring within the first 72 h of
hospital admission. As is noted above, as many as 45% of patients with CAP who ultimately
require ICU admission are initially admitted to a non-ICU setting and are transferred
because of deterioration [75]. Deterioration and development of respiratory failure
or hypotension >72 h after initial treatment is often related to intercurrent complications,
deterioration in underlying disease, or development of nosocomial superinfection.
The second pattern is that of persistent or nonresponding pneumonia. Nonresponse can
be defined as absence of or delay in achieving clinical stability, using the criteria
in table 10 [274, 294]. When these criteria were used, the median time to achieve
clinical stability was 3 days for all patients, but a quarter of patients took ⩾6
days to meet all of these criteria for stability [274]. Stricter definitions for each
of the criteria and higher PSI scores were associated with longer times to achieve
clinical stability. Conversely, subsequent transfer to the ICU after achieving this
degree of clinical stability occurred in <1% of cases. A separate multicenter trial
demonstrated similar findings [297]. Given these results, concern regarding nonresponse
should be tempered before 72 h of therapy. Antibiotic changes during this period should
be considered only for patients with deterioration or in whom new culture data or
epidemiologic clues suggest alternative etiologies.
Finally, nonresolving or slow-resolving pneumonia has been used to refer to the conditions
of patients who present with persistence of pulmonary infiltrates >30 days after initial
pneumonia-like syndrome [298]. As many as 20% of these patients will be found to have
diseases other than CAP when carefully evaluated [295].
Two studies have evaluated the risk factors for a lack of response in multivariate
analyses [81, 84], including those amenable to medical intervention. Use of fluoroquinolones
was independently associated with a better response in one study [84], whereas discordant
antimicrobial therapy was associated with early failure [81]. In table 12, the different
risk and protective factors and their respective odds ratios are summarized.
Specific causes that may be responsible for a lack of response in CAP have been classified
by Arancibia et al. [101] (table 11). This classification may be useful for clinicians
as a systematic approach to diagnose the potential causes of nonresponse in CAP. Although
in the original study only 8 (16%) of 49 cases could not be classified [101], a subsequent
prospective multicenter trial found that the cause of failure could not be determined
in 44% [84].Management of nonresponding CAP.Nonresponse to antibiotics in CAP will
generally result in ⩾1 of 3 clinical responses: (1) transfer of the patient to a higher
level of care, (2) further diagnostic testing, and (3) escalation or change in treatment.
Issues regarding hospital admission and ICU transfer are discussed above.
An inadequate host response, rather than inappropriate antibiotic therapy or unexpected
microorganisms, is the most common cause of apparent antibiotic failure when guideline-recommended
therapy is used. Decisions regarding further diagnostic testing and antibiotic change/escalation
are intimately intertwined and need to be discussed in tandem.
Information regarding the utility of extensive microbiological testing in cases of
nonresponding CAP is mainly retrospective and therefore affected by selection bias.
A systematic diagnostic approach, which included invasive, noninvasive, and imaging
procedures, in a series of nonresponding patients with CAP obtained a specific diagnosis
in 73% [101]. In a different study, mortality among patients with microbiologically
guided versus empirical antibiotic changes was not improved (mortality rate, 67% vs.
64%, respectively) [76]. However, no antibiotic changes were based solely on sputum
smears, suggesting that invasive cultures or nonculture methods may be needed.
Mismatch between the susceptibility of a common causative organism, infection with
a pathogen not covered by the usual empirical regimen, and nosocomial superinfection
pneumonia are major causes of apparent antibiotic failure. Therefore, the first response
to nonresponse or deterioration is to reevaluate the initial microbiological results.
Culture or sensitivity data not available at admission may now make the cause of clinical
failure obvious. In addition, a further history of any risk factors for infection
with unusual microorganisms (table 8) should be taken if not done previously. Viruses
are relatively neglected as a cause of infection in adults but may account for 10%–20%
of cases [299]. Other family members or coworkers may have developed viral symptoms
in the interval since the patient was admitted, increasing suspicion of this cause.
The evaluation of nonresponse is severely hampered if a microbiological diagnosis
was not made on initial presentation. If cultures were not obtained, clinical decisions
are much more difficult than if the adequate cultures were obtained but negative.
Risk factors for nonresponse or deterioration (table 12), therefore, figure prominently
in the list of situations in which more aggressive initial diagnostic testing is warranted
(table 5).
Blood cultures should be repeated for deterioration or progressive pneumonia. Deteriorating
patients have many of the risk factors for bacteremia, and blood cultures are still
high yield even in the face of prior antibiotic therapy [95]. Positive blood culture
results in the face of what should be adequate antibiotic therapy should increase
the suspicion of either antibiotic-resistant isolates or metastatic sites, such as
endocarditis or arthritis.
Despite the high frequency of infectious pulmonary causes of nonresponse, the diagnostic
utility of respiratory tract cultures is less clear. Caution in the interpretation
of sputum or tracheal aspirate cultures, especially of gram-negative bacilli, is warranted
because early colonization, rather than superinfection with resistant bacteria, is
not uncommon in specimens obtained after initiation of antibiotic treatment. Once
again, the absence of multidrug-resistant pathogens, such as MRSA or Pseudomonas,
is strong evidence that they are not the cause of nonresponse. An etiology was determined
by bronchoscopy in 44% of patients with CAP, mainly in those not responding to therapy
[300]. Despite the potential benefit suggested by these results, and in contrast to
ventilator-associated pneumonia [301, 302], no randomized study has compared the utility
of invasive versus noninvasive strategies in the CAP population with nonresponse.
Rapid urinary antigen tests for S. pneumoniae and L. pneumophila remain positive for
days after initiation of antibiotic therapy [147, 152] and, therefore, may be high-yield
tests in this group. A urinary antigen test result that is positive for L. pneumophila
has several clinical implications, including that coverage for Legionella should be
added if not started empirically [81]. This finding may be a partial explanation for
the finding that fluoroquinolones are associated with a lower incidence of nonresponse
[84]. If a patient has persistent fever, the faster response to fluoroquinolones in
Legionella CAP warrants consideration of switching coverage from a macrolide [303].
Stopping the β-lactam component of combination therapy to exclude drug fever is probably
also safe [156]. Because one of the major explanations for nonresponse is poor host
immunity rather than incorrect antibiotics, a positive pneumococcal antigen test result
would at least clarify the probable original pathogen and turn attention to other
causes of failure. In addition, a positive pneumococcal antigen test result would
also help with interpretation of subsequent sputum/tracheal aspirate cultures, which
may indicate early superinfection.
Nonresponse may also be mimicked by concomitant or subsequent extrapulmonary infection,
such as intravascular catheter, urinary, abdominal, and skin infections, particularly
in ICU patients. Appropriate cultures of these sites should be considered for patients
with nonresponse to CAP therapy.
In addition to microbiological diagnostic procedures, several other tests appear to
be valuable for selected patients with nonresponse:
Chest CT. In addition to ruling out pulmonary emboli, a CT scan can disclose other
reasons for antibiotic failure, including pleural effusions, lung abscess, or central
airway obstruction. The pattern of opacities may also suggest alternative noninfectious
disease, such as bronchiolitis obliterans organizing pneumonia.
Thoracentesis. Empyema and parapneumonic effusions are important causes of nonresponse
[81, 101], and thoracentesis should be performed whenever significant pleural fluid
is present.
Bronchoscopy with BAL and transbronchial biopsies. If the differential of nonresponse
includes noninfectious pneumonia mimics, bronchoscopy will provide more diagnostic
information than routine microbiological cultures. BAL may reveal noninfectious entities,
such as pulmonary hemorrhage or acute eosinophilic pneumonia, or hints of infectious
diseases, such as lymphocytic rather than neutrophilic alveolitis pointing toward
virus or Chlamydophila infection. Transbronchial biopsies can also yield a specific
diagnosis.
Antibiotic management of nonresponse in CAP has not been studied. The overwhelming
majority of cases of apparent nonresponse are due to the severity of illness at presentation
or a delay in treatment response related to host factors. Other than the use of combination
therapy for severe bacteremic pneumococcal pneumonia [112, 231, 233, 234], there is
no documentation that additional antibiotics for early deterioration lead to a better
outcome. The presence of risk factors for potentially untreated microorganisms may
warrant temporary empirical broadening of the antibiotic regimen until results of
diagnostic tests are available.
Prevention
39. All persons ⩾50 years of age, others at risk for influenza complications, household
contacts of high-risk persons, and health care workers should receive inactivated
influenza vaccine as recommended by the Advisory Committee on Immunization Practices
(ACIP), CDC. (Strong recommendation; level I evidence.)
40. The intranasally administered live attenuated vaccine is an alternative vaccine
formulation for some persons 5–49 years of age without chronic underlying diseases,
including immunodeficiency, asthma, or chronic medical conditions. (Strong recommendation;
level I evidence.)
41. Health care workers in inpatient and outpatient settings and long-term care facilities
should receive annual influenza immunization. (Strong recommendation; level I evidence.)
42. Pneumococcal polysaccharide vaccine is recommended for persons ⩾65 years of age
and for those with selected high-risk concurrent diseases, according to current ACIP
guidelines. (Strong recommendation; level II evidence.)
Vaccines targeting pneumococcal disease and influenza remain the mainstay for preventing
CAP. Pneumococcal polysaccharide vaccine and inactivated influenza vaccine are recommended
for all older adults and for younger persons with medical conditions that place them
at high risk for pneumonia morbidity and mortality (table 13) [304, 305]. The new
live attenuated influenza vaccine is recommended for healthy persons 5–49 years of
age, including health care workers [304].
Postlicensure epidemiologic studies have documented the effectiveness of pneumococcal
polysaccharide vaccines for prevention of invasive infection (bacteremia and meningitis)
among elderly individuals and younger adults with certain chronic medical conditions
[306–309]. The overall effectiveness against invasive pneumococcal disease among persons
⩾65 years of age is 44%–75% [306, 308, 310], although efficacy may decrease with advancing
age [308]. The effectiveness of the vaccine against pneumococcal disease in immunocompromised
persons is less clear, and results of studies evaluating its effectiveness against
pneumonia without bacteremia have been mixed. The vaccine has been shown to be cost
effective for general populations of adults 50–64 years of age and ⩾65 years of age
[311, 312]. A second dose of pneumococcal polysaccharide vaccine after a ⩾5-year interval
has been shown to be safe, with only slightly more local reactions than are seen after
the first dose [313]. Because the safety of a third dose has not been demonstrated,
current guidelines do not suggest repeated revaccination. The pneumococcal conjugate
vaccine is under investigation for use in adults but is currently only licensed for
use in young children [314, 315]. However, its use in children <5 years of age has
dramatically reduced invasive pneumococcal bacteremia among adults as well [314, 316].
The effectiveness of influenza vaccines depends on host factors and on how closely
the antigens in the vaccine are matched with the circulating strain of influenza.
A systematic review demonstrates that influenza vaccine effectively prevents pneumonia,
hospitalization, and death [317, 318]. A recent large observational study of adults
⩾65 years of age found that vaccination against influenza was associated with a reduction
in the risk of hospitalization for cardiac disease (19% reduction), cerebrovascular
disease (16%–23% reduction), and pneumonia or influenza (29%–32% reduction) and a
reduction in the risk of death from all causes (48%–50% reduction) [319]. In long-term-care
facilities, vaccination of health care workers with influenza vaccine is an important
preventive health measure [318, 320, 321]. Because the main virulence factors of influenza
virus, a neuraminidase and hemagglutinin, adapt quickly to selective pressures, new
vaccine formulations are created each year on the basis of the strains expected to
be circulating, and annual revaccination is needed for optimal protection.
43. Vaccination status should be assessed at the time of hospital admission for all
patients, especially those with medical illnesses. (Moderate recommendation; level
III evidence.)
44. Vaccination may be performed either at hospital discharge or during outpatient
treatment. (Moderate recommendation; level III evidence.)
45. Influenza vaccine should be offered to persons at hospital discharge or during
outpatient treatment during the fall and winter. (Strong recommendation; level III
evidence.)
Many people who should receive either influenza or pneumococcal polysaccharide vaccine
have not received them. According to a 2003 survey, only 69% of adults ⩾65 years of
age had received influenza vaccine in the past year, and only 64% had ever received
pneumococcal polysaccharide vaccine [322]. Coverage levels are lower for younger persons
with vaccine indications. Among adults 18–64 years of age with diabetes, 49% had received
influenza vaccine, and 37% had ever received pneumococcal vaccine [323]. Studies of
vaccine delivery methods indicate that the use of standing orders is the best way
to improve vaccination coverage in office, hospital, or long-term care settings [324].
Hospitalization of at-risk patients represents an underutilized opportunity to assess
vaccination status and to either provide or recommend immunization. Ideally, patients
should be vaccinated before developing pneumonia; therefore, admissions for illnesses
other than respiratory tract infections would be an appropriate focus. However, admission
for pneumonia is an important trigger for assessing the need for immunization. The
actual immunization may be better provided at the time of outpatient follow-up, especially
with the emphasis on early discharge of patients with CAP. Patients with an acute
fever should not be vaccinated until their fever has resolved. Confusion of a febrile
reaction to immunization with recurrent/superinfection pneumonia is a risk. However,
immunization at discharge for pneumonia is warranted for patients for whom outpatient
follow-up is unreliable, and such vaccinations have been safely given to many patients.
The best time for influenza vaccination in North America is October and November,
although vaccination in December and later is recommended for those who were not vaccinated
earlier. Influenza and pneumococcal vaccines can be given at the same time in different
arms.
Chemoprophylaxis can be used as an adjunct to vaccination for prevention and control
of influenza. Oseltamivir and zanamivir are both approved for prophylaxis; amantadine
and rimantadine have FDA indications for chemoprophylaxis against influenza A infection,
but these agents are currently not recommended because of the frequency of resistance
among strains circulating in the United States and Canada [252, 253]. Developing an
adequate immune response to the inactivated influenza vaccine takes ∼2 weeks in adults;
chemoprophylaxis may be useful during this period for those with household exposure
to influenza, those who live or work in institutions with an influenza outbreak, or
those who are at high risk for influenza complications in the setting of a community
outbreak [325, 326]. Chemoprophylaxis also may be useful for persons with contraindications
to influenza vaccine or as an adjunct to vaccination for those who may not respond
well to influenza vaccine (e.g., persons with HIV infection) [325, 326]. The use of
influenza antiviral medications for treatment or chemoprophylaxis should not affect
the response to the inactivated vaccine. Because it is unknown whether administering
influenza antiviral medications affects the performance of the new live attenuated
intranasal vaccine, this vaccine should not be used in conjunction with antiviral
agents.
Other types of vaccination can be considered. Pertussis is a rare cause of pneumonia
itself. However, pneumonia is one of the major complications of pertussis. Concern
over waning immunity has led the ACIP to emphasize adult immunization for pertussis
[327]. One-time vaccination with the new tetanus toxoid, reduced diphtheria toxoid,
and acellular pertussis vaccine—adsorbed (Tdap) product, ADACEL (Sanofi Pasteur)—is
recommended for adults 19–64 years of age. For most adults, the vaccine should be
given in place of their next routine tetanus-diphtheria booster; adults with close
contact with infants <12 months of age and health care workers should receive the
vaccine as soon as possible, with an interval as short as 2 years after their most
recent tetanus/diphtheria booster.
46. Smoking cessation should be a goal for persons hospitalized with CAP who smoke.
(Moderate recommendation; level III evidence.)
47. Smokers who will not quit should also be vaccinated for both pneumococcus and
influenza. (Weak recommendation; level III evidence.)
Smoking is associated with a substantial risk of pneumococcal bacteremia; one report
showed that smoking was the strongest of multiple risks for invasive pneumococcal
disease in immunocompetent nonelderly adults [328]. Smoking has also been identified
as a risk for Legionella infection [329]. Smoking cessation should be attempted when
smokers are hospitalized; this is particularly important and relevant when these patients
are hospitalized for pneumonia. Materials for clinicians and patients to assist with
smoking cessation are available online from the US Surgeon General (http://www.surgeongeneral.gov/tobacco),
the Centers for Disease Control and Prevention (http://www.cdc.gov/tobacco), and the
American Cancer Society (http://www.cancer.org). The most successful approaches to
quitting include some combination of nicotine replacement and/or bupropion, a method
to change habits, and emotional support. Given the increased risk of pneumonia, the
committee felt that persons unwilling to stop smoking should be given the pneumococcal
polysaccharide vaccine, although this is not currently an ACIP-recommended indication.
48. Cases of pneumonia that are of public health concern should be reported immediately
to the state or local health department. (Strong recommendation; level III evidence.)
Public health interventions are important for preventing some forms of pneumonia.
Notifying the state or local health department about a condition of interest is the
first step to getting public health professionals involved. Rules and regulations
regarding which diseases are reportable differ between states. For pneumonia, most
states require reporting for legionnaires disease, SARS, and psittacosis, so that
an investigation can determine whether others may be at risk and whether control measures
are necessary. For legionnaires disease, reporting of cases has helped to identify
common-source outbreaks caused by environmental contamination [130]. For SARS, close
observation and, in some cases, quarantine of close contacts have been critical for
controlling transmission [330]. In addition, any time avian influenza (H5N1) or a
possible terrorism agent (e.g., plague, tularemia, or anthrax) is being considered
as the etiology of pneumonia, the case should be reported immediately, even before
a definitive diagnosis is obtained. In addition, pneumonia cases that are caused by
pathogens not thought to be endemic to the area should be reported, even if those
conditions are not typically on the list of reportable conditions, because control
strategies might be possible.
For other respiratory diseases, episodes that are suspected of being part of an outbreak
or cluster should be reported. For pneumococcal disease and influenza, outbreaks can
occur in crowded settings of susceptible hosts, such as homeless shelters, nursing
homes, and jails. In these settings, prophylaxis, vaccination, and infection control
methods are used to control further transmission [331]. For Mycoplasma, antibiotic
prophylaxis has been used in schools and institutions to control outbreaks [332].
49. Respiratory hygiene measures, including the use of hand hygiene and masks or tissues
for patients with cough, should be used in outpatient settings and EDs as a means
to reduce the spread of respiratory infections. (Strong recommendation; level III
evidence.)
In part because of the emergence of SARS, improved respiratory hygiene measures (“respiratory
hygiene” or “cough etiquette”) have been promoted as a means for reducing transmission
of respiratory infections in outpatient clinics and EDs [333]. Key components of respiratory
hygiene include encouraging patients to alert providers when they present for a visit
and have symptoms of a respiratory infection; the use of hand hygiene measures, such
as alcohol-based hand gels; and the use of masks or tissues to cover the mouth for
patients with respiratory illnesses. In a survey of the US population, the use of
masks in outpatient settings was viewed as an acceptable means for reducing the spread
of respiratory infections [334]. For hospitalized patients, infection control recommendations
typically are pathogen specific. For more details on the use of personal protective
equipment and other measures to prevent transmission within health care settings,
refer to the Healthcare Infection Control Practices Advisory Committee [335].
Suggested Performance Indicators
Performance indicators are tools to help guideline users measure both the extent and
the effects of implementation of guidelines. Such tools or measures can be indicators
of the process itself, outcomes, or both. Deviations from the recommendations are
expected in a proportion of cases, and compliance in 80%–95% of cases is generally
appropriate, depending on the indicator.
Four specific performance indicators have been selected for the CAP guidelines, 3
of which focus on treatment issues and 1 of which deals with prevention:
Initial empirical treatment of CAP should be consistent with guideline recommendations.
Data exist that support the role of CAP guidelines and that have demonstrated reductions
in cost, LOS, and mortality when the guidelines are followed. Reasons for deviation
from the guidelines should be clearly documented in the medical record.
The first treatment dose for patients who are to be admitted to the hospital should
be given in the ED. Unlike in prior guidelines, a specific time frame is not being
recommended. Initiation of treatment would be expected within 6–8 h of presentation
whenever the admission diagnosis is likely CAP. A rush to treatment without a diagnosis
of CAP can, however, result in the inappropriate use of antibiotics with a concomitant
increase in costs, adverse drug events, increased antibiotic selection pressure, and,
possibly, increased antibiotic resistance. Consideration should be given to monitoring
the number of patients who receive empirical antibiotics in the ED but are admitted
to the hospital without an infectious diagnosis.
Mortality data for all patients with CAP admitted to wards, ICUs, or high-level monitoring
units should be collected. Although tools to predict mortality and severity of illness
exist—such as the PSI and CURB-65 criteria, respectively—none is foolproof. Overall
mortality rates for all patients with CAP admitted to the hospital, including general
medical wards, should be monitored and compared with severity-adjusted norms. In addition,
careful attention should be paid to the percentage of patients with severe CAP, as
defined in this document, who are admitted initially to a non-ICU or a high-level
monitoring unit and to their mortality rate.
It is important to determine what percentage of at-risk patients in one's practice
actually receive immunization for influenza or pneumococcal infection. Prevention
of infection is clearly more desirable than having to treat established infection,
but it is clear that target groups are undervaccinated. Trying to increase the number
of protected individuals is a desirable end point and, therefore, a goal worth pursuing.
This is particularly true for influenza, because the vaccine data are more compelling,
but it is important to try to protect against pneumococcal infection as well. Coverage
of 90% of adults ⩾65 years of age should be the target.