Revised February 16, 2004 Steven
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DefinitionPrevalence
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Related Material from The Cleveland Clinic Guidelines for Antimicrobial Usage
- Guidelines for Interpretation of Gram Stain Results
- Traditional Aminoglycoside Dosing
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Pneumonia is an infection of the lung parenchyma. Community-acquired pneumonia refers to pneumonia acquired outside of hospitals or extended-care facilities. Nursing home-acquired pneumonia refers to infection acquired in an extended care facility. Nosocomial pneumonia and hospital-acquired pneumonia are used to describe infections acquired in the hospital setting. The signs and symptoms of acute pneumonia develop over hours to days, while the clinical presentation of chronic pneumonia often evolves over weeks to months.
Despite a broad armamentarium of antimicrobials available to treat the disease, pneumonia remains the seventh leading cause of death in the United States.1 In 1999, the age-adjusted death rate due to influenza and pneumonia was 23.6 per 100,000 persons.1 Estimates of the incidence of community-acquired pneumonia range from 4 to 5 million cases per year, with about 25% requiring hospitalization.2 Nosocomial pneumonia is estimated to occur in 250,000 persons per year, representing about 15% to 18% of all nosocomial infections.3,4
Streptococcus pneumoniae remains the most commonly identified pathogen in community-acquired pneumonia. A variety of other pathogens have been reported to cause pneumonia in the community, with their order of importance dependent on the location and population studied (Table 1). These include long-recognized pathogens such as Haemophilus influenzae, Mycoplasma pneumoniae, and influenza A, along with newer pathogens such as Legionella species and Chlamydophilia pneumoniae. Other common causes in the immunocompetent patient include Moraxella catarrhalis, Mycobacterium tuberculosis, and aspiration pneumonia. The causative agent of community acquired pneumonia remains unidentified in 30% to 50% of cases.5
A new human pathogen, SARS-associated coronavirus, emerged and spread worldwide in the winter of 2002-2003. Data regarding this virus and its associated syndrome, Severe Acute Respiratory Syndrome (SARS)6 are rapidly evolving and a wealth of updated information can be found on the SARS page of the website of the Centers for Disease Control and Prevention (CDC).
A severe outbreak of influenza A has occurred nationwide in the United States in the fall of 2003 and is anticipated to continue into the winter months of 2003-4. Information on influenza prevention and treatment during this season is also rapidly evolving, and readers are encouraged to check the CDC influenza page for updated prevention and treatment guidelines.
Many pathogens listed as potential agents of bioterrorism are spread by the respiratory route. Among the most likely candidate agents are Bacillus anthracis, Francisella tularensis, and Yersinia pestis. A more extensive discussion of the agents of bioterror can be found in the chapters on chemical and biologic weapons in the Cleveland Clinic Disease Management Project.
Nursing home-acquired pneumonias are often caused by community-acquired pathogens. However, there is an increased influence of pathogens seen with relatively low frequency in the community, such as S. aureus (in the setting of aspiration or following influenza) or gram-negative organisms.
Six mechanisms have been identified in the pathogenesis of pneumonia in immunocompetent adults (Table 2).
Inhalation of infectious particles is probably the most important pathogenetic mechanism in the development of community-acquired pneumonia, with particular importance in pneumonia due to Legionella species and Mycobacterium tuberculosis.
Aspiration of oropharyngeal or gastric contents is by far the most prevalent pathogenetic mechanism in nosocomial pneumonia, with several factors contributing. Swallowing and epiglottic closure may be impaired by neuromuscular disease, stroke, states of altered consciousness, or seizures. Endotracheal and nasogastric tubes interfere with these anatomic defenses and provide a direct route of entry for pathogens. Finally, impaired lower esophageal sphincter function and nasogastric and gastrostomy tubes increase the risk of aspiration of gastric contents. Fortunately, aspiration rarely leads to overt bacterial pneumonia.
Direct inoculation rarely occurs as a result of surgery or bronchoscopy but may play a role in the development of pneumonia in patients supported with mechanical ventilation. Hematogenous deposition of bacteria in the lung is also uncommon but is responsible for some cases of pneumonia due to Staphylococcus aureus, Pseudomonas aeruginosa, and Escherichia coli. The direct extension of infection to the lung from contiguous areas such as the pleural or subdiaphragmatic spaces is rare.
Reactivation of pathogens can take place in the setting of deficits of cell-mediated immunity. Pathogens such as Pneumocystis carinii, Mycobacterium tuberculosis, and cytomegalovirus may remain latent for many years after exposure, with flares of active disease in the face of immune compromise. Reactivation tuberculosis occasionally occurs in immunocompetent hosts.
Once bacteria reach the tracheobronchial tree, defects in local pulmonary defenses may make infection more likely. The cough reflex can be impaired by stroke, neuromuscular disease, sedatives, or poor nutrition. Mucociliary transport is depressed with the aging process, tobacco smoking, dehydration, morphine, atropine, prior infection with influenza virus, and chronic bronchitis. Anatomic changes such as emphysema, bronchiectasis, and obstructive mass lesions prevent clearance of microbes. Inflammatory cells drawn to infected areas of the pulmonary tree release proteolytic enzymes, altering the bronchial epithelium and ciliary clearance mechanisms, and stimulating the production of excess mucus.
A blunted cellular and humoral immune response may also increase the risk of pneumonia. For example, granulocyte chemotaxis is reduced with aging, diabetes mellitus, malnutrition, hypothermia, hypophosphatemia, and corticosteroids. Granulocytopenia may be caused by cytotoxic chemotherapy. Alveolar macrophages are rendered dysfunctional by corticosteroids, cytokines, viral illnesses, and malnutrition. Diminished antibody production or function can accompany hematologic malignancies such as multiple myeloma or chronic lymphocytic leukemia.
Because the clinical
syndromes characterizing pneumonic infections caused by various agents
frequently overlap with each other and interobserver variability regarding
physical findings of pneumonia is high, the diagnosis of pneumonia can
be challenging. A diligent history (Table
3) and physical examination can help narrow
the differential diagnosis.
In general, typical
bacterial pathogens such as S pneumoniae, H influenzae, and the
enteric gram-negative organisms usually present acutely with high fever,
chills, tachypnea, tachycardia, and productive cough. Examination findings
are localized to a specific lung zone and may include rales, rhonchi,
bronchial breath sounds, dullness, increased fremitus, and egophony. In
contrast, atypical pathogens such as Mycoplasma, Chlamydophilia,
and viruses can present in a subacute fashion with fever, nonproductive
cough, constitutional symptoms, and absent or diffuse findings on lung
examination. Rapid progression of disease to respiratory failure can be
seen in severe pneumococcal or Legionella pneumonia. Influenza
may be complicated by bacterial pneumonia with S. aureus or S.
pneumoniae.
SARS presents with high fever and myalgia for 3-7 days followed by non-productive cough and progressive hypoxemia with progression to mechanical ventilation in 20%. This can be distinguished from other viral infections by the higher fever and lack of conjunctivitis, sneezing, rhinorrhea, and pharyngitis. Inhalation anthrax can present with "flu-like" symptoms of myalgia, fatigue, and fever before rapidly progressing to respiratory distress, mediastinitis, meningitis, sepsis, and death.
The age of the patient can play an important role in disease presentation. Older patients often have humoral and cellular immunodeficiency as a result of underlying diseases, immunosuppressive medications, and aging. They are more frequently institutionalized with anatomic problems that inhibit pulmonary clearance of pathogens. The presentation is often more subtle than in younger adults, with more advanced disease and sepsis despite minimal fever and sputum production.
Extrapulmonary physical findings can provide clues to the diagnosis. Poor dentition and foul-smelling sputum may indicate the presence of a lung abscess with an anaerobic component. Bullous myringitis can accompany infection with M pneumoniae. An absent gag reflex or altered sensorium raises the question of aspiration. Encephalitis can complicate pneumonia with M pneumoniae or Legionella pneumophila. Cutaneous manifestations of infection can include erythema multiforme (M pneumoniae), erythema nodosum (C pneumoniae and M tuberculosis), or ecthyma gangrenosum (P aeruginosa).
 |
Pulmonary infiltrate
in Legionella pneumonia. Source: |
Figure 1 |
The composition of
the diagnostic workup for pneumonia is the subject of some disagreement
between experts (see "National Guidelines"),
but a well-chosen evaluation can both support a diagnosis of pneumonia
and identify a pathogen.
Radiography
A cornerstone of diagnosis is the chest x-ray, which usually reveals an
infiltrate (Figure 1) at presentation. However, this finding may
be absent in the dehydrated patient. Also, the radiographic manifestations
of chronic diseases such as congestive heart failure, chronic obstructive
pulmonary disease (COPD), and malignancy may obscure the infiltrate of
pneumonia.
Although radiographic patterns are usually nonspecific, they can suggest a microbiologic differential diagnosis (Table 4).
Initial
Management
Risk Stratification and Treatment Setting
When community-acquired pneumonia is strongly suspected on the basis of
history, physical examination, and chest radiography, the next critical
management decision is whether the patient will require hospital admission.
Health care budgetary constraints have given rise to a number of studies
addressing the need for hospitalization in community-acquired pneumonia.
A recent study by the Patient Outcome Research Team (PORT) investigators
validated a risk scale for mortality in community-acquired pneumonia,
assigning point values based on patient characteristics, comorbid illness,
physical examination, and basic laboratory findings (Table
5).7
Patients less than 50 years of age without comorbid illness or significant
vital sign abnormalities (risk class I) were found to have a low risk
for mortality. The authors suggested that such patients might be eligible
for outpatient antibiotic therapy without extensive laboratory evaluation.
All others were evaluated with the laboratory testing listed in Table
5 and assigned to risk classes by point totals (Table
6).
Classes I and II are considered excellent candidates for outpatient oral therapy, assuming no hemodynamic instability, no chronic oxygen dependence, immunocompetence, and ability to ingest, absorb, and adhere to an oral regimen. Patients in risk class III may be considered for either outpatient or brief inpatient therapy, depending on clinical judgment. Patients in risk categories IV and V are recommended for hospital admission. Ultimately, each decision to admit must be individualized.
Diagnostic
Testing
When the patient with few risk factors falls into PORT class I,
the guidelines of the Infectious Disease Society of America suggest empiric
therapy without extensive lab evaluation (Table
7). For the patient falling outside of this group, basic labs
and a chest radiograph should be used to stratify the patient into classes
II through V.
If the patient is hospitalized, further workup may help to identify a pathogen (Table 7).
The value of such studies is not uniformly agreed upon (see "National Guidelines"). However, pathogen identification has important implications for breadth of therapeutic antibiotic spectrum, development of resistance, and epidemiology. A gram-stained sputum specimen can help focus empiric therapy. Unfortunately, sputum is frequently difficult to obtain from elderly patients because of a weak cough, obtundation, and dehydration. Nebulized saline treatments may help mobilize secretions. Nasotracheal suctioning can sample the lower respiratory tract directly but risks oropharyngeal contamination. A sputum specimen reflects lower respiratory secretions when more than 25 white blood cells (WBCs) and less than 10 epithelial cells are seen in a low-powered microscopic field.8 Empiric therapy based on a predominant organism in such a specimen is likely to contain appropriate coverage.9 Other stains, such as the acid-fast stain for mycobacteria, modified acid-fast stain for Nocardia, or the toluidine blue and Gomori methenamine silver stains should be employed when directed by the history or clinical presentation. Direct fluorescent antibody (DFA) staining of sputum, bronchoalveolar lavage fluid, or pleural fluid may help identify Legionella species. In a like fashion, DFA testing of nasopharyngeal specimens provides rapid diagnosis of influenza A and B, as well as other common respiratory viruses such as respiratory syncytial virus, adenovirus, and parainfluenza virus. In an outbreak setting, DFA and other rapid techniques can assist in therapeutic and infection control decision-making.
The sputum culture remains a controversial tool but is still recommended to help tailor therapy. Culture is particularly helpful in identifying organisms of epidemiologic significance, either for patterns of transmission or resistance. Expectorated morning sputum specimens should be sent for mycobacterial culture when the history is suggestive.
Blood cultures may also shed light on a pathogen, and should be drawn in hospitalized patients (see "Outcomes"). Pleural or cerebrospinal fluid should be sampled when infections in these spaces are suspected.
When these procedures fail to yield a microbiologic diagnosis and when the patient fails to respond to empiric antibiotic therapy, more invasive diagnostic techniques may be indicated. Fiberoptic bronchoscopy allows the use of several techniques in the diagnosis of pneumonia. Bronchoalveolar lavage with saline can obtain deep respiratory specimens for the gamut of stains and cultures mentioned above. Transbronchial biopsy of lung parenchyma can reveal alveolar or interstitial pneumonitis, viral inclusion bodies, and fungal or mycobacterial elements. The protected brush catheter is used to quantitatively distinguish between tracheobronchial colonizers and pneumonic pathogens.
A more substantial
amount of lung tissue may be obtained for culture and histologic examination
by thoracoscopic or open-lung biopsy. Because these procedures can carry
considerable morbidity, they are usually reserved for the deteriorating
patient with a pneumonia that defies diagnosis by less invasive techniques.
Serologic Testing
Often relegated to retrospective or epidemiologic interest because of
delays in testing or reporting, serologic testing for such pathogens as Legionella species, Mycoplasma species, and C pneumoniae should include sera drawn in both the acute and convalescent phases for
comparison. A fourfold increase in the immunoglobulin G (IgG) titer is suggestive of recent
infection with these organisms. An IgM microimmunofluorescence titer of
> 1:16 is considered diagnostic of C pneumoniae infection. Infection
with SARS associated coronavirus is most often diagnosed by antibody testing
and polymerase chain reaction testing.
A sensitive enzyme immunoassay has been developed for the detection of L pneumophila type 1 antigen in urine. Because the antigen persists for up to a year after infection, it is difficult to differentiate between past and current infections when using this assay.
A newer urinary assay for detection of S pneumoniae cell wall polysaccharide has recently been approved by the FDA. This assay may offer some advantage in the rapid diagnosis of pneumococcal pneumonia in culture proven or unknown cases, but assay specificity is an ongoing question.
Molecular
Techniques
Powerful molecular techniques are now being applied to the early diagnosis
of pneumonia. DNA probes have been used for the detection of Legionella species, M pneumoniae, and M tuberculosis in sputum. These
probes have excellent sensitivity and specificity but can produce some
false-positive results. The polymerase chain reaction has been shown to
be a sensitive tool for the early detection of M tuberculosis in
sputum specimens. Given the large percentage of pneumonia cases for which
no microbial etiology is identified, it is likely that molecular tools
will eventually be applied to identification and antimicrobial susceptibility
testing of nearly all agents of pneumonia.
Community-acquired
Pneumonia
Antibiotic therapy for community-acquired pneumonia should always be selected
with patient characteristics, place of acquisition, and severity of disease
in mind. With concerns about antimicrobial overuse, health care costs,
and bacterial resistance increasing, many experts feel that therapy should
always follow confirmation of the diagnosis of pneumonia and should always
be accompanied by a diligent effort to identify an etiologic agent (see
"National Guidelines"). When a specific pathogen is identified,
pathogen-specific therapy can be employed (Table
8).
When
a pathogen is yet to be identified, empiric therapy is employed. Multiple
expert panels have authored recommendations for empiric pneumonia therapy,
most prominently the Infectious Disease Society of America (IDSA) and
the American Thoracic Society (ATS) (Table
9).
Aspiration
Pneumonia
Clindamycin is preferred over penicillin for the treatment of community-acquired
aspiration pneumonia because of its superiority in the treatment of oral
anaerobes such as Bacteroides melaninogenicus. Amoxicillin/clavulanic
acid also provides excellent coverage in this setting. When large-volume
aspiration is documented in the hospital, a beta-lactam/beta-lactamase
inhibitor combination or the combination of clindamycin and an antipseudomonal
agent should be used.
Anthrax
Suspected or proven inhalation anthrax should be treated with ciprofloxacin
or doxycycline and two other agents (Table
8). Recent clinical experience suggests that rifampin may be an
important agent in empiric regimens.
Length
of Therapy
Though few data specifically address length of therapy, many cases of
pneumonia are adequately treated with 10 to 14 days of antibiotics. Longer
courses may be required for certain organisms (eg, Legionella sp, S aureus, Pseudomonas aeruginosa, or C pneumoniae) or
comorbidities that compromise local (COPD) or systemic (hematologic malignancy)
immunity.
Oral
and Switch Therapies
The use of oral or "switch" therapies offers potential reductions
in length of stay, antibiotic administration costs, complications of venous
access, and disruption of families and careers. Many antibiotics are well
absorbed from the gastrointestinal tract, suggesting the possibility of
effective, fully oral treatment. Because well-controlled, risk-stratified
data comparing oral and intravenous therapies are few, appropriate patient
populations and treatment settings for full-course oral therapy are yet
to be fully defined. Better data exist for the use of intravenous-to-oral
switch therapies for the stable patient who has good gastrointestinal
and swallowing function and adequate social support.11
Failure
to Respond to Initial Therapy
Worsening of clinical status despite adequate antibiotic therapy should
trigger a reassessment of the original clinical impression. First, the
diagnosis of infection must be questioned. Entities such as cancers, pulmonary
edema, pulmonary embolus, pulmonary hemorrhage, connective tissue diseases,
or drug toxicity may mimic the clinical and radiographic appearance of
pneumonia. Organisms with inherent (fungi, mycobacteria, P carinii)
or acquired (Pseudomonas aeruginosa) resistance to drugs commonly
used in pneumonia therapy must also be considered. A secondary infection,
such as post-influenza staphylococcal pneumonia, may prove resistant to
initial therapy. The patient may fail to respond for reasons of poor adherence,
poor drug absorption, or drug interaction. Finally, immunodeficiency (HIV
and hematologic malignancy) or anatomic derangement (COPD, bronchiectasis
and neoplasm) may alter the clinical course of pneumonia and treatment.
Discharge
Criteria
Criteria for hospital discharge in community acquired pneumonia are commonsense.
Candidates for discharge should have no more than one of the following
poor prognostic indicators: temperature > 37.8 degrees Celsius, pulse
> 100 beats per minute, respiratory rate > 24 per minute, systolic
blood pressure < 90 mmHg, oxygen saturation < 90 percent, or inability
to maintain oral intake.
Immunization against influenza and increasingly resistant pneumococci can play a critical role in the prevention of pneumonia, particularly in immunocompromised and older adults. The influenza vaccine is formulated and administered annually. The CDC recommends that vaccine be offered to persons aged > 50 years; residents of chronic-care facilities; patients who have chronic heart or lung disorders, and patients with chronic metabolic diseases (including diabetes mellitus), renal dysfunction, hemoglobinopathies, or immunosuppression.12
The pneumococcal vaccine has been shown to be 60% to 70% effective in immunocompetent patients. Side effects are rarely serious and consist of local pain and erythema, which occur in up to 50% of recipients. The CDC recommends that vaccine be offered to all persons aged greater than or equal to 65 years, persons at increased risk for illness and death from pneumococcal disease because of chronic illness, persons with functional or anatomic asplenia, and immunocompromised persons.13 Patients who are immunosuppressed by chronic disease or treatment may not have sustained titers of protective antibody and should be considered for revaccination after 6 years.
The emergence of SARS, with significant spread within hospitals, has forced an extensive reassessment of respiratory infection control in many institutions. Measures to prevent the spread of SARS associated coronavirus include close attention to cough hygiene, hand hygiene, contact precautions, and respiratory droplet precautions.
Multiple expert bodies have developed guidelines for the diagnosis and management of community-acquired pneumonia. The two most often cited and compared are the guidelines of the Infectious Disease Society of America5 and the American Thoracic Society.2 Thoughtful and comprehensive, both of these guidelines provide recommendations for evaluation and treatment of the patient with community-acquired pneumonia driven by data, when available. Recommendations are classified by strength of supporting data in each; recommendations formed on the basis of opinion rather than data are identified. Both bodies support the use of the PORT pneumonia severity scoring system for risk stratification. A long-awaited set of consensus guidelines uniting the two groups is planned for 2004.
Treatment recommendations, while not identical, are closely aligned. The updated IDSA guidelines have recently joined the ATS guidelines in the omission of newer fluoroquinolones as a therapeutic option for uncomplicated outpatient pneumonias. This reflects justifiable concern and recognition on the part of some experts regarding evolving data on side effects of and resistance to these drugs.
More striking is the difference of opinion between the two guidelines regarding the diagnostic evaluation of community-acquired pneumonia. The ATS guidelines detail a more minimal approach to diagnosis, citing a lack of specificity/sensitivity and outcome data to support more aggressive microbiologic testing. For example, the ATS discourages the use of the sputum gram-stain to help guide initial therapy, preferring that initial therapy be empiric. Likewise, the ATS panel suggests that a sputum culture only be obtained when an unusual or drug-resistant pathogen is suspected. The ISDA guidelines support a more aggressive approach to pathogen identification, citing concerns of drug resistance and epidemiologic tracking. The IDSA panel argues that pathogen-specific treatment should be adopted whenever possible, allowing for the narrowest possible spectrum of activity and discouraging the development of resistance.
When new respiratory pathogens emerge or major flares of well-known respiratory diseases occur, information develops quickly and guidelines are altered on a "real time" basis. In such situations, the web sites of the CDC, World Health Organization, Infectious Disease Society of America, and state and local health departments often contain updated authoritative information and guidelines to assist the practitioner.
Pneumonia-related outcomes have been measured in several areas. In the area of microbiology, Metlay et al have noted that patients with penicillin-nonsusceptible pneumococci were more likely to develop suppurative complications than patients infected with susceptible isolates.14 Overall, the pneumococcus has been shown by Fine et al to carry a 12% mortality.15 This level of mortality is exceeded only by Legionella species among community-acquired pathogens. Several pathogens more associated with long-term care facilities, including Pseudomonas aeruginosa (61%) and Staphylococcus aureus (32%) carried substantially higher mortality. Blood cultures drawn within 24 hours of hospital admission have been associated with improvement in 30-day mortality.15 Antibiotic therapy initiated within 4 hours of hospital admission has been shown to improve mortality and length of hospital stay in all pneumonia patients.5,16 With regard to site of care, the PORT data have suggested < 1% risk of 30-day mortality for pneumonia sufferers falling into risk categories I and II, suggesting the possibility of outpatient care for this group. Intravenous-to-oral "switch" therapy has shown to have no significant reduction in outcome when the switch is instituted after clinical stability.10
- Minino
AM, Smith BL. Deaths: preliminary data for 2000. National Vital Statistics
Reports. 2001;49:1-40.
- American
Thoracic Society: Guidelines for the initial management of adults with
community-acquired pneumonia: Diagnosis, assessment of severity, and
initial antimicrobial therapy. Am J Resp Crit Care Med. 2001;163:1730-1754.
- Wiblin
RT, Wenzel RP. Hospital-acquired pneumonia. Curr Clin Top Infect
Dis. 1996;16:194-214.
- Bassin
AS, Niederman MS. New approaches to prevention and treatment of nosocomial
pneumonia. Semin Thorac Cardiovasc Surg. 1995;7:70-77.
- Mandell
LA, Bartlett JG, Dowell SF, File Jr TM, Musher DM, Whitney C. Update
of practice guidelines for the management of community-acquired pneumonia
in immunocompetent adults. Clin Infect Dis. 2003;37:1405-33.
- Peiris
JS, Yuen KY, Osterhaus AD, Stohr K. The severe acute respiratory syndrome. N Eng J Med. 2003;349:2431-41.
- Fine
MJ, Auble TE, Yealy DM, et al. A prediction rule to identify low-risk
patients with community-acquired pneumonia. N Engl J Med. 1997;336:243-250.
- Murray
PR, Washington JA. Microscopic and bacteriologic analysis of expectorated
sputum. Mayo Clin Proc. 1975;50:339-344.
- Gleckman
R, DeVita J, Hibert D, Pelletier C. Martin R. Sputum gram stain assessment
in community-acquired bacteremic pneumonia. J Clin Microbiol. 1988;26:846-849.
- Centers
for Disease Control and Prevention. Update: Investigation of Bioterrorism-Related
Anthrax and Interim Guidelines for Exposure Management and Antimicrobial
Therapy, October 2001. MMWR. 2001;50:909-919.
- Cassiere
HA, Fein AM. Duration and route of antibiotic therapy in patients hospitalized
with community-acquired pneumonia: switch and step-down therapy. Semin
Resp Infect. 1998;13:36-42.
- Centers
for Disease Control and Prevention. Prevention and control of influenza:
recommendations of the Advisory Committee on Immunization Practices
(ACIP). MMWR. 2001;50(RR-04):1-46.
- Centers
for Disease Control and Prevention. Prevention of pneumococcal disease:
recommendations of the Advisory Committee on Immunization Practices
(ACIP). MMWR. 1997;46(RR-08):1-24.
- Metlay
JP, Hofmann J, Cetron MS, et al. Impact of penicillin susceptibility
on medical outcomes for adult patients with bacteremic pneumococcal
pneumonia. Clin Infect Dis. 2000;30:520-528.
- Fine
MJ, Smith MA, Carson CA, et al. Prognosis and outcomes of patients with
community-acquired pneumonia. A meta-analysis. JAMA.1996;274:134-141.
- Houck PM, Bratzler DW, Nsa W, Ma A, Bartlett JG. Timing of antibiotic administration and outcomes for Medicare patients hospitalized with pneumonia. Arch Intern Med (in press).