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Part II: Community-Acquired Pneumonia
Author: Jonathan Glauser, MD, FACEP, Attending Staff, Cleveland Clinic Foundation, Department of Emergency Medicine; Faculty, MetroHealth Medical Center, Cleveland, OH.
Peer Reviewers: Sandra M. Schneider, MD, FACEP, Professor and Chair, Department of Emergency Medicine, University of Rochester, Rochester, NY; and Steven M. Winograd, MD, FACEP, Attending Physician, Emergency Department, St. Joseph Medical Center, Reading, PA.
Part I of this two-part series on respiratory diseases covered two viral infections, severe acute respiratory syndrome (SARS) and influenza. Part II of this series will focus on a bacterial infection, community-acquired pneumonia (CAP). —The Editor
CAP affects 5.6 million adults annually in the United States, and causes 1.7 million hospitalizations per year.1 Combined mortality rates for pneumonia and influenza indicate that this is the sixth leading cause of death in the United States, accounting for 83,000 deaths annually. It is the cause for 46% of all deaths from infectious disease.2 While causative pathogens are identified in fewer than 50% of cases,3 the specific organisms that require coverage have been identified. The typical organisms include Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis. The atypical organisms include Mycoplasma pneumoniae, Chlamydia pneumoniae, and Legionella pneumophila.4 The atypical agent may have a presentation more subacute, with nonproductive cough, and a chest radiograph that appears characteristically worse than the patient’s clinical appearance.
This update on the management of CAP addresses the following topics:
1. Appropriate triage disposition from the emergency department (ED);
2. Recommended treatment;
3. The role of newer antibiotics and of antibiotic resistance;
4. Updated testing for specific pathogens; and
5. Use of anticoagulation in the management of the CAP patient.
Disposition from the ED
Fine’s landmark study helped to identify patients with CAP who are at low risk of mortality and who can be treated safely on an outpatient basis. The prediction rule stratifies patients into five categories based upon age, sex, coexisting illnesses, physical, and laboratory findings. Patients in Class IV and V require hospitalization, while patients in Class III may be managed in a 24-hour stay unit.5 Patients older than 50 years were assigned automatically to Class II-V. However, patients who were younger than 50 years of age without a history of neoplastic disease, congestive heart failure, renal or liver disease, or cerebrovascular disease, who had normal mental status and vital signs were assigned to Class I and deemed suitable for management as outpatients. Mortality for classes I and II was fewer than 1%. In this study, 6% of patients in Class III, 11% of patients in Class IV, and 17% of patients in Class V, respectively, required intensive care unit (ICU) admission.
The point scale was derived from 14,199 cases and validated in another 38,039.6 The Pneumonia Patient Outcomes Research Team (PORT) score derived from that study has been cited as suitable for determination of the initial disposition of the patient with CAP.79 Selection of the initial site of treatment is one of the most important clinical decisions made in the treatment of patients with CAP. The ED plays a key role, as portal of entry for 75% of admissions for pneumonia in the United States.7
The Pneumonia PORT Severity Index is listed. (See Table 1.) The initial site of treatment must take into account not only the pneumonia severity index, but also any pre-existing social and medical conditions that may compromise the safety of home care. Hypoxemia, inability to take oral medications, severe social or psychiatric problems, or an unstable living situation all mitigate toward hospitalization for CAP.
There are other indicators for predicting mortality in the CAP patient. In one study, predictors of mortality included: patient age older than 65 years, confusion, temperature less than 37° C, respiratory rate greater than 24 breaths/ minute, serum sodium less than 135 mmol/L, BUN greater than 19.6 mg/dL, and pleural effusion on chest radiograph.8
Guidelines for ICU admissions also have been proposed, and include a PaO2 to FiO2 ratio of less than 250, multilobar infiltrates, and a systolic blood pressure of less than 90 mmHg, septic shock, or need for mechanical ventilation.9 Another study listed the following risk factors for death due to CAP: at least three lobes affected, a respiratory rate of greater than 30 breaths/minute, the presence of shock, altered mental status, bedridden status, leukocytosis of greater than 14,900, or severe hypoxemia.10
Antibiotic treatment guidelines have been adopted by the British Thoracic Society,11 American Thoracic Society (ATS),12 Infectious Disease Society of America,13 the Centers for Disease Control and Prevention’s Drug-Resistant Streptococcus Pneumonia Therapeutic Working Group,14 and by the Antibiotic Selection for Community-Acquired Pneumonia Consensus Panel (ASCAP).4 Each of these groups recommends a beta-lactam plus a macrolide or an antipneumococcal ("respiratory") fluoroquinolone alone as empiric therapy for patients admitted to a general medicine ward.
For patients with no underlying cardiopulmonary disease, the ATS recommends monotherapy with a macrolide, azithromycin.9 Data indicate that azithromycin monotherapy is efficacious in treating hospitalized patients with CAP, even in the presence of cardiopulmonary disease and age greater than 65 years15 and with fewer adverse effects than a regimen of cefuroxime with or without erythromycin.16 Therapy, however, should take into account local resistance patterns, epidemiological data, and patient demographics.
For patients who need ICU therapy, and for whom Pseudomonas infection is not a significant concern, a combination of a beta-lactam plus a macrolide or a respiratory fluoroquinolone should be used.7 The empiric therapy for CAP in immunocompetent adults as recommended by the Infectious Diseases Society of America is listed. (See Table 2.)
Newer Antibiotics and the Role of Antibiotic Resistance
A drug resistant S. pneumoniae is now defined with a breakpoint minimum inhibitory concentration (MIC) of greater than 4 mcg/mL for non-meningeal sources, as adopted by the National Committee on Clinical Laboratory Standards (NCCLS) in January 2002. Susceptibility of pneumococcal isolates to cefotaxime and ceftriaxone in non-meningeal infections now is defined by the NCCLS as follows: susceptible if the MIC is less than 1 mcg/mL, intermediate as an MIC of 2 mcg/mL, and resistant as an MIC of greater than 4 mcg/mL. Cefotaxime or ceftriaxone, therefore, are the preferred parenteral agents for treatment of pneumococcal pneumonia without meningitis with reduced susceptibility to penicillin but with MIC of less than 2 mcg/mL. The new breakpoints mean that nonmeningeal infections formerly deemed intermediately susceptible or resistant can be treated with the usual doses of beta-lactam drugs. They also reflect the feeling that levels of drug in alveolar macrophages, alveolar lining fluid, and epithelial lining cells are more important than serum levels.7,17
The following developments relate to the efficacy of antibiotics, and are discussed by class. (See Table 3.)
Fluoroquinolones. These are active against greater than 98% of strains of S. pneumoniae in the United States.18,19 In order of most active to least active agents against S. pneumoniae, moxifloxacin historically is most active, followed by gatifloxacin and levofloxacin. Gemifloxacin, a new agent, is available as an oral agent only. There has been growing concern regarding the increasing levels of levofloxacin-resistant S. pneumoniae, including treatment failures. Increased fluoroquinolone use has been noted to be associated with S. pneumoniae resistance since 1999.20 There has been emerging resistance of both gram-negative organisms and methicillin-resistant Staphylococcus aureus.18 Resistance to fluoroquinolones due to overuse could have possible public policy implications, as they currently are active against category A bacterial agents of bioterrorism such as tularemia, anthrax, and Yersinia pestis infections.
Given these epidemiological and drug resistance trends, at least one panel4 recommends moxifloxacin as the initial fluoroquinolone of choice when a respiratory fluoroquinolone is deemed appropriate for CAP. Furthermore, recent reports of levofloxacin failures in cases of CAP caused by S. pneumoniae are a continuing cause of concern, and other resistance data demonstrating precipitous increases in levofloxacin resistance among S. pneumoniae species support the panel’s recommendations to avoid levofloxacin as the initial agent selected for empiric management of CAP.
Amoxicillin can be used for treatment of pneumococcal pneumonia involving susceptible strains, but because it is almost always impossible to determine if a strain is susceptible at time of presentation, this agent rarely is used on an empiric basis. If the isolate is penicillin-susceptible, penicillin G may be used. For empiric therapy, ceftriaxone or a respiratory fluoroquinolone may be used.
Macrolides. These are recommended for monotherapy of outpatients with no pre-existing disease and those not previously treated with other antibiotics. An advanced macrolide such as azithromycin or clarithromycin may be used as monotherapy for patients with co-morbid diseases such as diabetes, malignancy, renal failure, or congestive heart failure if they have not been treated previously with antibiotics. Azithromycin and clarithromycin generally are well-tolerated and may be administered once daily. Erythromycin is less active against H. influenzae, and causes more gastrointestinal side effects. A macrolide plus a beta-lactam (cefotaxime, ceftriaxone, or ampicillin-sulbactam) is a preferred regimen for outpatients if resistance is an issue, and for hospitalized patients. Approximately 25% of pneumococci show some degree of resistance to macrolides.18,21 Retrospective analysis indicates that dual therapy including a macrolide reduces mortality associated with bacteremic pneumococcal pneumonia.22,23
Ketolides. Destined to play an important role for oral management of CAP in ED patients, ketolides represent a new class of antibiotics with activity against gram-positive cocci that are macrolide-resistant. Recently approved by the FDA for use in CAP, acute bacterial exacerbations of chronic bronchitis (ABE/CB), and acute bacterial sinusitis, telithromycin is active against S. pneumoniae, H. influenzae, and M. catarrhalis, as well as Legionella, Mycoplasma, and Chlamydia species.24,25 The dose is 800 mg per day.7 Telithromycin has been investigated intensively for its efficacy and safety in treating outpatients with CAP.
From a pharmacological perspective, the ketolide class, of which telithromycin is an example, is composed of agents that are semisynthetic derivatives of 14-membered macrolides. They were developed specifically to be effective against macrolide-resistant, gram-positive cocci, in particular S. pneumoniae. Their enhanced activity against S. pneumoniae is facilitated by structural modifications at the positions of 3, 6, and 11-12, which yields modifications and improvements in the pharmacokinetic and antimicrobial activity of the parent compounds.
Antibacterial activity of macrolides and ketolides is dependent on inhibition of bacterial protein synthesis. The main differences between them, however, are that, although macrolides bind to only 1 contact site within the 23S ribosomal subunit (domain V), ketolides bind more avidly to domain V and, in addition, bind to a second site on the 23S subunit (domain II). Telithromycin also has some affinity for the effluxpump.26,27 These differences explain why ketolides remain active against pathogens with both erm- and mef-mediated resistance.
In vitro, telithromycin is active against S. pneumoniae, including macrolide-resistant strains, as well as H. influenzae and Moraxella catarrhalis.28,29 The drug also inhibits Legionella, Mycoplasma, and Chlamydophilia species.30,31 The drug is given once daily at a dose of 800 mg and appears to be well tolerated while achieving ratios of tissue to plasma of about 500 and 16.8 in alveolar macrophages and epithelial lining fluid, respectively.32,33
Data from three randomized, controlled, double-blind CAP trials comparing telithromycin with amoxicillin, clarithromycin, and trovafloxacin suggest that the ketolide is as effective as the comparators.34-36 Data available to date suggest that the ketolides may have an important role to play in the treatment of CAP caused by macrolide-resistant S. pneumoniae.
Updated Testing for Specific Pathogens
Chlamydia pneumoniae. Diagnosis of C. pneumoniae may be made by demonstration of a four-fold increase in IgG titer or a single IgM titer of greater than 1:16 using a microimmunofluorescence (MIF) or immunohistochemistry test.37 Alternate methods for diagnosis include tissue culture or a PCR assay of respiratory secretions. Acute and convalescent-phase MIF samples should be studied on the same run on the same ELISA plate.
Streptococcus pneumoniae. There is a pneumococcal urinary antigen test that is acceptable for use in addition to the standard sputum gram stain and culture. The antigen detection assay detects pneumococcal cell wall polysaccharide, which is common to all serotypes. The immunochromatographic membrane test, or ICT, can be performed on a concentrated urine in 15 minutes. The sensitivity ranges from 50-80%, with specificity of approximately 90%.38,39 The sensitivity in defining bacteremic disease in adults is cited as 70-90%.7 However, in children, the specificity appears to be much lower, as nasopharyngeal carriers of pneumococci may register falsely positive.40
It is notable that a traditional test for pneumococcus, a gram stain and culture of sputum, may have little to no value in the diagnosis and management of the CAP patient. One study of 74 adult patients hospitalized with nonsevere CAP were evaluated with gram stains and sputum cultures. Even with strict criteria of 25 neutrophils and fewer than five squamous epithelial cells per low powered field, gram stain of valid sputum specimens failed to identify the etiologic agent in a single case. Sputum cultures identified an agent in only four cases, all patients responded to appropriate initial antibiotic therapy, without use or knowledge of culture results.38
Legionella pneumophila. The preferred diagnostic tests for Legionella are urinary antigen testing and culture of respiratory secretions. The urinary antigen test rapidly detects 80-95% of community-acquired cases. Culture on selective media detects nearly all strains, but takes 3-7 days to complete.41 Testing may be appropriate in certain epidemiologic settings, for cases in which the cause of CAP is unclear and the patient is not improving on standard CAP therapy.
Viral Agents. Influenza testing is discussed in Part I of this series. Antigen tests for respiratory syncytial virus in adults are insensitive for detecting infection, and are not recommended.
Current literature indicates that with extensive studies, including blood and sputum cultures, bronchoscopy, needle aspirate of pleural fluid, and acute and convalescent serum testing, an etiologic agent diagnosis can be found in approximately 50% of cases of CAP (53/101 cases).10 Many of these tests are clearly of little or no utility in the emergency setting.
Quality Indicators and Assurance
The ED is the portal of entry for the majority of cases of pneumonia admitted to the hospital. There has been increased emphasis on the administration of antibiotics within four hours of patient arrival. Blood cultures should be drawn and sent prior to antibiotic administration in hospitalized patients. In unselected patients, the yield of blood cultures in determining an etiologic agent in CAP is on the order of 6-11%; however, in the elderly, blood cultures within 24 hours of admission to guide therapy were associated with reduced 30-day mortality.42 Appropriateness of initial antibiotic selection has come under increased scrutiny as well. Utilization goals are tied closely to accuracy and promptness of initial therapy in the ED.
As well, there has been increasing emphasis on the proper disposition from the ED, including criteria for admission to the hospital and admission to intensive care. It has been estimated that hospitalizations account for 89-96% of pneumonia costs.3,43
Length of stay has been shown to be related to three quality-of-care measures: initial administration of antibiotics in the ED, appropriate antibiotic selection, and shortened door to needle time. Initiation of antibiotic therapy in the ED led to shorter hospital stays for CAP by approximately two days in one report.44
The following have been listed as quality indicators in the assessment of care of the CAP patient:
1. Antibiotics given in a timely way, within either 4 or 8 hours of hospital admission;
2. Oxygen assessment or therapy within 8-24 hours of hospital arrival;
3. Blood culture drawn prior to antibiotic administration in the hospitalized patient;
4. Administration of antibiotics with activity against all likely causative pathogens, preferably the least expensive efficacious regimen;
5. Counseling patients regarding smoking cessation;
6. Switching from IV to oral antibiotics if clinically improving and hemodynamically stable, with discharge within 24 hours of switching to oral therapy;
7. Chest radiography within 24 hours of hospital admission;
8. Employment of methods to increase vaccination rates against influenza and pneumococcus; and
9. No discharge home for patients who are unstable on the day of discharge.45
More rapid and appropriate discharge from the hospital has been shown to save money without compromising patient safety in a recent study. Discharge criteria included ability to take medications by mouth, heart rate less than 100 beats/minute, respiratory rate less than 24 breaths per minute, baseline mental status, and temperature less than 38° C. Systolic blood pressure should be greater than 90 mmHg, and pulse oximetry should be greater than 90% saturation.46 As well, no other medical reasons for hospitalization should be present. Thirty-day mortality and re-hospitalization, and return to function were similar to the group that was hospitalized longer despite stability of the above.
Studies of Medicare patients in the 1980s indicate that, since the prospective payment system was implemented, there has been a 43% relative increase in patients being sent home either prematurely or in an unstable state.47 Of patients discharged from the hospital in an unstable state, this group has been documented to show increased mortality on hospital re-admission.48
Prevention of Thromboembolic Phenomena
Hospitalization for pneumonia puts the patient at risk for thromboembolic disease, especially when co-morbid conditions such as respiratory failure and congestive heart failure are factored into the equation. The presence of pneumonia itself in patients older than 75 years of age has been deemed to be an indication for prophylaxis against deep venous thrombosis (DVT).4 This is of particular significance in the presence of respiratory failure of CHF,49 and has been emphasized in guidelines promulgated by the American College of Chest Physicians.47 The recent MEDENOX trial noted a 63% decrease after 14 days of treatment with 20-40 mg of enoxaparin daily in the incidence of DVT compared to placebo in patients treated for CHF, pneumonia, or respiratory failure. No increase in frequency of hemorrhage, thrombocytopenia, or any other adverse event was noted, compared to placebo.49
Antibiotic therapy should be tailored to treating the most likely pathogens, and also to keeping the therapy from being overly broad and thereby inducing resistant strains of bacteria. Emphasis has been placed on early antibiotic therapy, both to improve mortality and to decrease duration of hospitalization. The house of medicine and the emergency physician in particular may be called upon to assume a greater role in preventative care and public health, especially in regard to immunization, smoking cessation, and recognition of new epidemics.
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21. Doern GV, Heilmann KP, Huynh HK, et al. Antimicrobial resistance among clinical isolates of Streptococcal pneumonia in the United States during 1999-2000, including a comparison of resistance rates since 1994-1995. Antimicrob Agents Chemother 2001;45:1721-1729.
22. Waterer GW, Somes GW, Wonderink RG. Monotherapy may be suboptimal for severe bacteremic pneumococcal pneumonia. Arch Intern Med 2001;161:1837-1842.
23. Martinez JA, Horcajada JP, Almeld M, et al. Addition of a macrolide to a beta-lactam based empirical empirical antibiotic regimen is associated with lower in-hospital mortality for patients with bacteremic pneumococcal pneumonia. Clin Infect Dis 2003;36: 396-398.
24. Panduch GA, Visalli MR, Jacobs MR, et al. Susceptibilities of penicillin and erythromycin susceptible and resistant pneumococci to MHR 3647, a new ketolide, compared with susceptibility to 17 other agents. Antimicrob Agents Chemother 1998;42:624-630.
25. Wooton M, Bowker KE, Janowska A, et al. In vitro activity of HMR 3647 against Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis and beta-haemolytic streptococci. J Antimicrob Chemother 1999;44:445-453.
26. Hansen LH, Mauvais P, Douthwaite S. The macrolide-ketolide antibiotic binding site is formed by structures in domains II and V of 23S ribosomal RNA. Mol Microbiol 1999;31:623-631.
27. Leclercq R. Will resistance to ketolides develop in Streptococcus pneumoniae? Antimicrob Agents Chemother 2002;46:2727-2734.
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29. Wooton M, Bowker KE, Janowska A, et al. In vitro activity of HMR 3647 against Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis and beta-haemolytic streptococci. J Antimicrob Chemother 1999;44:445-453.
30. Edelstein PH, Edelstein MA. In-vitro activity of the ketolide HMR3647 (RU 6647) for Legionella spp., its pharmacokinetics in guinea pigs, and use of the drug to treat guinea pigs with Legionella pneumophila pneumonia. Antimicrob Agents Chemother 1999;43: 90-95.
31. Miyashita N, Fukano H, Niki Y, Matsushima T. In vitro activity of telithromycin, a new ketolide, against Chlamydia pneumoniae. J Antimicrob Chemother 2001;48:403-405.
32. Pascual AA, Ballesta S, Garcia I, et al. Uptake and intracellular activity of Ketolide HMR 3647 in human phagocytic and non phagocytic cells. Clin Microbiol Infect 2001;7:65-69.
33. Kadota J, Ishimatsu Y, Iwashita T, et al. Intrapulmonary pharmacokinetics of telithromycin, a new ketolide, in healthy Japanese volunteers. Antimicrob Agents Chemother 2002;46:917-21.
34. Hagberg L, Carbon C, vanRensburg DJ, et al. Telithromycin in the treatment of community-acquired pneumonia: A pooled analysis. Respir Med 2003;97:625-633.
35. Hagberg L, Torres A, VanRensburg DJ, et al. Efficacy and tolerability of once daily telithromycin compared with high-dose amoxicillin in the treatment of community-acquired pneumonia. Infection 2002; 30:378-386.
36. Pullman J, Champlin J, Vrooman PS Jr. Efficacy and tolerability of once daily oral therapy with telithromycin compared with trovafloxacin in the treatment of community-acquired pneumonia. Int J Clin Pract 2003;57:377-384.
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40. Dowell SF, Garman RL, Liu G, et al. Evaluation of Binax NOW, an assay for the detection of pneumococcal antigen in urine samples, performed among pediatric patients. Clin Infect Dis 2001;32: 824-825.
41. Centers for Disease Control and Prevention. Case definitions for infectious conditions under public health surveillance. MMWR Morb Mortal Wkly Rep 1997;46 (RR-10):1-55.
42. Meehan TP, Fine MJ, Krumholz HM, et al. Quality of care, process, and outcomes in elderly patients with pneumonia. JAMA 1997;278: 2080-2084.
43. Burman CA, Pacetti S, Gelone SP. An Update on the treatment of community-acquired pneumonia, at www.pharmacytimes.com. Accessed March 9, 2004.
44. Battleman DS, Callahan M, Thaler HT. Rapid antibiotic delivery and appropriate antibiotic selection reduce length of hospital stay of patients with community-acquired pneumonia. Arch int Med 2002; 162:682-688.
45. Rhew DC, Goetz MB, Shekelle PG. Evaluating quality indicators for patients with community-acquired pneumonia. Joint Commission Journal on Quality Improvement 2001;27:S75-90.
46. Fine MJ, Stone RA, Lave JR, et al. Implementation of an evidence-based guideline to reduce duration of intravenous antibiotic therapy and length of stay for patients hospitalized with community-acquired pneumonia: A randomized controlled trial. Am J Med 2003;115:343-351.
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49. Samama MM, Cohen AT, Darmon JY, et al. A comparison of enoxaparin with placebo for the prevention of thromboembolism in acutely ill medical patients. Prophylaxis in Medical Patients with Enoxaparin Study Group. N Engl J Med 1999;341:793-800.
In the March 22, 2004, issue, a reference was listed incorrectly. The correct reference should be:
20. White HD. Thrombolytic therapy in the elderly. Lancet 2000;356:2028-2030.