Outpatient and In-Hospital Management of Community-Acquired Pneumonia: Prediction Rules for Patient Disposition and Outcome-Effective Antibiotic Selection
Authors: Charles L. Emerman, MD, Associate Professor of Emergency Medicine, Case Western Reserve University; Department of Emergency Medicine, MetroHealth Medical Center, Cleveland Ohio. Gideon Bosker, MD FACEP, Assistant Clinical Professor, Section of Emergency Services, Yale University School of Medicine; Associate Clinical Professor, Oregon Health Sciences University. Lisa A. Miller, MD, Department of Emergency Medicine, Metro-Health Medical Center, Cleveland, Ohio. Peer Reviewers: Jonathan Edlow, MD, Acting Chief of Service, Department of Emergency Medicine, Beth Israel Deaconess Medical Center, Boston, MA; Instructor in Medicine, Harvard Medical School, Cambridge, MA. Stephen P. Ernst, PharmD, Clinical Pharmacy Coordinator, Columbia Terre Haute Regional Hospital, Terre Haute, IN; Sandra M. Schneider, MD, Professor and Chair, Department of Emergency Medicine, University of Rochester, Rochester, NY. Steven M. Winograd, MD, FACEP, Attending Physician, Department of Emergency Medicine, Lakeland Regional Health System, St. Joseph, MI.
Community-acquired pneumonia: Complex, common, costly and, above all, caution inspiring. In fact, few conditions produce such a broad range of outcomes, require such customized approaches, or present so many options for treatment. Despite important advances in patient assessment techniques, disposition support tools, and antimicrobial therapy, community-acquired pneumonia (CAP) continues to be a leading cause of morbidity and mortality in the United States, accounting for about 10% of all hospitalizations and billions of health care dollar expenditures each year.1-4 From patient disposition to antimicrobial selection, optimizing management of CAP requires the clinician to integrate a number of clinical, laboratory, radiologic, and etiologic factors, and develop a course of action that accounts for all the risks, costs, and benefits of an individualized treatment plan.
Providing expert guidance for emergency physicians, intensivists, and pulmonologists in the management of CAP, both in the outpatient and in-hospital setting, a number of excellent expert panel consensus reports-including those from the American Thoracic Society (ATS) and the Infectious Disease Society of America (IDSA)-have attempted to characterize host risk factors, etiologic pathogens, and disposition criteria that can be used to maximize cure rates.
Despite the plethora of guidelines, and the availability of new, targeted spectrum antibiotics, the management of pneumonia remains extremely challenging and, more than ever, requires a multifactorial analysis of myriad clinical and laboratory parameters that prognosticate success or possible failure for each individual case. In this regard, clinical decison-making in CAP can be deceptively treacherous for the emergency physician. Achieving optimal patient outcomes for this life-threatening condition requires the clinician to consider several features of each individual case ranging from the patient's age, underlying disease, and local antimicrobial resistance patterns to patient disposition, empiric antibiotic selection, and necessity for additional diagnostic investigation.
The antibiotic selection process for CAP is no less daunting. Currently, the pathogens most often responsible for causing CAP include the bacterial organisms, S. pneumoniae, H. influenzae, and M. catarrhalis, as well as the atypical pathogens whose importance and propensity for causing morbidity and mortality is being increasingly emphasized: Mycoplasma, Legionella, and Chlamydia pneumoniae.5 Because it may be difficult, if not impossible, to differentiate between typical and atypical pathogens at the time of initial patient assessment, empiric antimicrobial coverage against all these expected pathogens may be necessary to minimize treatment failures.6,7
In this vein, the development of advanced generation macrolides (azithromycin and clarithromycin) and extended spectrum quinolones (trovafloxacin and levofloxacin) has made it possible to treat this spectrum of pathogens using monotherapy. Finally, because there is a growing incidence of resistance among common bacterial agents that cause CAP (in some areas of the United States, intermediate-to-complete resistance to penicillin among streptococcus pneumoniae species is reported to be greater than 25%) antibiotic selection must be guided by local and/or regional resistance patterns.8
The purpose of this comprehensive review is to provide a state-of-the-art clinical resource outlining, in precise and practical detail, clinical protocols for outpatient and in-hospital management of CAP. To achieve this goal, all of the critical aspects entering into the equation for maximizing outcomes while minimizing costs, including systematic patient evaluation, disposition decision trees, and outcome-effective antibiotic therapy, will be discussed in detail. In addition, because appropriate disposition of patients with CAP has become essential for cost-effective patient management, this issue includes a Critical Pathway in Emergency Medicine that analyzes risk stratification protocols that can be used to identify those patient subgroups that are suitably managed in the outpatient setting, and those more appropriately admitted to the hospital for more intensive care.
-The Editor
Introduction
Community-acquired pneumonia (CAP) is a common problem and a potentially life-threatening condition that accounts for about 500,000 adult hospitalizations and 1.2 million emergency department (ED) visits annually.1 Although this infectious disease affects individuals of all ages, pneumonia is a more frequent problem in young children and in older adults. The annual incidence of pneumonia in patients older than 65 years is about 1%.1 The typical presentation of pneumococcal pneumonia with fever, rigors, shortness of breath, chest pain, sputum production, and abnormal lung sounds is easy to recognize. Unfortunately, the changing epidemiology of pneumonia presents a greater diagnostic challenge. Atypical agents, or opportunistic infections in immunocompromised patients, have a much more subtle presentation. And pneumonia in young children may not present with classical findings, whereas older patients frequently have an insidious presentation, with fewer characteristic features of pneumonia.2
Triage. Hospitalization of patients with pneumonia is costly, although many patients with CAP can be safely managed as outpatients. In the absence of respiratory distress or other complicating factors, many children and young adults can be adequately treated with appropriate oral antibiotic therapy. Even following appropriate treatment, however, patients may have symptoms, including cough, fatigue, dyspnea, sputum production, and chest pain that last for several months.3 A variety of investigators have proposed criteria to identify patients requiring hospitalization. Patients felt to be at "low" risk have a median length of stay of seven days, while those at "medium" risk have a median length of stay of 12-13 days.4
Among the factors physicians use to make admission decisions for pneumonia are the presence of hypoxemia, the ability to maintain oral intake, and the patient's home situation.9 Using clinical judgement, however, physicians tend to overestimate the likelihood of death from pneumonia.9 These findings have led some investigators to employ more stringent prediction rules. For example, the chest radiograph may help to identify patients at high risk for mortality.10 The presence of bilateral effusions, moderate-size pleural effusions, multi-lobar involvement, and bilateral infiltrates are associated with a higher risk of mortality. On the other hand, the presence of air bronchograms lessens the likelihood of death.11
Table 1. Assignment to Risk Classes II-V for Prediction of Mortality from Pneumonia
| Criteria | Points |
| Assignment of risk points | |
| Female gender | -10 |
| Nursing home | 10 |
| Coexistent illness | |
| Neoplastic disease | 30 |
| CHF | 20 |
| CVA | 10 |
| Renal disease | 10 |
| Liver disease | 10 |
| Abnormal exam | |
| abnormal mental status | 20 |
| Pulse Þ 125 | 20 |
| RR Þ 30 | 20 |
| BP Ü 90 | 15 |
| 35 < temperature > 40 | 10 |
| Lab and x-ray | |
| pH < 7.35 | 30 |
| BUN Þ 30 | 20 |
| Na < 130 | 20 |
| Glucose Þ 250 | 10 |
| Hematocrit < 30% | 10 |
| PaO2 < 60 mmHg | 10 |
| Pleural effusion | 10 |
| Class stratification | ||
| Class | Points | Mortality |
| Class II | < 70 | 0.6% |
| Class III | 71-90 | 0.9% |
| Class IV | 91-130 | 9.3% |
| Class V | > 130 | 21.0% |
Source: Adapted from MJ Fine. N Engl J Med 1997;336: 243-250.
A recent landmark study outlined a prediction rule to identify low risk patients with CAP.12 (See Table 1.) Using patient age, coexistent medical conditions, and vital signs, patients are assigned either to a low-risk class, which has a mortality rate of about 0.1% in outpatients, or to higher risk categories. Patients with any risk factors are then evaluated with a second scoring system that assigns individuals to one of three higher risk categories, which have mortality rates that range from 0.7% to 31%.12 In addition to the factors noted in this prediction rule, patients who are immunocompromised as a result of AIDS or chronic alcohol use frequently require hospitalization.
Once the clinician has determined hospitalization is required, the need for intensive care unit admission must also be evaluated. In this regard, a variety of factors are associated with an increased risk for mortality, including increasing age, alcoholism, chronic lung disease, immunodeficiency, and specific laboratory abnormalities.13,14 The American Thoracic Society guidelines for the identification of patients at high risk for mortality is presented in Table 2.15
Table 2. Identification of Patients at High Risk for Mortality
1. Respiratory rate > 30 per minute
2. PaO2/FIO2 ratio less than 250
3. Ventilatory support
4. Multi-lobar, bilateral, or greater than 50% infiltrates
5. Systolic blood pressure less than 90 mmHg
6. Diastolic blood pressure less than 60 mmHg
7. Necessity for vasopressors
8. Urine output less than 20 mL/hour
Diagnosis and Evaluation
The definitive diagnosis of pneumonia is verified by the recovery of a pathogenic organism(s) from either the blood, sputum, or pleural fluid in the setting of a patient with a radiographic abnormality suggestive of pneumonia. In the case of atypical organisms, the diagnosis is made by the comparison of acute and convalescent sera demonstrating a rise in appropriate titers, or by other sophisticated techniques such as direct florescent antibody testing. The Gram's stain is occasionally helpful in establishing the diagnosis, but requires practitioners or technicians highly skilled in this diagnostic methodology. An adequate Gram's stain must have fewer than 25 epithelial cells per low-powered field.16 The finding of more than 10 gram-positive, lancet shaped diplococci in a high-powered field is a sensitive and specific predictor of pneumococcal pneumonia.16 Unfortunately, the Gram's stain will rarely be helpful in determining other causes of pneumonia.17
Transtracheal aspiration or bronchial washings is a more accurate means of obtaining specimens for Gram's stains and culture, although this procedure is rarely indicated in the outpatient setting. Overall, fewer than 50% of patients with a CAP will be able to produce sputum.18 Of these, half of the sputum specimens obtained will be inadequate.17,19 When an adequate Gram's stain is obtained, however, it has a negative predictive value of 80% when compared to a sputum culture.20 The blood culture is helpful in about 15% of patients, while serology will establish the diagnosis in 25% of patients.21 About 40% of sputum cultures will identify a pathologic organism. Bronchoscopy and thoracentesis may occasionally be necessary, but these procedures generally are reserved for seriously ill patients, particularly those who require management in the intensive care unit setting.
The signs and symptoms of pneumonia may be mimicked by many disorders, including pulmonary embolism, lung cancer, hypersensitivity pneumonitis, tuberculosis, chronic obstructive pulmonary disease (COPD), granulomatosis disease, and fungal infections.22 A variety of drugs also can induce pulmonary disease. Cytotoxic agents, non-steroidal anti-inflammatory drugs, and some antibiotics, including sulfononamides, as well as certain antiarrhythmics, such as amiodarone or tocainide, can mimic pulmonary infection. In addition, common analgesics, including salicylates, propoxyphene, and methadone may also precipitate acute respiratory symptoms. Such collagen vascular diseases as systemic lupus erythematosus, polymyositis, and polyarteritis nodosa may cause fever, cough, dyspnea, and pulmonary infiltrates, thereby mimicking symptoms of pneumonia. Rheumatoid arthritis can cause an interstitial lung disease, although it does not usually cause fever or alveolar infiltrates.23
Table 3. Signs and Symptoms of Community-Acquired Pneumonia
| Organism | Population at risk | Typical symptoms | Other findings | Radiographic appearance |
| S. pneumoniae | all, but children and elderly at greater risk | sudden onset, fever, chills, pleuritic chest pain | herpes simplex | lobar pneumonia pleural effusions "round" infiltrates |
| H. influenzae | older patients, COPD, alcoholics | gradual onset bronchitis, dyspnea chest pain | rales | consolidative or patchy lobular pattern |
| S. aureus | nursing home patients post-influenza infection | gradual onset fever, sputum, dyspnea | hemoptysis | multi-lobar infiltrate effusion, empyema, abscess |
| K. pneumoniae | alcoholics, nursing home patients | sudden onset, chest pain, dyspnea, bloody sputum | toxic appearance | multi-lobular infiltrate effusion, empyema, abcess |
| B. catarrhalis | COPD, most commonly occurs during winter months | gradual onset, cough, fever retrosternal chest pain, wheezing | petechial rashes | interstitial pattern |
| L. pneumophila | COPD, smokers | gradual onset, pleuritic chest pain, GI disturbance, shaking chills | hyponatremia, altered mental status, sinusitis | patchy localized infiltrate |
| M. pneumoniae | children, young adults | gradual onset, malaise, fever, headache | pharyngitis, adenopathy, cunjunctivitis, sinusitis | patchy localized infiltrate |
| Chlamydia TWAR | all, but incidence increases with age | gradual onset, cough, fever, wheezing | sinusitis | subsegmental infiltrates |
| Anaerobic organisms | alcoholics | gradual onset, putrid sputum | weight loss | upper segments of lower lobes, lower segments of upper lobes |
| Q fever | exposure to livestock or parturient cats | sudden onset, high fever, chills | severe headache, hepatomegaly | rounded densities |
| Tularemia | exposure to ticks, rabbits, squirrels | pleuritic chest pain | rashes | variable, may have ovoid infiltrates |
| Psittacosis | exposure to birds | sudden onset, chest pain | severe headache, hemoptysis, pharyngitis, splenomegaly | patchy hilar infiltrates |
Radiographic Features
Although atypical etiologies (Mycoplasma, Chlamydia, Legionella) of pneumonia tend to have a different radiographic presentation than that seen in patients with bacterial pneumonia, clinical distinctions based on radiographic features are difficult, if not impossible, in the majority of cases. Patients with bacterial pneumonia are more likely to have unilobar pneumonia as compared to patients infected with atypical agents.24 Lobar or segmental collapse is most common in patients with atypical pneumonia, as is hilar adenopathy. In general, patients with bacterial pneumonia are more likely to have cavitary lesions, effusion, and bulging of the fissures compared to patients with an atypical cause of their pneumonia. In addition, patients with atypical pneumonia are more likely to have nodular or reticular infiltrates, and perihilar adenopathy.25 (See Table 3.)
Pleural effusions are generally encountered in staphylococcal or streptococcal pneumonia.26 Gram-negative and anaerobic infections can cause effusions, which develop later in the course of the pneumonia.26 In these cases, the effusions frequently represent empyema.27 Occasionally, patients with Legionnaires' disease, viral pneumonia, or Mycoplasma pneumonia may develop a small effusion.28,29
Lung abscesses are a rare complication of CAP. When they occur, they are generally secondary to Staphylococcus aureus or Klebsiella pneumoniae.27 Most pneumonias tend to occur in the lower lobe. Lobar infiltrates are associated with a number of bacteriologic etiologies, with pneumococcal pneumonia being the most common cause of lobar pneumonia. Klebsiella can also cause a lobar consolidation, particularly in association with a bulging fissure and empyema.30 Sublobar, unifocal consolidation can also occur with pneumococcal pneumonia and viral pneumonia, although it is not a common presentation for these entities.31
Chlamydia TWAR (or C. pneumoniae) is almost always unifocal in presentation. Multifocal infiltrates are the usual presentation of Staphylococcal pneumonia.32 Gram-negative infection, anaerobic infection, Mycoplasma pneumonia, and viral infections, as well as Legionella, also are common causes of multifocal infiltrates.32-34 Pulmonary infections may present as single or multiple lung masses. The so-called "round" infiltrate of pneumococcal and staphylococcal pneumonia occurs as a result of spread of infection from a single focus.35,36 Rarely Legionella may also present with a mass-like appearance.31 Q fever and tularemia also may present with multiple, discreet masses.32,37,38 Cavitary lesions usually are the result of anaerobic abscesses, staphylococcus aureus, or Gram-negative organisms such as Klebsiella or Pseudomonas.25,32 Cavitary lesions may occur in patients with psittacosis, although even in this disease it occurs only in 10%. Rarely, cavitation may be caused by Legionella.38 Interstitial or nodular infiltrates are seen in patients with psittacosis, Mycoplasma pneumonia, Pneumocystis carinii pneumonia (PCP), or viral pneumonia.39,40
Table 4. Etiologic Agents of Pneumonia in Children
NEONATE
Group B Streptococcus
Listeria monocytogenes
Gram negatives-E. coli, Klebsiella
Chlamydia trachomatis (neonate to 3 months)
Cytomegaloviris
Herpes simplex virus
Rubella virus
< 1 YEAR
Streptococcus pneumoniae
Haemophilus influenzae
Staphylococcus aureus
Respiratory syncytial virus
Parainfluenza virus
> 1 YEAR
Streptococcus pneumoniae
Haemophilus influenzae
Staphylococcus aureus
Influenza virus
Rhinovirus
Parainfluenza virus
Adenovirus
Enterovirus
Varicella virus
Epstein-Barr virus
Chlamydia penumoniae (school-aged)
Mycoplasma pneumoniae (school-aged)
Many studies on the etiology of CAP have focused on in-patients. Recent investigations emphasize that the spectrum of pathogens responsible for infection in ambulatory patients is different from that in patients ill enough to require hospitalization. In hospitalized patients, multiple agents are found in up to 42% of patients, while an etiologic agent cannot be confirmed in about 38% of cases.41 Pneumococcus is the most commonly identified pathogen, followed by M. pneumoniae, Chlamydia pneumoniae, Legionella, and viral disease. Older patients and those with co-morbid disease are more likely to have bacterial causes of their pneumonia as compared to the higher incidence of atypical agents in younger patients. The etiology of pneumonia may also reflect the underlying immune status of the patient population. In inner city hospitals associated with a high incidence of AIDS, Pneumocystis carinii is a common etiologic agent.42 Pneumonia caused by atypical agents is less common in this patient population. In typical ambulatory settings, pneumonia caused by atypical agents may occur in as many as one-third of patients.43
Pneumococcal Pneumonia. Streptococcus pneumoniae remains the most common etiologic agent identified in patients with CAP.44,45 Pneumococcal pneumonia affects all age groups but is more common in children and the elderly. Patients with altered mucociliary clearance, such as smokers, alcoholics, and patients recovering from viral infection are also at higher risk for developing pneumococcal infection.46 Of note, patients at risk for pneumococcal pneumonia should be vaccinated. The risk for acquiring complications of pneumonia is reduced by two-thirds following vaccination.47 Similarly, yearly influenza immunization reduces the risk of both pneumococcal and other forms of bacterial pneumonia.48
In young children, pneumococcal pneumonia affects about 1:1000 children, while, in the elderly, pneumococcal pneumonia affects about 1:2000 patients.46 Otherwise healthy adults may develop pneumococcal pneumonia, particularly during epidemics occurring in crowded situations, although atypical agents are a more frequent cause of pneumonia in this population. Patients at particular risk for pneumococcal pneumonia include alcoholics, cigarette smokers, patients with chronic lung disease, patients with congestive heart disease, diabetics, individuals with cancer, those infected with the HIV virus, and patients who are otherwise immunosuppressed.49,50
The classical presentation of pneumococcal pneumonia consists of sudden onset of rigors, fever, cough, pleuritic chest pain, and rust colored sputum. This occurs more commonly in young patients and frequently is associated with a segmental or lobar pneumonia. Parapneumonic pleural effusions are common in this setting, occurring in about 25% of patients. Empyema is relatively uncommon, although about 10% of pleural effusions will evolve into an empyema.51,52 Bacteremia occurs commonly in pneumococcal pneumonia, particularly in patients who have asplenism or HIV infection.52 Bacteremia is associated with a higher mortality rate. Meningitis is an uncommon complication of pneumococcal pneumonia, although this diagnosis should be considered in patients with confusion or severe headache. Lung abscesses are a rare complication of pneumococcal pneumonia, as is purulent pericarditis.52
Atypical presentations must be appreciated by the clinician. In this vein, elderly patients, those with chronic lung disease, and individuals recovering from influenza may have a more insidious presentation of pneumonia. In this setting, the disease may be heralded by a mild cough, scant sputum production, or, possibly, by a change in sputum color and signs of dehydration. Pleural effusion is uncommon in this setting. Finally, patients who have functional or anatomic asplenism, transplant patients, or patients who have hypogammaglobulinemia may undergo a rapidly progressive course with high temperatures, hypotension, DIC, and multisystem organ failure.
Findings on the chest radiograph in patients with pneumococcal pneumonia are variable. Patients with so-called "classic" disease frequently have lobar or segmental pneumonia, while a patchy bronchopneumonia is a more characteristic finding in elderly patients. As noted above, pleural effusions are a common finding in pneumococcal pneumonia.26 Most patients with pneumococcal pneumonia will have a leukocytosis.46 Elevation of serum bilirubin or other liver enzymes may also occur.
There is a significant incidence of pneumococcal resistance to tetracycline and trimethoprin-sulfamethoxazole, particularly in children attending day care.54 Overall, macrolide resistance to pneumococci is about 7-9% the United States.55 A macrolide such as azithromycin or an extended spectrum quinolone such as trovafloxacin should be used for outpatient treatment. Other advanced generation macrolides or extended spectrum quinolones also may be considered. (See Table 6.) Clindamycin, while effective against pneumococcus is associated with a high incidence of adverse reactions. In the case of a patient with demonstrated high-level resistance or with severe infection, vancomycin, 1 gm intravenously every 12 hours is indicated.
Staphylococcus aureus. Staphylococcus aureus is an infrequent cause of CAP. It is more likely to occur in patients with COPD, patients with bronchogenic or laryngocarcinoma, patients with preceding viral illness, immunosuppressed patients, as a consequence of seizures, and in nursing home patients.55 Seeding of the lung by hematogenous spread is an occasional complication of intravenous drug abuse. Patients typically present with gradual onset fever, purulent sputum, and dyspnea, although rarely there may be a more dramatic and aggressive onset of the disease.56 The chest radiograph usually demonstrates empyema and pleural effusions, accompanied by multi-lobar infiltrates; abscess formation may also occur with S. aureus pneumonia. Patients with S. aureus pneumonia will require admission for treatment with penicillinase resistant antibiotics and, in some cases, with vancomycin.
Klebsiella pneumoniae. Klebsiella pneumonia occurs primarily in alcoholics, nursing home patients, and, occasionally, in patients with COPD. Almost all cases occur in patients older than 40 years. The onset is generally sudden and associated with cough, sputum production, rigors, malaise, and pleuritic chest pain. The sputum of patients with Klebsiella pneumonia is thick and bloody, with a currant jelly appearance. Herpes labialis occurs in about 10% of patients with Klebsiella pneumonia.57 The characteristic chest radiograph shows a lobar pneumonia, bulging fissures, and occasionally, abscess formation.58 Treatment usually includes a third-generation cephalosporin or an extended spectrum quinolone with or and aminoglycoside. An extended spectrum penicillin such as Ticarcillin/clavulinic acid may also be effective.
Pseudomonas. Pseudomonas pneumonia is responsible for a rapidly progressive and severe disease. Patients are frequently toxic in appearance, confused, and cyanotic.57 A relative bradycardia may occur. Empyema is common, along with bilateral lower lobe streaky infiltrates. The mortality rate ranges up to 80%.59 Pseudomonas infection should be considered in the seriously ill, hospitalized patient.
Hemophilus influenzae. H. influenzae occurs both in children and in adults. Adults with this form of pneumonia tend to have underlying pulmonary disease such as carcinoma, COPD, or chronic alcoholism.60 Occasionally, the elderly, diabetics, immunocompromised patients, and those with sickle cell anemia may develop H. influenzae infection. Immunization has decreased the incidence of H. influenzae infection in children. Patients usually present with a fairly abrupt course characterized by fever, cough, sputum production, chest pain, and dyspnea. Bacteremia has been a common finding in Hemophilus pneumonia in children in the past, and may also occur in patients older than age 50. (See Table 4.) The chest radiograph usually demonstrates a multi-lobar pattern.60 Pleural effusions are seen in about one-half of patients.
Legionella. Legionella pneumophila was recognized as a causative agent in pneumonia following the epidemic at the 1976 American Legion Convention.61 A variety of species of Legionella can cause pneumonia, although Legionella pneumophila, sera group 1, is by far the most common causative agent.62 Legionella species are found in water sources, including rivers, cooling towers, and hot water tanks. The organism is pleomorphic and faintly gram negative.63 Patients at risk for Legionnaires' disease include patients with a history of cigarette smoking, COPD, and immunosuppression.64,65 Transplant patients are also at significant risk for Legionella pneumonia following surgery.66 Although Legionella is commonly thought of as a disease of older patients, it can be seen in pediatric patients, particularly in immunosuppressed patients, post operatively, and in the neonatal period.67,68
Legionella infection can be seen at any time of the year; however, bacterial pneumonia is more common in the winter, while Legionella is a more common cause of pneumonia during the summer months. Legionella can cause a range of pulmonary disease from a benign, self-limited illness manifested by cough and low grade fever, to acute respiratory distress and multi-system failure. A brief illness with fever, malaise, and headache is sometimes termed Pontiac fever.69 Shaking chills are common in patients with Legionella.70 Pleuritic chest pain and hemoptysis, although not common, may mimic pulmonary embolism. Gastrointestinal symptoms such as abdominal pain, nausea, vomiting, and watery diarrhea may occur.70
Legionella also can cause extra-pulmonary symptoms, including sinusitis, cellulitis, pancreatitis, peritonitis, palnephritis, and myocarditis.71,72 Although hyponatremia is encountered in a number of pneumonias, it occurs more commonly in Legionella.62,69 There is no consistent pattern to the white blood count, although patients are more likely to have a leukocytosis than a leukopenia. A mild elevation of liver enzymes can also be seen620 The chest radiograph frequently shows a patchy localized infiltrate. Lower lobe infiltrates and hilar adenopathy may also occur. Pleural effusions are seen in one-third of patients,70 and immunosuppressed patients may demonstrate cavitary lesions.73
Legionella is sensitive to macrolide antibiotics; because erythromycin is associated with a high incidence of side effects,15 azithromycin is the macrolide of choice, and may be given intravenously. Quinolone antibiotics such as trovafloxacin and levofloxacin are also effective. Additional antibiotics that demonstrate activity include tetracyclines, sulfonamide, clindamycin, and imipenem.74 Rifampin should be added to patients who fail to demonstrate a prompt clinical response.
Moraxella catarrhalis. Moraxella catarrhalis is a respiratory pathogen that is most likely to cause infection in patients with underlying COPD. However, it also occurs occasionally in patients with other chronic diseases, such as diabetes mellitus, congestive heart failure, lung cancer, or cerebral vascular diseases.75 Patients typically have a one-week prodromal syndrome of bronchial infection with cough and sputum production. In pediatric patients, Moraxella may cause otitis media, sinusitis, or conjunctivitis.76 Most cases occur during the winter months. Moraxella frequently occurs in combination with H. influenzae and Streptococcus pneumoniae.77 Fever occurs in most, although not all patients.78 Pleuritic chest pain occurs in about one-half of patients.75 The chest radiograph typically demonstrates diffuse infiltrates, although occasionally lobar consolidation may occur. Moraxella catarrhalis responds to macrolide antibiotics, tetracycline, trimethroprim/sulfamethoxalone, extended spectrum penicillins, beta-lactam/lactamase inhibitors, second and third generation cephalosporins, and quinolone antibiotics. Patients with Moraxella catarrhalis frequently have indications for admission.
Chlamydia pneumoniae. Chlamydia pneumoniae or Chlamydia TWAR is a respiratory pathogen that exists as an obligate intracellular bacteria. C. TWAR infections are common, and almost 50% of the population has antibodies indicating prior infection.79 It appears that most patients who have antibodies to Chlamydia develop them between the ages of 5 and 14.80 Most patients with Chlamydia infection have only mild symptoms of respiratory illness which may include sore throat, hoarseness, and a cough that develops a week after the onset of symptoms. Early in the course of illness, patients have a fever that remits after several days.81 Rales or rhonchi are frequent findings on physical examination.81 Sinusitis may be associated with Chlamydia pneumonia. Most patients have a subsegmental focal infiltrate, and pleural effusions are rarely seen.82 Older individuals may have more extensive findings, including multifocal infiltrates or pleural effusions.82
Chlamydia responds to a number of antibiotics, including macrolides and extended spectrum quinolones such as trovafloxacin and levofloxacin, which demonstrate effective coverage against Chlamydia as well as Mycoplasma and Legionella.12 Penicillins and trimethroprim/sulfamethoxazone are not effective.
Table 5. Etiologic Agents of Pneumonia in the Immunocompromised Patient
BACTERIAL
Streptococcus pneumoniae
Haemophilus influenzae
Staphylococcus aureus
Pseudomonas aeruginosa
Klebsiella pneumoniae
Legionella pneumophilia
Mycoplasma pneumoniae
FUNGAL
Histoplasmosis capsulatum
Coccidioidomycosis immitis
Blastomycosis dermatitidis
Cryptococcus neoformans
Aspergillis
OTHER
Mycobacterium tuberculosis
Mycobacterium avium complex
Pneumocystis carinii
Cytomegalovirus
Influenza virus
Adenovirus
Mycoplasma pneumoniae. Mycoplasma pneumoniae is a gram-negative aerobe that lacks a cell wall. It is a common causative agent of pneumonia in children and young adults. Mycoplasma pneumonia occurs year round and since other causes of bacterial pneumonia occur in the winter, it, along with Legionella, will be a more common cause of pneumonia in the summer months. Mycoplasma pneumonia occurs in epidemics every 4-8 years,82 and it tends to cause a relatively mild respiratory illness. Most patients will have cough, malaise, chills, pharyngitis, and headache. Many patients will have symptoms consistent with a upper respiratory infection, including rhinorrhea and earache. Patients with Mycoplasma infection frequently do not develop pneumonia. Retrosternal chest pain associated with cough and deep breathing is a common finding.83 GI symptoms are rare in Mycoplasma pneumonia.
Mycoplasma pneumonia has a varied radiographic presentation which may include unilateral infiltrates, patchy multifocal infiltrates, or bilateral infiltrates. About 20% of patients will have hilar adenopathy.28 Additionally, about 20% of patients will have small pleural effusions.28 Mycoplasma pneumonia tends to be more severe in patients with sickle cell disease.84 Sinusitis is found in about two-thirds of patients with Mycoplasma pneumonia.85 Rarely, patients may have extrapulmonary complications, including hemolytic anemia, DIC, and renal failure. A significant minority of patients will have skin rashes.86 Rarely, patients may have neurologic symptoms, including encephalitis, transverse myelitis, and radiculopathies. Since Mycoplasma lacks a cell wall, penicillins and cephalosporins will not be effective against this disease. Antibiotics may reduce the duration of illness.
Unusual Causes of Community-Acquired Pneumonia
Although viral infection, pneumonococcal pneumonia, H. influenzae, M. catarrhalis, Mycoplasma pneumoniae, Chlamydia TWAR, and Legionella account for the majority of patients with CAP, some additional agents may be considered in certain settings.
Group A streptococcus. Group A streptococcal infection is most often associated with pharyngitis and rheumatic fever. Group A streptococcal pneumonia may occur after viral illness, particularly in toddlers and young people living in close quarters.87 These patients present with abrupt onset of fever, shortness of breath, and chest pain. Empyema is a common finding in these patients.
This organism has generally been associated with perinatal infection. Pneumonia caused by this agent usually occurs in older debilitated patients with underlying co-morbid disease.88 The clinical presentation is associated with hypotension, tachycardia, and tachypnea. This organism is frequently associated with other pathogenic bacteria.
Enterococcus. In the past, group D streptococci was associated with pneumonia in elderly and/or chronically ill medical patients. Pneumonia secondary to this agent is associated with the presence of feeding tubes and institutionalization.89
Acinetobacter. This organism is ubiquitous in the environment and colonizes the skin in 25% of normal patients. CAP from this agent may occur in alcoholics, patients undergoing renal dialysis, patients with COPD, or other chronically ill patients.90 Pneumonia due to Acinetobacter is frequently associated with severrespiratory distress, pleural effusions, and abscess formation.91
Listeria. Listeria is another organism that is common to the environment and is frequently carried by asymptomatic patients. It is also associated with perinatal infection and infection in immunocompromised patients. The most common setting in which this organism is found is in patients with underlying hematologic malignancies.92 Pleural effusions are common with pneumonia secondary to this agent.
Bacillus cerius. This organism is usually associated with food poisoning; however, it may cause pneumonia in alcoholic patients. Most patients with Bacillus cerius pneumonia will have hemoptysis.93 Eikenella corrodens is also associated with pneumonia in alcoholics. These patients have cavitary lesions and pleural effusions.
Hanta virus. Hanta virus is carried by rodents. There was a high incidence of infection with this virus among military personnel in Korea, where the disease was known Korean hemorrhagic fever.94 Most recently, this infection has been associated with an outbreak in the Southwest United States, although cases have been found east of the Mississippi River. In areas that are reservoirs for Hanta virus, the disease may be suspected on the basis of the development of adult respiratory distress syndrome or bilateral pulmonary infiltrates in previously healthy persons without underlying medical illness.
Q Fever. Most patients who develop Q fever have a benign febrile illness lasting several days to two weeks; it is usually characterized by malaise, myalgia, and severe headache.95 Patients with Q fever and pneumonia will generally have a non-productive cough and diaphoresis. The disease may occur with sudden onset of chills and high fever, is caused by Coxiella burnetii, and occurs as a result of exposure to livestock, drinking unpasteurized milk, exposure to parturient cats, or via tick bite.96 Q fever can also present with more serious manifestations, including endocarditis, meningitis, osteomyelitis, hemolytic anemia, and hepatitis.
Pneumonia occurs occasionally in Q fever and may be associated with epidemics. Most patients have a mild to moderate pneumonia. On physical examination, inspiratory crackles may be heard. Rarely, patients may have splenomegaly. The chest x-ray occasionally shows lobar consolidation but more usually reveals a rounded segmental lower lobe densities.36,97 Doxycycline is felt to be an effective form of treatment for this disease and is administered in doses of 100 mg, twice a day, for 10 days. Macrolide antibiotics, quinolones, rifampin, chloramphenicol, and trimethroprim may also be effective.98
The Immunocompromised Patient
Patients may be immunocompromised for a number of reasons, including HIV infection, immunosuppression in transplant patients, chronic steroid use, functional asplenism secondary to sickle cell disease, or treatment of malignancy. This section will focus primarily on the spectrum of pulmonary infections encountered in the HIV patient. A number of infectious processes are associated with HIV infection. Although a variety of bacterial infections can occur in the HIV patient, Streptococcus pneumoniae is still the most common etiologic agent causing CAP. (See Table 5.) The annual incidence of pneumonia is about 1%, or 5 times the rate in seronegative patients.99
With the onset of the AIDS epidemic in the 1980s, the differential diagnosis of pneumonia was expanded to include agents formerly seen only on an infrequent basis. Foremost among these agents is Pneumocystis carinii, a protozoan with a low degree of virulence for healthy, immunocompetent hosts. PCP is the most common cause of death in the AIDS patient and carries a 5-10% mortality rate for the first episode.100 The presentation of PCP is often insidious, with a gradually worsening, non-productive cough, dyspnea on exertion, and weight loss. Patients may have symptoms for as long as a month. Fever may be absent in up to 20% of cases, and symptoms may progress over the course of several weeks. A chest x-ray typically shows bilateral perihilar interstitial infiltrates but consideration variation can be seen. Up to 20% of patients presenting with PCP lack radiographic findings on the initial chest radiograph.101
If the HIV status of the patient is not known, but the individual has positive risk factors or evidence of opportunitistic infection, PCP must be considered as a cause for any respiratory complaints. If the patient is known to have HIV, the most recent CD4 lymphocyte count is useful in ascertaining the risk of opportunistic pulmonary infection. Studies have shown that a CD4 count less than 200/mm3 is more common in patients presenting with PCP.102 LDH levels greater than 220 IU have also been shown to be associated with PCP infection.103 Definitive diagnosis requires sputum induction and silverstaining. Invasive procedures may be required to obtain an adequate specimen. Given the time required for pathogen confirmation, cases are usually admitted for presumptive antibiotic therapy while awaiting diagnostic test results. Antibiotic therapy includes IV Bactrim or Pentamidine. These agents are also used as outpatient prophylaxis for PCP. Either daily single-dose Bactrim or a monthly dose of aerosolized Pentamidine are accepted therapeutic options. Intravenous steroids may also be used for moderate to severe cases of PCP. Recent reports, however, have proposed a rule for outpatient management plan for outpatient treatment of pneumonia in HIV-positive patients. The sulfamethoxazole/ trimethroprim (TMP/SMX) combination that is used for PCP prohphylaxis generally-but not always-is effective for suppressing PCP, as well as pneumonias caused by other etiologies.
Consequently, the emergence of a bacterial or atypical pneumonia in an HIV-positive individual who is on prophylactic TMP/SMX should raise the clinician's index of suspicion for: 1) infection with a resistant species of Streptococcous pneumoniae; 2) infection with a virulent, potentially gram-negative or atypical pathogen against which TMP/SMX may not show sufficient activity; or 3) significant immunocompromise, suggesting the need for aggressive in-hospital management. As a result, outpatient treatment of pneumonia in HIV-positive patients probably should be reserved for individuals who either: 1) are not on TMP/SMX prophylaxis, or 2) are taking a PCP prophylaxis regimen that does not include TMP/SMX.104
To qualify for outpatient management, the patient should also have reasonable oxygenation (i.e., PO2 > 70 mmHg or an O2 saturation > 95%), and the chest x-ray should be consistent with PCP, that is, it should show a pattern of diffuse, interstitial infiltrates. Because a definitive radiological diagnosis of PCP is not always possible, and because PCP can be confused with lower respiratory tract infections caused by bacterial or atypical pathogens, outpatient treatment of patients with HIV-positive status should consist of TMP/SMX in combination with a macrolide (i.e., azithromycin) or an extended spectrum quinolone (trovafloxacin or levofloxacin). If the patient does not improve within two days, then admission to the hospital is indicated.
As might be expected, bacterial pneumonias are also commonly encountered in the HIV patient. As with the general adult population, the most common pathogens are S. pneumoniae and H. influenzae,105 with studies showing that S. pneumoniae accounts for about 34-58% of confirmed cases of bacterial pneumonia in HIV-positive individuals.105 Overall, the incidence of S. pneumoniae pneumonia has been found to be approximately 7-10 times greater in the HIV population,106 and one study has shown the incidence of H. influenzae to be up to 100 times higher in this high-risk subgroup.107 Pneumonia caused by Staphylococcus aureus also occurs more commonly in the HIV-positive patient, with a reported incidence among pneumonia patients as high as 23%.108
Etiologic diagnosis can be complicated by atypical radiographic findings in this patient population. For example, bacterial pneumonia may present with an interstitial infiltrate pattern, instead of the more common lobar infiltrate characteristic of bacterial infection.109 In addition, patients with HIV infection are more likely to have multilobar infiltrates and their clinical course is more likely to be complicated by bacteremia.110 These adverse clinical features may influence patient disposition (i.e., encourage the clinician to manage the patient in the hospital) and choice of antibiotics.
It should be stressed that the immunocompromised host has an increased likelihood of acquiring pulmonary TB and is at risk for infection with other mycobacterial species (M. avium complex). Chest x-ray findings are not always helpful for establishing a definitive TB diagnosis in this population, and skin testing may reveal an anergic response. Patients should be placed in respiratory isolation until TB can be ruled out by acid-fast staining or culture of respiratory secretions.
The Elderly Patient
As has been emphasized throughout this article, the older individual with a lower respiratory tract infection represents a high-risk subgroup that is of special concern. Not surprisingly, this patient population has a higher incidence of coexisting disease, such as diabetes, CHF, CAD, chronic lung disease, renal insufficiency, chronic alcoholism, and neoplasms. The presentation of CAP in the geriatric patient can also be atypical. Compared to younger adults, the elderly are less likely to have pleuritic chest pain, hemoptysis, cough, or dyspnea as a manifestation for pneumonia.2 Moreover, this patient subgroup is more likely to present with dyspnea, and the duration in symptoms prior to diagnosis is longer for patients older than age 75 compared to younger adults.
The site or environment where patients acquire CAP and their previous history regarding lower respiratory tract infections can influence antibiotic selection. For example, elderly patients may present from a nursing home, or they may have been recently hospitalized. These historical features increase the likelihood of infection wth nosocomial pathogens such as Klebsiella pneumoniae and Pseudomonas aeruginosa. Accordingly, initial antibiotic selection in the emergency department would, from an appropriate intensity and spectrum-of-coverage perspective, include agents indicated for CAP caused by these organisms. An effective monotherapeutic option would include trovafloxacin, which is indicated for treatment of nosocomial pneumonia caused by Pseudomonas and E. coli; however, if there is a high likelihood of Pseudomonas infection, it would be prudent to add an antipseudomonal beta-lactam (carbapenem or cefepime) or an aminoglycoside.
Chronic alcoholism and stroke predispose to aspiration pneumonia. Anaerobic sources of infection (i.e. Bacteroides fragilis) must be considered in these patients, and initial choices should reflect this concern.111 Spectrum-sensitive coverage for these patients would include the fluoroquinolone trovafloxacin (which has excellent in vitro activity against Bacteroides fragilis, although it does not have an approved indication for treatment of CAP caused by anaerobic organisms) in combination with clindamycin or a beta-lactam/beta-lactamase inhibitor.
A supportive home environment with close physician follow-up will optimize chances for successful treatment. For patients who live alone or in an unstable home environment, who have several concomitant medical problems, who have underlying nutritional compromise, or for whom compliance with medical treatment is a concern, admission for treatment is warranted. This is especially applicable if the patient presents with progonositically adverse laboratory abnormalities or physical findings, such as fever higher than 40°C, pulse higher than 125/min, respirator rate greater than 30/min, hypotension, or hypoxia.112
The importance of early identification and treatment of pneumonia in elderly patients cannot be overemphasized. In a large analysis of 4069 patients older than age 65,104 the overall, 30-day mortality rate was 15%. Most importantly, early administration of antibiotics was shown to be associated with a lower mortality rate. Patients to whom antibiotics were administered more than 10 hours after arrival to the hospital were 20% more likely to die than those who had early administration of antibiotics.104
The Antibiotic Arsenal: Correct Spectrum Coverage and Appropriate Intensity Therapy for Community-Acquired Pneumonia
A Brief Overviewof the Antibiotic Landscape. The first generation cephalosporins have significant coverage against gram-positive organisms. By comparison, third generation cephalosporins have less gram-positive coverage and increased coverage against aerobic gram-negative rods.113 Ceftazidime has coverage against Pseudomonas, while cefoperazone has a somewhat higher MIC. Some of the second generation cephalosporins, such as cefoxitin, cefotetan, and cefmetazole, provide coverage against Bacteroides species. Imipenem has broad coverage against aerobic and anaerobic organisms. Aztreonam provides significant coverage for gram-negative bacilli such as Pseudomonas.
The aminoglycosides are active against gram-negative aerobic organisms. These agents are generally used for patients with severe CAP, particularly involving Pseudomonas. As a rule, they are combined with a third generation cephalosporin or an extended spectrum quinolone antibiotic, monobactam, or an extended spectrum penicillin when used in these circumstances.114
The tetracyclines are active against Streptococcus pneumoniae, H. influenza, Mycoplasma, Chlamydia, and Legionella. There is, however, a growing incidence of S. pneumoniae resistance to tetracyclines.115 These agents are alternatives to the macrolide antibiotics for empiric therapy for CAP in young healthy adults.45 Convenience and coverage advantages of the new macrolides, however, have thrust the tetracyclines into a secondary role for managing CAP. Clindamycin has activity against the anaerobes, such as B. fragilis,116 as well as gainst S. pneumoniae and S. aureus.117 Its anaerobic coverage makes it a consideration for the treatment of pneumonia in nursing home patients suspected of aspiration. Metronidazole also has activity against anaerobic bacteria such as B. fragilis. It is used in combination with other antibiotics for the treatment of lung abscesses, aspiration pneumonia, or anaerobic infections.
Appropriate and Adequate Intensity Coverage. Because macrolides and extended spectrum quinolones are effective, appropriate agents for treatment of CAP, they frequently get equal billing as "initial choice" agents for management of CAP. Despite their excellent track record and proven efficacy, however, the macrolides and extended spectrum quinolone have clinically significant differences that should be considered in the antibiotic treatment equation for CAP. Accordingly, a careful analysis of the benefits and potential pitfalls of these agents-one that includes a full accounting of the relevant similarities and differences-will help emergency physicians and intensivists develop criteria that suggest the appropriateness and suitability that each of these classes may have in specific patient subgroups.
Features that may suggest the need for intensification and expansion of bacterial and/or atypical pathogen coverage by using an extended spectrum quinolone include the following: 1) increasing age of the patient; 2) acquisition of the pneumonia in a skilled nursing facility; 3) the presence of an aspiration pneumonia, suggesting involvement with gram-negative or anerobic organisms; 4) chronic alcoholism, increasing the likelihood of infection with Klebsiella pneumoniae; 5) pneumococcal pneumonia in underlying disease-compromised individual who has not been vaccinated with pneumococcal polysaccharide antigen (Pneumovax®); 6) previous history of infection with gram-negative, anaerobic, or resistant species of S. pneumoniae; 7) history of treatment failure with macrolides, cephalosporins, or beta-lactam antibiotics; 8) previous hospitalizations for pneumonia; 9) patient requires or has had previous ICU hospitalization for pneumonia; 10) acquisition of pneumonia in a community with high and increasing resistance to macrolides among S. pneumoniae species; 11) patient profile (elderly, functionally impaired, alcoholism, noncompliance) that suggests outpatient management may be optimized by monotherapeutic antibiotic regimen; and 12) immunodeficiency and/or severe underlying disease. (See Table 7.) Many of the aforementioned risk groups can also be treated with the combination of a third generation cephalosporin plus a macrolide, in combination with an aminoglycoside when indicated.
As emphasized earlier in this review, most consensus panels, infectious disease experts, textbooks, and peer-reviewed antimicrobial prescribing guides recommend, as the initial or preferred choice, those antibiotics that, within the framework of monotherapy, address current etiologic and mortality trends in CAP. As a general rule, they recommend-for empiric initial therapy in patients without modifying host factors that predispose to gram negative or pseuodomonal infection-those antibiotics that provide coverage against the bacterial pathogens S. pneumoniae, H. influenzae, and M. catarrhalis, as well as against atypical pathogens Mycoplasma, Legionella, and C. pneumoniae.
Correct Spectrum Coverage. When antimicrobial monotherapy is desirable, cost-effective, and/or clinically indicated (and usually, it should be stresssed, this is the case) extended spectrum quinolones and advanced generation macrolides best satisfy the empiric, aforementioned pathogen coverage requirements for patients with CAP. Accordingly, they currently represent the therapeutic classes of choice for management of CAP in the outpatient setting.
Although third generation cephalosporins, beta-lactam antibiotics, and TMP/SMX are still deemed valuable by many authorities and practitioners (in particular, in combination with other agents for in-hospital management of CAP) these agents have been allocated, for the most part, to secondary or alternative status for oral therapy because, as a rule, they are not clinically indicated for treatment of atypical organisms, including Mycoplasma, Legionella, and C. pneumoniae, whose increasing importance now demands initial, out-of-the-gate coverage for these pathogens. (For specific information and a more detailed discussion of these antibiotic classes, please refer to Emergency Medicine Reports, "Antibiotic Update 1998: Outcome-Effective Treatment For Bacterial Infections Managed in The Primary Care and Emergency Department Setting.")118
Because advanced generation macrolides and extended spectrum quinolones consitute the principal oral and intravenous treatment options for CAP, and because they are relatively new agents with activity and properties about which the emergency physician must be knowledgeable, the following sections will discuss indications, side effects, and strategies for their use in CAP. The focus of the discussion will be on newer antibiotics that: 1) provide coverage of bacterial and atypical organisms causing CAP; 2) are available for both outpatient (oral) and in-hospital (IV) management; and 3) are able, when indicated, to provide compliance-enhancing and cost-effective treatment within the context of antimicrobial monotherapy. Antibiotics satisfying these criteria include trovafloxacin, levofloxacin, and azithromycin.
Table 6. Empiric Antimicrobial Therapy of Choice for Outpatient and In-Hospital Management of Community-Acquired Pneumonia
| Patient Profile/Etiologic Agents | First-Line Antibiotic Therapy | Alternative First-Line Antibiotic Therapy |
| Otherwise Healthy < 60 years of age (outpatient management/oral therapy)* | Azithromycin OR Trovafloxacin§ OR Levofloxacin§ | Clarithromycin OR Erythromycin (in patient with no history of COPD and who has a low probability of H. influenzae infection) |
| Otherwise Healthy > 60 years of age (Patients deemed to be suitable for outpatient/oral therapy, i.e. no systemic toxicity, high likelihood of compliance, and supportivehome environment)* | Trovafloxacin OR Levofloxacin | Cefuroxime plus azithromycin OR Amoxicillin-clavulanate plus azithromycin |
| > 60 Years of Age Underlying Risk Factors or Comorbid Conditions: In-Hospital Management (malignancy, COPD, history of pneumonia, diabetes, etc.) | Trovafloxacin (alatrofloxacin) IV OR Azithromycin IV OR Ceftriaxone IV plus azithromycin IV | Levofloxacin IV OR Ceftriaxone plus erythromycin IV OR Imipenem IV plus azithromycin I |
| CAP acquired in the nursing home environment(increased likelihood of gram-negative, E. coli, Klebsiella pneumoniae) | Trovafloxacin (alatrofloxacin) IV OR Ceftriaxone IV plus azithromycin IV | Levofloxacin IV OR Ceftriaxone plus erythromycin IV OR Imipenem IV plus azithromycin IV |
| CAP in the individual with Chronic Alcoholism (Increased likelihood of Klebsiella pneumoniae infection) | Trovafloxacin (alatrofloxacin) IV OR Ceftriaxone IV plus azithromycin IV OR Levofloxacin IV | Ceftriaxone plus erythromycin IV OR Cefepime IV plus azithromycin IV |
| Severe CAP acquired in an area or institution with significant prevalence (> 20%) of S. pneumoniae species showing intermediate-to-complete resistance to macrolides, cephalosporins, and/or penicillin, but maintaining high sensitivity to extended spectrum quinolones) | Trovafloxacin (alatrofloxacin) IV OR Vancomycin¶ plus azithromycin | Levofloxacin IV OR Vancomycin¶ plus erythromycin |
| Severe CAP complicated by structural disease of the lung (bronchiectasis): increased likelihood of Pseudomonas and polymicrobial infection | Cefepime IV plus trovafloxacin IV plus aminoglycoside | Ciprofloxacin IV plus aminoglycoside IV plus azithromycin IV OR Carbapenem IV plus azithromycin IV plus aminoglycoside |
| CAP in a patient with suspected aspirationn (increases the likelihood of gram-negative and anaerobic infection**) | Trovafloxacin (alatrofloxacin) IV plus Clindamycin IV OR plus ticarcillin/clavulanate IV | Trovafloxacin (alatrofloxacin) IV plus ampicillin-sulbactam IV |
| Severe CAP in a compromised host with a previous hospitalization for, or who resides in a community or facility with a high reported incidence of methicillin-resistant S. aureus (MRSA)*** | Trovafloxacin (alatrofloxacin) IV plus vancomycin IV OR Ceftriaxone IV plus azithromycin IV plus vancomycin IV | Levofloxacin IV plus vancomycin IV |
| CAP patient with severe pneumonia requiring ICU hospitalization*** | Cefepime IV plus trovafloxacin IV plus aminoglycoside (Pseudomonas strongly suspected) OR Trovafloxacin (alatrofloxacin) IV plus/minus ceftriaxone IV OR plus beta-lactam/beta-lactamase inhibitor | Ciprofloxacin IV plus aminoglycoside IV plus azithromycin IV OR Ceftriaxone IV plus azithromycin I plus aminoglycoside OR Levofloxacin IV plus carbapenem IV plus aminoglycoside |
* Oral therapy/outpatient treatment recommendations are appropriate only for those otherwise healthy patients with CAP of mild enough severity that they are judged to be suitable candidates for outpatient management with oral antibiotics.
§ Quinolones are restricted for use in patients > 18 years of age
¶ If S. pneumoniae demonstrates complete resistance to extended spectrum quinolones (very rare), third-generation cephalosporins, and macrolides, then vancomycin may be required as part of initial therapy, although this would be necessary only in rare circumstances.
First line therapy recommendations take into consideration cost of the drug (which may vary from one institutition to another), convenience of dosing, daily dose frequency, spectrum of coverage, side effects, and risk of drug-drug interactions.
** When anaerobic organisms are suspected as one of the possible etiologic pathogens in a patient with CAP, trovafloxacin in combination with clindamycin or a -lactamase inhibitor (ampicillin/sulbactam, tricarcillin/clavulanate, or ticarcillin/tazobacatam) is recommended.
***High community prevalence of, previous history of hospitalization, or increasing local incidence of methicillin-resistant Staphylococcal aureus (MRSA) in a patient with a clinical presentation consistent with S. aureus pneumonia; vancomycin should be considered as component for initial therapy.
Adapted from refences 2, 4, 7, 12, 14, 42, 43, 46, 106, 112, 115, 143, 144
Extended Spectrum Fluoroquinolones
The extended spectrum quinolones trovafloxacin, levofloxacin, sparfloxacin, and grepafloxacin are indicated for treatment of CAP. Because trovafloxacin and levofloxacin are widely used both as oral agents and for intravenous use in the hospital setting, and because photosensitivity-related side effects may limit sparfloxacin use in certain geographical regions, the discussion below will focus on trovafloxacin and levofloxacin.
Trovafloxacin. An extended spectrum fluoroquinolone antibiotic, trovafloxacin (Trovan®) is approved for several indications involving the respiratory tract. An intravenous form of trovafloxacin is marketed as alatrofloxacin, an L-alanine-L-alanine form of trovafloxacin, and is similar pharmacokinetically to oral administration of similar doses.119 As a rule, no adjustment is needed when switching from IV or oral for comparable dosages.120
Although similar in many respects to its "cousins," or, so-called, extended spectrum quinolones (i.e., levofloxacin, sparfloxacin, and grepafloxacin), trovafloxacin is unique within this group for its clinical effectiveness in selected infections involving anaerobic organisms, including Bacteroides fragilis, Peptostreptococcus species, and Prevotella species.121-125 This expanded spectrum accounts for its efficacy as treatment for and/or prophylaxis of intra-abdominal, post-surgical, gynecologic, and pelvic infections.
Many polymicrobial infections of the lower respiratory, especially those occurring in elderly patients who have aspirated, and in others with structural lung disease who may be colonized and/or infected with gram-negative organisms, are treated on an empiric basis. Because etiologic confirmation is frequently not possible in the ED, the antibiotic trovafloxacin may offer special therapeutic advantages in selected CAP patients, including outpatients with compliance-compromising clincal profiles.
With respect to antibacterial activity, trovafloxacin is a broad spectrum naphthyridone fluoroquinolone, with activity against such aerobic gram-positive organisms as Streptococcus pneumoniae and Staphylococcus aureus, as well as atypical organisms, among them, Chlamydia pneumoniae, Mycoplasma pneumoniae, and Legionella pneumophila. The activity of trovafloxacin against gram-negative organisms is similar to that of ciprofloxacin, although it exhibits slightly poorer coverage of Pseudomonas aeruginosa; based on surveys of the MIC90 data in the medical literature, the trovafloxacin MIC90 for Pseudomonas is either equivalent to or one tube dilution less than ciprofloxacin.124-125
From a practical, clinical perspective, trovafloxacin is of special interest to the emergency physician and intensivist for two reasons. 1) The oral formulation of trovafloxacin is indicated for a wide range of infections that involve the respiratory tract. 2) An intravenous formulation (alatrofloxacin mesylate) can be initiated in the ED for patients with more severe CAP requiring hospital admission, including management in the ICU. Dosages, routes of administration, and duration of therapy vary according to the type of pneumonia.
Respiratory Tract Infection. With respect to respiratory tract infections, trovafloxacin has been approved for treatment of adults (> 18 years of age) for the following indications: 1) Nosocomial pneumonia caused by E. coli, P. aeruginosa, H. influenzae, or S. aureus; 2) CAP caused by S. pneumoniae, H. influenzae, K. pneumoniae, S. aureus, M. pneumoniae, M. catarrhalis, L. pneumophila, or C. pneumoniae; and 3) acute bacterial exacerbation of chronic bronchitis caused by H. influenzae, Moraxella catarrhalis, S. pneumoniae, S. aureus, or Haemophilus parainfluenzae.
When prescribing trovafloxacin, physicians should note that some pulmonary infections-depending upon their severity and anatomic location-can be treated with oral tablets only (i.e., acute bacterial exacerbation of chronic bronchitis,100 mg PO ´ 7-10 days; outpatient treatment of CAP, 200 mg PO ´ 7-14 days). Other, more serious pulomonary infections that are treated in the hospital require a combination of intravenous administration and oral therapy (i.e., CAP treated in-hospital, 200 mg IV followed by 200 mg oral ´ 7-14 days; nosocomial pneumonia, 300 mg IV followed by 200 mg oral for 10-14 days). The daily cost of trovafloxacin is about $5.00 per day for the oral 100 mg tablet, and about $6.00 for the 200 mg oral tablet.
As emphasized in previous sections, with development of increasing intermediate- and, even, complete-resistance of S. pneumoniae species to penicillins, macrolides, and other antimicrobial classes, the potential usefulness of such quinolones as trovafloxacin and levofloxacin for management of CAP should be noted. Overall, the percentage of S. pneumoniae species showing intermediate to complete resistance to trovafloxacin is less than 1%.124-127 In some studies, resistance to other antibiotics did not appear to affect the susceptibility to trovafloxacin.121,127 And, in general, based on MIC criteria, trovafloxacin appears to be slightly more active against S. pneumoniae than levofloxacin and sparfloxacin.126,127 Sequential therapy (i.e., IV followed by oral administration) with IV alatrofloxacin and oral trovafloxacin appear comparable to sequential IV ciprofloxacin/ampicillin and oral ciprofloxacin/amoxicillin or IV ceftriaxone and oral cefpodoxime (with or without erythromycin) in individuals hospitalized with CAP.119
Side Effects. In worldwide, multidose clinical efficacy trials, the majority of adverse reactions were characterized as mild in nature, with more than 90% being described as mild or moderate. Trovafloxacin was discontinued for adverse events thought to be related to the drug in 5% of patients (dizziness, 2.4%; nausea, 1.9%; headache, 1.1%; and vomiting, 1.0%). The most common side effects of trovafloxacin are lightheadedness (1-4%) and/or dizziness (reported in 2-11% of patients depending on dose and route of administration). The incidence of dizziness was reported more frequently in females younger than age 45 and may be reduced substantially if trovafloxacin is taken at bedtime or with food.119
Nausea is reported with a frequency of 4-8%. Other drug-related adverse reactions with a frequency of greater than or equal to 1% include headache, vomiting, diarrhea, abdominal pain, insertion site reaction, and vaginitis. Patients should know how they react to the drug before operating an automobile or machinery, and they should be advised to avoid excessive sunlight or artificial ultraviolet light and to discontinue therapy if a sunburn-like reaction or skin eruption occurs (phototoxicity observed in less than 0.03% of patients).
Concomitant administration of intravenous morphine and oral trovafloxacin resulted in a significant reduction in bioavailability of trovafloxacin. Morphine should be administered at least two hours after oral trovafloxacin is taken on an empty stomach or at least four hours after oral trovafloxacin is taken with food.109 Trovafloxacin can cause elevation of liver enzymes during or soon after prolonged therapy (21 days or more), and, therefore, periodic assessment is advised.119
Trovafloxacin may be taken without regard to meals. However, because of impaired absorption, vitamins or minerals containing iron, aluminum, or magnesium-based antacids, antacids containing citric acid buffered with sodium citrate, or sucralfate should be taken at least two hours before or after trovafloxacin.119 No adjustment is required in patients with impaired renal function, as the drug is eliminated primarily in the feces. Dosage adjustment, however, is recommended in patients with chronic hepatic disease.119
In summary, trovafloxacin is a reasonably priced, once-daily extended spectrum quinolone that should be considered an important "foundation" drug for managing sicker patients with CAP. Its spectrum of coverage makes trovafloxacin especially valuable for use in: 1) older, sicker patients with serious, chronic, or recurrent infections; 2) individuals who are likely to have polymicrobial infections involving gram-positive, gram-negative, and/or atypical organisms; and 3) individuals who have failed other therapies. In addition, in geographic areas characterized by a high incidence of Streptococcus pneumoniae species that are resistant to macrolides, penicillin, and/or cephalosporins, trovafloxacin represents an attractive first-line option for treatment of CAP. See Table 7 for risk factors, pathogen profiles, and patient subgroups that should prompt consideration of extended spectrum quinolones.
Table 7. Extended Spectrum Quinolones: Indications for Intensification and Expansion of Coverage in Patients with Community-Acquired Pneumonia
Possible Risk Factors, Pathogen Profiles, and Patient Subgroups that Should Prompt Consideration of Extended Spectrum Quinolones*§ as a Component of Initial Therapy
Increasing age of the patient and/or severity of CAP
Acquisition of pneumonia in a skilled nursing facility or a nosocomial environment (increases the likelihood of infection with gram-negative organisms)
Aspiration pneumonia (increases likelihood of infection with gram-negative or anaerobic organisms)
Chronic alcoholism (increased the likelihood of infection with Klebsiella pneumoniae)
Pneumococcal pneumonia in underlying disease-compromised individual who has not been vaccinated with pneumococcal polysaccharide antigen (Pneumovax®)
Previous history of infection with gram-negative, anaerobic, or resistant species of S. pneumoniae
History of treatment failure with macrolides, cephalosporins, or beta-lactam antibiotics (possibility of S. pneumoniae resistant species should be considered)
Previous history of recurrent hospitalizations for pneumonia
Patient presently requires or has had previous ICU hospitalization for pneumonia
Acquisition of pneumonia in a community with high and increasing resistance to macrolides and other antibiotics among S. pneumoniae species
Patient profile suggesting complicated course (elderly, functionally impaired, alcoholism, noncompliance)
Immunodeficiency and/or severe underlying disease
Trovafloxacin: indicated for treatment of nosocomial infection caused by E. coli, P. aeruginosa, H. influenzae, or S. aureus; and community-acquired pneumonia (CAP) caused by S. pneumoniae, H. influenzae, K. pneumoniae, S. aureus, M. pneumoniae, M. catarrhalis, L. pneumophila, or C. pneumoniae
§ Levofloxacin: indicated for CAP caused by S. pneumoniae, H. influenzae, H. parainfluenzae, K. pneumoniae, S. aureus, M. pneumoniae, M. catarrhalis, L. pneumophila, or C. pneumoniae
When anaerobic organisms are suspected, trovafloxacin in combination with clindamycin or a -lactamase inhibitor (ampicillin/sulbactam, ticarcillin/clavulanate, or piperacillin/tazobactam) is recommended.
Levofloxacin. Levofloxacin (Levaquin®), the S-enantiomer of ofloxacin, is a new fluoroquinolone antibiotic that, compared with older quinolones, also has improved activity against gram-positive organisms including Streptococcus pneumoniae. This has important drug selection implications for management of patients with CAP and exacerbations of COPD. The active stereoisomer of ofloxacin, levofloxacin is available in a parenteral preparation or as a once daily oral preparation that is given for 7-14 days.
Levofloxacin is indicated for the treatment of adults (> 18 years) with mild, moderate, and severe pulmonary infections including, acute bacterial exacerbation of chronic bronchitis and CAP.42 It is active against many gram-positive organisms that may infect the lower respiratory tract, including S. pneumoniae and Staphylococcus aureus, and it also covers atypical pathogens, including Chlamydia pneumoniae, Legionella pneumophila, and Mycoplasma pneumoniae. It is also active against gram-negative organisms, including E. coli, H. influenzae, H. parainfluenzae, Klebsiella pneumoniae, and Moraxella catarrhalis. Although it is active against Pseudomonas aeruginosa in vitro and carries an indication for treatment of complicated UTI caused by Pseudomonas aeruginosa, levofloxacin does not have an official indication for CAP caused by this gram-negative organism.
When given orally, levofloxacin is dosed once daily, is well absorbed orally, and penetrates well into lung tissue.128 It is active against a wide range of respiratory pathogens including atypical pathogens and many species of S. pneumoniae resistant to penicillin.129,130 In general, levofloxacin has similar activity against gram-positive organisms such as ofloxacin and ciprofloxacin, and it is more active than ofloxacin and slightly less active than ciprofloxacin against gram-negative organisms.131,132 In particular, it should be noted that levofloxacin is slightly less active against Pseudomonas aeruginosa than ciprofloxacin.131,132
Levofloxacin is available as both an oral and parenteral form, and the oral and IV routes are interchangeable (i.e., same dose). Levofloxacin is generally well tolerated (incidence of adverse reactions, < 7%). Levofloxacin is supplied in a parenteral form for IV use and in 250 mg and 500 mg tablets. The recommended dose is 500 mg IV or orally qd for 7-14 days for lower respiratory tract infections. Food does not affect the absorption of the drug, but it should be taken at least two hours before or two hours after antacids containing magnesium or aluminum, as well as sucralfate, metal cations such as iron, and multivitamin preparations with zinc.
Dosage adjustment is recommended in patients with impaired renal function (clearance < 50 mL/min).42 The drug is well-tolerated, with the most common side effects, including nausea, diarrhea, headache, and constipation.128 All quinolones have been associated with cartilage damage in animal studies, and, therefore, they are not recommended for use in children, adolescents, and pregnant and nursing women.
Comparative trials (generally available in abstract form) suggest that levofloxacin is as effective as cefuroxime axetil, cefaclor, and amoxicillin/clavulanate in upper or lower respiratory infections.133-135 In patients with CAP, IV levofloxacin with step-down to oral therapy was superior to ceftriaxone with step-down therapy to cefuroxime axetil.136 About 22% of patients in the cephalosporin arm required the addition of erythromycin or doxycycline due to the presence of atypical respiratory pathogens. The clinical response rates (cure plus improvement) were 88-97% for levofloxacin. Microbiological eradication was reported to be 94-98%; however, a large number of patients (32-43%) were not evaluable for this end point.133,135-136
It should be emphasized that, currently, such macrolides as azithromycin or clarithromycin also are recommended for pneumonia in ambulatory, otherwise healthy adults. And, for older patients, an oral cephalosporin, such as cefuroxime axetil plus a macrolide to provide coverage of atypical pathogens may be considered and is recommeded by certain consensus panel reports.137 In this patient subgroup, however, trovafloxacin or levofloxacin provides an effective, safe, and cost-attractive, outpatient monotherapeutic alternative to two-drug combinations- especially in the elderly patient who is deemed well enough to be treated out of hospital and in whom coverage of gram-negative organisms in addition to coverage of Streptococcus pneumoniae and atypical pathogens is desirable.
Table 8. Consensus Report Guidelines
Outpatient management: Preferred antimicrobials in most patients (in no special order)
Macrolide*, Extended-spectrum fluoroquinolones**, or doxycycline***
Alternative options: Amoxicillin/clavulanate and some second-generation cephalosporins (cefuroxime, cefpodoxime, or cefprozil). Note: These will not be active versus atypical agents.
* Macrolide: azithromycin, erythromycin, or clarithromycin; azithromycin or clarithromycin is preferred if H. influenzae infection is suspected
** Fluoroquinolone: trovafloxacin and levofloxacin are preferred. Alternatives include sparfloxacin and grepafloxacin.
*** Increasing resistance to S. pneumoniae is observed in some geographical regions
In-hospital-general medical ward management: preferred antimicrobials in most patients (in no special order)
Preferred:
•-lactama with or without a macrolideb OR
•An intravenous fluoroquinolone (trovafloxacin or levofloxacin) with expanded coverage against S. pneumoniae
Alternative:
•Cefuroxime with or without a macrolideb OR
•Azithromycin (alone)
In-hospital-intensive care unit management: preferred antimicrobials in most patients (in no special order)
Preferred:
•Azithromycin, erythromycin, or a fluoroquinolone plus cefotaxime, ceftriaxone, or a -lactam-/b-lactamase inhibitord
Modifying factors:
•Structural disease of lung (bronchiectasis): add antipseudomonal penicillin, carbapenem, or cefepime plus macrolideb or fluoroquinolonec plus an aminoglycoside
•Likelihood of, or previous history of pseudomonal infection: add antipseudomonal penicillin, carbapenem, or cefepime plus macrolideb or fluoroquinolonec plus an aminoglycoside.
•High community prevalence or local incidence of methicillin-resistant staphylococcus aureus (MRSA) in a patient with clinical presentation suggestive of S. aureus pneumonia: consider adding vancomycin.
•Penicillin allergy: fluoroquinolonec with or without clindamycin
•Suspected aspiration: fluoroquinolonec plus clindamycin or a b-lactam-/b-lactamase inhibitor b-lactam: cefotaxime or ceftriaxone Macrolide: azithromycin, clarithromycin, or erythromycin Fluoroquinolone: trovafloxacin, levofloxacin, or another fluoroquinolone with enhanced activity against S. pneumoniae -lactam-/b-lactamase inhibitor: ampicillin/sulbactam, ticarcillin/clavulanate, or piperacillin/tozabactam; for structural disease of the lung; ticarcillin/clavulanate of piperacillin/clavulanate
Adaptation and Summary of Preferred Antimicrobial Recommendations from the Infectious Disease Society of America
Advanced Generation Macrolides
The newer macrolide antibiotics include the erythromycin analogs azithromycin and clarithromycin.138,139 Compared to erythromycin, the major advantages of these antibiotics are significantly decreased gastrointestinal side effects, which produce enhanced tolerance, improved bioavailability, higher tissue levels, and pharmacokinetic features that permit less frequent dosing and better compliance, as well as enhanced activity against H. influenzae.140,141 In particular, the long tissue half-life of azithromycin allows this antibiotic to be prescribed for a shorter duration (5 days) than comparable antibiotics given for the same indications.
Macrolides in CAP Therapy: An Overview. Given the cost differences between azithromycin and clarithromycin, as well as the improved compliance patterns associated with short-duration therapy, any rational approach to distinguishing between these agents must consider prescription, patient, and drug resistance barriers.
From the outset, it is fair to say that these newer macrolides, to a great degree, have supplanted the use of erythromycin (as well as cephalosporins and tetrayclines) in community-acquired infections of the lower respiratory tract. Although erythromycin, in particular, has been considered by some to be the antibiotic of choice for CAP, its lack of efficacy against H. influenzae, as well as its adverse gastrointestinal side effects, potential for drug-drug interactions, and poor compliance profile are now recognized as clinically important liabilities in emergency practice. It is, however, effective against pneumococcal pneumonia, Mycoplasma pneumonia, and many atypical infections, including Legionella. Food decreases the absorption of erythromycin, which interferes with drug metabolism, and the drug should be used with caution in patients on theophylline or warfarin. It should not be used concurrently with terfenadine.
From the perspective of providing definitive, cost-effective, and compliance-promoting therapy, the newer macrolide antibiotics, which include both azithromycin and clarithromycin, have recently emerged as some of the drugs of choice-along with the new quinolones-for outpatient management of CAP.144 When used as oral agents, they play a central role in management of pneumonia in otherwise healthy individuals who do not require hospitalization.
From an emergency medicine and in-hospital management perspective, the value of macrolide therapy has been significantly enhanced by availability of the intravenous formulation of azithromycin, which has been approved for hospitalized patients with CAP. Unlike penicillins, cephalosporins, and sulfa-based agents, azithromycin has the advantage of showing in vitro activity against both atypical and bacterial offenders implicated in CAP.
The macrolides also have the advantage of a simplified dosing schedule, especially azithromycin, which is given once daily for only five days (500 mg po on day 1 and 250 mg po qd on days 2-5). Clarithromycin requires a longer course of therapy and is more expensive. In general, the decision to use a macrolide such as azithromycin rather than erythromycin is based on weighing the increased cost of a course of therapy with azithromycin against its real-world advantages, which include a more convenient dosing schedule, its broader spectrum of coverage, its favorable drug interaction profile, and its decreased incidence of gastrointestinal side effects, which occur in 3-5% of patients taking a five-day, multiple-dose regimen.145 The recent introduction of a new oral tablet formulation permits consumption of the antibiotic without regard to food ingestion.
Azithromycin. From a practical clinical and cost-effectiveness-perspective, the newest and, perhaps most important, advance in the area of macrolide therapy is the availability of intravenous azithromycin for the management of hospitalized patients with moderate or severe CAP.146,147 Currently, azithromycin is the only advanced generation macrolide indicated for parenteral therapy in hospitalized patients with CAP due to Chlamydia pneumoniae, H. influenzae, Legionella pneumophila, Moraxella catarrhalis, Mycoplasma pneumoniae, Streptococcus pneumoniae, or Staphylococcus aureus.
The comparative trials demonstrating clinical success (patients who were cured or improved at 10-14 days post-therapy) rates of about 77%-with concomitant bacteriologic response rates of about 96% for frequently isolated pathogens-with azithromycin in CAP were conducted in a wide variety of patients with moderate and severe pneumonia. These included a significant percentage who were 65 years of age or older, had an abnormal respiratory rate (> 30 breaths per minute), a PaO2 less than 60 mmHg and and/or BUN greater than 20 mg/dL. Many of these patients had concurrent diseases or syndromes, including emphysema, chronic obstructive airway obstruction, asthma, diabetes, and/or were cigarette smokers.148
As would be expected, the efficacy of this macrolide was compared to clinical outcomes with a cephalosporin used with or without erythromycin. In a randomized comparative investigation, therapy with intravenous azithromycin alone followed by oral azithromycin was as effective as intravenous treatment with the designated "second-generation" cephalosporin, cefuroxime followed by oral cefuroxime axetil, with or without the addition of oral or intravenous erythromycin.148
Azithromycin dosing and administration schedules for hospitalized patients are different than for the five-day course used exclusively for outpatient management, and these differences should be noted. When this advanced generation macrolide is used for hospitalized patients with CAP, 2-5 days of therapy with azithromycin IV (500 mg once daily) followed by oral azithromycin (500 mg once daily to complete a total of 7-10 days of therapy) is clinically and bacteriologically effective. For patients requiring hospitalization, the initial 500 mg intravenous dose of azithromycin can be given in the ED.
Interestingly, among all intent-to-treat patients with CAP receiving azithromycin evaluated in two studies, 24 were found to have S. pneumoniae bacteremia at baseline. Of these 24 patients, 19 (79%) achieved clinical cure, which was accompanied by eradication of the pathogen from the blood. Among the five patients considered to be clinical failures, three of the five had documented eradication of S. pneumoniae from the blood, and the remaining two did not have post-baseline cultures reported. All five patients had significant comorbid conditions that were predictive of poor outcomes, but none of the failures resulted in mortality.148
Like the oral formulation, IV azithromycin appears to be well-tolerated, with a low incidence of gastrointestinal adverse events (4.3% diarrhea, 3.9% nausea, 2.7% abdominal pain, 1.4% vomiting), minimal injection-site reactions (less than 12% combined injection-site pain and/or inflammation or infection), and a low incidence of discontinuation (1.2% discontinuation of IV therapy) due to drug-related adverse patient events or laboratory abnormalities.148
Empiric Antibiotic Coverage for Community-Acquired Pneumonia: Matching Drugs with Patient Profiles
A variety of antibiotics are available for outpatient management of pneumonia. (See Table 6.) Although the selection process can be daunting, as mentioned, a sensible approach to antibiotic selection for patients with pneumonia is provided by treatment categories for pneumonia generated by the Medical Section of the American Lung Association, and published under the auspices of the American Thoracic Society.143 This classification scheme, which is now almost six years old, not only helps make clinical assessments useful for guiding therapy, but it is also predictive of ultimate prognosis and mortality outcome. New, more recently devised consensus panel recommendations also are available, and will be discussed.
The most common pathogens responsible for causing CAP include the typical bacteria: S. pneumoniae, H. influenzae, and M. catarrhalis, as well as the atypical pathogens: Mycoplasma, Legionella, and Chlamydia pneumoniae.5 H. influenzae and M. catarrhalis are both found more commonly in patients with COPD. Clinically and radiologically, it is difficult to differentiate between the typical and atypical pathogens; therefore, coverage against all these organisms may be necessary. In patients producing sputum-containing polymorphonuclear leukocytes, the sputum Gram's stain may contain a predominant organism to aid in the choice of empiric therapy. For most patients, therapy must be entirely empiric and is based on the expected pathogens.6,7 (See Table 6.)
Hence, for the vast majority of otherwise healthy patients who have CAP, but who do not have comorbid conditions and who are deemed well enough to be managed as outpatients, therapy directed at S. pneumoniae, H. influenzae, M. pneumoniae, Chlamydia pneumoniae, Legionella pneumophila, and M. catarrhalis is appropriate. From an intensity and spectrum of coverage perspective, coverage of both the aforementioned bacterial and atypical species has become mandatory.
In these cases, one of the newer macrolides, such as azithromycin or clarithromycin, should be considered one of the initial agents of choice. The other monotherapeutic agents of choice consist of the extended spectrum quinolones, such as trovafloxacin and levofloxacin, which provide similar coverage and are also approved as initial therapy in this patient subgroup. Because of their excellent in vitro activity against S. pneumoniae, the use of trovafloxacin should be strongly considered as initial therapy in urban areas where surveillance studies demonstrate a high incidence of macrolide-resistant S. pneumoniae species.
For the older patient with CAP who is considered stable enough to be managed as an outpatient, but in whom the bacterial pathogen list may also include gram-negative aerobic organisms, the combined use of a second- or third-generation cephalosporin or amoxicillin-clavulanate plus a macrolide has been recommended. With the introduction of new quinolones, a more attractive option may consist of an advanced quinolone such as trovafloxacin or levofloxacin. These agents are recommended, because the advanced quinolones may be used as monotherapy, and, therefore, provide convenience and cost advantages in this high-risk subgroup. In those unusual cases in which a definitive, specific, etiologic diagnosis can be made (e.g., Mycoplasma, C. pneumoniae, Legionella species), agents with known activity against these organisms can be employed.
Some experts emphasize that in non-smoking adults without COPD (i.e., patients at a low risk for having H. influenzae), therapy with erythromycin should be strongly considered.7 This is a matter of clinical judgment, but in any event, the newer macrolides, azithromycin and clarithromycin, are recommended in cases of erythromycin intolerance. In patients with COPD, TMP-SMX or doxycycline usually provides adequate coverage against S. pneumoniae and H. influenzae, but TMP-SMX will not cover atypical pathogens.
Except for the newer quinolones such as levofloxacin or trovafloxacin, empiric use of the older quinolones is not recommended for treatment of community-acquired respiratory infections, primarily because of their variable activity against S. pneumoniae and atypical organisms. Although the older quinolones (i.e. ciprofloxacin) should generally not be used for the empiric treatment of CAP, they may provide an alternative therapy for treatment of bronchiectasis, particularly when gram-negative organisms such as Pseudomonas are cultured from respiratory secretions.149
The use of trovafloxacin or levofloxacin as first-line drugs-in particular, as a substitute for the advanced generation macrolides-to treat uncomplicated CAP or acute bacterial exacerbations of COPD in patients younger than 60 years has become a matter of intense debate. Although many consensus reports list both classes as "first choice" agents, these drugs are quite different, and it is helpful to establish criteria that suggest the use of one class initially rather than the other. The most important issue for the emergency physician or pulmonary intensivist is to ensure that the appropriate intensity and spectrum of coverage are provided, according to patient and community/epidemiological risk factors; in many cases, this will require shifting to and intensifying therapy with an extended spectrum quinolone.
In this regard, determining which of these antibiotics-macrolides vs. extended spectrum quinolones-should be considered "workhorse" drugs in the ED or primary care setting, for initial CAP treatment requires thoughtful analysis that takes into account cost, convenience, spectrum of coverage, host risk factors, and patient risk stratificatin. Table 7 outlines clinical factors, pathogen profiles, and patient subgroups that should prompt consideration of extended spectrum quinolones and trigger their initial use for management of CAP.
With its once-daily, minimum duration, seven-day course, levofloxacin and trovafloxacin have dosing and duration advantages as compared to the macrolide clarithromycin, which requires 20 doses over 10 days. Moreover, the seven-day course of the extended spectrum quinolones is comparatively priced with clarithromycin. Based on this analysis, these quinolones appear to provide a very reasonable alternative and perhaps even a slight advantage to clarithromycin in managing patients with CAP.
In the case of azithromycin, its five-day duration of therapy, $39-42 cost per course of treatment, and targeted coverage of S. pneumoniae, H. influenzae, M. catarrhalis, Chlamydia, and M. pneumoniae, must be weighed against the longer duration and slightly greater cost per treatment course for the quinolones, and the fact that their spectrum of coverage includes not only the appropriately targeted, aforementioned organisms commonly implicated in CAP, but extensive activity against gram-negative organisms, which may not always be required.
From a cost-effectiveness perspective, it appears, then, that when gram-negative coverage of Klebsiella and other species is not required, the advanced generation macrolide azithromycin represents a sensible choice as initial therapy, especially in individuals younger than 60 years without underlying problems. However, in the older, sicker patient, in whom gram-negative infection is more of a concern, as well as in areas in which there is a high prevalence of S. pneumoniae resistance, the extended spectrum quinolones are an important alternative to two-drug combinations, especially in the elderly patient where spectrum of coverage of polymicrobial infections may be especially important.
Finally, there is an increasing problem in the United States concerning the emergence of S. pneumoniae that is relatively resistant to penicillin and, less commonly, to extended-spectrum cephalosporins. These isolates are often also resistant to macrolides, sulfonamides, and tetracyclines.150-152 Except for vancomycin, the most favorable in vitro response rates to S. pneumoniae is seen with extended spectrum quinolones, especially trovafloxacin. See Table 6 for a summary of current recommendations for initial managament of outpatients and in-hospital patients with CAP.
Role of Specific Pathogens in CAP. Prospective studies for evaluating the causes of CAP in adults have failed to identify the cause of 40-60% of cases of CAP, and two or more etiologies have been identified in 2-5% of cases. The most common etiologic agent identified in virtually all studies of CAP is Streptococcus pneumoniae, and this agent accounts for approximately two-thirds of all cases of bacteremic pneumonia.
Other pathogens implicated less frequently include H. influenzae (most isolates of which are other than type B), Mycoplasma pneumoniae, Chlamydia pneumoniae, S. aureus, Streptococcus pyogenes, Neisseria meningitidis, Moraxella catarrhalis, Klebsiella pneumoniae and other gram-negative rods, Legionella species, influenza virus (depending on the time of year), respiratory syncitial virus, adenovirus, parainfluenza virus, and other microbes. The frequency of other etiologies, (e.g., Chlamydia psittaci [psittacosis], Coxiella burnetii [Q fever], Francisella tularensis [tularemia], and endemic fungi [histoplasmosis, blastomycosis, and coccidioidomycosis]), is dependent on specific epidemiological factors.
The selection of antibiotics, in the absence of an etiologic diagnosis (gram stains and culture results are not diagnostic), is based on multiple variables, including severity of the illness, patient age, antimicrobial intolerance or side effects, clinical features, comorbidities, concomitant medications, exposures, and the epidemiological setting. (See Table 2.)
Consensus Report Guidelines: Infectious Disease Society of America (IDSA)
The Infectious Disease Society of America (IDSA) through its Practice Guidelines Committee provides assistance to clinicians in the diagnosis and treatment of CAP. The targeted providers are internists and family practitioners, and the targeted patient groups are immunocompetent adult patients. Criteria are specified for determining whether the inpatient or outpatient setting is appropriate for treatment. Differences from other guidelines written on this topic include use of laboratory criteria for diagnosis and approach to antimicrobial therapy. Panel members and consultants were experts in adult infectious diseases.
The guidelines are evidence based where possible. A standard ranking system is used for the strength of recommendations and the quality of the evidence cited in the literature reviewed. The document has been subjected to external review by peer reviewers as well as by the Practice Guidelines Committee, and was approved by the IDSA Council in September, 1998. (See Table 8.)
Disposition and Observation Units
Criteria for disposition of patients with CAP is presented in the accompanying supplement, "Critical Pathways In Emergency Medicine." Although the enclosed guidelines do not present an option for observation units, in a health care environment that is sensitive to issues of cost containment, a number of institutions have explored possible use of a 24-hour observation unit for management of patients with CAP. Clealrly, the majority of young and middle-aged adults can be treated safely on an outpatient basis with oral antibiotic therapy and close follow up. These patients tend to have a good baseline health status, are not systemically toxic on presentation, have stable vital signs (no evidence of tachypnea, tachycardia, or hypoxia), are not dehydrated, and are able to tolerate oral antibiotics. Appropriate antibiotic therapy for these patients has been discussed earlier.
Conversely, there are patients for whom a full hospital admission and IV antibiotics are indicated. In adults, concurrent medical problems increase the risk of complications from pneumonia.153 Consideration should be given to admission when faced with a patient who also has cardiac, renal, respiratory disease, diabetes, history of CVA, other neuromuscular disorders, malignancy, or is immunocompromised. As was emphasized previously, the immunocompromised patient often presents insidiously, and specialized studies may be required to identify the causative organism so that antibiotic therapy can be appropriately targeted.
For patients that are not well enough to be discharged from the ED, yet may have only one or two indications for admission, a brief period of observation may be warranted. Possibilities include dehydration with inability to tolerate oral intake, tachypnea with a slight decrease in oxygen saturation, patients with an unstable home environment, or exacerbations of asthma or COPD in a pneumonia patient. Such patients may benefit from a 24-48 hour period of IV antibiotics and fluid hydration, with reassessment at the end of this time period.
With a longer treatment time than is usually available during an ED visit, such studies as a sputum gram stain and culture would be more likely to yield preliminary results, allowing specific tailoring of antibiotic therapy. A chest x-ray need not be repeated before discharge, given the lag time in infiltrate development. An obvious exception to this would be the patient whose clinical condition worsened during the observation period, or those with evidence of a pleural effusion on a prior x-ray. These patients would be admitted to the hospital. If the patient has improved clinically, is tolerating oral intake, and has adequate oxygenation and stable vital signs, they may be discharged with close outpatient follow-up.
The use of an observation unit allows the emergency physician greater flexibility in decision-making, and provides a benefit to the patient if a full hospital admission can be avoided. The patient has received an optimized start on antibiotic treatment, coexistent factors may have caused a failure of initial home therapy, such as dehydration, have been corrected. There is a larger time span for clinical testing to pinpoint specific antibiotic therapy. Appropriate social work referral can be made for those requiring home-care assistance. Patient exposure to nosocomial pathogens is limited, avoiding a potential extended hospital stay. As with all decisions faced by the emergency physician, prudence is required when choosing a disposition for the patient with CAP.
Summary
The increasing incidence of atypical agents in older children and adults supports the importance of using an antimicrobial agent-both in the outpatient and in-hospital setting-with correct spectrum, adequate intensity coverage, in the majority of patients who are being treated empirically for CAP. Because compliance can be an important determinant of treatment outcome, the agent chosen should be conveniently dosed and be well-tolerated. Currently, these criteria for monotherapeutic efficacy in CAP are best satisfied by use of an advanced generation macrolide or extended spectrum quinolone. The specific choice in a particular patient may vary depending on cost, anticipated patient compliance, the use of other medications, and/or the presence of other coexistent diseases. This article has provided systematic criteria for choosing both between these two therapeutic classes, and for selecting outcome-effective antibiotics within each class. Finally, as important as the initial antibiotic choice is the mandate for comprehensive patient assessment. This is necessary so that an appropriate, outcome-sensitive disposition decision can be made with the aim of optimizing patient care within the framework of fiscal prudence.
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