Community-Acquired Pneumonia (CAP) in the Geriatric Patient: Evaluation, Risk-Stratification, and Antimicrobial Treatment Guidelines for Inpatient and Outpatien
Community-Acquired Pneumonia (CAP) in the Geriatric Patient: Evaluation, Risk-Stratification, and Antimicrobial Treatment Guidelines for Inpatient and Outpatient Management
Author: Gideon Bosker, MD, FACEP, Assistant Clinical Professor, Section of Emergency Services, Yale University School of Medicine; Associate Clinical Professor, Oregon Health Sciences University, Portland, OR. Editor-in- Chief, Textbook of Adult and Pediatric Emergency Medicine.
Peer Reviewers: Stephen W. Meldon, MD, Department of Emergency Medicine, MetroHealth Medical Center; Assistant Professor, Case Western Reserve University, Cleveland, OH; Steven Winograd, MD, FACEP, Attending Physician, Department of Emergency Medicine, Allegan General Hospital, Allegan, MI.
A common cause for admission of elderly patients from the emergency department (ED) to the hospital, community-acquired pneumonia (CAP) is a serious, growing health problem in the United States. It has an incidence estimated at 4 million cases annually.1,2 Approximately 600,000 hospitalizations for CAP are reported each year at an annual cost of about $23 billion.1,3 Mortality rates among the most seriously affected patients (the majority of whom are in the geriatric age group) approaches 40%, and causative pathogens are identified in fewer than 50% of patients.4-6 Accordingly, empiric antibiotic regimens frequently are chosen in the elderly population on the basis of results of clinical trials.
Despite a general consensus that empiric treatment of CAP in elderly patients requires, at the least, mandatory coverage of such organisms as Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis, as well as atypical organisms (Mycoplasma pneumoniae, Chlamydia pneumoniae, and Legionella pneumophila), antibiotic selection strategies for achieving this spectrum of coverage vary widely. New treatment guidelines for CAP have been issued by some national associations (Infectious Disease Society of America [IDSA]) and the Centers for Disease Control and Prevention (CDC) Drug-Resistant Streptococcus pneumoniae Therapeutic Working Group. These newer strategies are in addition to those contained in the guidelines published by the American Thoracic Society (ATS).
Deciphering the strengths, subtleties, and weaknesses of recommendations issued by different authoritative sources can be problematic and confusing. Because patient disposition practices and treatment pathways vary among institutions and from region to region, management guidelines for CAP in the geriatric patient must be "customized" for the local practice environment. Unfortunately, no single set of guidelines is applicable to every patient or practice environment; therefore, clinical judgment must prevail. This means taking into account local antibiotic resistance patterns, epidemiological and infection incidence data, and patient demographic features.
It also is becoming clear that the outcomes for CAP in the elderly can be maximized by using risk-stratification criteria that predict mortality associated with CAP. Associated clinical findings such as hypotension, tachypnea, impaired oxygen saturation, multi-lobar involvement, elevated blood urea nitrogen, and altered level of consciousness are predictive of more serious disease, as are age and acquisition of CAP in a nursing home environment. These factors may assist clinicians in initial selection of intravenous antibiotic therapy for hospitalized patients.
Because of important advances, changes, and refinements that have occurred in the area of CAP treatment over the past year, this landmark review presents a comprehensive, state-of-the-art assessment of guidelines for management of the geriatric patient with CAP. Special emphasis has been given to both epidemiological data demonstrating the importance of correct spectrum coverage with specific macrolides or fluoroquinolones and the selection of initial intravenous antibiotics for in-hospital management of CAP. The need to provide prophylaxis against venous thromboembolic disease (VTED) in elderly patients with pneumonia and/or congestive heart failure (CHF) or respiratory failure also is addressed.
In addition, a detailed analysis and comparison of monotherapeutic (azithromycin or levofloxacin) vs. two-drug (cephalosporin plus a macrolide) approaches for initial therapy is provided. To ensure our readers are current with and can apply the latest evidence-based strategies for CAP treatment to their elderly population, detailed antibiotic selection guidelines are provided. Drawing upon consensus panels and association guidelines, these antimicrobial protocols are linked to risk-stratification criteria and specific clinical profiles of elderly patients presenting to the hospital or acute ambulatory setting with CAP.
— The Editor
Diagnosis and Evaluation
The annual incidence of pneumonia in patients older than 65 years is about 1%.7 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. Pneumonia in older patients frequently has an insidious presentation with fewer characteristic features of pneumonia, which may be confused with CHF or respiratory compromise associated with chronic long disease.
The definitive, etiologic 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 who are highly skilled in this diagnostic methodology. An adequate Gram’s stain must have fewer than 25 epithelial cells per low-powered field. 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. Unfortunately, the Gram’s stain will rarely be helpful in determining other causes of pneumonia.
Transtracheal aspiration or bronchial washings are 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 CAP will be able to produce sputum. Of these, one-half of the sputum specimens obtained will be inadequate. When an adequate Gram’s stain is obtained, however, it has a negative predictive value of 80% when compared to a sputum culture. The blood culture is helpful in about 15% of patients, while serology will establish the diagnosis in 25% of patients.7,8 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 ICU setting.3,5,8
Signs and Symptoms. Especially in the elderly patient, the signs and symptoms of pneumonia may be mimicked by many disorders, including pulmonary embolism (PE), CHF, lung cancer, hypersensitivity pneumonitis, tuberculosis, chronic obstructive pulmonary disease (COPD), granulomatosis disease, and fungal infections. A variety of drugs also can induce pulmonary disease. Cytotoxic agents, non-steroidal anti-inflammatory drugs (NSAIDs), and some antibiotics, including sulfonamides and certain antiarrhythmics, such as amiodarone or tocainide, can mimic pulmonary infection. In addition, common analgesics, including salicylates, propoxyphene, and methadone, also may 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.
Initial Stabilization and Adjunctive Measures
Prompt, aggressive, and adequate supportive care must be provided to geriatric patients who present to the hospital with pneumonia. As is the case with other serious conditions, supportive care frequently must be performed in conjunction with the history, physical examination, and diagnostic testing. Among initial stabilization measures, managing the airway and ensuring adequate breathing, oxygenation, ventilation, and perfusion are of paramount importance.
Upon arrival to the hospital, oxygenation status should be assessed immediately using pulse-oximetry. Patients with an arterial oxygen saturation of less than 90% should receive supplemental oxygen. Arterial blood gases are especially helpful in patients suspected of hypercarbia and respiratory failure. This laboratory modality may be useful in patients with COPD, decreased mental status, and fatigue. Patients with hypoxia who do not respond to supplemental oxygen, as well as those with hypercarbia accompanied by respiratory acidosis, may be candidates for mechanical ventilation. This may be accomplished with either intubation and mechanical ventilation or non-invasive ventilation (bilevel positive pressure ventilation [BiPAP]). Recent studies have shown BiPAP to be successful in treating patients with respiratory failure due to pneumonia.9 When this technique is available to the emergency physician, it may avert the need for endotracheal intubation and its potential complications.
Patients with evidence of bronchospasm on physical exam, as well as those with a history of obstructive airways disease (asthma or COPD), may benefit from inhaled bronchodilator therapy.
Evidence of inadequate perfusion may range from mild dehydration with tachycardia to life-threatening hypotension due to septic shock. Patients with septic shock usually will show evidence of decreased tissue perfusion, such as confusion and oliguria in association with a hyperdynamic circulation. In either case, initial therapy consists of intravenous fluids (normal saline or lactated Ringer’s solution) administered through a large bore IV. In elderly patients, fluid overload is a potential complication, and it is wise to administer IV fluids in bolus doses with frequent assessment of response.
Risk Stratification and Patient Disposition: Outpatient Vs. Inpatient Management
Overview. Determining whether to admit or discharge an elderly patient with pneumonia is one of the most important, and potentially, cost-incurring decisions an emergency physician, pulmonologist, or internist can make. For this reason, there have been increasing efforts to identify patients with CAP who can appropriately be treated as outpatients.10-13 The disposition decision for geriatric patients with pneumonia should take into account the severity of the pneumonia, as well as other medical and psychosocial factors that may affect the treatment plan and clinical outcome.14-16
In the absence of respiratory distress or other complicating factors, many young adults can be adequately treated with appropriate oral antibiotic therapy. This is less often the case for the elderly patient with CAP, because comorbid conditions and other risk factors may complicate the course of the illness. Even when following appropriate treatment and dispositon, patients may have symptoms, including cough, fatigue, dyspnea, sputum production, and chest pain that can last for several months. To address this issue of patient disposition and treatment setting, 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.
Among the factors most physicians use to make admission decisions for pneumonia are the presence of hypoxemia, overall clinical status, the ability to maintain oral intake, hemodynamic status, and the patient’s home environment. Using clinical judgment, however, physicians tend to overestimate the likelihood of death from pneumonia.14 These findings have led some investigators to employ more stringent prediction rules. For example, the chest radiograph may help identify patients who are at high risk for mortality. The presence of bilateral effusions, moderate-size pleural effusions, multi-lobar involvement, and bilateral infiltrates are associated with a higher risk of mortality.
A recent landmark study outlined below presented a prediction rule (Pneumonia Severity Index [PSI]) to identify low-risk patients with CAP.11 Using such objective criteria as 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 ranging from 0.7% to 31%.14 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 (ICU) admission also must be evaluated. A variety of factors are associated with an increased risk for mortality, including increasing age (> 65 years), alcoholism, chronic lung disease, immunodeficiency, and specific laboratory abnormalities, including azotemia and hypoxemia. These patients may require admission to the ICU.
Prognostic Scoring. There have been many efforts to assess severity and risk of death in patients with pneumonia.15,17-20 The study by Fine and colleagues has received considerable attention and is used as a benchmark by many clinicians.14 This study developed a prediction rule, the PSI, to assess 30-day mortality in patients with CAP. The rule was derived and validated with data from more than 52,000 inpatients, and then validated with a second cohort of 2287 inpatients and outpatients as part of the Pneumonia PORT study. Subsequent evaluation and validation has been performed with other cohorts, including geriatric patients and nursing home residents.21,22
In this risk-stratification scheme, patients are assigned to one of five risk classes (1 is lowest risk, 5 is highest risk) based upon a point system that considers age, co-existing disease, abnormal physical findings, and abnormal laboratory findings. Elderly patients cannot be assigned to Class 1, as a requirement is age younger than 50 years.14
In older patients, age contributes the most points to the overall score. For example, it should be noted that males ages older than 70 years and females ages older than 80 years would be assigned to Class 3 on the basis of age alone, without any other risk factor. In the Fine study, patients assigned to Class 1 and 2 were typically younger patients (median age, 35-59 years) and patients in Class 3-5 were older (median age, 72-75 years).
Outpatient management is recommended for Classes 1 and 2, brief inpatient observation for Class 3, and traditional hospitalization for Classes 4 and 5.15,15,23 For a geriatric patient to qualify for outpatient treatment based on these recommendations, he or she would have to be younger than 70 years of age if male or younger than 80 years of age if female, and have no additional risk factors. Inpatient observation or traditional hospitalization would be recommended for all other patients based on this rule. Other studies have suggested outpatient management for Class 3 patients.11,24
Geriatric patients considered eligible for management as outpatients must be able to take oral fluids and antibiotics, comply with outpatient care, and must be able to carry out activities of daily living (ADLs) or have adequate home support to assist with ADLs.14-16 Other factors cited in previous studies but not included in the PSI also have been found to increase the risk of morbidity or mortality from pneumonia. These include: other comorbid illnesses (diabetes mellitus, COPD, post-splenectomy state), altered mental status, suspicion of aspiration, chronic alcohol abuse or malnutrition, and evidence of extrapulmonary disease.8 Additional laboratory studies that may suggest increased severity of illness include white blood cell count less than 4 or greater than 30, absolute neutrophil count less than 1, elevated protime or partial thromboplastin time, decreased platelet count, or radiographic evidence of multilobar involvement, cavitation, and rapid speeding.8
Severe pneumonia may require ICU admission. In the Fine study, 6% of patients in Class 3, 11% of patients in Class 4, and 17% of patients in Class 5 required ICU admission.14 The ATS guidelines define severe pneumonia as the presence of at least one of the following: respiratory rate greater than 30, severe respiratory failure (PaO2/FIO2 < 250), mechanical ventilation, bilateral infiltrates or multilobar infiltrates, shock, vasopressor requirement, or oliguria (urine output < 20 cc per hour). The presence of at least one of these is highly sensitive (98%) but only 32% specific for the need for ICU management.25 It is emphasized that the above guidelines for admission should not supersede clinical judgment when assessing the need to hospitalize patients.8,14,15,23
Antibiotic Selection for the Elderly Patient with Pneumonia
Introduction. Antibiotic therapy is the mainstay of management for geriatric patients with CAP. It should be stated at the outset that antibiotic therapy should be initiated promptly, as soon as the diagnosis is strongly suspected or confirmed, and after appropriate microbiological studies or samples have been obtained. Because the elderly are at high risk for acquiring pneumonia, many of the guidelines issued by consensus panels, clinical experts, and scientific associations, including those of the IDSA, the ATS, and the CDC Drug-Resistant Streptococcus pneumoniae Therapeutic Working Group, apply directly to this patient population. Therefore, these recommendations should be studied in detail to arrive at sensible, empiric pharmacotherapeutic interventions for the elderly patient with pneumonia. Although the CDC group makes no specific recommendations for geriatric patients, their guidelines apply to all adult patients; hence, their conclusions are applicable to the geriatric patient with CAP.
Consensus Panels. It should be stressed that there is no absolute or consistent consensus on precisely which drug, or combination of drugs, constitutes the most outcome-effective choice for pneumonia in the geriatric patient. Most panels and guideline documents agree that antimicrobial coverage must include sufficient activity against the bacterial pathogens S. pneumoniae, H. influenzae, and M. catarrhalis, as well as against the atypical pathogens Mycoplasma, Legionella, and C. pneumoniae. Therefore, such agents as azithromycin and levofloxacin which, because of their activity against both bacterial and atypical pathogens commonly encountered in CAP, have supplanted cephalosporins as preferred monotherapeutic options for treatment of appropriate patients with pneumonia.
Beyond this non-negotiable caveat mandating coverage for the six aforementioned pathogens, there are important differences among recommendations and expert panels for empiric treatment of pneumonia. Variations among the guidelines usually depend upon: 1) their emphasis or focus on the need to empirically cover drug-resistant Streptococcus pneumoniae (DRSP) species as part of the initial antimicrobial regimen; 2) their concern about using antimicrobials (fluoroquinolones) with an over-extended (too broad) spectrum of coverage; 3) their concern about the potential of growing resistance to a class (fluoroquinolones) which has agents that currently are active against DRSP species; 4) their preference for monotherapeutic vs. combination therapy; 5) when the guidelines were released (recent vs several years old); and 6) their emphasis on drug costs, patient convenience, and options for step-down (IV to oral) therapeutic approaches. Clearly, these factors and the relative emphasis placed on each of them will influence antimicrobial selection for the geriatric patient with pneumonia.
| Table 1.
Cost of IV Antibiotic for CAP in the Elderly |
|
| Drug and Dosage | Daily Drug Cost (WAC)* Cost/Day |
| Azithromycin IV 500 mg | $18.96 |
| Ceftriaxone 1 gm IV qd | 36.06 |
| Levofloxacin 500 mg IV qd | 33.00 |
| Erythromycin 500 mg IV qid | 5.20 |
| Ciprofloxacin 400 mg IV bid | 48.00 |
| Cefotaxime 1 g IV tid | 25.00 |
| Tricarcillin-clavulanate 3.1 g qid | 48.32 |
|
* WAC = Wholesale acquisition cost. Hospital formulary pricing guide, August 1999. WAC may not necessarily reflect actual pharmacy costs or costs associated with drug administration cost comparisons. |
|
With these issues and drug selection factors in mind, the most recent guidelines issued by the CDC Drug-Resistant Streptococcus pneumoniae Therapeutic Working Group attempts to both risk-stratify and "drug-stratify" patients according to their eligibility for receiving agents as initial empiric therapy that have activity against DRSP. Before presenting a detailed discussion of the current treatment landscape for CAP, the following points from this expert panel should be emphasized. First, the relative importance of S. pneumoniae as a cause of outpatient CAP in the elderly patient is difficult to determine. Nevertheless, a review of the literature suggests that S. pneumoniae accounts for 2-27% of all cases of CAP treated on an outpatient basis.7,26,27 In addition, surveillance studies have suggested that about 7% of invasive S. pneumoniae species in the United States showed a significant degree of penicillin resistance.28 Hence, this group estimates that only 0.14% (7% of 2%) to 1.9% (7% 0f 27%) of outpatients with bacterial pneumonia have pneumococcal infections with levels of resistance high enough to warrant consideration of alternative treatment.
This analysis has made the CDC panel conclude that because outpatient CAP in patients who are appropriately triaged and risk-stratified is generally not immediately life-threatening and because S. pneumoniae isolates with penicillin MICs of no less than 4 mcg/mL are uncommon, antibiotics with predictable activity against highly penicillin-resistance pneuomococci are not necessary as part of the initial regimen. From a practical, drug-selection perspective, the working group, therefore, suggests that oral fluoroquinolones are not first-line treatment in elderly outpatients with CAP because of concerns about emerging resistance. Consequently, oral macrolide or beta-lactam monotherapy is recommended by the CDC working group as initial therapy in patients with pneumonia considered to be amenable to outpatient management.
It should be noted, however, that even for hospitalized (non-ICU) patients, the panel, while noting the effectiveness of monotherapy with selected fluoroquinolones, recommends the combination of a parenteral beta-lactam (cefotaxime, ceftriaxone, etc.) plus a macrolide (azithromycin, erythromycin, etc.) for initial therapy.2 Regardless of the panel or critical pathway, one of the important consistent changes among recent recommendations for initial, empiric management of patients with CAP is mandatory inclusion of a macrolide (which covers atypical pathogens) when a cephalosporin (which has poor activity against atypical pathogens) is selected as part of the regimen.
For critically ill patients, first-line therapy should include an intravenous beta-lactam, such as ceftriaxone or cefotaxime, and an intravenous macrolide, such as azithromycin or erythromycin (see discussion below). The option of using a combination of a parenteral beta-lactam (cefotaxime, ceftriaxone, etc.) plus a fluoroquinolone with improved activity against DRSP also is presented. Once again, however, this committee issues clarifying, and sometimes cautionary, statements about the role of fluoroquinolone monotherapy in the critically ill patient, stating that caution should be exercised because the efficacy of the new fluoroquinolones as monotherapy for critically ill patients has not been determined.2
Clearly, however, fluoroquinolones are an important part of the antimicrobial arsenal in the elderly, and The CDC Drug-Resistant Streptococcus pneumoniae Therapeutic Working Group has issued specific guidelines governing their use in the setting of outpatient and inpatient CAP. In general, this panel has recommended that fluoroquinolones be reserved for selected patients with CAP, and these experts have identified specific patient subgroups that are eligible for initial treatment with extended-spectrum fluoroquinolones. For hospitalized patients, these include adults for whom one of the first-line regimens (e.g., cephalosporin plus a macrolide) has failed, those who are allergic to the first-line agents, or those who have a documented infection with highly drug-resistant pneumococci (i.e., penicillin MIC ³ 4 mcg/mL).2 The rationale for this approach is discussed in subsequent sections below.
With these considerations in focus, the purpose of this antimicrobial treatment section is to review the various recommendations, consensus panel statements, clinical trials, and published guidelines. A rational analysis of this information also will be performed, in order to generate a set of guidelines and protocols for specific populations as these issues relate to the geriatric patient.
Antibiotic Overview. A brief overview of agents that have been used for treatment of CAP will help set the stage for outcome-effective drug selection. (See Table 1.) 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.29 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.
Among the beta-lactams, the CDC Drug-Resistant Streptococcus pneumoniae Therapeutic Working Group identifies cefuroxime axetil, cefotaxime sodium, ceftriaxone sodium, or ampicillin-sulbactam as recommended empiric agents. The group notes, however, that among these agents, cefotaxime and ceftriaxone have superior activity against resistant pneumonococci when compared with cefuroxime and ampicillin-sulbactam.2
The aminoglycosides are active against gram-negative aerobic organisms. These agents are generally used for elderly patients with severe CAP, particularly when it involves 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.30
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.31 These agents are alternatives to the macrolide antibiotics for empiric therapy for CAP in young, healthy adults.32 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, S. pneumoniae, and S. aureus.33,34 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 of Antimicrobial 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 quinolones 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 should include a full accounting of the relevant similarities and differences. It 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.
Although the previously cited six organisms (S. pneumoniae, H. influenzae, and M. catarrhalis, and atypical pathogens Mycoplasma, Legionella, and C. pneumoniae) are the most commonly implicated pathogens in elderly patients with CAP, the patients also are susceptible to infection with gram-negative enteric organisms such as Klebsiella, Escherichia coli, and Pseudomonas. In other cases, the likelihood of infection with DRSP is high. When infection with these pathogens is likely, intensification of empiric coverage should include antibiotics with activity against these gram-negative species and/or DRSP.
Clinical features or risk factors that may suggest the need for intensification and expansion of bacterial and/or atypical pathogen coverage include the following: 1) increasing fragility (> 85 years of age, comorbid conditions, previous infection, etc.) 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 anaerobic 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) history of infection with gram-negative, anaerobic, or resistant species of S. pneumoniae; 7) history of treatment failure; 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 among S. pneumoniae species; and 11) immunodeficiency and/or severe underlying disease. Many of the aforementioned risk groups also can 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 or combination therapy, address current etiologic and mortality trends in CAP. As a general rule, for empiric initial therapy in patients without modifying host factors that predispose to enteric gram-negative or pseudomonal infection they recommend 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.35
Correct Spectrum Coverage. When antimicrobial monotherapy is desirable, cost-effective, and/or clinically indicated, extended spectrum quinolones and advanced generation macrolides best satisfy the empiric coverage requirements for patients with CAP. These antimicrobial agents are among the therapeutic classes of choice for management of CAP in the outpatient setting. (See Tables 2 and 3.)
Although third-generation cephalosporins, beta-lactam antibiotics, and TMP/SMX (trimethoprim-sulfamethoxazole) 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. This is because they are not, as a rule, clinically indicated for treatment of atypical organisms, including Mycoplasma, Legionella, and C. pneumoniae, whose increasing importance now demand initial, out-of-the-gate coverage.
Because advanced generation macrolides and extended spectrum quinolones constitute the principal oral and intravenous treatment options for CAP, the following sections will discuss indications, clinical trials, 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. It should be stressed that these agents also may be used as part of combination therapy for CAP. Antibiotics satisfying these criteria are azithromycin and levofloxacin.
Advanced Generation Macrolides: Correct Spectrum First-Line Coverage
The established new generation macrolide antibiotics include the erythromycin analogues azithromycin and clarithromycin.36,37 Compared to erythromycin, which is the least expensive macrolide, the major advantages of these newer 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.38,39 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.
| Table 2. Empiric Antimicrobial Therapy of Choice for Outpatient and In-Hospital Management of Elderly Patients with Community-Acquired Pneumonia |
||
| Patient Profile/Etiologic Agents | First-Line Antibiotic Therapy | Alternative First-Line Antibiotic Therapy |
|
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 supportive home environment)* |
Azithromycin PO | Levofloxacin PO OR Cefuroxime plus azithromycin PO OR Clarithromycin |
| In-Hospital (not in intensive care unit) underlying risk factors or comorbid conditions: In-Hospital management (COPD, history of pneumonia, diabetes, etc.) | Azithromycin IV OR Azithromycin IV plus ceftriaxone OR Cefotaxime plus azithromycin IV |
Imipenem IV plus azithromycin IV OR Levofloxacin IV |
| CAP acquired in the nursing home environment (increased likelihood of gram-negative, E. coli, Klebsiella pneumoniae) | Ceftriaxone IV plus azithromycin IV OR Levofloxacin IV |
Ceftriaxone plus erythromycin IV OR Cefotaxime plus azithromycin IV |
| CAP in the elderly individual with chronic alcoholism (Increased likelihood of Klebsiella pneumoniae infection) | 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 high-level or complete resistance to macrolides, cephalosporins, and/or penicillin, but maintaining high sensitivity to extended spectrum quinolones) | Levofloxacin IV OR Levofloxacin IV plus Ceftriaxone IV |
Vancomycin¶ plus azithromycin IV |
| Severe CAP complicated by structural disease of the lung (bronchiectasis): Increased likelihood of Pseudomonas and polymicrobial infection | Cefepime IV plus levofloxacin IV plus/minus aminoglycoside OR Ciprofloxacin IV plus aminoglycoside IV plus azithromycin IV |
Ciprofloxacin IV plus cefepime IV plus azithromycin IV OR Carbapenem IV plus azithromycin IV plus aminoglycoside |
| CAP in a patient with suspected aspiration (increases the likelihood of gram-negative and anaerobic infection**) | Levofloxacin IV plus clindamycin IV OR Azithromycin IV plus ampicillin-sulbactam IV |
Levofloxacin 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)*** | Levofloxacin 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*** | Ceftriaxone IV plus levofloxacin IV plus/minus aminoglycoside
(Pseudomonas strongly suspected) OR Cefotaxime IV plus Ceftriaxone IV plus azithromycin IV plus/minus anti-pseudomonal agent |
Ciprofloxacin IV plus aminoglycoside IV plus azithromycin IV OR azithromycin IV plus/minus 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 institution 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, clindamycin or a b-lactam/b-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 S. 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 references 2, 3, 5, 6-8, 11, 35, 41, 43, 44, 46, 47, 54, 64, 66 |
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| Table 3. Infectious Disease Society of America (IDSA) Consensus Report Guidelines |
| Outpatient management: Preferred antimicro bials in most patients (in no special order) |
* Macrolide: azithromycin, erythromycin, or clarithromycin; azithromycin or clarithromycin is preferred if H. influenzae infection is suspected ** Fluoroquinolone: levofloxacin is preferred. *** 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:
Alternative:
|
in-hospital-intensive care unit management: preferred antimicrobials in most patients (in no special order) |
|
Preferred:
|
| Modifying factors |
|
| Adaptation and Summary of Preferred Antimicrobial Recommendations from the Infectious Disease Society of America, IDSA 1998 |
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. (See Table 4.)
From the outset, it is fair to say that these 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. In some institutions, this is not the case. 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.40,41 It is, however, effective against pneumococcal pneumonia, Mycoplasma pneumonia, and many atypical infections, including Legionella. (See Table 4.) Food decreases the absorption of erythromycin, which interferes with drug metabolism; therefore, many experts caution this drug should not be considered for use in elderly patients on theophylline or warfarin.22,35
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, extended spectrum quinolones-for outpatient management of CAP.42 When used as oral agents, they play a central role in management of pneumonia in otherwise healthy elderly individuals who do not require hospitalization.
From an emergency medicine and in-hospital management perspective, the value and desirability 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.43,44
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). (See Table 5.) Clarithromycin requires a longer course of therapy and is more expensive. Clarithromycin costs approximately $68-72 for a complete, 10-day course of therapy vs. $42-44 for a complete course of therapy with azithromycin. Clarithromycin, however, is another alternative among macrolides for outpatient treatment of CAP. It is now available in once-daily formulation (1000 mg/d for 10 days) for oral use, but an intravenous preparation is not currently available. 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.45 The introduction of a tablet formulation permits consumption of the antibiotic without regard to food ingestion.
Azithromycin. From a practical, clinical, and cost 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.46-48 Currently, azithromycin is the only advanced generation macrolide indicated for parenteral therapy in hospitalized patients with CAP due to C. pneumoniae, H. influenzae, L. pneumophila, M. catarrhalis, M. pneumoniae, S. pneumoniae, or Staphylococcus aureus.43,44,48,49 This coverage would be considered correct spectrum coverage for empiric therapy of CAP in the elderly patient.
The comparative trials demonstrating clinical success (patients who were cured or improved at 10-14 days post-therapy) rates of about 77% and 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 of patients who were 65 years of age or older, had an abnormal respiratory rate (> 30 breaths per minute), a PaO2 of less than 60 mmHg, and/or BUN greater than 20 mg/dL.43,44,48 Many of these patients had concurrent diseases or syndromes, including emphysema, chronic airway obstruction, asthma, diabetes, and/or were cigarette smokers.50
As would be expected, the efficacy of this macrolide was compared to clinical outcomes with a cephalosporin (cefuroxime) 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.50
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 should be given in the ED.
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.51
| Table 4. Macrolides: Approved Spectrum of Coverage in Community-Acquired Pneumonia |
|||||||
| Antibiotic | Indicated* for Treatment of CAP Caused by These Organisms | ||||||
| S. pneumoniae | H. influenzae | M. catarrhalis | M. pneumoniae | C. pneumoniae | L. pneumophilia | S. aureas | |
| Azithromycin** | Yes | Yes | Yes | Yes | Yes | Yes | Yes |
| Clarithromycin | Yes | Yes | Yes | ||||
| Erythromycin | Yes | Yes | Yes | ||||
|
*Indicated, i.e., according to FDA approved indications as specified in the package insert for each agent. The agent may, however, show in vitro activity against organisms for which clinical indications have not yet been established. ** Intravenous formulation of azithromycin. |
|||||||
Initial Intravenous Management: Macrolide Monotherapy (Azithromycin) vs. Combination Therapy
As emphasized earlier, prompt administration of intravenous antibiotics in the ED can improve clinical outcomes in patients with CAP. Consequently, once diagnostic tests, including cultures and radiographs (when appropriate), have been performed, initial antibiotic therapy for hospitalized patients should be administered in the ED, especially if delays in getting the patient admitted are anticipated.
Although antibiotic recommendations based on risk-stratification criteria, historical features, site where the infection was acquired, and other modifying factors are provided in Table 3, institutional protocols, hospital-based critical pathways, resistance features, and other factors will influence antibiotic selection.
Despite variations in hospital or departmental protocols, certain requirements regarding drug selection for CAP are relatively consistent. For example, from an empiric antibiotic selection perspective, what appears to be non-negotiable for managing the majority of patients with CAP, is providing mandatory antimicrobial coverage against S. pneumoniae, H. influenzae, M. catarrhalis, Legionella, M. pneumoniae, and C. pneumoniae. As mentioned earlier, consensus reports and national guidelines support this strategy (see section on Consensus Guidelines for Antibiotic Therapy below). Within the framework of monotherapy, IV azithromycin (500 mg IV for 2-5 days, followed by 500 mg PO to complete a 7-10 day course) is recommended by many institutional protocols for ward (i.e., non-ICU) patients with CAP who do not have modifying factors (i.e., aspiration, immunosuppression, alcoholism, etc.) that suggest the likelihood of gram-negative pneumonia.35,49,51,52
For hospitalized patients, at least two days of intravenous azithromycin therapy is recommended (the first dose of which can be given in the ED), followed by transition to oral therapy at the discretion of the physician based on clinical factors. It should be noted that intravenous azithromycin is currently the only macrolide that carries an indication for in-hospital, intravenous-to-oral step-down, monotherapeutic management of appropriately risk-stratified patients with CAP. When combination cephalosporin/macrolide therapy is the accepted hospital protocol, among the macrolides available, IV azithromycin is recommended by this author as the co-therapeutic agent (i.e., in combination with a cephalosporin) of choice in the elderly for the following reasons: 1) it can be administered on a once-daily basis, thereby minimizing human resource costs associated with drug administration; 2) it is the only macrolide indicated for in-hospital, intravenous-to-oral stepdown, monotherapeutic management of CAP caused by S. pneumoniae, H. influenzae, M. catarrhalis, Legionella pneumophila, M. pneumoniae, C. pneumoniae, or S. aureus—an important efficacy and spectrum of coverage benchmark; 3) at $19-22 per day for the intravenous dose of 500 mg azithromycin, its cost is reasonable; 4) the intravenous-to-oral step-down dose of 500 mg has been established as effective in clinical trials evaluating hospitalized patients with CAP; and 5) azithromycin has excellent activity against Legionella pneumophila, a pathogen commonly implicated in the geriatric patient with CAP. The decision to use azithromycin as a monotherapeutic agent, or in combination with a cephalosporin for initial therapy of CAP, will be determined by intra-institutional pathways and protocols, based on consensus recommendations and association guidelines as presented in this article.
| Table 5. Available Macrolides for Monotherapy or Co-Therapy in Elderly Hospitalized Patients with Community-Acquired Pneumonia |
||||
| Antibiotic | Spectrum of coverage | Daily dosing frequency | IV to oral stepdown** | Is agent available for IV monotherapy of CAP? |
| Azithromycin IV | S. pneumoniae |
once daily | available and indicated | yes |
| Erythromycin IV | S. pneumoniae |
four times daily | available | no |
| Clarithromycin oral (IV not available) | S. pneumoniae |
twice daily | not available | no |
| *Spectrum of coverage refers to approved indications as
they pertain to in-hospital treatment of CAP for organisms specified.
**Refers to availability of IV to oral step-down using the agent, i.e., IV azithromycin to oral azithromycin, IV erythromycin to oral erythromycin, ect. |
||||
Critical Pathways and Protocols. The decision to employ a monotherapeutic regimen with IV azithromycin for inpatient treatment of CAP usually will be based on intra-hospital infectious disease protocols and local susceptibility patterns, which may risk-stratify patient subgroups appropriate for monotherapy. When patients with CAP are hospitalized in the ICU or there is a significant likelihood of gram-negative infection (i.e., Klebsiella, E. coli, or P. aeruginosa), monotherapy with a macrolide is not appropriate, and CDC group’s recent consensus report stresses the importance of using an IV macrolide in combination with other agents, in particular, third-generation cephalosporins such as ceftriaxone or cefotaxime.2 In these patients, a macrolide should be used in combination with a cephalosporin (and when anti-pseudomonal coverage is necessary, an anti-pseudomonal cephalosporin and/or an aminoglycoside also may be required) or alternatively, an extended spectrum fluoroquinolone such as levofloxacin should be considered, although combination therapy also has been advocated with this agent in severely ill patients.2 When anaerobic organisms are suspected, clindamycin or a beta-lactam/beta-lactamase inhibitor is appropriate.
Accordingly, a number of critical pathways for pneumonia therapy recommend use of two-drug therapy for CAP. The therapy typically is the combination of an IV cephalosporin such as ceftriaxone plus a macrolide, which usually is administered, initially, by the intravenous route when the patient’s condition so warrants. Perhaps the important change in CAP treatment since publication of the American Thoracic Guidelines in 1993 is the current general consensus that atypical organisms such as L. pneumophila, C. pneumoniae, and M. pneumoniae must be covered empirically as part of the initial antibiotic regimen. Whereas previous consensus guidelines indicated that macrolides could be added to a cephalosporin on a "plus or minus" basis for initial CAP treatment, it is now felt that coverage of the atypical spectrum, along with coverage of S. pneumoniae, H. influenzae, and M. catarrhalis, is mandatory.2 New guidelines from the IDSA and CDC now reflect this strategy which, in practical terms, means that a macrolide such as azithromycin or erythromycin (or a fluoroquinolone with activity against atypical organisms) will be part of almost every empirical antimicrobial regimen used for CAP.
Although virtually all protocols using combination cephalosporin/macrolide therapy specify intravenous administration of the cephalosporin, guidelines specifying whether initial macrolide therapy should be by the intravenous or oral route are less concrete. Recent CDC guidelines recommend intravenous macrolide therapy for patients hospitalized in the ICU, while oral therapy is permissible in conjunction with an IV cephalosporin in the medical ward patient.2 Because atypical infections such as L. pneumophila are associated with high mortality rates, especially in the elderly, and because hospitalized patients with CAP, by definition, represent a sicker cohort, it is prudent and, therefore, advisable that initial macrolide therapy in the hospital be administered by the intravenous route. The author of this review, therefore, recommends IV azithromycin therapy as the preferred initial, empiric agent in the elderly, whether used as monotherapy or in combination with another agent. Step-down to oral therapy can be accomplished when the patient’s clinical status so dictates, or when culture results suggest this is appropriate.
It should be pointed out that while some consensus panels (IDSA 1997 CAP Guidelines) support the use of IV azithromycin in hospitalized CAP patients as monotherapy or as the macrolide component of combination therapy, other panels (CDC Therapeutic Working Group) support its use specifically as the macrolide component of combination therapy along with such as agents as ceftriaxone, cefuroxime, or cefotaxime. Although each institution will determine its preferred approach to these options, recent studies lend support to the notion that IV azithromycin monotherapy for hospitalized patients (45% of which were > 64 years of age) with CAP admitted to a general medical ward is equal in efficacy to a 1993 ATS-suggested regimen of cefuroxime with the addition of erythromycin when clinicians believe it is necessary.43 In one study, which excluded patients with aspiration, as well as those with evidence of gram-negative infection known to be resistant to the study medications, the authors also conclude that gastrointestinal tolerance of the azithromycin regimen was better than the suggested ATS regimen, and that azithromycin therapy was associated with a shorter length of stay as compared with the ATS-suggested regimen.43
Another prospective, randomized multicenter trial compared the efficacy and safety of azithromycin monotherapy with those of a combination of cefuroxime plus erythromycin as empirical therapy in hospitalized patients with CAP.44 Data from 245 patients (67 received azithromycin monotherapy, 78 received combination cefuroxime and erythromycin) were evaluated, and it was found that clinical cure was achieved in 91% (61 of 67) of the patients in the azithromycin group and in 91% (71 of 78) of those in the combination group. Streptococcus pneumoniae and Haemophilus influenzae were isolated in 19% and 13% of the total patient population, respectively; atypical pathogens accounted for 33% of the etiologic diagnoses, with Legionella pneumophila, Chlamydia pneumoniae, and Mycoplasma pneumoniae being identified in 14%, 10%, and 9% of patients, respectively. The investigation, which excluded nursing home residents, concluded that treatment with azithromycin was as effective as cefuroxime plus erythromycin in the empirical management of CAP in immunocompetent patients who were hospitalized.44
Both the aforementioned studies conclude that, in a selected population of patients with CAP, azithromycin monotherapy is as effective as a combination regimen (i.e., cefuroxime plus erythromycin) that is consistent with guidelines published by the ATS, Canadian Community-Acquired Pneumonia Consensus Group, and the IDSA.
Extended Spectrum Fluoroquinolones, Indication for Initial Empiric Use: Intensifications of Coverage and Patient Selection
The extended spectrum quinolone levofloxacin is indicated for treatment of CAP. Because levofloxacin is used both as an oral agent and intravenously in the hospital setting, has indications for use in suspected DRSP pneumonia, and is the most widely used fluoroquinolone for this indication, the discussion below will focus on levofloxacin.
However, another recently introduced extended spectrum fluoroquinolone, gatifloxacin (Tequin) is also available for both intravenous and oral therapy for the treatment of pneumonia, and has appropriate spectrum of coverage for bacterial and atypical pathogens causing pneumonia. It may play an increasingly important role in the management of these patients. Currently, though, clinicians have had more practical experience with the fluoroquinolone, levofloxacin, and therefore, this review will focus primarily on this fluoroquinolone representative from this antimicrobial class. Among oral agents, the fluoroquinolone moxifloxacin (Avelox) is also available.
Levofloxacin. Levofloxacin, the S-enantiomer of ofloxacin, is a fluoroquinolone antibiotic that, when compared with older quinolones, also has improved activity against gram-positive organisms, including Streptococcus pneumoniae. This has important drug selection implications for the 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.53 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.
Several studies and surveillance data suggest that some newly available, expanded spectrum fluoroquinolones, including levofloxacin (which is approved for PRSP), are efficacious for the treatment of S. pneumoniae, including penicillin-resistant strains.2,54,55 In one study, microbiologic eradication from sputum was reported among all 300 patients with pneumococcal pneumonia treated with oral levofloxacin.54 In a study of in vitro susceptibility of S. pneumoniae clinical isolates to levofloxacin, none of the 180 isolates (including 60 isolates with intermediate susceptibility to penicillin and 60 penicillin-resistant isolates) was resistant to this agent.55 In addition, a surveillance study of antimicrobial resistance in respiratory tract pathogens found levofloxacin was active against 97% of 9190 pneumococcal isolates and found no cross-resistance with penicillin, amoxicillin-clavulanate, ceftriaxone, cefuroxime, or clarithromycin.
Despite high level activity against pneumococcal isolates and a formal indication for levofloxacin use in suspected DRSP lower respiratory tract infection, the CDC Drug-Resistant Streptococcus pneumoniae Therapeutic Working Group’s recent guidelines do not advocate the use of expanded spectrum fluoroquinolones (among them, levofloxacin, sparfloxacin, or grepafloxacin) for first-line, empiric treatment of pneumonia. This is because: 1) of their broad, perhaps, over-extended spectrum of coverage that includes a wide range of gram-negative organisms; 2) of concern that resistance among pneumococci will emerge if there is widespread use of this class of antibiotics; 3) their activity against pneumococci with high penicillin resistance (MIC ³ 4 mcg/mL) makes it important that they be reserved for selected patients with CAP; 4) use of fluoroquinolones has been shown to result in increased resistance to S. pneumoniae in vitro; and 5) population-based surveillance in the United States has shown a statistically significant increase in ofloxacin resistance among pneumococcal isolates between Jan. 1, 1995, and Dec. 31, 1997 (unpublished data, Active Bacterial Core Surveillance, CDC).2
From a practical, drug selection perspective, The CDC Drug-Resistant Streptococcus pneumoniae Therapeutic Working Group has recommended that fluoroquinolones be reserved for selected patients with CAP, and these experts have identified specific patient subgroups that are eligible for initial treatment with extended-spectrum fluoroquinolones such as levofloxacin. For hospitalized patients, these include adults and elderly patients for whom one of the first-line regimens (cephalosporin plus a macrolide) has failed, those who are allergic to the first-line agents, or those who have a documented infection with highly drug-resistant pneumococci (i.e., penicillin MIC ³ 4 mcg/mL).29
When given orally, levofloxacin is dosed once daily, is well absorbed orally, and penetrates well into lung tissue.56 It is active against a wide range of respiratory pathogens, including atypical pathogens and many species of S. pneumoniae resistant to penicillin.57,58 In general, levofloxacin has greater activity against gram-positive organisms than ofloxacin and is slightly less active than ciprofloxacin against gram-negative organisms.59,60
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 levofloxacin 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).53 The drug is well-tolerated, with the most common side effects including nausea, diarrhea, headache, and constipation. 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.61,62 In patients with CAP, IV levofloxacin with step-down-to-oral therapy was superior to ceftriaxone with step-down therapy to cefuroxime axetil.63 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% in patients in whom a microbiological pathogen could be identified; however, a large number of patients (32-43%) were not evaluable for this end point.61-63
It should be emphasized that, currently, such macrolides as azithromycin 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.56
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 3.) 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 ATS.64 This classification scheme, which is now almost seven 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.65 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 based on the expected pathogens.66,52 (See Table 3.)
Therefore, 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, should be considered one of the initial agents of choice. The other monotherapeutic agents available consist of the extended spectrum quinolones, which provides similar coverage and carries and indication for initial therapy in this patient subgroup.
For the older patient with CAP who is considered stable enough to be managed as an outpatient, but in whom the bacterial pathogen list also may include gram-negative aerobic organisms, the combined use of a second- or third-generation cephalosporin or amoxicillin-clavulanate plus a macrolide has been recommended. Another option may consist of an advanced generation quinolone.
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.66 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, either TMP-SMX or doxycycline usually provides adequate coverage against S. pneumoniae and H. influenzae, but TMP-SMX will not cover atypical pathogens.
Use of the older quinolones is not recommended for empiric 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 important option for treatment of bronchiectasis, particularly when gram-negative organisms such as Pseudomonas are cultured from respiratory secretions.67 In these cases, ciprofloxacin should be used in combination with another anti-pseudomonal agent when indicated.
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, especially when infection with gram-negative organisms is suspected or there is structural lung disease, this will require shifting to and intensifying therapy with an extended spectrum quinolone. However, in most cases of non-ICU patients admitted to the hospital, azithromycin IV as monotherapy or a cephalosporin plus azithromycin is recommended, depending on institutional protocols.
In this regard, determining which of these antibiotics (macrolides vs extended spectrum quinolones) should be considered "workhorse" drugs in the ED or hospital setting, for initial CAP treatment requires thoughtful analysis that takes into account cost, convenience, spectrum of coverage, host risk factors, and patient risk stratification.
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 also extensive activity against gram-negative organisms, which may not always be required, especially in otherwise healthy individuals. This over-extended spectrum of coverage may exert resistance pressure on gram-negative organisms frequently encountered in a hospital setting; therefore, quinolone use should be risk-stratified to an appropriate subset.
From a cost-effectiveness perspective, it appears 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 without underlying problems. However, in patients in whom gram-negative infection is more of a concern, the extended spectrum quinolone is an important alternative to combination therapy consisting of a third-generation cephalosporin plus a macrolide such as azithromycin.
Finally, there is an increasing problem in the United States concerning the emergence among hospitalized pneumonia patients of S. pneumoniae that is relatively resistant to penicillin and, less commonly, to extended-spectrum cephalosporins. These isolates also may be resistant to sulfonamides and tetracyclines.64,68,69 Except for vancomycin, the most favorable in vitro response rates to S. pneumoniae are seen with extended spectrum quinolones. See Table 3 for a summary of current recommendations for initial management of outpatient and in-hospital management of patients with CAP.
Antimicrobial Therapy and Medical Outcomes. A recent study has helped assess the relationship between initial antimicrobial therapy and medical outcomes for elderly patients hospitalized with pneumonia.70 In this retrospective analysis, hospital records for 12,945 Medicare inpatients (³ 65years of age) with pneumonia were reviewed. Associations were identified between the choice of the initial antimicrobial regimen and three-day mortality, adjusting for baseline differences in patient profiles, illness severity, and process of care. Comparisons were made between the antimicrobial regimens and a reference group consisting of patients treated with a non-pseudomonal third-generation cephalosporin alone.
Of the 12,945 patients, 9751 (75.3%) were community-dwelling and 3194 (24.7%) were admitted from a long-term care facility (LCF). Study patients had a mean age of 79.4 years ± 8.1 years; 84.4% were white, and 50.7% were female. As would be expected, the majority (58.1%) of patients had at least one comorbid illness; and 68.3% were in the two highest severity risk classes (IV and V) at initial examination. The most frequently coded bacteriologic pathogens were S. pneumoniae (6.6%) and H. influenzae (4.1%); 10.1% of patients were coded as having aspiration pneumonia, and in 60.5% the etiologic agent for the pneumonia was unknown.
The three most commonly used initial, empiric antimicrobial regimen in the elderly patient with pneumonia consisted of the following: 1) a non-pseudomonal third-generation cephalosporin only (ceftriaxone, cefotaxime, ceftizoxime) in 26.5%; 2) a second-generation cephalosporin only (cefuroxime) in 12.3%; and 3) a non-pseudomonal third-generation cephalosporin (as above) plus a macrolide in 8.8%. The 30-day mortality was 15.3% (95% CI, 14.6%-15.9%) in the entire study population, ranging from 11.2% (95% CI, 10.6%-11.9%) in community-dwelling elderly patients to 27.5% (95% CI, 26%-29.1%) among patients admitted from a LCF.70
As might be predicted, this study of elderly patients with hospitalization for pneumonia demonstrated significant differences in patient survival depending upon the choice of the initial antibiotic regimen. In particular, this national study demonstrated that, compared to a reference group receiving a non-pseudomonal third-generation cephalosporin alone, initial therapy with a non-pseudomonal plus a macrolide, a second-generation cephalosporin plus a macrolide, or a fluoroquinolone alone was associated with 26%, 29%, and 36% lower 30-day mortality, respectively. Despite the fact that these regimens are compatible with those recommended by the IDSA and CDC, only 15% of patients received one of the three aforementioned regimens associated with reduced mortality rates.
For reasons that are not entirely clear, patients treated with a beta-lactam/beta-lactamase inhibitor plus a macrolide or an aminoglycoside plus another agent had mortality rates 77% and 21% higher than the reference group, respectively.
Role of Specific Pathogens in CAP. Prospective studies for evaluating the causes of CAP in elderly 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 in the elderly 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, C. pneumoniae, S. aureus, Streptococcus pyogenes, Neisseria meningitidis, M. catarrhalis, Klebsiella pneumoniae and other gram-negative rods, Legionella species, influenza virus (depending on the time of year), respiratory syncytial 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.
Consensus Guidelines for Antibiotic Therapy
Consensus Report Guidelines: Infectious Disease Society of America. The 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 3.)
Centers for Disease Control Drug-Resistant Streptococcus pneumoniae Therapeutic Working Group Guidelines. One of the important issues in selecting antibiotic therapy for the elderly patient is the emerging problem of DRSP. To address this problem and provide practitioners with specific guidelines for initial antimicrobial selection in these patients, the CDC Drug-Resistant Streptococcus pneumoniae Therapeutic Working convened and published its recommendations in May 2000.2 Some of the important clinical issues they addressed included the following: 1) what empirical antibiotic combinations (or monotherapeutic options) constituted reasonable initial therapy in outpatients, in hospitalized (non-ICU) patients, and in hospitalized intubated or ICU patients; 2) what clinical criteria, patient risk factors, or regional, epidemiological features constituted sufficient trigger points to include agents with improved activity against DRSP as initial agents of choice; and 3) what antibiotic selection strategies were most appropriate for limiting the emergence of fluoroquinolone-resistant strains.
Their conclusions with respect to antibiotic recommendations overlap significantly with the IDSA recommendations and the existing 1993 ATS guidelines. The specific differences contained in the Drug-Resistant Streptococcus pneumoniae Therapeutic Working Guidelines involve primarily the sequence in which antibiotics should be chosen in order to limit the emergence of fluoroquinolone-resistant strains, a preference for using combination drug therapy, cautionary notes about using fluoroquinolones as monotherapy in critically ill patients, reserving use of fluoroquinolones for specific patient populations, and detailed guidance regarding the comparative advantages among agents in each class.
Oral macrolide (azithromycin, clarithromycin, or erythromycin) or beta-lactam monotherapy is recommended by the CDC working group as initial therapy in patients with pneumonia considered to be amenable to outpatient management. For inpatients not in an ICU, this group recommends for initial therapy the combination of a parenteral beta-lactam (cefotaxime, ceftriaxone, etc.) plus a macrolide (azithromycin, erythromycin, etc.).2 Hence, one of the most important, consistent changes among recent recommendations for initial, empiric management of patients with CAP is mandatory inclusion of a macrolide (which covers atypical pathogens) when a cephalosporin (which has poor activity against atypical pathogens) is selected as part of the initial combination regimen.
For critically ill patients, first-line therapy should include an intravenous beta-lactam, such as ceftriaxone or cefotaxime, and an intravenous macrolide such as azithromycin or erythromycin. The option of using a combination of a parenteral beta-lactam (cefotaxime, ceftriaxone, etc.) plus a fluoroquinolone with improved activity against DRSP is also presented. Once again, however, this committee issues clarifying, and sometimes cautionary, statements about the role of fluoroquinolone monotherapy in the critically ill patient, stating that caution should be exercised because the efficacy of the new fluoroquinolones as monotherapy for critically ill patients has not been determined.2
Clearly, fluoroquinolones are an important part of the antimicrobial arsenal in the elderly, and The CDC Drug-Resistant Streptococcus pneumoniae Therapeutic Working Group has issued specific guidelines governing their use in the setting of outpatient and inpatient CAP. It recommend fluoroquinolones be reserved for selected patients with CAP, among them: 1) adults, including elderly patients, for whom one of the first-line regimens (cephalosporin plus a macrolide) has failed; 2) those who are allergic to the first-line agents; or 3) those patients who have a documented infection with highly drug-resistant pneumococci (i.e., penicillin MIC ³ 4 mcg/mL).
Prevention of Venous Thromboembolism
Background. Although antibiotic therapy, oxygenation, and maintenance of hemodynamic status are the primary triad of emergency interventions in elderly patients with pneumonia, there has been an increasing recognition of the risk for venous thromboembolic disease (VTED) incurred by immobilized elderly patients with infections such as pneumonia, especially when accompanied by CHF and/or respiratory failure. Emergency physicians, as well as attending physicians admitting such patients to the hospital, should be aware that the risk of VTED is significant enough to require prophylaxis in elderly patients with CAP who are likely to be immobilized for a period of three days or more (i.e. can ambulate less than 10 meters per day), and who have such risk factors as obesity, previous history of VTED, cancer, varicose veins, hormone therapy, chronic heart failure (NYHA Class III-IV), or chronic respiratory failure.71
From a practical perspective, this subset of patients should be strongly considered for prophylaxis to reduce the risk of VTED. Based on recent studies, the presence of pneumonia in a patient 75 years or older is, in itself, a criterion for prophylaxis against VTED, and when these factors are accompanied by CHF (Class III-IV) or respiratory failure, prophylaxis should be considered mandatory if there are no significant contraindications.71 It should be added that The American College of Chest Physicians (ACCP) guidelines72 and International Consensus Statement73 also cite risk factors for VTED and emphasize their importance when assessing prophylaxis requirements for medical patients.
Evidence for Prophylaxis. The data to support a prophylactic approach to VTED for serious infections in the elderly is growing. The studies with subcutaneous unfractionated heparin (UFH) are inconclusive, although this agent is used for medical prophylaxis. Despite the recognition of risk factors and the availability of effective means for prophylaxis, DVT and PE remain common causes of morbidity and mortality. It is estimated that approximately 600,000 patients per year are hospitalized for DVT in North America.74 In the United States, symptomatic PE occurs in more than 600,000 patients and causes or contributes to death in up to 200,000 patients annually.75
With respect to the risk of VTED in older patients with infection, one study group randomized infectious disease patients ages older than 55 years to UFH 5000 IU bid or placebo for three weeks. Autopsy was available in 60% of patients who died. Deaths from PE were significantly delayed in the UFH group, but the six-week mortality rate was similar in both groups. Non-fatal VTE was reduced by UFH. The findings of previous trials of prophylaxis in medical patients have been controversial, as the patient populations and methods used to detect thromboembolism, and the dose regimens vary, undermining the value of the findings. Comparative studies with clearly defined populations and reliable end points were therefore required to determine appropriate patient subgroups for antithrombotic therapy.76
The MEDENOX Trial. In response to the need for evidence to clarify the role of prophylaxis in specific non-surgical patient sub groups, the MEDENOX trial was conducted using the LMWH enoxaparin in a clearly identified risk groups.71 In contrast to previous investigations, the MEDENOX trial included a clearly defined patient population (patients immobilized with severe chest [cardiopulmonary] disease) and was designed to answer questions about the need for prophylaxis in this group of medical patients and to determine the optimal dose of LMWH.71
Patients in the MEDENOX Trial were randomized to receive enoxaparin, 20 or 40 mg subcutaneously, or placebo once daily, beginning within 24 hours of randomization. They were treated for 10 (4 days in hospital and followed up in person or by telephone contact on day 90 (range, day 83-110). During follow-up patients were instructed to report any symptoms or signs of VTE or any other clinical event. The primary and secondary efficacy end points for MEDENOX were chosen to allow an objective assessment of the risk of VTE in the study population and extent of any benefit of prophylaxis. The primary end point was any venous thromboembolic event between day 1 and day 14. All patients underwent systematic bilateral venography at day 10 or earlier if clinical signs of DVT were observed. Venous ultrasonography was performed if venography was not possible. Suspected PE was confirmed by high probability lung scan, pulmonary angiography, helical computerized tomography, or at autopsy.71 The primary safety end points were hemorrhagic events, death, thrombocytopenia, or other adverse event or laboratory abnormalities.71
A total of 1102 patients were included in the MEDENOX Trial, in 60 centers and nine countries. The study excluded patients who were intubated or in septic shock. Overall, the mean age was 73.4 the gender distribution was 50:50 male/female and the mean body mass index was 25.0. The mean patient ages, gender distribution, and body mass index was similar in all three treatment groups; there were slightly more males than females in the placebo and enoxaparin 20 mg groups, and more females than males in the enoxaparin 40 mg group, but this difference was not significant. The reasons for hospitalization of randomized patients varied.
The majority of patients were hospitalized for acute cardiac failure, respiratory failure, or infectious disease, with pneumonia being the most common infection in those older than age 70. For the study population as a whole, the most prevalent risk factor in addition to the underlying illness was advanced age (50.4%). By day 14, the incidence of VTE was 14.9% in the placebo group and 5.5% in the enoxaparin 40 mg group, representing a significant 63% relative risk reduction (97% CI: 37-78%; P = 0.0002) in VTE.
The primary conclusions of the MEDENOX Trial can be applied directly to clinical practice. First, acutely ill elderly medical patients with cardiopulmonary or infectious disease are at significant risk of VTE. Second, enoxaparin, given once daily at a dose of 40 mg for 6-14 days reduces the risk of VTE by 63%; and third, the reduction in thromboembolic risk is achieved without increasing the frequency of hemorrhage, thrombocytopenia, or any other adverse event compared with placebo. This study strongly suggests that elderly, immobilized patients admitted to the hospital with severe pneumonia, especially if accompanied by respiratory failure or Class III-IV CHF, should, if there are no contraindications to the use of anticoagulants, be considered candidates for prophylaxis with enoxaparin, 40 mg SC qd upon admission to the hospital to prevent VTED.
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