Community-Acquired Pneumonia (CAP): Evidence- Based Antibiotic Selection and Outcome-Effective Patient Management

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Community-Acquired Pneumonia (CAP): Evidence- Based Antibiotic Selection and Outcome-Effective Patient Management — Year 2003 Update

Evaluation, Risk Stratification, and Current Antimicrobial Treatment Guidelines for Hospital-Based Management of CAP: Outcome-Effective Strategies Based on Recent Clinical Studies, Resistance Surveillance Data, and Epidemiological Trends

Authors: Year 2003 ASCAP (Antibiotic Selection for Community-Acquired Pneumonia) Panel Consensus Report®

from Hospital Medicine Consensus Reports

Editor-in-Chief’s Note—

The therapeutic landscape for managing patients with community-acquired pneumonia (CAP) continues to shift, especially as new clinical trials, surveillance studies, and epidemiological data are factored into a complex management equation that is designed to cure CAP patients today and protect the community against accelerating drug resistance tomorrow. In this regard, a number of therapy-altering advances, process-of-care changes, and triage refinements have emerged in the area of CAP management over the past year.

Among the important new developments and reports evaluated by the ASCAP (Antibiotic Selection for CAP) Clinical Consensus Panel is the growing awareness and reporting of levofloxacin-resistant respiratory isolates of S. pneumoniae, including documented treatment failures; the importance of the emergency department (ED) as the clinical “hot zone” for diagnosing, assessing, and treating patients with CAP; the mounting evidence favoring combination ceftriaxone/azithromycin therapy for severely ill patients with bacteremic pneumococcal pneumonia; and the association between levofloxacin use and the emergence of resistance among both gram-negative organisms and methicillin-resistant Staphylococcus aureus (MRSA). (See Table 1).

In addition, increasing emphasis has been placed on prompt administration (i.e., within 4 hours of presentation) of antibiotics in patients in whom the diagnosis of CAP is strongly suspected or confirmed, and on the potential in-hospital drug administration delays and compliance-compromising errors associated with antibiotics requiring multiple daily doses. Resistance-induction studies and sensitivity surveillance data have highlighted the potential advantages of moxifloxacin as compared to levofloxacin for initial CAP therapy in patients in whom advanced generation fluoroquinolones are indicated. It also has been recognized that effecting positive outcomes with potent, excessively broad-spectrum agents must be balanced against the pitfalls of inducing resistance to agents, especially fluoroquinolones, that are currently effective but have a propensity for developing resistance at a disproportionately accelerated rate in respiratory pathogens. Finally, the need to prophylax against development of DVT in hospitalized patients with CAP has become a quality-of-care measure.

The importance of the ED as a clinical zone where process-of-care measures for patients with CAP should be instituted is supported by a recent study linking quality of care and resource utilization.(1) This has been confirmed in an analysis of quality-of-care variables observed in randomly selected cases of CAP.(1) In this study, three quality-of-care measures for CAP were analyzed: 1) site of initial antibiotic treatment (ED vs floor); 2) door-to-needle time; and 3) appropriateness of antibiotic selection. A regression analysis revealed that all three quality-of-care measures were associated with prolonged length of stay (LOS). The implication is that implementation of process-of-care measures in the ED environment can have a positive effect on patient outcome, and in particular length of stay.

The landscape shift in CAP management and antibiotic selection has spawned the concept of curing patients today, while protecting the community tomorrow; that is, identifying pharmacotherapeutic strategies which not only optimize short-term, in-hospital clinical outcomes for CAP—in which curing patients is the preeminent goal—but also achieve this end point while reducing the likelihood of developing drug resistance. Additional resource utilization goals, including reducing length of stay (LOS), eliminating nursing time for drug administration, and minimizing treatment failures and pharmacological reservicing, must be factored into the drug selection equation. The mandate to both cure patients acutely and preserve long-term antimicrobial efficacy represents one of the most important challenges that emergency physicians, hospitalists, other clinicians, pharmacists, formulary managers, and health policy planners face when developing protocols and pathways for in-hospital management of such life-threatening infectious conditions as CAP.

A common cause for admission to the hospital, CAP continues to be a serious, growing health problem in the United States. It has an incidence estimated at 5.6 million cases annually.(2,3) Approximately 1.7 million hospitalizations for CAP are reported each year at an annual cost of about $23 billion.(2,4) The elderly consume the majority of these expenses, account for the majority of CAP-related hospitalizations, and have longer LOS. Mortality rates among the most seriously affected patients with CAP (the majority of whom are in the geriatric age group) approaches 40%, and causative pathogens are identified in fewer than 50% of patients.(5) Accordingly, empiric antibiotic regimens frequently are chosen in hospitalized patients with CAP on the basis of results of clinical trials and expert panel recommendations.

S. pneumoniae is the leading cause of both CAP and bacteremia, which can lead to meningitis. According to the Centers for Disease Control and Prevention (CDC), S. pneumoniae infections cause 100,000-135,000 pneumonia-related hospitalizations and more than 60,000 cases of invasive disease each year, including 3300 cases of meningitis. Bacteria resistant to any one antibiotic drug, regardless of class, cause up to 40% of these infections; 15% are due to a bacterial strain that is resistant to three or more drugs.(20)

Despite a general consensus that empiric treatment of CAP 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. To provide physicians and pharmacists current, evidence-supported standards for antimicrobial therapy in CAP, new treatment guidelines have been issued by a number of national panels and/or associations, including the American Thoracic Society Guidelines (2001), Infectious Disease Society of America (IDSA), the ASCAP (Antibiotic Selection for Community-Acquired Pneumonia) Consensus Panel, and the Centers for Disease Control and Prevention’s Drug-Resistant Streptococcus pneumoniae Therapeutic Working Group (CDC-DRSPWG).

As might be expected, although there are consistencies among expert-endorsed recommendations, there also are variations, with some panels prioritizing one treatment strategy over another. In some cases, panel recommendations lag behind the emergence of new data that would force a reevaluation of current practices. For example, beginning in January 2002, the National Committee on Clinical Laboratory Standards (NCCLS) officially adopted new breakpoint minimum inhibitory concentrations (MICs) for two third generation cephalosporins for non-meningeal sources of S. pneumoniae. Stemming from discrepancies between microbiologic failure and clinical cure, the NCCLS reviewed and accepted revised breakpoint MICs for ceftriaxone and cefotaxime. Based on the new microbiologic standards, a drug-resistant Streptococcus pneumoniae (DRSP) of non-meningeal sources is defined with a breakpoint MIC of > 4 mcg/mL to cefotaxime or ceftriaxone. The only treatment guidelines that recognized the new NCCLS breakpoints for cefotaxime and ceftriaxone are those published by the CDC-DRSPWG. Nevertheless, the clinical implications of the revised breakpoints already have become widespread, as subsequent treatment guidelines are reevaluating the role of third generation cephalosporins for initial therapy of all inpatients with CAP.

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 patient must be “customized” for the local practice environment. Unfortunately, no single set of guidelines is applicable to every patient or practice setting; 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 outcomes in patients with CAP can be maximized by using risk-stratification criteria that predict mortality in various patient subgroups. 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.

With these considerations in clear focus, this landmark review presents a comprehensive, state-of-the-art assessment of diagnostic strategies and antimicrobial guidelines for management of patients with CAP. Special emphasis has been given to both epidemiological data demonstrating the importance of correct spectrum coverage with specific cephalosporins (ceftriaxone, Rocephin®) in combination with a macrolide (azithromycin, Zithromax®) or monotherapy with a fluoroquinolone, as well as the selection of initial intravenous antibiotics for in-hospital management of CAP. In addition to antibiotic therapy, comprehensive management of the patient with CAP includes not only supportive respiratory and hemodynamic measures, but also risk-stratifying patients according to the Fine Pneumonia Severity Index (PSI). The ASCAP Consensus Panel has addressed the need to provide prophylaxis against venous thromboembolism (VTE) with enoxaparin in hospitalized patients with pneumonia with or without such comorbid conditions as congestive heart failure (CHF) and/or respiratory failure.

A detailed analysis and comparison of two-drug (ceftriaxone plus a macrolide) approaches vs. monotherapeutic options (azithromycin or advanced generation fluoroquinolones [moxifloxacin, levofloxacin, gatifloxacin]) are provided. In this regard, although one national association (2001 American Thoracic Society Guidelines) has proposed the option of intravenous monotherapy with a macrolide for inpatient management of CAP in selected, younger patients without co-morbidity, most experts and national panels agree that monotherapy with IV azithromycin is not advisable for inpatients with CAP. Hospitalized patients are at sufficiently high risk for CAP-related morbidity, complications, and mortality to require combination therapy that includes a cephalosporin (i.e., ceftriaxone, cefotaxime, etc.) with significant activity against S. pneumoniae, H. influenzae, and M. catarrhalis, along with a macrolide to provide activity against atypical organisms. One recent study suggests that CAP patient outcomes in those with bacteremic, pneumococcal pneumonia may be improved with two-drug, combination regimens as compared to monotherapeutic approaches using fluoroquinolones or other agents.(21) Additionally, increasing rates of macrolide-resistant S. pneumoniae may warrant avoiding monotherapy in the inpatient setting with this class of antibiotics. Detailed discussions of this important controversy and practical antibiotic selection implications of the year 2002 NCCLS breakpoints are presented to provide evidence-based guidance in the area of empiric drug selection for CAP.

Finally, to ensure that clinicians are current with and can apply the latest evidence-based strategies for CAP treatment to their patient populations, detailed antibiotic selection guidelines (see Table 2) issued by the ASCAP Consensus Panel are provided. Drawing upon clinical trials, epidemiological data, and other association guidelines, these antimicrobial protocols are linked to risk-stratification criteria and specific clinical profiles of patients presenting to the hospital or acute ambulatory setting with CAP.

Introduction: The ASCAP (Antibiotic Selection for CAP) 2003 Consensus Panel and Scientific Roundtable

To address the complex issues surrounding antibiotic selection and care of the hospitalized patient with pneumonia, the ASCAP Year 2003 Consensus Panel and Scientific Roundtable was convened. Its mission statement was to review, analyze, and interpret published, evidence-based trials assessing the safety and efficacy of antibiotic therapy for CAP. In addition, the ASCAP Consensus Panel was charged with both developing strategies that would ensure appropriate use of antibiotics in this population and making recommendations for how patients with respiratory infections should be evaluated and managed in the inpatient setting.

Treatment guidelines generated by the ASCAP 2003 Consensus Panel are reported in this consensus statement. They are based on evidence presented in well-designed clinical trials, and focus on hospital management delivered by the emergency physician, hospitalist, internist, critical care specialist, and/or infectious disease specialist. Detailed review and analyses of national consensus guidelines issued by the American Thoracic Society (ATS), Infectious Disease Society of America (IDSA), CDC Drug-Resistant Streptococcus pneumoniae Working Group (CDC-DRSPWG), and the Year 2002 Antibiotic Selection in Community-Acquired Pneumonia (ASCAP) Consensus Panel also were evaluated and included in the decision-making process. (See Table 3, below, and Table 4.)

With these objectives in clear focus, the purpose of this comprehensive review, which includes the ASCAP 2003 Consensus Panel report on assessment strategies and treatment recommendations, is to provide an evidence-based, state-of-the-art clinical resource outlining, in precise and practical detail, clinical protocols for the acute management of CAP. To achieve this goal, all of the critical aspects entering into the equation for maximizing patient 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 review includes critical pathways and treatment tables that incorporate risk stratification tools that can be used to identify and distinguish those patient subgroups that are appropriately managed in the outpatient setting from those more appropriately admitted to the hospital for more intensive care.

Community-Acquired Pneumonia: Epidemiology, Diagnosis, and Evaluation

CAP affects 5.6 million adults annually in the United States, with 1.7 million patients requiring hospitalization.(22) It is the sixth leading cause of death overall and the most common cause of death from infection,(22,23) with an overall case-fatality rate of about 5%. Mortality is substantially greater (about 13.6%) among hospitalized patients.(24) Expert committees have published treatment guidelines intended to improve the care of pneumonia patients, but the guidelines have not been prospectively validated.(6,25) Prior studies of pneumonia guidelines have reported decreased lengths of stay, admission rates, and costs, but no change in clinical outcomes.(7,26,27) Expert endorsed guidelines are difficult to implement, and traditional continuing medical education has an incomplete effect on physician practice.(28-33) However, studies by Dean and others(115) indicate that adoption of institutional pathways for CAP management have an effect on mortality and outcome (see below: Treatment Guidelines for CAP Outcomes, Value, and Institutional Implementation).

The introduction of antibiotic agents dramatically reduced mortality from pneumococcal pneumonia. However, the mortality rate from bacteremic pneumococcal CAP has shown little improvement in the past three decades, remaining between 19% and 28% depending on the population and institution studied. The aging population, increased prevalence of comorbid illnesses, human immunodeficiency virus, and increasing microbial resistance probably all have contributed to maintaining the high mortality rate despite advances in medical care. However, even allowing that some patients are seen too late to benefit from the antibiotic therapy, the continued high mortality rate, despite apparently appropriate antibiotic therapy, is a cause for concern.

The annual incidence of pneumonia in patients older than age 65 is about 1%.(8) 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, especially in the aging patient. Atypical agents or opportunistic infections in immunocompromised individuals have a much more subtle presentation. In particular, pneumonia in older patients frequently has an insidious presentation and fewer characteristic features of pneumonia, which may be confused with CHF or respiratory compromise associated with chronic lung 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 usually 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. A gram stain is occasionally helpful with establishing the diagnosis, but requires practitioners or technicians who are highly skilled in this diagnostic methodology. An adequate gram 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, gram stain rarely is helpful with determining other causes of pneumonia. The IDSA Guidelines recommend gram stain, whereas the ATS considers gram stain optional.

Transtracheal aspiration or bronchial washings are a more accurate means of obtaining specimens for gram stain and culture, although this procedure rarely is 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 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.(6,8) About 40% of sputum cultures will identify a pathologic organism. Bronchoscopy and thoracentesis occasionally may be necessary, but these procedures generally are reserved for seriously ill patients, particularly those who require management in the intensive care unit (ICU).(4,6,9) While the above statistics note the occasional times that a gram stain or blood culture are useful, in most cases patients may be adequately managed without these studies. The treatment of CAP is almost always empiric.

Differential Diagnosis. 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 (e.g., 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 usually does not cause fever or alveolar infiltrates.

Initial Stabilization and Adjunctive Measures. Prompt, aggressive, and adequate supportive care must be provided to 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, and should be considered candidates for admission, prompt evaluation, and treatment if the diagnosis is confirmed. 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 patient population also has a poorer prognosis. Support 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 for treatment of patients with respiratory failure due to pneumonia.(25) When this technique is available, it may avert the need for endotracheal intubation and its potential complications. Finally, patients with evidence of bronchospasm on physical examination, as well as those with a history of obstructive airway 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 prudent to administer IV fluids with frequent assessment of clinical response.

Risk Stratification and Patient Disposition: Outpatient Vs. Inpatient Management

Determining whether to admit or discharge patients suspected of having CAP is one of the most important 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 (i.e., safely) be treated as outpatients.(7,26,27,34) The disposition decision for 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.(35-37)

Patient Disposition. In the absence of respiratory distress or other complicating factors, many young adults can be adequately treated with appropriate oral antibiotic therapy. In fact, guidelines issued by the IDSA and ATS support oral antibiotic therapy in patients deemed to be at low risk for complications and/or mortality associated with CAP. This option is utilized less frequently in the case of elderly patients with CAP because comorbid conditions and other risk factors that may complicate the course of the illness frequently are present. Even following appropriate treatment and disposition, patients may have symptoms, including cough, fatigue, dyspnea, sputum production, and chest pain that can last for several months. To address the issue of patient disposition and treatment setting, a variety of investigators have proposed risk-stratification criteria to identify patients requiring hospitalization.

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. Such factors as hypotension, tachypnea, multi-lobar involvement, elevated BUN, and confusion have been linked to inferior outcomes in patients with CAP. Using clinical judgment, however, physicians tend to overestimate the likelihood of death from pneumonia.(35) 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 poorer outcomes.

A landmark study (outlined below) presented a prediction rule (Pneumonia Severity Index [PSI]) to identify low-risk patients with CAP.(7) Using such objective criteria as patient age, coexisting 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%.(53) 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 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.(36,38,39) The study by Fine and colleagues has received considerable attention and is used as a benchmark by many clinicians.(35) 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 (Pneumonia Patient Outcomes Research Team Cohort) study. Subsequent evaluation and validation has been performed with other cohorts, including geriatric patients and nursing home residents.(40,41)

In this risk-stratification model, 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. 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 Classes 1 and 2 were typically younger (median age, 35-59 years) and patients in Classes 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.(36) For a geriatric patient to qualify for outpatient treatment based on these recommendations, he or she would have to be younger than age 70 if male or younger than age 80 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, but most authorities consider Class 3 patients to be appropriate candidates for hospital admission or for management in an observation unit or skilled nursing facility.(7,42)

As a rule, patients considered eligible for management as outpatients must be able to take oral fluids and antibiotics, comply with outpatient care, and carry out activities of daily living (ADLs) or have adequate home support to assist with ADLs. 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.(6) Additional laboratory studies that may suggest increased severity of illness include white blood cell count less than 4000 or greater than 30,000; absolute neutrophil count less than 1000; elevated protime or partial thromboplastin time; decreased platelet count; or radiographic evidence of multilobar involvement, cavitation, and rapid spreading.(6)

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.(35) 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 provides low specificity (32%) for the need to manage the patient in the ICU.(43) It is emphasized that the above guidelines for admission should not supercede clinical judgment when assessing the need to hospitalize patients.(6,35,36,44)

Antibiotic Management for Hospitalized CAP Patients: An Overview of Current Controversies, Issues, and Guidelines

Timing of Antibiotic Administration. Antibiotic therapy is the mainstay of management for 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. However, antibiotic administration should not be delayed for microbiologic sampling. More and more, institutional guidelines are mandating administration of antibiotics within 4-8 hours of patient presentation to the hospital, since mortality rates rise when antibiotic administration is delayed beyond eight hours.(45) The Joint Commission on Accreditation of Healthcare Organizations’ (JCAHO) guidelines currently mandate that for hospitalized patients with CAP, antibiotics must be administered no later than eight hours after patient presentation. The Healthcare Financing Administration (HCFA) recommends IV antibiotic administration within four hours in Medicare patients with CAP.

Previous studies evaluating the effect of changing process of care, including administration of antibiotics within four hours of hospital admission for patients with CAP, have demonstrated a relationship between early antibiotic administration and lower three-day mortality rate.(46,47) More recently, data from the Medicare Quality Indicator System pneumonia module revealed a 15% lower odds ratio of 30-day mortality when antibiotics were administered within eight hours of hospital arrival.(48)

Based on a review of medical evidence, the 6th Scope of Work National Pneumonia project has issued revised performance measures for CAP. One of these modifications is the shortening of the time from initial hospital arrival to the first dose of antibiotics from eight hours to four hours. The ASCAP Consensus Panel noted that the eight-hour target is based on published guidelines. However, recent data from the 6th Scope of Work project indicate that several thousand deaths could be prevented every year among hospitalized Medicare patients with pneumonia if the initial dose of antibiotic were administered within four hours of arrival. In recognition of improved outcomes linked to early antibiotic administration, the Medicare Quality Improvement Organization will revise the published guidelines downward. Specifically, in the 7th Scope of Work project, the Quality Improvement Organization will attempt to positively impact patient outcomes by decreasing door-to-drug time to a four-hour threshold instead of the current eight-hour threshold.

The link between quality of care and resource utilization also has been confirmed in an analysis of quality-of-care variables observed in randomly selected cases of CAP.(1) In this study, three quality-of-care measures for CAP were analyzed: 1) site of initial antibiotic treatment (ED vs floor); 2) door-to-needle time; and 3) appropriateness of antibiotic selection. A regression analysis revealed that all three quality-of-care measures were associated with prolonged length of stay (LOS). Further analysis revealed that, on average, patients who received their initial antibiotic treatments in the ED had a door-to-treatment time of 3.5 ± 1.4 hours, while patients who had their initial antibiotic treatments on the inpatient floor had a door-to-needle time of 9.5 ± 3 hours (p < 0.001).(1) Based on these data, and in anticipation of new federal guidelines, the ASCAP Consensus Panel recommends that initial antibiotic therapy be administered in the ED, and that whenever possible such administration occur within a four-hour door-to-needle time frame.

Antibiotic Administration Errors: Compliance Issues in the Hospital and Emergency Department. The importance of ensuring medication compliance in the outpatient setting has had a measurable effect on physician prescribing practices, which now emphasize the use of once-daily formulations whenever possible. Recently, however, it has become clear that in-hospital medication errors have become a national concern, and that daily dose frequency may play a role in ensuring adequate drug intake for hospitalized patients, and perhaps may even influence clinical outcomes.(49,50)

To identify the prevalence of medication errors, a prospective cohort study was conducted in hospitals accredited by JCAHO,(49) nonaccredited hospitals, and skilled nursing facilities in Georgia and Colorado. The study evaluated medication doses given (or omitted) during at least one medication pass during a one- to four-day period by nurses in high medication volume nursing units. The target sample was 50-day shift doses per nursing unit or until all doses for that medication pass were administered.

In the 36 institutions, 19% of the doses (605 of 3216) were in error. The most frequent errors by category were wrong time (43%), omission (30%), wrong dose (17%), and unauthorized drug (4%). The authors concluded that medication errors were extremely common (nearly 1 of every 5 doses in the typical hospital and skilled nursing facility). The percentage of errors rated potentially harmful was 7%, or more than 40 per day in a typical 300-patient facility.(49)

Further confirmation of this problem, and its potential effect on antibiotic administration, was reported in an abstract (No. 127) at the American College of Emergency Physicians (ACEP) Scientific Assembly (2002).(50) The investigators evaluated antibiotic compliance in patients with CAP, the majority of whom received their initial dose in the ED, and the second dose in the inpatient unit, or occasionally, in an observation unit. Delays of the first antibiotic dose have been documented and targeted for quality improvement (see above). Delays in the second dose have not been studied, but are likely to be important if the delay results in serum-antibiotic concentrations of less than therapeutic levels.(50)

Investigators from the University of Rochester School of Medicine and Dentistry and the University of Chicago Hospitals attempted to characterize the epidemiology of delayed antibiotics after transfer to an inpatient unit in patients with CAP, and to compare differences in delays among antibiotics dosed every six hours (q6) and every 24 hours (q24). The study was conducted by performing a retrospective chart review of patients with CAP admitted to the medicine service between July 1997 and June 1999. In all, 359 patients were identified. The mean age was 61 years; 62% were female. Of those, 185 (34%) were ordered q6 and 332 (62%) were ordered q24. Twenty-four percent of those receiving a q6 antibiotic received their second dose within six hours, whereas 80% of patients receiving a q24 antibiotic received their second dose within 24 hours (p < 0.001). The authors concluded that patients with CAP who are prescribed antibiotics that require frequent dosing are more likely to receive a delayed second antibiotic dose, and that physicians should consider using long-acting, once-daily antibiotics when possible.(50)

In light of the importance of process-of-care issues related to optimizing outcomes in patients with CAP, the ASCAP Consensus Panel recommends the preferential use of ceftriaxone over cefotaxime as the cephalosporin of choice for patients with CAP. Although both agents underwent NCCLS breakpoint revisions in 2002, the NCCLS noted that the breakpoint for cefotaxime applied specifically to a dose of at least 1 g q8 hours. Given the potential problems associated with delayed antibiotic administration, the increased nursing time and resource costs required for more frequent administration, and additional data from the Antimicrobial Resistance Management (ARM) surveillance network suggesting greater in vitro efficacy of ceftriaxone as compared to cefotaxime for S. pneumoniae respiratory isolates, the panel identified ceftriaxone as the cephalosporin of choice for initial empiric use in hospitalized patients with CAP.

Consensus Panel Recommendations. It should be stressed that there is no absolute or consistent consensus about precisely which drug, or combination of drugs, constitutes the most outcome-effective choice for pneumonia in patients with CAP. However, a recent study suggests improved mortality rates with regimens using two-drug combinations rather than monotherapy in patients with bacteremic pneumococcal pneumonia.(21) Most panels and guideline documents agree that antimicrobial coverage must include sufficient activity against the principal bacterial pathogens S. pneumoniae, H. influenzae, and M. catarrhalis, as well as against the atypical pathogens Mycoplasma, Legionella, and C. pneumoniae. In about 5% of cases, antimicrobial activity against S. aureus also is required. Therefore, such regimens as ceftriaxone/cefotaxime plus azithromycin or monotherapy with an advanced generation fluoroquinolone such as moxifloxacin—given some qualifications regarding outcomes and resistance issues to be discussed later—have emerged as preferred options for treatment of inpatients with CAP.

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) as part of the initial antimicrobial regimen; 2) their concern about using antimicrobials (fluoroquinolones, i.e., levofloxacin) 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; 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 (see Table 5, below), 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 patient with pneumonia.

With these issues and drug selection factors in mind, the most recent guidelines issued by the CDC-DRSPWG and American Thoracic Society attempt 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 the ASCAP expert’s panel should be emphasized. First, the relative importance of S. pneumoniae as a cause of outpatient CAP 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.(8,51) In addition, surveillance studies have suggested that about 7% of invasive S. pneumoniae species in the United States show a significant degree of penicillin resistance.(52) This group estimates that only 0.14% (7% of 2%) to 1.9% (7% of 27%) of outpatients with bacterial pneumonia have pneumococcal infections with levels of resistance high enough to warrant consideration of alternative treatment.

This analysis has prompted the CDC panel to conclude that because 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-resistant pneumococci 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 outpatients with CAP because of concerns about emerging resistance. Consequently, oral macrolide or beta-lactam monotherapy is recommended by the CDC-DRSPWG as initial therapy in patients with pneumonia considered to be amenable to outpatient management. Because atypical pathogens are an important cause of outpatient CAP, the ASCAP Consensus Panel recommends macrolides over beta-lactam monotherapy for outpatients. If a fluoroquinolone is used for outpatients with CAP, moxifloxacin is the preferred agent.

It should be noted, however, that even for hospitalized (non-ICU) patients, this panel, while noting the effectiveness of monotherapy with selected fluoroquinolones, recommends the combination of a parenteral beta-lactam (ceftriaxone, cefotaxime, etc.) plus a macrolide (azithromycin, erythromycin, etc.) for initial therapy.(3) 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 plus an intravenous macrolide such as azithromycin or, alternatively, a respiratory fluoroquinolone such as moxifloxacin (see discussion below).

The option of using a combination of a parenteral beta-lactam (ceftriaxone, etc.) plus a fluoroquinolone with improved activity against DRSP also is presented. Once again, however, the committee issues clarifying, and sometimes cautionary, statements about the role of fluoroquinolone monotherapy in the critically ill patient, stating that care should be exercised because the efficacy of the new fluoroquinolones as monotherapy for critically ill patients has not been determined.(3) Based on this cautionary statement, it is recommended that a parenteral beta-lactam such as ceftriaxone be used in combination with a fluoroquinolone in ICU patients with serious CAP.

Clearly, however, fluoroquinolones are an important part of the antimicrobial arsenal in the elderly, and the CDC-DRSPWG 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., ceftriaxone 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 > 4 mcg/mL).(3) The rationale for this approach is discussed in subsequent sections.

Emergence of Fluoroquinolone Resistance Among Streptococcus pneumoniae

The only treatment guideline that recognizes the potential effect of widespread fluoroquinolone resistance also is the only treatment guideline that recommends fluoroquinolones be reserved for selected patients with CAP (CDC-DRSPWG). With revised breakpoint MICs for cefotaxime and ceftriaxone, the percent of resistant S. pneumoniae to these third generation cephalosporins is below 3-5% nationally. This has required clinicians to reexamine the published treatment guidelines that recommend fluoroquinolones as initial therapy for CAP.

Widespread, indiscriminate use of fluoroquinolones may be associated with rising resistance rates to selected gram-positive and gram-negative organisms. Previous assumptions that fluoroquinolones will be more clinically effective vs. DRSP than ceftriaxone or cefotaxime must be reevaluated. Based on the 2002 NCCLS guidelines, both ceftriaxone and cefotaxime are expected to provide comparable microbiologic end points and clinical cures in patients with non-meningeal S. pneumoniae infections as compared to the anti-pneumococcal fluoroquinolones. The clinician will be asked to incorporate geographic specific resistance rates and the ecology of microorganisms into his/her decision about how to empirically treat the patient with CAP.

When first introduced in 1987, ciprofloxacin was promoted for the treatment of respiratory tract infections, including those due to S. pneumoniae. Early trials demonstrated clinical success for patients with respiratory infections.(53,54) However, subsequent studies found that the use of ciprofloxacin against S. pneumoniae was associated with poor eradication rates both in acute exacerbations of chronic bronchitis (AECB) and pneumonia.(55-57 )Reports of the development of resistance soon appeared.(58-62) Knowing the pharmacodynamic parameters of ciprofloxacin and S. pneumoniae, this was not unexpected. The AUC24/MIC generally accepted to be most predictive of bacterial eradication and clinical success is greater than 35.(63-66) The Cmax/MIC ratio generally accepted to be most predictive for prevention of resistance selection is greater than 4.(67,68) Following a 750 mg oral dose of ciprofloxacin, the Cmax is only 3 mg/L and the AUC24 is 31 mg/h/L.(69) The MIC90 of S. pneumoniae is 1 mg/L giving a Cmax/MIC of 3 and an AUC/MIC of 31.(63)

Although ciprofloxacin was not promoted or widely used for the treatment of CAP, it was used for the treatment of AECB at a dose of 500 mg twice daily. Eradication rates of S. pneumoniae in AECB varied from 63% to 90%.(71,72) This failure to eradicate was associated with the development of resistance during therapy in some patients.(71,72) This may, in part, explain the emergence of pneumococci with reduced susceptibility to the fluoroquinolones and, in particular, to ciprofloxacin.

Emergence of resistance in S. pneumoniae to the fluoroquinolones has been described in Canada, Spain, Hong Kong, and Northern Ireland. In Canada, Chen et al found that the prevalence of ciprofloxacin-resistant pneumococci (MIC > 4 mcg/mL) increased from 0% in 1993 to 1.7% in 1997-1998 (p = 0.01).(73) In adults, the prevalence increased from 0% in 1993 to 3.7% in 1998. This was associated with an increase in the consumption of fluoroquinolones. Overall, the number of fluoroquinolone prescriptions increased from 0.8 to 5.5 per 100 persons per year between 1988 and 1997.(73) In addition to the increase in prevalence of pneumococci with reduced susceptibility to fluoroquinolones, the degree of resistance also increased. From 1994 to 1998, there was a statistically significant increase in the proportion of isolates with a MIC for ciprofloxacin of 32 mcg/mL or greater (p = 0.04).

Linares et al found an increase of ciprofloxacin-resistant pneumococci in Spain from 0.9% in 1991-1992 to 3% in 1997-1998.(74) Ho and colleagues documented a marked increase in the overall prevalence of non-susceptibility to the fluoroquinolones when comparing results of surveillance carried out in Hong Kong in 1998 and 2000.(675,76) Over a two-year period, the prevalence of levofloxacin non-susceptibility increased from 5.5% to 13.3% among all isolates and from 9.2% to 28.4% among the penicillin-resistant strains. In Northern Ireland, ciprofloxacin resistance was linked to penicillin resistance. Eighteen (42.9%) of 42 penicillin-resistant pneumococci were resistant to ciprofloxacin.(77) Current rates of resistance in the United States are low.(78-79) Doern et al reported ciprofloxacin resistance rates of 1.4%.(79) The CDC Active Bacterial Core Surveillance (ABCs) program carried out during 1995-1999 reported levofloxacin resistance rates of 0.2%.(78) They have not included ciprofloxacin as one of the agents they test.

One study group reviewed 181 S. pneumoniae isolates in Hong Kong in 1998. Hong Kong is an environment with uniquely high rates of resistance, which may provide a vision of what can occur when fluoroquinolone resistance is observed with S. pneumoniae.(75) Within three years, the resistance of S. pneumoniae to fluoroquinolones has increased from less than 0.5% for ofloxacin, to 5.5% for levofloxacin. In addition, 4% of penicillin resistance isolates also were resistant to trovafloxacin, an agent that was only approved for use in October 1998; this demonstrates the cross resistance to newer quinolones. Resistance to levofloxacin and trovafloxacin was found only in isolates that also were penicillin resistant.

A recent study has documented that the increased use of fluoroquinolones has resulted in an increase in pseudomonas and gram-negative resistance to these drugs, particularly ciprofloxacin; although levofloxacin resistance is not mentioned in this particular report, similar reports have identified development of gram resistance for this agent as well. Furthermore, the development of resistance to fluoroquinolones also has accompanied an increased incidence of resistance to other potent antibiotics. This study provides further argument for limiting the use of fluoroquinolones, especially levofloxacin and gatifloxacin, according to the CDC recommendations.(191)

One abstract detailed changes in S. pneumoniae resistance among different drug classes. Unfortunately, although no MICs or breakpoints are given, S. pneumoniae resistance for levofloxacin grew from 0.1% to 0.6%, a growth rate over the period of about 600%. While S. pneumoniae grew in several antibiotic classes and among various agents, including macrolides, trimethoprim-sulfamethoxazole (TMP-SMX), and cefuroxime, the greatest growth in resistance was seen with levofloxacin.(82) In another study evaluating emergent resistance,(83) it was found that compared to cephalosporins and combination therapy, fluoroquinolones were associated with the greatest risk for acquiring emergent resistance during therapy, had the highest treatment failure due to emergent resistance, the largest increase in treatment duration due to resistance, and the largest decrease in clinical response due to emergent resistance.(83)

Recent Trends in S. pneumoniae Resistance to Levofloxacin. The increasing use of broad-spectrum fluoroquinolones for the treatment of respiratory tract infections has led to concerns regarding the potential for emergence and spread of resistance to these agents, particularly among S. pneumoniae. Recently, there has been evidence suggesting an increasing prevalence of fluoroquinolone resistance among S. pneumoniae isolated in the United States during the winter of 2000-2001.(84) As part of a longitudinal surveillance study (PROTEKT US), 10,103 isolates of S. pneumoniae were collected during the 2000-2001 winter from outpatients with respiratory tract infections in 154 cities/metropolitan areas in 44 states across the United States. MICs and susceptibilities to 13 antimicrobials were determined centrally using NCCLS broth microdilution method breakpoints.

Overall, the fluoroquinolone mode MIC and MIC90 (levofloxacin) were both 1 mcg/L, MIC range 0.12-16 mcg/L. Fluoroquinolone resistance (levofloxacin MIC > 8 mcg/L) was found in 81 (0.8%) isolates, and intermediate resistance (levofloxacin MIC 4 mcg/L) in eight (0.08%) isolates. States with high fluoroquinolone resistance prevalence were: Massachusetts (4.8%) and Colorado (4.6%); cities with high fluoroquinolone resistance prevalence were: Salem (21.8%), Stamford (11.8%), Abington (7.7%), Dayton (5.9%), and Denver (5.6%). The ASCAP Consensus Panel concurred that, considering levofloxacin frequently is used to manage hospitalized, high-risk, Fine Category 3-5 patients, this agent should be avoided as an initial, empiric agent in communities demonstrating fluoroquinolone resistance exceeding 5-10% in surveillance studies. Although the precise relationship between documented resistance rates of this magnitude in particular states and clinical outcomes in CAP was not addressed by the study, the likelihood of treatment failures with levofloxacin in such communities may be increased. Accordingly, a more prudent approach would suggest the use of combination therapy with ceftriaxone and azithromycin, or alternatively, the use of a respiratory fluoroquinolone (i.e., moxifloxacin) with documented lower MICs against S. pneumoniae.

Levofloxacin resistance among S. pneumoniae may play an especially important role in older patients. With higher mortality rates from CAP in the elderly, the initial choice of antibiotic is crucial and surveillance data confirming antibiotic activity becomes more important. To address this question, the Canadian Bacterial Surveillance Network, in 1988 and from 1993-2001, tested 2187 S. pneumoniae isolates from patients ages 65 or older for antibiotic susceptibility as per NCCLS guidelines. Respiratory samples included sputums, bronchial washings, and endotracheal tube aspirates. Results indicate that since 1988, rates of S. pneumoniae resistance have increased substantially for penicillin, erythromycin, and the fluoroquinolones in this age group. Most alarming was the rapid rise of levofloxacin resistance over the past three years. The authors concluded that with increasing fluoroquinolone resistance in S. pneumoniae isolates from the elderly population, hospitals and microbiology laboratories will need to more vigilantly look for clinical resistance to fluoroquinolones. As the prevalence of resistance in these Canadian isolates is 4.3% and first-step mutants are 7.2%, they conclude it may not be prudent to use a fluoroquinolone as empiric therapy in this group of patients.(85)

In aggregate, what these studies make clear is that with the rising prevalence of levofloxacin-resistant S. pneumoniae, it is prudent for hospitals to test those agents they use (i.e., fluoroquinolones) to document clinically effective sensitivities and MICs, and conversely to use only those agents that have been tested and that demonstrate MICs predictive of bacterial eradication and positive clinical outcomes.

Clinical Implications. Although treatment failures due to beta-lactams, macrolides, and TMP-SMX resistance in pneumococci have been reported with meningitis and otitis media, the relationship between drug resistance and treatment failures among patients with pneumococcal pneumonia is less clear.(86,87) However, fluoroquinolone resistance in pneumococci causing pneumonia in association with clinical failures, although anecdotal, has been well described.(55-58,88,89)

Reports of the development of resistance and clinical failures appeared shortly after the introduction of ciprofloxacin in 1987.(58-62) Weiss and colleagues described a nosocomial outbreak of fluoroquinolone-resistant pneumococci.(89) Over the course of a 20-month period, in a hospital respiratory ward where ciprofloxacin often was used as empirical antimicrobial therapy for lower respiratory tract infections, 16 patients with chronic bronchitis developed lower respiratory tract infections caused by a strain of penicillin- and ciprofloxacin-resistant S. pneumoniae (serotype 23 F). The MIC of ciprofloxacin for all isolates was 4 mcg/mL or greater. All five patients with AECB due to the resistant strain who were treated with ciprofloxacin failed therapy. Davidson et al report four cases of pneumococcal pneumonia, treated empirically with oral levofloxacin, that failed therapy.(88) All cases were associated with the isolation of an organism that was either resistant to levofloxacin prior to therapy or had acquired resistance during therapy. Two of the four patients had been or were on fluoroquinolones prior to initiating levofloxacin.

From these and other studies, a number of risk factors may identify the patients who are likely to be colonized or infected with a fluoroquinolone-resistant pneumococci: patients who are older than age 64, have a history of chronic obstructive lung disease, and/or a prior fluoroquinolone exposure.(73,76,78,81,90) None of the CAP position papers published since the introduction of the fluoroquinolones for the treatment of pneumococcal pneumonia has suggested that a history of previous fluoroquinolone use should be a reason for caution when using one of these antimicrobials. However, the aforementioned study by Davidson suggests recent (i.e., < 3 months) fluoroquinolone use may predispose patients to developing resistance to this class, and that other options should be considered.

One recent review(91) has noted a significant correlation between increased levofloxacin use and declining fluoroquinolone susceptibilities among ICU isolates of K. pneumoniae (96% to 79% [p < 0.008]) and P. aeruginosa (82% to 67% [p < 0.01]). Similarly, another group(92) reported that after levofloxacin was added to the formulary, levofloxacin use as a proportion of total fluoroquinolone use increased from less than 2% to greater than 22% over a six-month period (from 3rd quarter 1999 to 1st quarter 2000). During the period of first quarter 1998 to second quarter 2000, the susceptibility of P. aeruginosa to ciprofloxacin decreased by 11% (82% to 71%).

Because the ICU has been a focal point of antimicrobial resistance, the CDC initiated Project ICARE in 1996.(93) Specific data regarding fluoroquinolone use and fluoroquinolone susceptibility among P. aeruginosa isolates were presented for the period 1996-1999 by Hill et al.(94) No correlation was found between prevalence of quinolone resistance and total use of ciprofloxacin/ ofloxacin. However, significant associations were found between fluoroquinolone resistance and the combined use of ciprofloxacin, ofloxacin, and levofloxacin (p < 0.019); and by use of levofloxacin alone (p < 0.006).(94)

Likewise, recent studies suggest that using a less potent fluoroquinolone against S. pneumoniae for treating community and hospital respiratory tract infections may be affecting the sensitivity to the drug class and may be associated with an increase in treatment failures. Inappropriate use of antimicrobial agents has been associated with adverse consequences, including therapeutic failure, development of resistance, and increased healthcare costs. One example of a mismatch between pharmacodynamics and clinical infection was in the use of ciprofloxacin for CAP. The pharmacodynamics of the dose typically prescribed in these cases (ciprofloxacin 250 mg bid) are inappropriate for treating pneumococcal pneumonia, especially in seriously ill patients. By 1994, approximately 15 cases of S. pneumoniae infections that did not respond to ciprofloxacin had been reported, primarily in seriously ill patients.(68) These events prompted the U.S. Food and Drug Administration to modify the package insert to warn against empiric use of ciprofloxacin for respiratory infections in which S. pneumoniae would be a primary pathogen.

By contrast, greater than 50% of levofloxacin use has been for the treatment of respiratory infections. Since 1999, at least 20 case reports of pulmonary infections that did not respond to levofloxacin therapy have been published.(95-104) Three of the patients died due to fulminant pneumococcal infections that were unresponsive to levofloxacin therapy at approved dosage. Very few of these cases were in immunosuppressed patients. Reports of pneumococcal failures on the standard dosage of levofloxacin, 500 mg every 24 h, also have been described in two clinical trials, one in a patient with acute exacerbation of chronic bronchitis and the other in a patient with CAP.(95-100) In some of the 21 case reports, the treatment failed and the pathogen developed levofloxacin resistance during therapy, as was previously mentioned in the series by Davidson et al.

Both Weiss et al(105) and Ho et al(106) demonstrated clear risk factors associated with the development of fluoroquinolone resistance, including prior exposure of the patient to first- or second-generation fluoroquinolones (i.e., ciprofloxacin, levofloxacin, and ofloxacin), and history of COPD.

Inappropriate Fluoroquinolone Use in Emergency Departments. Increasing resistance to fluoroquinolone antibiotics has been associated with increasing use of these agents. In one recent study, a group from the University of Pennsylvania Hospital System found that in more than 80% of patients who received a fluoroquinolone in two academic EDs, the indication for use was not appropriate when judged by established institutional guidelines.(194)

In this retropective investigation, 100 consecutive ED patients who received a fluoroquinolone and were subsequently discharged were studied. Appropriateness of the indication for use was judged according to existing institutional guidelines. A case-control study was conducted to identify the prevalence of, and risk factors for, inappropriate fluoroquinolone use.

Among the 100 total patients, 81 received a fluoroquinolone for an inappropriate indication. Of these cases, 43 (53%) were judged inappropriate because another agent was considered first line, 27 (33%) because there was no evidence of infection based on the documented evaluation, and 11 (14%) because of inability to assess the need for antimicrobial therapy. Although the prevalence of inappropriate use was similar across various clinical scenarios, there was a borderline significant association between the hospital in which the ED was located and inappropriate fluoroquinolone use. Of the 19 patients who received a fluoroquinolone for an appropriate indication, only one received both correct dose and duration of therapy.

The investigators concluded that inappropriate fluoroquinolone use in EDs is extremely common and that efforts to limit the emergence of fluoroquinolone resistance must address the high level of inappropriate fluoroquinolone use in EDs. Future studies should evaluate the effect of interventions designed to reduce inappropriate fluoroquinolone use in this setting.(194)

Year 2002 NCCLS Breakpoints: Evidence-Based Support for Adoption of New Standards

Prior to revising the NCCLS MIC breakpoints for S. pneumoniae, the clinical significance of the original S, I, and R breakpoints (originally published in NCCLS document M100-S9) of the parenteral aminothiazolyl cephalosporins ceftriaxone/cefotaxime in systemic non-meningeal pneumococcal infections was not fully elucidated.

To evaluate clinical outcomes in patients managed with ceftriaxone/cefotaxime, one group, during the period January 1994 through October 2000, studied 522 episodes (in 499 adult patients) of non-meningeal pneumococcal infections (448 of severe pneumonia [clinical and x-ray findings together with positive blood or invasive lower respiratory tract cultures] and 74 of bacteremia from other origin). Of the 522, 74% had serious underlying diseases, 14% nosocomial infections, and 7% polymicrobial infections.(107) The 30-day mortality rate was 21%. Ceftriaxone/cefotaxime MICs according to NCCLS were determined by microdilution methods and Mueller-Hinton broth with lysed horse blood. The frequency distribution in terms of ceftriaxone/cefotaxime MICs of strains was S < 0.5 mcg/mL 413 (79%), I = 1 mcg/mL 79 (15%), and R = 2 mcg/mL 30 (6%); no strain with a ceftriaxone/cefotaxime MIC of greater than 2 mcg/mL was found.

In ceftriaxone/cefotaxime-resistant strains, the most commonly encountered serotypes were 14, 9, 23, and 6. In the 429 episodes of community-acquired pneumococcal infection (polymicrobial and nosocomial cases were excluded), the ceftriaxone/cefotaxime MICs and antibiotic therapy (prescribed according to the attending physician’s criteria) were correlated with the 30-day mortality rate. In 185 episodes treated with 1 g/d of ceftriaxone (n = 171) or 1.5-2 g/8 h of cefotaxime (n = 14), the mortality rates for patients with S, I, and R strains were 18% (26/148), 13% (3/24), and 15% (2/13), respectively (p = 0.81). In the 244 patients treated with other antibiotics, the mortality rates for patients with S, I, and R strains were 18% (36/200), 12% (4/33), and 9% (1/11), respectively (p = 0.55).(107)

Patients infected with pneumococci with ceftriaxone/cefotaxime MIC of 1 or 2 mcg/mL categorized as I or R by NCCLS did not show an increased mortality rate compared to S strains in non-meningeal pneumococcal infections when treated with ceftriaxone (1 g/d) or cefotaxime (1.5-2 g/8 h). These data support the higher breakpoints for ceftriaxone/cefotaxime by the NCCLS that went into effect in January 2002 for non-meningeal pneumococcal infections. This study demonstrates that parenteral aminothiazolyl cephalosporins such as ceftriaxone (1 g/day) or cefotaxime (1.5-2 g/8 h) work well in adult patients with systemic non-meningeal pneumococcal infections caused by strains with ceftriaxone/cefotaxime MIC up to 1 mcg/mL. Based on their limited experience, they concluded it also is probable that this observation is true for strains with ceftriaxone/cefotaxime MICs of 2 mcg/mL.

The available data in children(108) and adults suggest the NCCLS interpretive breakpoints were appropriately modified for systemic non-meningeal pneumococcal infections, and considered susceptible up to a ceftriaxone/cefotaxime MIC of 1 mcg/mL (NCCLS publication M100-S12 which went into effect January 2002). Until further experience with isolates with ceftriaxone/cefotaxime MIC of 2 mcg/mL accumulates, the investigators strongly recommend continued monitoring of the MIC of aminothiazolyl cephalosporins in all invasive pneumococcal isolates, and assessment of clinical and bacteriological outcomes.(108)

Antimicrobial Therapy

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 to generate a set of evidence-based guidelines and protocols for specific populations with CAP.

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 2.) The first generation cephalosporins have significant coverage against gram-positive organisms. By comparison, third generation cephalosporins have equal gram-positive coverage and increased coverage against aerobic gram-negative rods.(109) 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-DRSPWG identifies cefuroxime axetil, cefotaxime sodium, ceftriaxone sodium, or ampicillin-sulbactam as recommended empiric agents. The group notes, however, that among these agents, ceftriaxone and cefotaxime have superior activity against resistant pneumococci when compared with cefuroxime and ampicillin- sulbactam.(3) Because it is recommended that cefotaxime be administered in a dose of at least 1 g q8h for treatment of CAP,(3,110) and because the efficacy and safety of once-daily ceftriaxone for inpatient CAP is well established, ceftriaxone is recommended by most experts and the ASCAP Consensus Panel as the cephalosporin of choice for management of CAP.(110)

The aminoglycosides are active against gram-negative aerobic organisms. These agents generally are used for elderly patients when severe CAP infection is suspected. As a rule, the aminoglycosides are combined with a third generation antipseudomonal or an extended spectrum quinolone antibiotic, monobactam, or an extended spectrum penicillin when used in these circumstances.(111)

The tetracyclines are active against S. pneumoniae, H. influenza, Mycoplasma, Chlamydia, and Legionella. There is, however, a growing incidence of S. pneumoniae resistance to tetracyclines.(112) These agents are alternatives to the macrolide antibiotics for empiric therapy for CAP in young, healthy adults.(113) Convenience and coverage advantages of the new macrolides, however, have thrust the tetracyclines into a secondary role for managing CAP. Clindamycin has activity against anaerobes, such as B. fragilis.(112,114) 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 have indications for monotherapeutic treatment of CAP, they frequently get equal billing as initial agents of choice. 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, hospitalists, infectious disease specialists, 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 patients with CAP, the elderly patient population also is 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.(4,8,9) From a practical, antibiotic selection perspective, this requires that macrolides be used in combination with a cephalosporin such as ceftriaxone as initial, empiric therapy, or alternatively, an advanced generation fluoroquinolone.

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 an 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) current or 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 report, 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.(38)

Treatment Guidelines for CAP: Outcomes, Value, and Institutional Implementation

Based on a review of the available literature and personal communications among the panel members, the ASCAP Consensus Panel recommends implementation of institution-wide guidelines for patients with CAP. A strong case can be made for adopting such a strategy, especially when educational, process of care, and quality review/improvement measures are put into place.

In one study reviewed,(115) a pneumonia guideline developed at Intermountain Health Care included admission decision support and recommendations for antibiotic timing and selection, based on the 1993 ATS guideline.(115) The study included all immunocompetent patients older than age 65 with CAP from 1993 through 1997 in Utah; nursing home patients were excluded. The investigators compared 30-day mortality rates among patients before and after the guideline was implemented, as well as among patients treated by physicians who did not participate in the guideline program.

Overall, the research group observed 28,661 cases of pneumonia, including 7719 (27%) that resulted in hospital admission. Thirty-day mortality was 13.4% (1037 of 7719) among admitted patients and 6.3% (1801 of 28,661) overall. Mortality rates (both overall and among admitted patients) were similar for both patients of physicians affiliated and not affiliated with Intermountain Health Care before the guideline was implemented. For episodes that resulted in hospital admission after guideline implementation, 30-day mortality was 11.0% among patients treated by Intermountain Health Care-affiliated physicians compared with 14.2% for other Utah physicians. The guideline used ceftriaxone without or without a macrolide such as azithromycin or clarithromycin.

An analysis that adjusted by logistic regression for age, sex, rural vs. urban residences, and year confirmed that 30-day mortality was lower among admitted patients who were treated by Intermountain Health Care-affiliated physicians (odds ratio [OR]: 0.69; 95% confidence interval [CI]: 0.49 to 0.97; p = 0.04) and was somewhat lower among all pneumonia patients (OR: 0.81; 95% CI: 0.63 to 1.03; p = 0.08). The investigators concluded that implementation of a pneumonia practice guideline in the Intermountain Health Care system was associated with a reduction in 30-day mortality among elderly patients with pneumonia.

Explanations offered by the investigators for the decreased mortality after guideline implementation include selection of more appropriate antibiotics, timing of initial antibiotic administration, and use of heparin prophylaxis against thromboembolic disease. For example, one study(116) reported that mortality was about 25% lower among inpatients when the initial, empiric antibiotic regimen combined a third-generation cephalosporin with a macrolide compared with cephalosporins alone; whereas another investigation(43) showed a 15% reduction in mortality when antibiotics were administered within eight hours of hospitalization. The guideline that was evaluated by Intermountain Health Care recommended that antibiotics should be administered before a patient with pneumonia leaves the outpatient site of diagnosis. In addition, admission orders included prophylactic heparin.

Another group conducted a comprehensive review of the medical literature to determine whether guideline implementation for CAP reduces mortality and resource costs.(117) These investigators noted that studies have shown significant changes in the processes of care after implementation of guideline recommendations for treatment of patients with CAP.(118-120) The most extensive of these studies consisted of a randomized trial that was conducted in 19 hospitals and which included 1743 patients.(7) This study design provided reasonable internal validity (i.e., it is likely that the differences in the process of care between the nine intervention hospitals and the 10 control hospitals were due to the implementation of the critical pathway). The motivation for the trial was a desire to find means of cost-containment, inasmuch as the primary hypothesis was that the critical pathway would reduce the use of institutional resources without compromising the safety and efficacy of therapy.(7)

Two other studies have demonstrated an improvement in outcome after implementation of guidelines: improvement of patient response to antibacterial treatment in one(121) and lower mortality rates in the other.(122) Both studies used an uncontrolled, before-and-after design, but in one of the studies, the changes in the mortality rate in the intervention hospital were compared with data from 23 other hospitals.(122) In both of these studies, the improvement in outcome was accompanied by a reduction in the cost of care. A third study used an uncontrolled, before-and-after design to show that a quality improvement program reduced time to initiation of antibacterial treatment of patients with CAP, which is likely to improve patient outcome. However, there was no direct measurement of outcome. The reviewers conclude that the best-quality evidence about the effects of guideline implementation shows that they can be used to reduce unnecessary use of resources without compromising the quality of care or patient outcomes.(42,121)

Correct Spectrum Coverage: Outcome-Optimizing Regimens for CAP

Because beta-lactams, 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 discussion will focus on antibiotics that: 1) provide, as combination therapy or monotherapy, appropriate coverage of bacterial and atypical organisms causing CAP; 2) are available for both outpatient (oral) and in-hospital (IV) management; and 3) are supported by national consensus panels or association guidelines.

Beta-Lactams: Ceftriaxone for Combination Therapy in CAP. The safety and efficacy of ceftriaxone for managing hospitalized patients with CAP has been well-established in numerous clinical trials, including recent investigations confirming its equal efficacy as compared to new generation fluoroquinolones. In this regard, one recent study attempted to determine the comparative efficacy and total resource costs of sequential IV to oral gatifloxacin therapy vs. IV ceftriaxone with or without IV erythromycin to oral clarithromycin therapy for treatment of CAP patients requiring hospitalization.(123)

Two hundred eighty-three patients were enrolled in a randomized, double-blind, clinical trial; data collected included patient demographics, clinical and microbiological outcomes, length of stay (LOS), and antibiotic-related LOS (LOSAR). Overall, 203 patients were clinically and economically evaluable (98 receiving gatifloxacin and 105 receiving ceftriaxone). It should be noted that IV erythromycin was administered to only 35 patients in the ceftriaxone-treated group, thereby putting a significant percentage (about 62%) of the ceftriaxone cohort at a “spectrum of coverage” disadvantage because of the failure to include an agent with coverage against atypical organisms. Despite this, oral conversion was achieved in 98% of patients in each group, and the investigators concluded that clinical cure and microbiological eradication rates did not differ statistically between ceftriaxone (92% and 92%) and gatifloxacin (98% and 97%).(123)

Given the concern about DRSP in hospitalized CAP patients, there has been robust debate about the effectiveness of ceftriaxone in pulmonary infections caused by DRSP. Attempting to shed light on this issue, an important study evaluating actual clinical outcomes in patients treated with beta-lactams for systemic infection outside of the central nervous system (CNS) that was caused by isolates of S. pneumoniae considered nonsusceptible to ceftriaxone (MIC > 1.0 mcg/mL) by pre-2002 NCCLS breakpoints has recently been published by the Pediatric Infectious Diseases Section, Baylor College of Medicine.(124)

The objective of the study was to determine the actual clinical outcomes of patients treated primarily with beta-lactam antibiotics for a systemic infection outside of the CNS caused by isolates of S. pneumoniae nonsusceptible to ceftriaxone (MIC > 1.0 mcg/mL). A retrospective review was performed of the medical records of children identified prospectively with invasive infections outside of the CNS caused by isolates of S. pneumoniae that were not susceptible to ceftriaxone between September 1993 and August 1999. A subset of this group treated primarily with beta-lactam antibiotics was analyzed for outcome. Among 2100 patients with invasive infections outside the CNS that were caused by S. pneumoniae, 166 had isolates not susceptible to ceftriaxone.

One hundred patients treated primarily with beta-lactam antibiotics were identified. From this group, 71 and 14 children had bacteremia alone or with pneumonia, respectively, caused by strains with an MIC of 1.0 mcg/mL. Bacteremia or pneumonia caused by isolates with a ceftriaxone MIC of 2.0 mcg/mL or greater occurred in six and five children, respectively. Three children with septic arthritis and one with cellulitis had infections caused by strains with an MIC to ceftriaxone of 1.0 mcg/mL. Most were treated with parenteral ceftriaxone, cefotaxime, or cefuroxime for one or more doses followed by an oral antibiotic. All but one child were successfully treated. The failure occurred in a child with severe combined immune deficiency and bacteremia (MIC = 1.0 mcg/mL) who remained febrile after a single dose of ceftriaxone followed by 12 days of cefprozil. The investigators concluded that ceftriaxone, cefotaxime, or cefuroxime are adequate to treat invasive infections outside the CNS caused by pneumococcal isolates with MICs up to 2.0 mcg/mL. Accordingly, the NCCLS breakpoints, as of January 2002, for the beta-lactam ceftriaxone and cefotaxime were modified and up-calibrated so that currently about 95% of all S. pneumoniae species are considered sensitive to ceftriaxone, as well as cefotaxime.(25)

Observational Trends from The ARM Database: Ceftriaxone Vs. Cefotaxime for Streptococcus pneumoniae

The Antimicrobial Resistance Management (ARM) program was established to help individual institutions define their antimicrobial resistance problems and establish cause-effect relationships that could lead to strategic interventions. To date, the ARM program has entered more than 121 community and teaching hospitals into a web-centered database. This observational database currently has susceptibility data on up to 19 different organisms and up to 46 different antibiotics. As of February 2003, the ARM program had collected data on more than 15 million total isolates, and sensitivity data on more than 60,000 separate isolates of S. pneumoniae.(125)

In a presentation made at the American College of Clinical Pharmacy (Albuquerque, New Mexico, Oct. 21, 2002, John Gums, PharmD), data from the ARM program demonstrated higher rates of resistance for cefotaxime as compared to ceftriaxone for S. pneumoniae isolates. In this study, University of Florida researchers analyzed data from the ARM Program in 1995-2001. National and regional susceptibility data from 143 hospitals in five U.S. regions (North Central, Northeast, South Central, Southeast, and Southwest) were examined. Sensitivity reports for pneumococcal isolates were reviewed for susceptibility to cefotaxime and ceftriaxone and compared across years and U.S. regions using a web-based analysis tool.

The results of the study showed that S. pneumoniae bacteria were more susceptible overall to ceftriaxone compared to cefotaxime (80.9% vs 71.7%). National susceptibility rates for cefotaxime were lower than the rates for ceftriaxone in each of the years studied, beginning at 54.7% in 1995 and progressing to 73.6% in 2001. Over the same time period, national susceptibility rates for ceftriaxone were higher, beginning at 75.2% in 1995 and increasing to 82.3% in 2001. For the most part, these national susceptibility trends also were consistent regionally, with one exception. In the Northeast, susceptibility rates were comparable for cefotaxime and ceftriaxone in each year except for 2001, when susceptibility rates for the two drugs were 70.2% and 80.7%, respectively.

Since the ARM program was originally designed as an observational database to use antibiogram trending to identify resistance patterns for individual hospitals, it is not capable of isolating the specific reason why national sensitivity differences exist between ceftriaxone and cefotaxime. Additionally, for similar reasons, the ARM program is not designed to identify why certain geographic sections of the United States demonstrate the discrepancies in sensitivities and others do not. However, subanalysis of the data suggests that the discrepancy between the third-generation cephalosporins did not exist through the whole database. The difference in sensitivity percentages appeared to emerge during the last half of the 1990-2000 decade. This coincides with the push to use cefotaxime on a twice a day basis vs. a more traditional three times daily dosing regimen.(125)

Since cefotaxime exerts its antimicrobial activity as a function of its time above the MIC of S. pneumoniae, a drop in dosing frequency from TID to BID will increase the percent of time that the organism is exposed to subinhibitory concentrations.(126) Without any significant post-antibiotic effect, the sensitivities of cefotaxime to S. pneumoniae may fall. More specific MIC analysis is required to determine if the reduced dosing frequency is causally related to the emergence of a sensitivity discrepancy between cefotaxime and ceftriaxone. The clinical implications, in terms of patient outcomes, have not been established.

Cephalosporins Vs. Fluoroquinolones: Comparing Propensity for Development of Drug Resistance.(127) Current guidelines from the Infectious Disease Society of America recommend a third generation cephalosporin such as ceftriaxone (along with a macrolide) and quinolones such as levofloxacin, gatifloxacin, and moxifloxacin (as single agents) for treatment of patients with CAP requiring hospitalization.(128) The respiratory advanced generation fluoroquinolones have a broad spectrum of activity against S. pneumoniae, H. influenzae, Moraxella catarrhalis, Mycoplasma pneumoniae, and Legionella pneumophila and are currently one of the treatments of choice for penicillin-resistant S. pneumoniae. However, overuse of this class of antimicrobial agents could lead to emergence of resistant mutants. A 1999/2000 National Antimicrobial Resistance Surveillance Study showed a greater than 1% resistance to quinolones and analysis of recent SENTRY studies show a 0.9% resistance to levofloxacin.(129-131) In Canada, the prevalence of pneumococci with reduced susceptibility to fluoroquinolones in adults, increased from 0% in 1993 to 1.7% in 1997 and 1998.(132)

The prevalence of pneumococci with raised ciprofloxacin MIC (ciprofloxacin MIC 4 mcg/L) also increased from 0.9% in 1991-1992 to 3.0% in 1997-1998 in Spain.(133) A recent study from Hong Kong showed an overall prevalence of quinolone resistance of 13.3%, with 27.3% quinolone resistance among penicillin-resistant isolates.(134) It is of concern that these resistant clones may spread to other parts of the world. The primary targets of fluoroquinolones are topoisomerase II (DNA gyrase) and topoisomerase IV, which alter DNA topology through transient double-stranded selected mutants, and did not have alteration in the QRDR of proteins GyrA, GyrB, ParC, and ParE.

Selecting Resistant Mutants. In one study,(127) attempts were made to select resistant pneumococcal mutants by sequential subculturing of 12 clinically isolated pneumococci (4 were penicillin sensitive [MIC 0.03-0.06 mcg/L], 4 penicillin intermediate [MIC 0.25-0.5 mcg/L], and 4 penicillin resistant [MIC 2-4 mcg/L]) in subinhibitory concentrations of ceftriaxone, levofloxacin, gatifloxacin, and moxifloxacin. Subculturing in gatifloxacin, levofloxacin, moxifloxacin, and ceftriaxone selected 12 mutants (12/12), 10 mutants (10/12), 10 mutants (10/12), and three mutants (3/12), respectively. DNA sequencing of the quinolone-resistant mutants showed that most strains had mutations in GyrA at E85 or S81. This in vitro mutation study demonstrated a clear distinction between the low frequency of development of resistance with ceftriaxone exposure as opposed to the high frequency with quinolone exposure.

Initial MICs of parent strains and resistant mutants resulting from serial daily subculturing in subinhibitory concentrations of antimicrobials were evaluated. The lowest mutant selection rate was obtained by ceftriaxone. Three mutants were selected by ceftriaxone with at least an eight-fold increase in their MICs for ceftriaxone. The three mutants had initial MICs of 0.125, 1, and 1 mcg/L (1 ceftriaxone sensitive and the other 2 ceftriaxone intermediate). These ceftriaxone mutants were selected in 14, 32, and 42 days. Among the quinolones tested, levofloxacin, moxifloxacin, and gatifloxacin selected 10, 10, and 12 resistant mutants, respectively. All selected mutants had the same pulsed-field electrophoresis pattern as their parent strains. The average time necessary for mutant selection was 22.7 days for levofloxacin, 24 days for moxifloxacin, and 24.3 days for gatifloxacin. All of the parent strains were sensitive to levofloxacin, gatifloxacin, and moxifloxacin. The majority of the parent strains were of intermediate resistance to ceftriaxone. After subculturing in selected antibiotics, ceftriaxone showed resistance in all of the three mutant strains, two of three had initial MICs in the ceftriaxone intermediate range, and one of three was in the ceftriaxone sensitive range.

Of 12 parent strains used for mutant selection, 10 already had substitution of I at position 460 of ParC protein by V compared with reference strains. Selection by levofloxacin, gatifloxacin, and moxifloxacin caused alterations of GyrA in eight, eight, and seven mutants selected by these antibiotics, respectively. The second most affected protein was parC for mutants produced by levofloxacin and gatifloxacin exposure. GyrB was the second most affected protein for mutants produced by moxifloxacin exposure. Among 32 mutants selected by quinolones, 25 had alterations in GyrA, 12 in ParC, nine in ParE, and eight in GyrB. The changes in GyrA were mostly at positions 81 (S81/A,F,L,Y) and 85 (E85/K,A,G). In two mutant strains selected by levofloxacin, exposure changes in two amino acids, S81Y and V101I in GyrA, were associated with the increase in the quinolone MICs. One mutant selected by levofloxacin had substitution of D by G at position 80 in GyrA. Alterations in GyrB were detected in eight mutants selected by moxifloxacin, gatifloxacin, and levofloxacin exposure. In two mutants GyrB was altered by insertion of two amino acids. The mutant selected by moxifloxacin exposure from parent 3 had insertion of I and S after position 398, and the mutant selected by levofloxacin exposure from parent 11 had insertion of E and I after.

In this study, the parenteral beta-lactam antibiotic, ceftriaxone, and three quinolone antibiotics, levofloxacin, gatifloxacin, and moxifloxacin were tested for their ability to select resistant mutants. The lowest mutation rates occurred with ceftriaxone in multi-step resistance selection experiments. No obvious differences in ability to select resistant mutants were observed among the three quinolones tested. Alterations in GyrA, GyrB, ParC, and ParE were detected among resistant mutants selected by quinolone exposure. Seventy-eight percent of resistant mutants had modifications in GyrA, showing the importance of this protein in the action of these quinolones. Mutations in ParC were found in 37% of these mutants. However, moxifloxacin exposure, in addition to selecting mutants with GyrA changes, also selected mutants with GyrB changes. GyrB is, therefore, likely to be an important target for moxifloxacin. Overall, ceftriaxone had lower rates of resistance selection compared with the respiratory quinolones. This is a similar finding to previous studies when ceftriaxone was compared with macrolides.(135) When resistant clones were selected by ceftriaxone, on average it took more subcultures for the development of resistance compared with the quinolones. Therefore, the investigators concluded, ceftriaxone may not pose an important selective pressure for resistance development compared with the fluoroquinolones and the macrolides, and may be used confidently in the treatment of CAP requiring hospitalization.(127)

Advanced Generation Macrolides. The established new generation macrolide antibiotics include the erythromycin analogues azithromycin and clarithromycin.(136,137) 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.(138,139) 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. 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.

At the outset, it is fair to say that these macrolides—especially azithromycin—to a great degree, have supplanted the use of erythromycin in community-acquired infections of the lower respiratory tract. In addition, from the perspective of providing definitive, cost-effective, and compliance-promoting therapy, the newer macrolide antibiotics, which includes intravenous azithromycin for hospital-based management, have recently emerged as some of the drugs of choice—along with the new, extended spectrum quinolones—for outpatient management of CAP.(140) When used as oral agents, they play a central role in the management of pneumonia in otherwise healthy 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 the availability of the intravenous formulation of azithromycin as a cotherapeutic agent 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.(13,14)

The macrolides also have the advantage of a simplified dosing schedule, especially azithromycin, which for outpatients is given once daily for only five days (500 mg po on day 1 and 250 mg po qd on days 2-5). For oral, step-down therapy of hospitalized patients with CAP, the dose of azithromycin is 500 mg po qd for a total treatment course of 10 days. 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 an 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; no pain on injection or venous thrombosis issues; and its decreased incidence of gastrointestinal side effects, which occur in 3-5% of patients taking an oral, five-day, multiple-dose regimen.(141)

Azithromycin—Coagent (i.e., with Ceftriaxone) For Combination Therapy in Hospitalized CAP. Intravenous azithromycin can be used for the management of hospitalized patients with moderate or severe CAP.(15,16,142) 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.(13,14,142,143) This would be considered correct spectrum coverage for empiric therapy of CAP in most patients. However, for hospitalized patients, who tend to have co-morbid conditions, including underlying cardiorespiratory disease, the addition of a beta-lactam (ceftriaxone/cefotaxime) to azithromycin is considered mandatory by the ASCAP Consensus Panel.

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.(144)

One recent study(145) has investigated the value of adding a macrolide to an initial beta-lactam-based antibiotic regimen in patients with bacteremic pneumococcal pneumonia. The objective was to assess the influence of including a macrolide into a beta-lactam-based empiric antibiotic regimen on bacteremic pneumococcal pneumonia mortality. This observational, 10-year study of patients with bacteremic pneumococcal pneumonia receiving a beta-lactam as initial antibiotic therapy attempted to assess the independent predictors of mortality; the available set of prognostic factors were subjected to a step-wise logistic regression procedure taking in-hospital death as the outcome variable. Among the 409 patients who were included in the study, 238 (58%) received a beta-lactam plus a macrolide with or without other antibiotics and 171 (42%) a beta-lactam with or without other antibiotics different from a macrolide. Patients not receiving a macrolide were more likely to have comorbidity (p = 0.0002); an ultimately/rapidly fatal underlying disease (p < 0.0001); neutropenia (p = 0.002); a nosocomial origin of the infection (p < 0.0001); a microorganism resistant to penicillin (p = 0.02); and an increased exposure to corticosteroids, cancer chemotherapy, and prior antibiotics. However, they were less likely to be in shock at presentation (p < 0.0001) and require ICU admission (p < 0.0001). Overall, 35 patients (9%) died. Four variables were independently associated with death: shock (p < 0.0001), age 65 or older (p = 0.02), resistance to both penicillin and erythromycin (p = 0.04), and no inclusion of a macrolide in the initial antibiotic regimen (p = 0.03). The investigators concluded that not adding a macrolide to a beta-lactam-based initial antibiotic regimen for bacteremic pneumococcal pneumonia is an independent predictor of in-hospital mortality.(145)

Community-Acquired Pneumonia (CAP): ASCAP Consensus Panel Recommendations for Outpatient Management

Despite a general consensus that empiric, outpatient treatment of CAP requires, at the least, mandatory coverage of such organisms as S. pneumoniae, H. influenzae, and M. catarrhalis, as well as atypical organisms (M. pneumoniae, C. pneumoniae, and L. pneumophila), antibiotic selection strategies for achieving this spectrum of coverage vary widely. New treatment guidelines for CAP have been issued by such national associations as the IDSA (2000), the ATS (2001), and the CDC (CDC-DRSPWG, 2000).

Deciphering the strengths, subtleties, and differences among 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 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.

Patient Management Recommendations. The ASCAP 2003 Consensus Panel concurred that appropriate use of antibiotics requires radiographic confirmation of the diagnosis of CAP. In this regard, physicians should use clinical judgment when ordering chest x-rays, with the understanding that the diagnostic yield of this radiographic modality in CAP is increased in patients with fever greater than 38.5°C; presence of new cough; and abnormal pulmonary findings suggestive of consolidation, localized bronchoconstriction, or pleural effusion.

Accordingly, a chest x-ray is recommended and encouraged by the ASCAP Consensus Panel, as well as by such national associations as the IDSA, ATS, and American College of Emergency Physicians (ACEP), to confirm the diagnosis of outpatient CAP; however, the panel acknowledges that, on occasion, logistical issues may prevent radiographic confirmation at the time of diagnosis and treatment.

The approach to antibiotic therapy usually will be empiric, and must account for a number of clinical, epidemiological, and unpredictable factors related to antibiotic resistance patterns and respiratory tract pathogens. As a general rule, appropriate antibiotic choice for the patient with CAP requires consideration of strategies that will yield clinical cure in the patient “today,” combined with antibiotic selection strategies that prevent accelerated emergence of drug-resistant organisms that will infect the community “tomorrow.”

Based on the most current clinical studies, the principal six respiratory tract pathogens that must be covered on an empiric basis in individuals with outpatient CAP include: S. pneumoniae, H. influenzae, M. catarrhalis, C. pneumoniae, M. pneumoniae, and L. pneumophila. In addition, the ASCAP Consensus Panel emphasized that there may be a “disconnect” (i.e., an incompletely understood and not entirely predictable relationship between an antibiotic’s MIC level and its association with positive clinical outcomes in CAP). This “disconnect” may be explained by the unique qualities of an antimicrobial, such as tissue penetration and/or pharmacokinetics, patient medication compliance, and other factors.

Double-blinded, prospective clinical trials comparing new generation macrolides vs. new generation fluoroquinolones demonstrate similar outcomes in terms of clinical cure and bacteriologic eradication rates in outpatients with CAP.(124) However, emergence of resistance among S. pneumoniae species to new generation fluoroquinolones has been reported in a number of geographic regions, including the United States, Hong Kong, and Canada, and this may have implications for treatment.

The frequency of DRSP causing outpatient CAP, as estimated by the CDC, is very low (i.e., in the range of 0.14-1.9%). The CDC-DRSPWG cautions against overuse of new generation fluoroquinolones in outpatient CAP, and recommends their use as alternative agents when: 1) first-line therapy with advanced generation macrolides such as azithromycin fails; 2) patients are allergic to first-line agents; or 3) the case is a documented infection with DRSP.(146)

Given concerns about antibiotic overuse, the potential for emerging resistance among DRSP to fluoroquinolones, and the increasing recognition of atypical pathogens as causative agents in patients with outpatient CAP, the panel concurs with the CDC-DRSPWG recommendation advocating macrolides as initial agents of choice in outpatient CAP. The ASCAP Consensus Panel also noted that the Canadian Consensus Guidelines for CAP Management and the 2001 ATS Consensus Guideline Recommendations also include advanced generation macrolides as initial therapy for outpatient CAP.

In this regard, two safe and effective advanced generation macrolides, azithromycin and clarithromycin, currently are available for outpatient, oral-based treatment of CAP. Based on outcome-sensitive criteria such as cost, daily dose frequency, duration of therapy, side effects, and drug interactions, the ASCAP Consensus Panel recommends as first-line, preferred initial therapy in CAP, azithromycin, with clarithromycin or doxycycline as alternative agents; and as alternative first-line therapy, moxifloxacin, gatifloxacin, or levofloxacin when appropriate, according to CDC guidelines and other association-based protocols. Among the advanced generation fluoroquinolones, moxifloxacin is preferred by the ASCAP Consensus Panel as the initial fluoroquinolone of choice because it has the most favorable MICs against S. pneumoniae, and a more focused spectrum of coverage against gram-positive organisms than levofloxacin or gatifloxacin. For older individuals or “higher risk” patients managed in the outpatient setting, moxifloxacin or azithromycin are the initial agents of choice.

Physicians are urged to prescribe antibiotics in CAP at the time of diagnosis and to encourage patients to fill and begin taking their prescriptions for CAP on the day of diagnosis. Ideally, patients should initiate their first course of oral therapy within eight hours of diagnosis, a time frame that appears reasonable based on studies in hospitalized patients indicating improved survival in patients who received their first IV dose within eight hours of diagnosis. Primary care practitioners also are urged to instruct patients in medication compliance. In the case of short (5-day) courses of therapy, patients should be educated that although they are only consuming medications for a five-day period, the antibiotic remains at the tissue site of infection for about 7-10 days and continues to deliver therapeutic effects during that period.

Either verbal or on-site, reevaluation of patients is recommended within a three-day period following diagnosis and initiation of antibiotic therapy. Follow-up in the office or clinic within three days is recommended in certain risk-stratified patients, especially the elderly, those with co-morbid illness, and those in whom medication compliance may be compromised. More urgent follow-up may be required in patients with increasing symptoms, including dyspnea, fever, and other systemic signs or symptoms. Follow-up chest x-rays generally are not recommended in patients with outpatient CAP, except in certain high-risk groups, such as those with right middle lobe syndrome, and in individuals in whom the diagnosis may have been uncertain.

In-Hospital Management of CAP: Monotherapy Vs. Combination Therapy. Outcomes Analysis and ASCAP Treatment Guidelines

Although antibiotic recommendations based on risk-stratification criteria, historical features, sites where the infection was acquired, and other modifying factors play a role, institutional protocols, hospital-based critical pathways, resistance features, and other factors also 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, providing mandatory antimicrobial coverage against S. pneumoniae, H. influenzae, M. catarrhalis, Legionella, M. pneumoniae, and C. pneumoniae appears to be non-negotiable for managing the majority of patients with CAP. Selected populations also may be at risk for infection with S. aureus or gram-negative organisms, a factor that will modify antibiotic selection. As mentioned earlier, consensus reports and national guidelines support this strategy (see section on Consensus Guidelines for Antibiotic Therapy, below).

When combination cephalosporin/macrolide therapy is the accepted hospital protocol, among the beta-lactams available, IV ceftriaxone is recommended by the ASCAP 2003 Consensus Panel because of its evidence-based efficacy in moderate-to severe CAP, once-daily administration, and spectrum of coverage; and because it is supported by all major guideline panels.

One study evaluated antibiotic resistance data using data derived from community-based medical practices. Data were gathered from July 1999 to April 2000. Four of the most common isolates were: Moraxella catarrhalis (27%), Haemophilus influenzae (25%), Staphylococcus aureus (14%), and Streptococcus pneumoniae (12%); atypical organisms were not assessed.

Among S. pneumoniae isolates, levofloxacin exhibited a 4.8% level of resistance; for ceftriaxone, the resistance rate was only 5.8% (based on pre-2002 NCCLS MIC breakpoint). For S. aureus, both ceftriaxone and levofloxacin inhibited all isolates. And for M. catarrhalis and H. influenzae, no resistance was observed for either levofloxacin or ceftriaxone. The investigators concluded that levofloxacin and ceftriaxone exhibited equivalent susceptibility/resistance patterns to organisms encountered in CAP.(147)

Although ceftriaxone was introduced to the market in 1985, and despite 18 years of use, its susceptibility to multiple gram-positive and gram-negative isolates has not changed significantly. In this regard, ceftriaxone has retained potent activity against the most commonly encountered enteric species (i.e., E. coli, K. pneumoniae, K. oxytocia, and P. mirabilis), at a level of 93-99%.(147)

Azithromycin is recommended as the co-therapeutic macrolide agent (i.e., in combination with ceftriaxone) in patients with CAP 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 step-down, monotherapeutic management of CAP caused by S. pneumoniae, H. influenzae, M. catarrhalis, L. 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 L. pneumophila, a pathogen commonly implicated in the geriatric patient with CAP. Decisions about use will be determined by intrainstitutional pathways and protocols, based on consensus recommendations and association guidelines as presented in this article.

Critical Pathways and Protocols. 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 the CDC group’s recent consensus report stresses the importance of using an IV macrolide in combination with other agents, and in particular third-generation cephalosporins such as ceftriaxone.(3) In these patients, a macrolide should be used in combination with a cephalosporin (i.e., ceftriaxone); when anti-pseudomonal coverage is necessary, an anti-pseudomonal cephalosporin and/or an aminoglycoside also may be required. Or alternatively, for the ICU patient with CAP, an extended spectrum fluoroquinolone such as moxifloxacin should be considered, along with a cephalosporin such as ceftriaxone.(3) 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 initially administered by the intravenous route when the patient’s condition so warrants. Perhaps the important change in CAP treatment since publication of the ATS guidelines in 1993 is the current general consensus, including guidelines presented at the 2001 ATS Scientific Conference, 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 emphasized that coverage of the atypical spectrum, along with coverage of S. pneumoniae, H. influenzae, and M. catarrhalis, is mandatory.(3) New guidelines from the IDSA, ATS, ASCAP, and CDC now reflect this strategy.

Although virtually all protocols using combination cephalosporin/macrolide therapy specify intravenous administration of the cephalosporin, guidelines specifying whether initial macrolide therapy should occur via the intravenous or oral route are less concrete. Recent CDC-DRSPWG guidelines recommend an 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 ASCAP Consensus Panel, therefore, recommends IV azithromycin therapy as the preferred initial, empiric agent in combination with ceftriaxone. The Panel acknowledges, however, that some institutions will use intravenous ceftriaxone in combination with an oral macrolide in non-ICU patients, an approach supported by a number of national panels. In patients on combination cephalosporin/macrolide therapy, step-down to oral therapy with azithromycin can be accomplished when the patient’s clinical status so dictates, or when culture results suggest this is appropriate.

Monotherapy Vs. Combination Therapy. It should be pointed out that while some consensus panels (ATS Guidelines, 2001) support the use of IV azithromycin in very carefully selected hospitalized CAP patients (mild disease) as monotherapy, or as the macrolide component of combination therapy, other panels, such as CDC-DRSPWG and the IDSA 2000 Guidelines, support its use specifically as the macrolide component of combination therapy (i.e., to be used in combination with such agents as ceftriaxone). The ASCAP Panel supports the use of IV azithromycin as part of a combination cephalosporin/macrolide regimen for CAP.

As emphasized, advanced generation fluoroquinolones also provide a monotherapeutic option for management of CAP, and advocates of this approach argue that these agents, on an empiric basis, provide an adequate spectrum of coverage against expected respiratory pathogens at lower drug acquisition costs. Other experts make the case that although monotherapy for pneumococcal pneumonia is standard practice in many institutions, and is identified as a treatment option in many national association guidelines, there may be a survival benefit from using a combination beta-lactam and macrolide therapy.(21) To address this issue, a group of investigators evaluated a patient database to determine whether initial empirical therapy with a combination of effective antibiotic agents would have a better outcome than a single effective antibiotic agent in patients with bacteremic pneumococcal pneumonia.

The investigators conducted a review of adult bacteremic pneumococcal pneumonia managed in the Methodist Healthcare System, Memphis, Tennessee, between Jan. 1, 1996, and July 31, 2000. Empirical therapy was defined as all antibiotic agents received in the first 24 hours after presentation. On the basis of culture results, empirical therapy was classified as single effective therapy (SET), dual effective therapy (DET), or more than DET (MET). Acute Physiology and Chronic Health Evaluation II (APACHE II)-based predicted mortality and PSI scores were calculated.(21)

Two hundred twenty-five subjects met the inclusion criteria for analysis. An additional seven cases of CAP with pneumococcal bacteremia were identified but were excluded from the study because the isolate was resistant to the empirical therapy the patient received. Investigators noted that the subjects who received MET were significantly sicker than the subjects who received SET or DET, as measured by the PSI (p = 0.04) and APACHE II-based predicted mortality (p = 0.03). Of special significance was that there was no statistically significant difference between the prevalence of chronic disease states between the SET and DET groups.

Levofloxacin was the most commonly chosen fluoroquinolone (70.4%), with only four subjects treated with ciprofloxacin (1 in the SET group, 2 in the DET group, and 1 in the MET group, all with no fatalities). Eight subjects who received more than one antibiotic agent as empirical therapy were classified as SET on the basis of the isolate being resistant to azithromycin (5 subjects), cefotaxime (2 subjects), or combined ticarcillin-clavulanate potassium (1 subject). Twenty-nine subjects (12.9%) died. A Kaplan-Meier plot of mortality over time for each antibiotic therapy group demonstrated that mortality with the SET group was significantly higher than with the DET group (p = 0.02; OR, 3.0 [95% CI, 1.2-7.6]). Even when the DET and MET groups are combined, the mortality was still significantly higher in the SET group (p = 0.04; OR, 2.3 [95% CI, 1.0-5.2]). Because only a few subjects received MET and the subjects who received MET were significantly sicker than the other subjects, subsequent analysis is confined to the SET and DET groups.

Because subjects who received SET had a lower predicted mortality than those who received DET, a logistic regression model was used to calculate the OR for death of SET vs. DET adjusted for predicted mortality, which was 6.4 (95% CI, 1.9-21.7). All deaths occurred in patients with a PSI score higher than 90 (PSI classes 4 and 5). In subjects with PSI class 4 or 5 CAP who were given SET, the predicted mortality-adjusted OR for death was 5.5 (95% CI, 1.7-17.5). Because antibiotic therapy would be expected to have little influence on early deaths, the investigators reanalyzed SET vs. DET groups after excluding all deaths that occurred within 48 hours of presentation (n = 4, 3 in the SET group and 1 in the DET group). Univariate analysis of this subgroup showed a trend to better outcome with DET compared with SET (94% survival vs 85%, respectively; p = 0.06). Multivariate analysis again confirmed that SET was an independent predictor of worse outcome (p = 0.01), with the predicted mortality-adjusted odds ratio for death in subjects given SET being 4.9 (95% CI, 1.6-18.3). Subgroup analysis did not show any significant trends to suggest any advantage or disadvantage of any specific antibiotic agents or combinations of antibiotic agents within the SET or DET groups.

Of the 225 patients with CAP who were identified, 99 were classified as receiving SET, 102 as receiving DET, and 24 as receiving MET. Compared with the other groups, patients who received MET statistically had significantly more severe pneumonia as measured by the PSI score (p = 0.04) and predicted mortality (p = 0.03). Mortality within the SET group was significantly higher than within the DET group (p = 0.02; OR, 3.0 [95% CI, 1.2-7.6]), even when the DET and MET groups (p = 0.04) were combined. In a logistic regression model including antibiotic therapy and clinical risk factors for mortality, SET remained an independent predictor of mortality with a predicted mortality-adjusted odds ratio of death of 6.4 (95% CI, 1.9-21.7). All deaths occurred in patients with a PSI score higher than 90, and the predicted mortality-adjusted odds ratio for death with SET in this subgroup was 5.5 (95% CI, 1.7-17.5).

In comparably matched patients, this group found that SET is associated with a significantly greater risk of death than DET. On the basis of these results, they concluded that monotherapy may be suboptimal for patients with severe bacteremic pneumococcal pneumonia who have PSI scores of greater than 90.(21)

While acknowledging its limitations, the results of this retrospective study strongly suggest that bacteremic patients with pneumococcal CAP who receive at least two effective antibiotic agents within the first 24 hours after presentation to a hospital have a significantly lower mortality than patients who receive only one effective antibiotic agent. In fact, among high-risk patients (PSI classes 4 or 5), receiving only one effective antibiotic agent increases mortality by more than five-fold as compared with patients receiving two effective antibiotic agents.

Although these findings need to be confirmed by a prospective study, the authors suggest that current approaches to the empiric therapy of severe CAP may need to be reevaluated.(21) Accordingly, the ASCAP 2003 Consensus Panel evaluated this study and found its results and conclusions—as well as its clinical implications—to be sufficiently compelling to recommend combination therapy with ceftriaxone plus a macrolide as the initial approach-of-choice in managing moderately-to-severely ill patients suspected of having bacteremia associated with pneumococcal pneumonia.

Further confirmation of the potential improvement in clinical outcomes associated with two-drug therapy, consisting of ceftriaxone plus a macrolide, as compared to monotherapy with an advanced-generation fluoroquinolone, has been reported in abstract form (Abstract L-981) and presented at the Interscience Conference on Antimicrobial Agents and Chemotherapy (San Diego, Sept. 27-30, 2002).(148) Specifically, this retrospective study was designed to compare length of stay (LOS) data for CAP patients treated with single-agent levofloxacin vs. those treated with ceftriaxone/azithromycin.

In a retrospective chart review conducted at two community teaching hospitals, inpatient data from 434 CAP patients were reviewed for LOS, clinical outcomes, and need for additional antibiotic therapy. Patients treated with levofloxacin were carefully matched to patients receiving ceftriaxone/azithromycin or other single-agent antibiotic therapy according to Fine risk classification. Risk class was designated according to the total number of points assigned for each patient. LOS data were gathered on all patients. Patients were considered treatment failures if signs and symptoms of CAP were still present 48-72 hours after treatment or if additional antibiotics were necessary for CAP treatment during the hospital stay.

The primary comparison was LOS between the levofloxacin and ceftriaxone/azithromycin groups using a two-way ANOVA. All ANOVA F-tests were based on a distribution-normalizing and variance-stabilizing log transformation of days in the hospital. A total of 434 eligible patient charts were identified and reviewed at the two hospital sites. Among these, 225 patients were treated with levofloxacin, 164 patients received ceftriaxone/azithromycin, and 45 patients were treated with other single agent antibiotic therapy (e.g., ceftriaxone, cefotetan, clindamycin, vancomycin). Certain dissimilarities were observed between the treatment groups. A higher percentage of patients in the ceftriaxone/azithromycin group (15.2%) were in the highest risk class (Fine class 5) compared with the levofloxacin group (8.8%). In addition, mean baseline Fine risk scores were 91.0 in the levofloxacin group and 98.0 in the ceftriaxone/azithromycin group, also indicating a higher risk status in the latter group (p < 0.001).

The mean LOS was significantly longer among patients treated with levofloxacin compared with patients treated with ceftriaxone/azithromycin, regardless of Fine risk class (p < 0.001). Mean LOS in the levofloxacin group was 6.8 days, compared with 4.4 days in the ceftriaxone/azithromycin group. Mean length of stay among patients treated with other single agent antibiotics was 7.2 days. There was no significant treatment x risk interaction effect (p = 0.459). LOS data were further analyzed after removing data from any patient who required more than 13 hospital days (outliers). There were 19 outlier patients in the levofloxacin group and none in the ceftriaxone/azithromycin group. This analysis continued to demonstrate a statistical advantage in favor of ceftriaxone/azithromycin relative to levofloxacin (p < 0.001). An overall effect of Fine risk class on hospital days also was apparent in this analysis (p < 0.001).

Overall, results of the study reveal that at baseline, mean Fine scores were lower (indicating lower severity) in the levofloxacin group (91) compared with the ceftriaxone/azithromycin group (98) (p < 0.001). Despite this, mean LOS was longer in the levofloxacin group (6.8 days) than in the ceftriaxone/azithromycin group (4.4 days) (p < 0.001). Nineteen patients in the levofloxacin group had a LOS of greater than 13 days; a separate analysis excluding these patients produced similar results. Risk class alone also had a significant effect on LOS (p < 0.001). In the levofloxacin group, 36% of patients required additional antibiotics, compared with 8% of ceftriaxone/azithromycin patients. The investigators concluded that despite lower Fine risk scores, levofloxacin was associated with longer hospital stays and more supplemental antibiotic usage compared with ceftriaxone/azithromycin; these both are factors that have the potential for translating into significant cost savings for hospital-based management of CAP.

Despite important limitations of this study (small sample size, retrospective analysis, limited number of sites, and presentation of data in abstract form only), the conclusions are consistent with the study by Waterer et al. This study demonstrated improved outcomes with combination cephalosporin/macrolide therapy, and suggests the need for additional prospective randomized trials to provide confirmation of current trends favoring two-drug therapy for high-risk patients with CAP.(148)

Although all current national guidelines for CAP management, including the IDSA, ATS, ASCAP, and CDC-DRSPWG consensus recommendations, stress the importance of combining cephalosporins such as ceftriaxone with a macrolide, studies demonstrating the favorable effect on mortality rates associated with combined therapy have been published only recently. Further support for a ceftriaxone/azithromycin combination has been strengthened by a recent investigation in which a group retrospectively analyzed all cases of bacteremic S. pneumoniae pneumonia in patients 18 and older hospitalized from 1995 to 2000.(149) Standard initial therapeutic regimen in this index institution was cefuroxime ± macrolide from 1995 to 1997, and ceftriaxone + azithromycin from 1998 to 2000.

In total, 95 patients (49 men, 46 women) were included in this study, with a mean age of 63 (range: 20-98). At admission, 30.5% of patients had a leucocyte count greater than 20,000, 11.5% a systolic BP lower than 90 mmHg, 44.2% a respiratory rate greater than 30/min, and 33.6% nausea-vomiting necessitating some form of therapy or that prevented the patient from eating. Interestingly, 16.8% had no fever at admission, and 72.5% became afebrile within 48 hours. Antibiotic resistance was not associated with increased mortality. In total, 15 (15.7%) patients died, four within the first 72 hours. During the 1995-1997 period, only 15% of the patients initially received a macrolide. The mortality rate for the period 1995-1997 (cefuroxime ± macrolide) was 20% and from 1998-2000 (ceftriaxone + azithromycin), it fell to 11%. During this period, PSI scores for evaluated patients were comparable (113-114) and reflected a similar percentage of patients in Fine risk classes 4-5.

The ceftriaxone-azithromycin combination significantly reduced the mortality rate compared to monotherapy (cefuroxime) for the group of patients with CAP that had the highest mortality rate.(149)

Extended Spectrum Fluoroquinolones: Intensification of Coverage and Patient Selection

The extended spectrum quinolones, moxifloxacin, levofloxacin, and gatifloxacin, are indicated for treatment of CAP. Each of these agents is available as an oral and intravenous preparation. Quinolones have been associated with cartilage damage in animal studies; therefore, they are not recommended for use in children, adolescents, and pregnant and nursing women. Upon review of multiple studies, resistance data, and pharmacodynamic data, the ASCAP Consensus Panel has concluded that all advanced generation fluoroquinolones are not “created equally,” and that prudent, resistance-sensitive choices require differentiation among the available agents.(150-163)

Moxifloxacin. Among the new fluoroquinolones, moxifloxacin has the lowest MICs against S. pneumoniae and more specific gram-positive coverage; therefore, it is recommended by the ASCAP Consensus Panel as the IV or oral fluoroquinolone of choice—when a fluoroquinolone is indicated—for managing patients infected with S. pneumoniae and other organisms known to cause CAP. It recently received approval and is indicated for treatment of drug-resistant S. pneumoniae (DRSP). Moxifloxacin reaches higher lung fluid concentrations compared to levofloxacin; this is important because quinolones demonstrate concentration-dependent killing.(192,193) Moxifloxacin also is generally well tolerated. In clinical trials, the most common adverse events were nausea (8%), diarrhea (6%), dizziness (3%), headache (2%), abdominal pain (2%), and vomiting (2%). The agent is contraindicated in persons with a history of hypersensitivity to moxifloxacin or any quinolone antibiotic. The safety and effectiveness of moxifloxacin in pediatric patients, pregnant women, and lactating women have not been established.

Although reports of clinical problems are very rare, moxifloxacin has been shown to prolong the QT interval of the electrocardiogram in some patients. The drug should be avoided in patients with known prolongation of the QT interval, patients with uncorrected hypokalemia, and patients receiving Class lA (e.g., quinidine, procainamide) or Class lll (e.g., amiodarone, sotalol) antiarrhythmic agents due to the lack of clinical experience with the drug in these patient populations. Pharmacokinetic studies between moxifloxacin and other drugs that prolong the QT interval such as cisapride, erythromycin, antipsychotics, and tricyclic antidepressants have not been performed. An additive effect of moxifloxacin and these drugs cannot be excluded; therefore, moxifloxacin should be used with caution when given concurrently with these drugs.

The effect of moxifloxacin on patients with congenital prolongation of the QT interval has not been studied; however, it is expected that these individuals may be more susceptible to drug-induced QT prolongation. Because of limited clinical experience, moxifloxacin should be used with caution in patients with ongoing proarrhythmic conditions, such as clinically significant bradycardia or acute myocardial ischemia. As with all quinolones, moxifloxacin should be used with caution in patients with known or suspected CNS disorders or in the presence of other risk factors that may predispose to seizures or lower the seizure threshold.

Gatifloxacin. Gatifloxacin, a broad-spectrum 8-methoxy fluoroquinolone antibiotic, has been approved for the safe and effective treatment of approved indications, including community-acquired respiratory tract infections, such as bacterial exacerbation of chronic bronchitis (ABE/COPD); acute sinusitis; and CAP caused by indicated, susceptible strains of gram-positive and gram-negative bacteria. The recommended dose for gatifloxacin is 400 mg once daily for all individuals with normal renal function. Dosage adjustment is required in patients with impaired renal function (creatinine clearance, < 40 mL/min).

Gatifloxacin is primarily excreted through the kidneys, and less than 1% is metabolized by the liver. In clinical trials, gatifloxacin has been found to be a well-tolerated treatment in 15 international clinical trials at 500 study sites. Gatifloxacin may have the potential to prolong the QTc interval of the electrocardiogram in some patients, and due to limited clinical experience, gatifloxacin should be avoided in patients with known prolongation of the QTc interval, in patients with uncorrected hypokalemia, and in patients receiving Class IA (e.g., quinidine, procainamide) or Class III (e.g., amiodarone, sotalol) antiarrhythmic agents. Gatifloxacin should be used with caution when given together with drugs that may prolong the QTc interval (e.g., cisapride, erythromycin, antipsychotics, tricyclic antidepressants), and in patients with ongoing proarrhythmic conditions (e.g., clinically significant bradycardia or acute myocardial ischemia).

Gatifloxacin should be used with caution in patients with known or suspected CNS disorders or patients who have a predisposition to seizures. The most common side effects associated with gatifloxacin in clinical trials were gastrointestinal. Adverse reactions considered to be drug related and occurring in greater than 3% of patients were: nausea (8%), vaginitis (6%), diarrhea (4%), headache (3%), and dizziness (3%).

Oral doses of gatifloxacin should be administered at least four hours before the administration of ferrous sulfate; dietary supplements containing zinc, magnesium, or iron (such as multivitamins); aluminum/magnesium-containing antacids; or Videx (didanosine, or ddI). Concomitant administration of gatifloxacin and probenecid significantly increases systemic exposure to gatifloxacin. Concomitant administration of gatifloxacin and digoxin did not produce significant alteration of the pharmacokinetics of gatifloxacin; however, patients taking digoxin should be monitored for signs and/or symptoms of digoxin toxicity.

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 S. 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 well-tolerated, with the most common side effects including nausea, diarrhea, headache, and constipation. 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 for levofloxacin is recommended in patients with impaired renal function (clearance < 50 mL/min).

Although no significant effect of levofloxacin on plasma concentration of theophylline was detected in 14 health volunteers studied, because other quinolones have produced increases in patients taking concomitant theophylline, theophylline levels should be closely monitored in patients on levofloxacin and dosage adjustments made as necessary. Monitoring patients on warfarin also is recommended in patients on quinolones.

When given orally, levofloxacin is dosed once daily, is well absorbed orally, and penetrates well into lung tissue.(164) It is active against a wide range of respiratory pathogens, including atypical pathogens and many species of S. pneumoniae resistant to penicillin.(165,166) In general, levofloxacin has greater activity against gram-positive organisms than ofloxacin and is slightly less active than ciprofloxacin against gram-negative organisms.(167,168)

Levofloxacin is available in both oral and parenteral forms, 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.

Levofloxacin is indicated for the treatment of adults (> 18 years) with mild, moderate, and severe pulmonary infections, including acute bacterial exacerbations of chronic bronchitis and CAP.(169) It is active against many gram-positive organisms that may infect the lower respiratory tract, including S. pneumoniae and S. aureus, and it also covers atypical pathogens, including C. pneumoniae, L. pneumophila, and M. pneumoniae. In addition, it is active against gram-negative organisms, including E. coli, H. influenzae, H. parainfluenzae, K. pneumoniae, and M. 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 DRSP), are efficacious for the treatment of S. pneumoniae, including penicillin-resistant strains.(3,17,170) In one study, microbiologic eradication from sputum was reported among all 300 patients with pneumococcal pneumonia treated with oral levofloxacin.(17) 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.(170) 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.

Fluoroquinolones: Resistance Concerns and Over-Extended Spectrum of Coverage. Despite high level activity against pneumococcal isolates and a formal indication for levofloxacin use in suspected DRSP lower respiratory tract infection, the CDC-DRSPWG recent guidelines do not advocate the use of expanded spectrum fluoroquinolones (among them, levofloxacin) for first-line, empiric treatment of pneumonia.

This is because of the following: 1) their broad, perhaps, over-extended spectrum of coverage that includes a wide range of gram-negative organisms; 2) 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 = 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).(3)

The CDC-DRSPWG concerns about inducing fluoroquinolone resistance not only to S. pneumoniae, but also to other pathogenic organisms has support in the medical literature.(171-173) Individual fluoroquinolone use in U.S. hospitals, as measured by inpatient dispensing, is changing over time. Selective pressure exerted by fluoroquinolone use may be causally related to the prevalence of ciprofloxacin resistant P. aeruginosa. In fact, databases support growing concern about emerging fluoroquinolone resistance. In this regard, recent NNIS surveillance data indicates that resistance for P. aeruginosa to fluoroquinolones is increasing, possibly as a result of increasing use of this drug class.(171-173) To shed light in this possible association, the SCOPE-MMIT network of 35 hospitals tracked inpatient fluoroquinolones dispensing since 1999, and obtained hospital antibiograms to assess for associations between use and resistance rates.

MediMedia Information Technology (MMIT, North Wales, PA) collected data of inpatient-dispensed drugs from each participating hospital information system. Grams of individual fluoroquinolones are converted each quarter to defined daily dose/1000 patient days (DDD/1000PD). Antibiograms (1999) testing susceptibility of P. aeruginosa to ciprofloxacin were available from 22 hospitals. The relationship between total fluoroquinolone use and percentage resistance for P. aeruginosa to ciprofloxacin was assessed by linear regression. Results indicated that total fluoroquinolone use between 1999 and 2001 remained at ~ 140DDD/1000PD, although mean levofloxacin use increased significantly and ciprofloxacin use declined slightly. There was a significant positive relationship between total fluoroquinolone use and resistance to P. aeruginosa (r = 0.54, p = 0.01).

Investigators concluded that mean total fluoroquinolone dispensing in the 35 hospitals studied was stable, although there were significant differences in use between individual fluoroquinolones. There was a positive relationship between total fluoroquinolone use and resistance to ciprofloxacin for P. aeruginosa, but it was not yet possible to determine if the relationship was causal or which fluoroquinolones are most likely responsible. The SCOPE-MMIT network will continue to evaluate the quantitative relationships between antibiotic use and resistance as antibiotic use changes over time, and as resistance rates respond to these changes in selective pressure.(171-173)

Fluoroquinolones and Development of Gram-Negative Resistance.(174) Recent studies also have identified independent risk factors for the development of fluoroquinolone resistance in E. coli and K. pneumoniae isolates derived from nosocomial infections. Among the risk factors identified were recent fluoroquinolone use, residence in a long-term care facility (LTCF), older age, and recent aminoglycoside use.

This study was a retrospective, blinded, case control study entering patients with E. coli and K. pneumoniae isolates resistant to fluoroquinolones (using levofloxacin as the index) by NCCLS definitions that were determined to be the cause of nosocomial clinical infection as defined by CDC guidelines. An equal number of controls were randomly selected from the pool of E. coli and K. pneumoniae isolates that were susceptible to fluoroquinolones. In total, 178 potential cases were identified, of which 42 were ineligible because the isolates represented colonization and/or community-acquired infection. Multivariable analysis was used to determine the association between potential risk factors and fluoroquinolone resistance. Data were collected from Jan. 1, 1998, to June 30, 1999.

Results of the study demonstrated that on multivariable analysis, the following were independent risk factors for fluoroquinolone-resistant infection with these adjusted risk ratios (RRs): Fluoroquinolone use (5.25); LTCF (3.65); prior aminoglycoside use (8.86); and age (1.03). In addition, fluoroquinolone-resistant isolates were more likely to be resistant to other classes of antibiotics than fluoroquinolone-susceptible isolates. Overall, 25% of fluoroquinolone-resistant isolates (cases) had the ESBL phenotype, compared to 4.3% of fluoroquinolone-susceptible isolates (controls). Cases had greater prior antibiotic exposure measured as both number of days of antibiotic therapy and number of antibiotics received. In a subanalysis, 35 of 41 patients (85.4%) who had received a fluoroquinolone in the 30 days prior to infection had a fluoroquinolone-resistant infection.

The results of this study, while interesting, do not shed much light on the best strategies to control fluoroquinolone resistance in nosocomial infections with E. coli and K. pneumoniae. Risk factors such as prior fluoroquinolone use and older age might lead to the conclusion that a policy of fluoroquinolone restriction is necessary. On the other hand, residence in a LTCF and prior aminoglycoside use suggest horizontal spread that would be better addressed through improved infection control. Prior aminoglycoside use, as well as use of certain other antibiotics, may alter membrane permeability to fluoroquinolones, thereby causing low level resistance and setting the stage for higher level resistance upon exposure to a fluoroquinolone.

Fluoroquinolones and MRSA. Methicillin-resistant Staphylococcus aureus (MRSA) is a substantial problem in antibiotic therapy, and its origin is now recognized to be both from the hospital and the community.(2) There are a variety of well-known risk factors for the development of MRSA in the hospital, including extensive prior broad-spectrum antibiotic use, admission to an ICU, prolonged hospitalization, presence of an indwelling catheter, severe comorbid diseases, surgery, and exposure to MRSA-colonized patients. However, a substantial amount of new data has arisen indicating that fluoroquinolones are a risk factor for the increase in MRSA. Given the widespread use of oral fluoroquinolones in the community over the last several years, and the increase in community-acquired MRSA, it is prudent to consider the possibility that fluoroquinolone overuse may be associated with increasing emergence of MRSA.(175)

To address this question, one study evaluated prior antibiotic exposure and the development of nosocomial MRSA bacteremia in patients admitted to a 750-bed tertiary care hospital.(173) All patients with nosocomial bacteremias from Jan. 1, 1996, to June 30, 1999, were evaluated. For each patient, investigators documented all antibiotics administered prior to the development of the bacteremia. They performed a case-controlled evaluation comparing fluoroquinolone-exposed patients to non-fluoroquinolone-exposed patients in relation to the development of MRSA bacteremia. A chi-squared analysis was conducted and relative risk (RR) calculated.

A total of 514 nosocomial bacteremias occurred over the study period, with 78 (15%) MRSA. The percentage of MRSA bacteremias/nosocomial bacteremias increased from 10% in 1996 to 22% in 1999 (p < 0.05). MRSA as a percent of all S. aureus clinical isolates increased from 29% to 40%. Prior fluoroquinolone exposure and MRSA bacteremia rose significantly from 25% of cases in 1986 to 65% of cases in 1999 (40% fluoroquinolone alone and 25% fluoroquinolone and other antibiotics) (p < 0.05). Cephalosporin exposure and the development of MRSA bacteremia dropped significantly from 50% of cases in 1996 to 0% of cases in 1999 (p < 0.01). Overall, 52% of fluoroquinolone-exposed patients developed MRSA bacteremia vs. 8% methicillin-sensitive S. aureus (MSSA) bacteremia (p < 0.05). In 1996 the RR of fluoroquinolone exposure and the development of MRSA bacteremia was 2.27 (ns), whereas during 1997-1999 the RR of fluoroquinolone exposure was significant, ranging from 3.25 to 4.68 (p < 0.05). Fluoroquinolone usage increased hospital-wide over the study period.(173)

The study group noted a significant increase in nosocomial MRSA bacteremias in fluoroquinolone-exposed patients and a significant decrease in patients with cephalosporin exposure over the study period. Fluoroquinolone-exposed patients had 3-4 times greater risk of developing nosocomial MRSA bacteremia than non-fluoroquinolone-exposed patients. Because increasing fluoroquinolone usage may have contributed to the increased selection and development of MRSA bacteremias, the study group implemented policies to limit fluoroquinolone utilization to attempt to control the selection and development of nosocomial MRSA bacteremias in the future.(173)

Selective Fluoroquinolone Use. Based on observational, surveillance, and other published data and emerging trends, from a practical, drug selection perspective, the CDC-DRSPWG has recommended that fluoroquinolones be reserved for selected patients with CAP; these experts have identified specific patient subgroups that are eligible for initial treatment with extended-spectrum fluoroquinolones. 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 = 4 mcg/mL).(109)

Whereas, until recently, fluoroquinolone resistance to S. pneumoniae was not considered an urgent clinical issue, the Morbidity and Mortality Weekly Report recently covered the appearance of, and increasing levels of, fluoroquinolone resistance to what was once a susceptible organism. Ofloxacin-resistance of 3.1% in 1995 had increased to 4.5% in 1997 (p = 0.02), whereas levofloxacin-resistance of 0.2% in 1998 was reported to be 0.3% in 1999 (p value not significant).(176)

In support of the CDC-DRSPWGs position on restricting fluoroquinolone use, the editors of Morbidity and Mortality Weekly Report also cited that while prescriptions in the United States for all antibiotics decreased between 1993 and 1998, the prescriptions for fluoroquinolones increased from 3.1 to 4.6 prescriptions per 100 persons per year, respectively, thus greatly increasing the exposure to these broad spectrum agents.(176)

For this reason, the Morbidity and Mortality Weekly Report concluded that, “appropriate use of antibiotics is crucial for slowing the emergence of fluoroquinolone resistance.” It is for these reasons, plus concerns for increased gram-negative resistance to fluoroquinolones, that specific recommendations were issued from the CDC-DRSPWG. This recommendation, in essence, reserved fluoroquinolone use for patients who were allergic to first-line therapy, who had failed first-line therapy, or who had proven high level (MIC > 4 mcg/mL) penicillin resistance. This report also does not recommend fluoroquinolone monotherapy for critically ill persons with pneumococcal pneumonia, because its efficacy in such patients has not been established.(176)

Advanced Generation Fluoroquinolones—Mutant Protection Concentrations, MICs, and Implications for Initial Drug Selection

The fluoroquinolone class of antimicrobial agents is being used empirically as initial agents for treatment of outpatient and inpatient management of CAP. Their use is increasing as resistance has developed to the more traditional antimicrobial agents, including macrolides, against which 21-23% of all S. pneumoniae isolates now show intermediate or complete resistance. Guidelines now recommend fluoroquinolones as first-line empiric therapy for urinary tract infections in regions were trimethoprim/sulfamethoxazole resistance is greater than 10-20%.(177) And fluoroquinolones are recommended as empiric agents in patients with CAP.(178,179) Though increased use of these agents would be expected to lead to increased resistance, a targeted approach to fluoroquinolone prescribing, emphasizing their appropriate and infection-specific use, may reduce development of antimicrobial resistance and maintain class efficacy.

In this regard, evidence is mounting that suggests a link between inappropriate fluoroquinolone use, development of antimicrobial resistance against the entire fluoroquinolone class, and clinical failure. To maintain the activity of the fluoroquinolone class, clinicians need to implement an evidence-based approach to antimicrobial selection, particularly a strategy in which the most pharmacodynamically potent fluoroquinolone is matched, on an empiric basis when required, to anticipated bacterial pathogens.

The three major factors associated with increasing resistance to fluoroquinolones include the following: 1) underdosing, i.e., use of a marginally potent agent whose MIC is barely reached in serum or infected tissues; 2) overuse of agents known to encourage resistant mutants; and 3) the inability to readily detect and respond to changes in antimicrobial susceptibilities.(150) Traditional reporting of susceptibility data may be misleading and may not readily identify initial changes in resistance patterns or differences between agents of the same class.

The ASCAP 2003 Clinical Consensus Panel has evaluated fluoroquinolones indicated for CAP and recommends that to preserve fluoroquinolone activity, these agents must be continually assessed and used appropriately. They should be tested by hospital laboratories to ensure activity against expected pathogens and local resistance trends must be monitored closely. The individual attributes of a given drug should be matched with the likely pathogen at specific sites of infection. Identifying a single fluoroquinolone that is suitable for all infections is unreasonable, and excessive use of any single fluoroquinolone for all indications will lead to resistance that will adversely affect the entire class. Given the defined strategy of selecting an agent with the best pharmacokinetic and pharmacodynamic profile against the known or suspected pathogen, an appropriate therapeutic choice for most serious infections, such as nosocomial pneumonia in which P. aeruginosa is a known or suspected pathogen, would currently include ciprofloxacin in combination with an antipseudomonal beta-lactam or an aminoglycoside.

This recommendation is based on the lower MIC90 and mutant prevention concentrations for this fluoroquinolone against P. aeruginosa and higher Cmax/MIC and AUC/MIC ratios compared to other members of the class, including levofloxacin. For CAP infections in which S. pneumoniae is anticipated to be the most likely pathogen, moxifloxacin, which currently has the best antipneumococcal pharmacodynamic activity and the lowest mutant prevention concentrations against this organism, would represent the preferred fluoroquinolone. By contrast, levofloxacin’s MIC90 against S. pneumoniae is significantly higher than those of moxifloxacin and gatifloxacin. The AUC/MICs and Cmax/MICs also are lower for levofloxacin against S. pneumoniae, and serum concentrations of a standard dose of levofloxacin for CAP do not reach the mutant prevention concentrations for S. pneumoniae.(91)

For these reasons, the ASCAP Consensus Panel has concluded that levofloxacin may not be the best choice for infections caused by S. pneumoniae, and has designated it as an alternative agent for this indication. Instead, the panel recommends moxifloxacin as the initial fluoroquinolone of choice when a respiratory fluoroquinolone is deemed appropriate for CAP. Furthermore, recent reports of levofloxacin failures in cases of CAP caused by S. pneumoniae are a continuing cause of concern, and other resistance data demonstrating precipitous increases in levofloxacin resistance among S. pneumoniae species support the panel’s recommendations to avoid levofloxacin as the initial agent selected for empiric management of CAP.

Empiric Antibiotic Coverage for CAP: Matching Drugs with Patient Profiles

A variety of antibiotics are available for outpatient management of pneumonia. 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.(18) This classification scheme helps make clinical assessments useful for guiding therapy, but it also is predictive of ultimate prognosis and mortality outcome.

The most common pathogens responsible for causing CAP, again, include the typical bacteria: S. pneumoniae, H. influenzae, and M. catarrhalis, as well as the atypical pathogens: Mycoplasma, Legionella, and C. pneumoniae.(180) 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 stain may contain a predominant organism to aid in the choice of empiric therapy. For most patients, though, therapy must be entirely empiric and based on the expected pathogens.(19,181)

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 toward S. pneumoniae, H. influenzae, M. pneumoniae, C. pneumoniae, L. 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 provide similar coverage and carry an 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.

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) generally should 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.(182) 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, IV ceftriaxone plus azithromycin IV is recommended, depending on institutional protocols.

Finally, there is an increasing problem in the United States concerning the emergence of S. pneumoniae among hospitalized pneumonia patients that is relatively resistant to penicillin and, less commonly, to extended-spectrum cephalosporins. These isolates also may be resistant to sulfonamides and tetracyclines.(18,183,184) Except for vancomycin, the most favorable in vitro response rates to S. pneumoniae are seen with extended spectrum quinolones. See Table 2 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.(116) In this retrospective analysis, hospital records for 12,945 Medicare inpatients (age 65) 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. 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 long-term care facility.(116)

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 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 that were 77% and 21% higher than the reference group, respectively.

Role of Specific Pathogens in CAP. Prospective studies 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 S. 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), M. pneumoniae, C. pneumoniae, S. aureus, S. pyogenes, Neisseria meningitidis, M. catarrhalis, K. 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.

Other 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 2000. (See Table 3.)

Centers for Disease Control Drug-Resistant Streptococcus pneumoniae Therapeutic Working Group (CDC-DRSPWG) 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-DRSPWG convened and published its recommendations in May 2000.(3) 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 ATS guidelines. The specific differences contained in the CDC-DRSPWG primarily involve the sequence in which antibiotics should be chosen 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. (See Table 4.)

Oral macrolide (azithromycin, clarithromycin, or erythromycin) or beta-lactam monotherapy is recommended by the CDC working group as initial therapy in patients with pneumonia who are considered to be amenable to outpatient management. For inpatients not in an ICU (i.e., medical ward disposition), this group recommends for initial therapy the combination of a parenteral beta-lactam (ceftriaxone or cefotaxime) plus a macrolide (azithromycin, erythromycin, etc.).(3) 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 and may result in improved mortality if the patient has pneumococcal bacteremia) when a cephalosporin (which has poor activity against atypical pathogens) is selected as part of the initial combination regimen.(21)

For critically ill patients, first-line therapy should include an intravenous beta-lactam, such as ceftriaxone, and an intravenous macrolide, such as azithromycin. The option of using a combination of a parenteral beta-lactam (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.(3)

Clearly, fluoroquinolones are an important part of the antimicrobial arsenal in the elderly, and the CDC-DRSPWG has issued specific guidelines governing their use in the setting of outpatient and inpatient CAP. It recommends 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 > 4 mcg/mL).

Prevention of Deep Venous Thrombosis (DVT)

Background. Although antibiotic therapy, oxygenation, and maintenance of hemodynamic status are the primary triad of emergency interventions in patients with pneumonia, there has been an increasing recognition of the risk for DVT and PE in 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 DVT is significant enough to require prophylaxis in patients with CAP who have restricted mobility, most of whom may have such risk factors as obesity, previous history of DVT, cancer, varicose veins, hormone therapy, chronic heart failure (NYHA [New York Heart Association] Class III-IV), or chronic respiratory failure.(185)

From a practical perspective, this subset of patients should be strongly considered for prophylaxis to reduce the risk of DVT. Based on recent studies, the presence of pneumonia in a patient age 75 or older is, in itself, a criterion for prophylaxis against DVT; when these factors are accompanied by CHF (Class III-IV) or respiratory failure, prophylaxis should be considered mandatory if there are no significant contraindications.(185) It should be added that The American College of Chest Physicians (ACCP) guidelines(186) and International Consensus Statement(187) also cite risk factors for DVT and emphasize their importance when assessing prophylaxis requirements for medical patients.

Evidence for Prophylaxis. The data to support a prophylactic approach to DVT for serious infections are growing. The studies with bid 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.(188) In the United States, symptomatic PE occurs in more than 600,000 patients and causes or contributes to death in up to 150,000 patients annually.(189)

With respect to the risk of DVT in 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 DVT 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.(190)

The MEDENOX Trial. In response to the need for evidence to clarify the role of prophylaxis in specific non-surgical patient subgroups, the MEDENOX (prophylaxis in MEDical patients with ENOXaparin) trial was conducted using the low molecular weight heparin (LMWH) enoxaparin in a clearly identified risk group.(185) In contrast to previous investigations, the MEDENOX trial included a clearly defined patient population; the study was designed to answer questions about the need for prophylaxis in this group of medical patients and to determine the optimal dose of LMWH.(185)

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 days (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 DVT or any other clinical events. The primary and secondary efficacy end points for MEDENOX were chosen to allow an objective assessment of the risk of DVT in the study population and the 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.(185) The primary safety end points were hemorrhagic events, death, thrombocytopenia, or other adverse event or laboratory abnormalities.(185)

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 were 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 infection, 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 DVT 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 DVT.

The primary conclusions of the MEDENOX trial can be applied directly to clinical practice. First, acutely ill medical patients with cardiopulmonary or infectious disease are at significant risk of DVT. Second, enoxaparin, given once daily at a dose of 40 mg for 6-14 days reduces the risk of DVT 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 patients admitted to the hospital with pneumonia 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 DVT. The ASCAP 2003 Panel supports this recommendation.

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ALL INFORMATION, DATA, AND MATERIAL CONTAINED, PRESENTED, OR PROVIDED HERE IS FOR GENERAL INFORMATION PURPOSES ONLY AND IS NOT TO BE CONSTRUED AS REFLECTING THE KNOWLEDGE OR OPINIONS OF THE PUBLISHER, AND IS NOT TO BE CONSTRUED OR INTENDED AS PROVIDING MEDICAL OR LEGAL ADVICE.  THE DECISION WHETHER OR NOT TO VACCINATE IS AN IMPORTANT AND COMPLEX ISSUE AND SHOULD BE MADE BY YOU, AND YOU ALONE, IN CONSULTATION WITH YOUR HEALTH CARE PROVIDER.