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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
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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. Empirica