Appropriate and Outcome-Effective Antibiotic Use in Acute Bacterial Exacerbations of Chronic Bronchitis (ABECB)
The SCMARTI (Selection of Cephalosporins, Macrolides, and AFQs for Respiratory Tract Infections) Clinical Consensus Panel Report®—Landmark Series in Antibiotic Management: Year 2003 Update: Part I
Authors: Gregory A. Volturo, MD, FACEP, Vice Chairman and Associate Professor, Department of Emergency Medicine, University of Massachusetts, Worcester; and Gideon Bosker, MD, Assistant Clinical Professor, Section of Emergency Services, Yale University School of Medicine, Associate Clinical Professor, Oregon Health Sciences University, Portland. —On behalf of the SCMARTI Clinical Consensus Panel
Peer Reviewers: Charles Emerman, MD, Chairman, Department of Emergency Medicine, MetroHealth Medical Center, Cleveland Clinic Foundation, Cleveland, OH; and J. Stephan Stapczynski, MD, Professor and former Chair, Department of Emergency Medicine, University of Kentucky College of Medicine, Lexington.
Cephalosporins, macrolides, and fluoroquinolones currently represent foundation antimicrobials for managing common respiratory infections caused by bacterial and/or atypical pathogens. Prudent, evidence-based utilization of these agents is of paramount importance not only to ensure optimal outcomes across a broad range of patient subtypes, but also to decrease the rate of drug resistance, which continues to grow at an alarming pace.
Many factors must be entered into the therapeutic equation for antibiotic use when managing patients with acute bacterial exacerbations of chronic bronchitis (ABECB). There is general agreement that selecting among available antibiotic classes and choosing specific agents within those classes is optimized when results of clinical trials, antimicrobial resistance data, surveillance networks, and epidemiological trends are factored into a complex management equation designed to cure patients today and protect the community from developing drug resistance in the future.
Matching "correct spectrum" antibiotics with bacterial pathogens is a multifactorial process. As a result, the therapeutic landscape for anti-infective management continues to shift as it undergoes intense analysis.
Despite new data pointing to possible limitations of some agents within certain classes, the cephalosporins, macrolides, and advanced-generation fluoroquinolones (AFQs) continue to be the most widely used and the most consistently recommended antimicrobials for managing patients with bacterial respiratory tract infections
(RTIs). Given the plethora of guidelines and consensus statements published in the medical literature and the formidable number of anti-infectives available in the therapeutic arsenal, it is not surprising that there is a diversity of opinion about specific antibiotic choices.
Clearly, there is no substitute for fair balance and for recommendations that encourage appropriate based medicine as a guide to ensure customized therapy for the individual, risk-stratified patient. This is a prudent approach that will help clinicians complete the journey from trial-generated information to the real world of clinical application. Although the clinical effectiveness and safety profiles for the aforementioned antimicrobials are well documented, there are other clinically relevant differences among specific antibiotics within each class that warrant more detailed consideration. For example, resistance-induction studies, minimal inhibitory concentration (MIC) data, and surveillance data have highlighted the potential advantages of moxifloxacin compared to other AFQs for initial treatment of ABECB patients in whom AFQs are deemed appropriate. Among the advanced-generation macrolides, short-duration (i.e., 3-day) courses of azithromycin for outpatient ABECB have introduced dosing regimens with the capacity to improve medication compliance. It also has been recognized that the ability to achieve excellent outcomes with potent, broad-spectrum agents must be balanced against the pitfalls of inducing drug resistance among nosocomial pathogens, especially if used excessively and inappropriately. In addition, it should be stressed that antibiotic therapy is not always necessary, and that most patients who have acute bronchitis that is not superimposed on a history of chronic obstructive pulmonary disease (COPD) do not benefit from antimicrobial therapy.
Identifying "correct spectrum" coverage for common bacterial infections involving the respiratory tract is essential, especially for the fluoroquinolones. While this class is effective against many bacterial RTIs, some agents may have a propensity for inducing resistance at a disproportionately accelerated rate compared to other agents. Evaluating the effects on clinical outcomes of increasing in vitro resistance among respiratory pathogens (especially S. pneumoniae) to advanced-generation macrolides and determining the role that such resistance trends should play on inpatient and outpatient management (i.e., antibiotic selection) of ABECB are among the issues that require consideration.
The landscape shift in drug resistance and antibiotic selection has spawned the concept of "curing patients today, while protecting the community tomorrow." This means identifying pharmacotherapeutic strategies that not only optimize short-term outcomes for RTIs—in which curing patients is the preeminent goal—but also achieve this end point while reducing the likelihood of developing drug resistance. The mandate to cure patients acutely and preserve long-term antimicrobial efficacy represents one of the most important challenges primary care physicians face when developing protocols and pathways for outpatient management of ABECB.
Because the aforementioned issues are of great interest to a wide range of practitioners and investigators, it is important that clinical scholars and experts continue to evaluate the most recent data to generate clear, concise, and evidence-based recommendations for this therapeutic arena. To achieve this goal, the SCMARTI (Selection of Cephalosporins, Macrolides, and AFQs for Respiratory Tract Infections) Clinical Consensus Panel and Scientific Roundtable* was convened for the purpose of publishing an evidence-based document outlining antibiotic selection strategies, treatment guidelines, and other recommendations that would provide expert guidance for use of cephalosporins, macrolides, and AFQs for patients with ABECB.
Specifically, the SCMARTI Clinical Consensus Panel reviewed epidemiological trends, national association guidelines, clinical trials, and resistance databases to help establish evidence-based approaches for managing RTIs commonly encountered in the outpatient/emergency department setting. Finally, in addition to critical pathways and treatment tables, this report also incorporates risk-stratification tools that can be used to identify patients with ABECB who require more intensive, broad-spectrum therapy and that will help distinguish those patient subgroups more appropriately managed in the outpatient setting from those that should be admitted to the hospital for more intensive care.The Editor
Acute Bacterial Exacerbations of Chronic Bronchitis (ABECB): Introduction
During the past 10 years, clinicians and investigators have developed a more complete understanding of the pathogenesis and consequences of acute bacterial exacerbations of COPD (ABE/COPD). Several studies during that period support bacterial precipitation in about one-half of all exacerbations. Contrary to previous data, recent studies with improved techniques have demonstrated that exacerbations probably contribute to the loss of lung function in COPD. In addition, it appears that colonization by bacterial pathogens may not be innocuous, and in fact may lead to airway inflammation and contribute to the pathogenesis of COPD.
Evidence that bacteria cause exacerbations that lead to loss of lung function and that chronic bacterial colonization may be harmful has underscored the importance of appropriate antibiotic use and selection in patients with ABECB. Unfortunately, unlike the case of community-acquired pneumonia (CAP), there is a paucity of data from large, well-controlled prospective trials that provide definitive guidance regarding choice of antibiotic therapy for exacerbations of COPD. What is clear, however, is that outcome-effective antibiotic selection for ABECB means taking into account local antibiotic resistance patterns, epidemiological and infection incidence data, and patient demographic features. Then, against the background of clinical judgment, it also means determining the most appropriate agent for an individual patient. Finally, emerging data that antibiotics differ in unconventional measures of efficacy such as time to next exacerbation, improvement in health-related quality of life, and bacteriologic eradication, are additional factors that will help formulate concrete recommendations in the future.
While bacteriologic eradication, objective improvement of pulmonary function, and amelioration of symptoms are accepted end points guiding antibiotic therapy in ABECB, other factors also may play a role. In this regard, new recommendations regarding antibiotic therapy have been prompted by recent introduction of short-duration regimens that may promote greater patient compliance and acceptability. Such short-duration options include a five-day course of moxifloxacin (400 mg PO qd) and an even shorter three-day course of azithromycin (500 mg PO once-daily x 3 days) to treat acute exacerbations of COPD precipitated by S. pneumoniae, H. influenzae, and M. catarrhalis.
In addition, because appropriate disposition of patients with ABECB has become essential for cost-effective patient management, the SCMARTI Clinical Consensus Panel recommends the use of critical pathways and treatment tables that incorporate risk stratification protocols and intensification-of-treatment trigger (IOTT) criteria that can be used to identify those patient subgroups that are suitably managed in the outpatient setting from those more appropriately admitted to the hospital for more intensive care. Identifying treatment trigger points, risk factors, and historical features that support amplifying spectrum of coverage from a "correct spectrum" macrolide to an extended spectrum fluoroquinolone are essential for outcome-effective antibiotic use.
Historically, cephalosporins, macrolides, and AFQs have been used as initial agents of choice. Patients with advanced disease and multiple risk factors may have exacerbations caused by Klebsiella species, Pseudomonas aeruginosa, and other gram-negative species. As will be discussed below, these patients may require intensification of therapy with agents—in particular, AFQs such as levofloxacin or gatifloxacin—that are active against gram-negative organisms. Development of advanced-generation macrolides (e.g., azithromycin and clarithromycin), as well as extended spectrum quinolones such as moxifloxacin have made it possible to treat most patients using monotherapy.
Etiology and Risk Stratification. The severity of ABE/COPD is common, costly, and, above all, complex to manage. In fact, few conditions produce such a broad range of outcomes, require such customized approaches, or present so many options for treatment.1,2 Although there have been important advances in patient assessment techniques and therapeutics, including pulmonary function testing, capnometry, pulse oximetry, disposition support tools, and antimicrobial therapy, ABECB continues to be a leading cause of morbidity and mortality in the United States.1 From patient disposition to antimicrobial selection, optimizing antimicrobial management of these patients requires the clinician to integrate a number of clinical, laboratory, radiologic, and etiologic factors, and then initiate a course of action that accounts for all the risks, costs, and benefits of an individualized treatment plan.
Despite a number of guidelines and the availability of new, targeted-spectrum antibiotics, the management of ABECB in the outpatient setting remains extremely challenging. More than ever, it requires a multifactorial analysis of myriad clinical, historical, and laboratory parameters that predict success or possible failure for each individual case. In this regard, clinical decision- making in ABECB can be problematic for the emergency medicine specialist and primary care physician.
Achieving optimal patient outcomes for this common and debilitating condition requires the physician to consider several features of each individual case. (See Table 1.) Factors that must be considered include the patient’s age, response to medical therapy, overall pulmonary function, character and severity of previous exacerbations, bacterial colonization status of the patient, previous requirements for mechanical ventilation, previous therapy, exacerbation-free interval, steroid use, and local antimicrobial resistance patterns. With this in mind, a severity-of-exacerbation and risk factor (SERF) pathway can be employed to help guide patient disposition, empiric antibiotic selection, and whether additional diagnostic investigation is necessary. (See Table 2.)
Currently, the bacterial pathogens most often responsible for causing "uncomplicated and typical" cases of ABECB amenable to treatment in the outpatient setting include S. pneumoniae, H. influenzae, and M. catarrhalis. Because it may be difficult, if not impossible, to identify a specific pathogen at the time of initial patient assessment, empiric antimicrobial coverage against all the expected (aforementioned) pathogens usually is necessary to minimize treatment failures.
Although the role of bacterial infection as the precipitating process in exacerbations of COPD has been controversial, a recent study has clarified the role of bacterial pathogens in ABE/COPD.3 In older studies, the rates of isolation of bacterial pathogens from sputum were the same during acute exacerbations and during stable disease. However, these studies failed to differentiate among strains within a bacterial species; therefore, they could not detect changes in strains over time. More recent investigations have attempted to document that acquisition of a new strain of a pathogenic bacterial species is associated with exacerbation of COPD.
To clarify the role of bacterial pathogens, investigators conducted a prospective study in which clinical information and sputum samples for culture were collected monthly and during exacerbations from 81 outpatients with COPD.3 Molecular typing of sputum isolates of nonencapsulated H. influenzae, M. catarrhalis, S. pneumoniae, and P. aeruginosa was performed.
Over a period of 56 months, the 81 patients made a total of 1975 clinic visits, 374 of which were made during exacerbations (mean, 2.1 per patient per year). On the basis of molecular typing, an exacerbation was diagnosed at 33% of the clinic visits that involved isolation of a new strain of a bacterial pathogen, as compared with 15.4% of visits at which no new strain was isolated (p < 0.001; RR of an exacerbation, 2.15; 95% confidence interval, 1.83-2.53). Isolation of a new strain of H. influenzae, M. catarrhalis, or S. pneumoniae was associated with a significantly increased risk of an exacerbation.
Investigators concluded that the association between an exacerbation and the isolation of a new strain of a bacterial pathogen supports the causative role of bacteria in exacerbations of COPD.3
Acute Bacterial Exacerbations of Chronic Bronchitis (ABECB): Antibiotic Selection Strategies
Although it is possible to make evidence-based recommendations for management of patients with ABECB, the SCMARTI Clinical Consensus Panel noted that the number, quality, and design of studies evaluating and comparing effectiveness of and indications for antibiotic therapy in ABECB are less than optimal and, in general, inferior to those available for CAP. In addition, upon review of multiple studies comparing advanced-generation macrolides (i.e., azithromycin or clarithromycin) and AFQs (i.e., moxifloxacin, levofloxacin, and gatifloxacin), it is difficult to identify significant differences in clinical outcomes that could be observed in outpatients managed with these antibiotic regimens.4-9
More important, perhaps, than specific antibiotic choices, is the tendency to overuse antibiotics in patients with acute, self-limited bronchitis. Only patients meeting clinical criteria for bacterial exacerbations of COPD should receive antibiotic therapy for their exacerbations. The SCMARTI Clinical Consensus Panel’s recommendations for antibiotic-based, outpatient management of ABECB are summarized in the following sections. These guidelines are based on supportive evidence, analysis of clinical trials, and emerging resistance trends.
Appropriate Use of Antibiotics. As a rule, the clinical criteria for initiating antibiotic therapy in a patient with a documented history of COPD, and who is suspected of having an acute bacterial exacerbation, include the presence of at least two of the following three symptoms: increasing purulence of sputum, increasing volume of sputum production, and increasing cough and/or dyspnea. In contrast, patients with symptoms of acute tracheobronchitis who have no history of COPD initially should not be treated with antibiotics, since antibiotics have not been shown to improve outcomes in this patient population.
However, it was recognized by the SCMARTI Clinical Consensus Panel that in real world practice a significant percentage of patients fall into a clinical gray zone. In particular, those outpatients with persistent (i.e., > 10-14 days) symptoms of acute tracheobronchitis who have no history of COPD may be considered appropriate candidates for antibiotic therapy, especially if clinical assessment suggests that persistent symptoms may be due to infection with such atypical organisms as C. pneumoniae or M. pneumoniae. Pertussis also should be considered as an etiologic agent in this subgroup.
Appropriate use of antibiotics in ABECB requires clinical confirmation of the diagnosis, which usually is made on the basis of symptom exacerbation and clinical history. As a rule, chest x-ray is not recommended or encouraged for typical cases of ABECB, but should be considered in patients who present with an atypical presentation and in whom CAP is suspected.4
Appropriate antibiotic use and selection is designed to accomplish the following: 1) return patient’s respiratory status (FEV1, oxygenation, respiratory rate, symptoms, etc.) back to baseline; 2) reduce the number and frequency of exacerbations; and 3) prevent hospitalization.
The principal respiratory tract pathogens that must be covered on an empiric basis in individuals with moderate-to-severe ABE/COPD in the outpatient setting include S. pneumoniae, H. influenzae, M. catarrhalis, H. parainfluenzae, and S. aureus. Some patients, especially those with severe disease, a recent history of mechanical ventilation and hospitalization, and/or highdose chronic steroid therapy, are more susceptible to infection with Pseudomonas species.
Antimicrobial Selection Strategies
The majority of double-blinded, prospective clinical trials comparing new-generation macrolides (i.e., azithromycin and clarithromycin) to new-generation fluoroquinolones (i.e., moxifloxacin, gatifloxacin, and levofloxacin) demonstrate comparable outcomes in terms of clinical cure and bacteriologic eradication rates at days 7, 14, and 28 in outpatients with either moderate or severe ABECB.5-7,10-13 Moreover, increasing resistance among S. pneumoniae to new generation fluoroquinolones, especially levofloxacin, has been reported in a number of geographic regions, including the United States, Hong Kong, and Canada.14-16
The precise clinical effects of these evolving resistance patterns is not completely understood. However, given the emergence of such strains and the presence of numerous studies demonstrating comparable effectiveness between macrolides and AFQs, the SCMARTI Clinical Consensus Panel supports cautious and prudent use of fluoroquinolones, especially those agents with extended spectrum coverage, such as levofloxacin, for appropriately selected patients with ABECB.
For reasons related to short-course therapy, tolerability, and clinical outcomes, the SCMARTI Panel recommends the advanced-generation macrolide azithromycin as the initial agent of choice for managing appropriately risk-stratified outpatients with ABECB. Among the AFQs, moxifloxacin is recommended as the initial agent of choice, except in patients in whom bacterial exacerbations of COPD are likely to be caused by gram-negative organisms such as Pseudomonas species. In this case, fluoroquinolones (i.e., levofloxacin or gatifloxacin) with activity against this pathogen should be considered as initial therapy.
The frequency of drug-resistant S. pneumoniae (DRSP) causing ABECB is not known, but is presumed to be less than or equal to the incidence of DRSP causing outpatient CAP. As a result, there is currently no evidence to support initial outpatient therapy directed at DRSP for patients with ABE/COPD. As it does in the management of CAP, the SCMARTI Clinical Consensus Panel cautions against overuse of AFQs as initial agents in outpatients with ABECB, except in cases where coverage against Pseudomonas and other gram-negative organisms is warranted. The panel recommends use of AFQs 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) patients have documented or suspected infection with gram-negative organisms resistant to macrolides.
Given concerns about antibiotic overuse, the potential for emerging resistance among DRSP to fluoroquinolones, the SCMARTI Clinical Consensus Panel concurs with other guideline panels specifying advanced-generation macrolides and fluoroquinolones as initial therapy for outpatient ABECB. Fluoroquinolones are recommended in patients who fail therapy or who have risk factors predictive of gram-negative infection. Patients who do not respond to oral therapy with one class of antibiotics (relapse) may be treated with a course of antibiotics with different gaps in coverage. Reinfections should be treated with antibiotics that have been shown to be effective in previous exacerbations. Cost factors also should be considered. Agents such as TMP/SMX, tetracycline, and amoxicillin are less costly than non-generic antibiotics, and when acquisition of drug therapy is compromised by cost factors, such second-line agents are preferable.
Unfortunately, limited data exist to guide physicians in the cost-effective treatment of ABECB. One important study, however, attempted to determine the antimicrobial efficacy of various agents and compared total outcome costs for patients with ABECB.18 For the purpose of this analysis, a retrospective review was performed of 60 outpatient medical records of individuals with a diagnosis of COPD associated with acute episodes seen in the pulmonary clinic of a teaching institution. Empirical antibiotic choices were divided into first-line (amoxicillin, co-trimoxazole, tetracyclines, and erythromycin); second-line (cephradine, cefuroxime, cefaclor, and cefprozil); and third-line (azithromycin, amoxicillin-clavulanate, and ciprofloxacin) agents. In this study, patients receiving first-line agents (amoxicillin, co-trimoxazole, tetracyclines, and erythromycin) failed significantly more frequently (19% vs 7%; p < 0.05) than those treated with third-line agents (azithromycin, amoxicillin-clavulanate, and ciprofloxacin). Moreover, patients prescribed first-line agents were hospitalized significantly more often for ABE/COPD within two weeks of outpatient treatment as compared with patients prescribed third-line agents (18.0% vs 5.3% for third-line agents; p < 0.02). Time between subsequent ABE/COPD episodes requiring treatment was significantly longer for patients receiving third-line agents compared with first-line and second-line agents (p < 0.005).18
Two advanced-generation macrolides (azithromycin and clarithromycin) are available for treating ABECB. Based on outcome-sensitive criteria and pharmatectural considerations such as cost, daily dose frequency, duration of therapy, side effects, and drug interactions, the SCMARTI Clinical Consensus Panel recommends azithromycin as preferred initial therapy in moderate-to-severe, non-hospitalized patients, with clarithromycin or doxycycline as an alternative agent; among AFQs, moxifloxacin is preferred for initial therapy, with gatifloxacin or levofloxacin as alternative agents. Amoxicillin-clavulanate is another effective option. When historical or clinical factors in the SERF (Severity of Exacerbation and Risk Factor) pathway suggest the presence of gram-negative infection, an expanded spectrum fluoroquinolone would be considered the agent of choice. Physicians are urged to prescribe antibiotics in ABECB at the time of diagnosis and to encourage patients to fill and begin taking their prescriptions on the day of diagnosis.
Primary care physicians are discouraged from using antibiotics for "chronic prophylaxis" against ABE/COPD, since studies do not support the efficacy of this strategy for preventing acute exacerbations. Patients should be instructed about issues related to the importance of medication compliance. In the case of short (3-day) courses of therapy, they should be educated that although they are only consuming medications for a three-day period, such antibiotics as azithromycin remain at the tissue site of infection for about nine days and continue 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, significantly impaired FEV1, and those in whom medication compliance may be compromised.19 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 ABE/COPD, except in certain high-risk groups.
* The SCMARTI Clinical Consensus Panel & Scientific Roundtable was supported by an unrestricted educational grant from Pfizer Pharmaceuticals.
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SCMARTI Panel Chairman: Gregory A. Volturo, MD, FACEP, Vice Chairman and Associate Professor, Department of Emergency Medicine, University of Massachusetts, Worcester, Massachusetts. Distinguished SCMARTI Panel Members: Dave Howes, MD, FACEP, Program Director and Chairman, Residency Program, Department of Emergency Medicine, University of Chicago Hospitals and Clinics, Associate Professor, Pritzker School of Medicine, Chicago, Illinois; David Lang, DO, FACEP, Operation Medical Director, Department of Emergency Medicine, Mt. Sinai Medical Center, Miami, Florida; Sandra Schneider, MD, FACEP, Professor and Chairman, Department of Emergency Medicine, University of Rochester/Strong Memorial Hospital, Rochester, New York; Ethel Smith, MD, Director, Quality Resource Unit, Case Western Reserve University, Department of Family Practice, MetroHealth Medical Center, Cleveland, Ohio; Paul Stander, MD, FACP, Medical Director, Department of Medicine, Banner Healthcare Systems, Author, Quick Consult Manual for Primary Care Medicine, Department of Internal Medicine, Arizona Health Science University; Gideon Bosker, MD, Section of Emergency Medicine, Yale University School of Medicine and Oregon Health Sciences University, Editor-in-Chief, Emergency Medicine Reports, Editor-in-Chief, Clinical Consensus Reports.
Statement of Financial Disclosure: In order to reveal any potential bias in this publication, and in accordance with the Accreditation Council for Continuing Medical Education guidelines, we disclose that Dr. Howes is on the speaker’s bureau for Roche; Dr. Stander owns stock in Pfizer; Dr. Schneider and Dr. Smith have no financial interests related to the field of study covered by this article; for Dr. Volturo and Dr. Bosker, see the disclosure statement on page 294; Dr. Lang did not return his disclosure form.