INTRODUCTION

Acute bronchitis, acute exacerbations of chronic bronchitis (AECB), and community-acquired pneumonia (CAP) are some of the most commonly encountered lower respiratory tract infections in clinical practice. During the past two decades, a great deal of attention has focused on the increasing rates of antibiotic resistance and the changing patterns of antimicrobial prescribing of outpatient infections.^1-3 Recent guidelines have been published to provide a more evidence-based approach to antibiotic treatment of lower respiratory tract infections.

This monograph will focus on the appropriate role of antibiotics in the treatment of acute bronchitis, AECB, and CAP.

ACUTE BRONCHITIS

Acute bronchitis is a respiratory tract infection in which cough, of less than two to three weeks of duration, is the main presenting feature in otherwise healthy patients.^4-6 This acute cough illness is a clinical diagnosis. Other common causes as well potentially serious causes, such as asthma and pneumonia, should be excluded.

The leading causes of uncomplicated acute bronchitis in healthy adults are lower and upper respiratory viruses such as influenza A and B, parainfluenza, respiratory syncytial virus, rhinoviruses, adenoviruses, and coronavirus.^4-6 Nonviral causes (such as Bordetella pertussis, Mycoplasma pneumoniae, and Chlamydophila [formerly Chlamydia] pneumoniae) are responsible for 5% to 10% of cases of uncomplicated acute bronchitis.⁵

Routine use of antibiotics for the treatment of uncomplicated acute bronchitis is not recommended.^4-6 Several meta-analyses and published reviews of randomized, placebo-controlled trials have concluded that antibiotic therapy has no significant impact on the relief of symptoms, duration of cough, or the ability of the patient to return to work or normal activities.^7-9 In support of these findings, the FDA no longer considers uncomplicated acute bronchitis or secondary bacterial infections of acute bronchitis as a potential indication for antibiotic therapy.^4,5

Patients should be counseled about the symptoms and lack of benefit from antibiotic treatment for uncomplicated acute bronchitis.⁴ Patients need to be informed their cough can typically last up to 10 to 14 days after a visit to the physician office. Patients need to be reaffirmed that antibiotics are not recommended for their illness, and that these agents have the risk of side effects or serious adverse reactions. In addition, it may be helpful to refer to their illness as a "chest cold" instead of bronchitis in order to discourage the perception that antibiotic therapy is needed.¹⁰ Finally, educate patients regarding the need to prevent antibiotic resistance by not using antibiotics for illnesses that are mainly caused by viruses.

ACUTE BACTERIAL EXACERBATIONS OF CHRONIC BRONCHITIS

Definitions

Chronic bronchitis is described as an inflammation of the bronchial mucous membranes in the lungs that has persisted for a long period of time or occurs repeatedly. Chronic bronchitis is characterized by a cough with sputum production for most days of at least three months a year for two consecutive years.^11,12 This definition assumes that other causes of cough and sputum have been excluded.

The term chronic obstructive pulmonary disease (COPD) is often used to describe a range of respiratory conditions involving airflow limitations in patients with chronic bronchitis and/or emphysema.^11,13 This disease state is often characterized by irreversible or partially reversible airway obstruction. Chronic bronchitis occurs in approximately 85% of patients with COPD. While COPD is a chronic obstructive bronchitis, it is important to note that chronic bronchitis often occurs without airway obstruction. Bronchodilators, corticosteroids, mucolytics, expectorants, oxygen supplementation, and mechanical ventilation are used along with antibiotics to treat acute exacerbations in COPD.^11,12,14,15

AECB is a clinical diagnosis. The definitions and criteria for "acute exacerbations" of chronic bronchitis are varied throughout the literature. Most definitions have included some combination of the following three clinical findings: increased sputum volume, increased sputum purulence, and increased dyspnea.^12,16 Changes associated with these cardinal symptoms may be acute in onset, demonstrate greater than normal day-to-day variations, and indicate a sustained worsening of the patient's condition.¹⁷ While no standardized system for staging the severity of AECB has been developed, one of the more commonly used approaches involves criteria developed by Anthonisen and colleagues¹⁸: type I (severe exacerbations) has all three clinical findings included; type II (moderate exacerbations) has two or three clinical findings; and type III (mild exacerbations) has at least one of the cardinal symptoms and at least one of the following: an upper respiratory tract infection in the previous five days, increased wheezing, fever without an obvious cause, increased cough, and an increase in respiratory rate or heart rate by 20% above baseline. Based on these criteria, the typical patient with COPD averages two to three episodes of AECB per year.¹²

Causes of AECB

Approximately 80% of cases of AECB are caused by tracheobronchial infections.¹⁹ Tobacco smoke and environmental exposures (eg. dust, allergens, and pollutants) are also important causes of AECB. Although the precise role of bacterial infection in AECB is debated, recent studies support the concepts that bacteria do cause exacerbations. AECB is often more common in patients who have acquired a new strain of pathogens that persistently colonize the airway.²⁰ In addition, recurrent exacerbations with Haemophilus influenzae have been associated with the production of strain-specific antibodies that leave patients with COPD at an increased risk for reinfection by other strains of H influenzae.²¹

Nearly half of all cases of AECB are caused by bacterial infections.^22,23 The most common bacterial pathogens isolated from sputum include nontypeable H influenzae (13% to 50%), Streptococcus pneumoniae (7% to 26%), and Moraxella catarrhalis (4% to 21%). These three pathogens predominate particularly in patients with well-preserved lung function. Other potential pathogens less frequently reported include Haemophilus parainfluenzae (2% to 32%), Staphylococcus aureus (1% to 20%), Pseudomonas aeruginosa (1% to 13%), and various gram-negative pathogens from the Enterobacteriaceae family (3% to 19%). The prevalence of gram-negative infections, including those caused by P aeruginosa, tends to increase in patients with declining lung function.

Approximately 33% to 56% of cases of AECB are caused by viral pathogens.²³ Rhinoviral infections have become the predominant cause since the introduction of influenza vaccine. However, several other viruses have been associated with AECB including influenza, parainfluenzae, respiratory syncytial virus, and adenovirus.

The role of atypical bacteria in AECB has been confusing, since most studies did not use strict criteria for laboratory testing and/or exclusion of pneumonia. The more recent data suggest that 5% to 10% of exacerbations are associated with C pneumoniae.²³ Rarely are M pneumoniae and Legionella species reported as causes of AECB.²³

Risk Factors

Numerous studies have identified risk factors related to poor clinical outcomes, early relapses, and increased risk for subsequent hospitalization in patients with chronic bronchitis.^14,23,24 Host factors that have been associated with a high risk of treatment failure include severe impairment of lung function, increased frequency of exacerbations per year, coexisting cardiopulmonary diseases (eg, ischemic heart disease, cor pulmonale, and congestive heart failure), increasing age (>65 years), use of home oxygen, chronic use of maintenance corticosteroids, a history of previous pneumonia, and the presence of chronic mucous hypersecretion. Patients with more than one of these factors are often more likely to fail therapy and to be at an increased risk of mortality.

Treatment failures can be costly and often lead to subsequent hospitalizations in patients with recurrent exacerbations.^14,24 Factors predictive of hospitalization include cardiopulmonary diseases, carbon dioxide retention (PaCO₂ >44 mm Hg), pulmonary hypertension (mean pulmonary artery pressure at rest >18 mm Hg), duration and/or severity of COPD, chronic mucous hypersecretion, the severity of lung impairment [as indicated by forced expiratory volume in one second (FEV₁)], and under-prescribing of long-term oxygen therapy. In several studies, the likelihood of hospitalization increased by several fold when the coexistence of multiple risk factors occurred in patients with chronic bronchitis.

Risk Stratification and Treatment Guidelines

Several classification schemes have been proposed based on risk factors and treatment outcomes of patients with chronic bronchitis.²⁴ The Chronic Bronchitis Working Group of the Canadian Thoracic Society and the Canadian Infectious Disease Society have updated their consensus guidelines (Table 1).^12,14 This simplified classification system places patients into one of four groups (0 through 3) based on clinical symptoms, risk factors, and probable pathogens. The algorithm in Figure 1 (Click here to view Figure 1) outlines the evaluation and treatment of patients presenting with signs and symptoms of AECB.^12,23

Table 1. Canadian Consensus Guidelines for the Treatment of AECB12,14 Group Clinical State Symptoms and Risk Factors Probable Pathogens Initial Antibiotic Therapy 0 Acute tracheobronchitis Cough and sputum without previous pulmonary disease Usually viral None unless symptoms persist for greater than 10 to 14 days 1 Chronic bronchitis without risk factors (simple or uncomplicated chronic bronchitis) Increased cough and sputum, sputum purulence, and increased dyspnea H influenzae, Haemophilus sp, M catarrhalis, S pneumoniae Extended-spectrum macrolides (eg, clarithromycin, azithromycin) Second- and third-generation cephalosporins (eg, cefuroxime, cefprozil, cefpodoxime, cefdinir) Amoxicillin Doxycycline Trimethoprim-sulfamethoxazole 2 Chronic bronchitis with risk factors (complicated chronic bronchitis) Symptoms as in group 1 plus at least one of the following risk factors: FEV1 <50% predicted value >4 exacerbations/year cardiac disease use of home oxygen chronic oral steroid use antibiotic use in the previous 3 months Probable pathogens listed in group 1 plus: Klebsiella sp. Other gram-negatives Increased probability of ß -lactam resistance Antipneumococcal fluoroquinolone (eg, levofloxacin, gatifloxacin, gemifloxacin, moxifloxacin) ß-lactam/ ß-lactamase inhibitor (eg, amoxicillin-clavulanate) 3 Chronic suppurative bronchitis Symptoms and risk factors as in group 2 with constant purulent sputum Some have bronchiectasis, FEV1 usually <35% predicted value, or multiple risk factors (eg, frequent exacerbations and FEV1 <50% of predicted value) Probable pathogens listed in group 2 plus: P aeruginosa Multidrug-resistant Enterobacteriaceae Ambulatory patients: Tailor treatment to airway pathogen P aeruginosa common (consider using an antipseudomonal fluoroquinolone [eg, high-dose ciprofloxacin or levofloxacin]) Hospitalized patients: Parenteral therapy usually required

Patients in group 0 have no underlying lung disease and represent tracheobronchitis. The illness is usually self-limited and runs a benign course since the symptoms are usually caused by viruses. As such, antibiotics would not be recommended to treat group 0 patients. If symptoms persist for greater than 10 to 14 days, atypical pathogens (eg, M pneumoniae, C pneumoniae, or B pertussis) should be suspected as causative agents and an extended-spectrum macrolide (eg, clarithromycin or azithromycin) or doxycycline would be recommended.

Group 1 patients have simple or uncomplicated chronic bronchitis without risk factors. As per definition, these patients usually have a worsening cough and increased production of purulent sputum during an exacerbation of their illness. Patients in this group tend to be younger (<60 years of age), have a FEV₁ >50% of predicted value (mild to moderate impairment of lung function), experience less than four exacerbations per year, and have no significant heart disease. The probable pathogens include H influenzae, S pneumoniae, and M catarrhalis. The preferred treatment regimens include extended-spectrum macrolides (eg, clarithromycin or azithromycin) or second- and third-generation oral cephalosporins (eg, cefuroxime, cefprozil, cefpodoxime, and cefdinir). Many clinicians still consider amoxicillin, doxycycline, and trimethoprim-sulfamethoxazole (TMP-SMX) as the classical choices. However, the use of these older antibiotics is limited by the high incidence of ß-lactamase-producing strains of H influenzae and M catarrhalis as well as the increased rate of drug-resistant S pneumoniae. Other new treatment options include the ketolide telithromycin, which is active against S pneumoniae (including drug-resistant strains) as well as H influenzae and M catarrhalis.^23,25

Patients in group 2 have complicated chronic bronchitis with risk factors that may lead to treatment failure. These patients tend to be older, have greater than four exacerbations per year, and have either severe impairment of lung function (FEV₁ <50% of predicted value) or moderate impairment of lung function (FEV₁ between 50% to 65% of predicted value) plus a significant comorbidity (eg, cardiac disease). The most likely pathogens include H influenzae, S pneumoniae, and M catarrhalis. In addition, enteric gram-negative organisms should be expected in patients with declining lung function. The recommended oral therapy includes amoxicillin-clavulanate or respiratory fluoroquinolones (eg, levofloxacin, gatifloxacin, gemifloxacin, or moxifloxacin), since treatment should be directed at resistant strains of these organisms. Fluoroquinolones may be the preferred agents in this group of patients because of enhanced rates of bacterial eradication, faster resolutions of symptoms, and more prolonged exacerbation-free intervals.²⁴

Group 3 patients have chronic suppurative bronchitis with multiple risk factors and severe impairment of lung function (FEV₁ <35% of predicted value). These patients have constant production of purulent sputum, frequent exacerbations, and increasing symptoms of chronic bronchitis. Some patients will have evidence of bronchiectasis. The usual respiratory pathogens in group 1 and 2 patients must be considered. In addition, multidrug-resistant strains of Enterobacteriaceae and P aeruginosa are possible pathogens, especially in patients who have been chronically treated with corticosteroids.

Fluoroquinolones such as ciprofloxacin are the preferred agents in these patients. Many of these patients are severely ill and require hospitalization, including admission to the intensive care unit (ICU). Appropriately obtained sputum cultures and in vitro susceptibility testing are recommended so that antimicrobial therapy is individualized for these difficult-to-treat and/or resistant pathogens.²³

This type of classification system attempts to identify patients at increased risk of failure so that appropriate empiric antimicrobial therapy may be initiated against the most likely pathogens. Although these recommendations are rational, further studies are needed to evaluate and confirm the role of these strategies in the management of AECB.^14,23,24

Duration of Therapy

The FDA-approved dosage regimens for oral antibiotics used in the treatment of AECB and CAP are illustrated in Table 2. Many of the consensus statements for the treatment of chronic bronchitis have recommended 7- to 14-day duration of therapy. Several recent studies have demonstrated that a five-day short-course therapy is equally effective as the traditional duration in outpatients with AECB.^26-28 This change in duration is reflected in a number of the recently approved indications listed in Table 2.

Table 2. FDA-Approved Dosage Regimens for the Treatment of AECB and CAP Antibiotic Class and Oral Agents Dosage Regimen for AECB Dosage Regimen for CAP ß-lactam plus ß-lactamase inhibitor   Amoxicillin-clavulanate 500 mg q8h or 875 mg q12h x 7-10 days  500 mg q8h or 875 mg q12h x 7-10 days   Amoxicillin-clavulanate   XR Not an FDA-approved indication 2000 mg q12h x 7-10 days Cephalosporins          Cefuroxime axetil 250 mg - 500 mg bid x 10 days  Not an FDA-approved indication       Cefpodoxime proxetil 200 mg q12h x 10 days 200 mg q12h x 14 days      Cefprozil 500 mg q12h x 10 days Not an FDA-approved indication      Cefdinir 300 mg q12h x 5-10 days or 600 mg once-daily x 10 days 300 mg q12h x 10 days Macrolides          Clarithromycin      Immediate-Release 250 mg ­ 500 mg q12h x 7-14 days  250 mg - 500 mg q12h x 7-14 days       Clarithromycin      Extended-Release      1000 mg once-daily x 7 days 1000 mg once-daily x 7 days      Azithromycin 500 mg once-daily x 3 days or 500 mg x 1 dose, then 250 mg once-daily on days 2-5 500 mg x 1 dose, then 250 mg once-daily on days 2-5 Ketolide      Telithromycin 800 mg once-daily x 5 days 800 mg once-daily x 7-10 days Fluoroquinolones          Levofloxacin 500 mg once-daily x 7days 500 mg once-daily x 7-14 days     or 750 mg once-daily x 5 days      Gatifloxacin 400 mg once-daily x 5 days 400 mg once-daily x 7-14 days      Moxifloxacin 400 mg once-daily x 5 days 400 mg once-daily x 7-14 days      Gemifloxacin 320 mg once-daily x 5 days 320 mg once-daily x 7 days

Prevention of AECB

Smoking cessation should be considered in all patients with chronic bronchitis.^14,24 The cessation of smoking has been shown to decrease the rate of decline in FEV₁ and produce dramatic symptomatic improvements in patients with chronic cough and sputum production. All patients with chronic bronchitis are strongly recommended to have an annual influenza vaccination.^14,24 The benefits of pneumococcal vaccination in patients with chronic bronchitis are not well established. However, it is generally recommended for all patients with COPD at least once in their lives, and the vaccine may need to be repeated every 5 to 10 years in high-risk patients.^14,24 Other measures such as the use of antibiotic prophylaxis in group 3 patients with frequent exacerbations should be determined on an individual basis.¹⁴

COMMUNITY-ACQUIRED PNEUMONIA

Community-acquired pneumonia (CAP) is one of the most frequent infections treated by a variety of medical specialties.^29-31 During the last few decades, numerous clinical trials have investigated its epidemiology and etiology, its impact on antibacterial drug resistance, its severity, tests to diagnose it, and its clinical outcomes as a result of antimicrobial therapy.^,29-38 Consensus guidelines for the management of CAP have been developed by several professional societies within and outside of the US.³² The most recent published guidelines from the Infectious Diseases Society of America (IDSA) and the American Thoracic Society (ATS) provide a concise review for the management of CAP.^33,34 Revised guidelines are currently being prepared as a single document from both the IDSA and ATS.³⁵

Definition

The definition of CAP varies depending on the criteria being used. The definition outlined by the IDSA in their 2000 consensus document was "an acute infection of the pulmonary parenchyma that is associated with at least some symptoms of acute infection, accompanied by the presence of an acute infiltrate on a chest radiograph or auscultatory findings consistent with pneumonia (such as altered breath sounds and/or localized rales), in a patient not hospitalized or residing in a long-term care facility for greater than 14 days before onset of symptoms."³⁶ Symptoms that are suggestive of pneumonia include cough, dyspnea, sputum production, pleuritic chest pain, fever or hypothermia, and sweats or rigors. In addition, many nonspecific symptoms (eg, fatigue, headache, myalgia, and anorexia) predominate the initial presentation. Elderly patients often have fewer or less severe symptoms.

Epidemiology

In the US, it is estimated that 5.6 million cases of CAP occur each year. Approximately 25% of these cases will require hospitalization, and inpatient costs will consume greater than 90% of the nine billion dollars spent annually to treat CAP.³⁰ Length of stay is the major determinant of inpatient costs and represents more than 20 times the typical costs of outpatient treatment.

Pneumonia is the most frequent cause of death due to an infectious disease in the US.³⁵ It represents the leading cause of death worldwide, and is the sixth most common cause of death in the US. The risk of death associated with CAP increases with the severity of illness and the site of treatment.³⁶ Patients who are at the lowest severity level (low-risk class) are treated as outpatients and have the lowest rate of mortality (less than 1%). In comparison, patients with an intermediate-level of severity are often admitted to the general medical ward of the hospital and their mortality rate approaches 8% to 13%. Patients who are the most severely ill and require admission to the ICU have the highest rate of mortality (approximately 30%).³⁶ Understanding how risk stratification impacts prognosis is crucial for the appropriate treatment of CAP.

Etiology

A large number of microorganisms can cause CAP. These include aerobic and anaerobic bacteria, atypical pathogens, viruses, fungi, and, more recently, organisms associated with bioterrorism.^33,36 Although there are many potential pathogens, the majority of CAP cases in immunocompetent adults are caused by a limited number of common pathogens.

S pneumoniae is the most common pathogen that causes bacterial CAP.²⁹ Estimated prevalence of this pathogen in North American studies is 20% to 60%. In addition, S pneumoniae is responsible for approximately two thirds of bacteremic pneumonia cases. This pathogen is the most important cause of mortality associated with CAP, including an estimated rate of 6% to 20% for bacteremic pneumococcal pneumonia.³³ Emergence of drug-resistant S pneumoniae (DRSP) has greatly impacted empirical treatment decisions regarding CAP.^31-35

H influenzae (usually nontypeable strains), S aureus, and other gram-negative bacilli are the other major bacterial causes of CAP. H influenzae is considered a frequent cause of CAP, and has a prevalence of 3% to 10%.²⁹ Community-associated methicillin-resistant S aureus is currently being recognized as a potential new cause of CAP.³⁵ Less common bacterial causes include M catarrhalis, S pyogenes, and Neisseria meningitides, each accounting for 1% to 2% of cases.

The atypical organisms (M pneumoniae, C pneumoniae, and Legionella species) account for 10% to 20% of all cases of CAP in North America.²⁹ The exact prevalence of these pathogens is not known because they are often considered as a co-infecting pathogen and there is a lack of testing for them. M pneumoniae and C pneumoniae are usually considered as common causes of CAP in ambulatory and non-ICU hospitalized patients. Legionella species is often a leading pathogenic cause of severe CAP in ICU patients.

Viruses can account for 2% to 15% of all cases of CAP.²⁹ Influenza remains the most common viral cause of CAP in adults. Other viruses commonly encountered as pathogens include respiratory syncytial virus and parainfluenzae virus. Less frequent viral agents include adenovirus, metapneumovirus, herpesvirus, varicella, sudden acute respiratory syndrome-associated coronavirus, and measles. The occurrence of other etiological pathogens is often dependent on specific epidemiologic factors and underlying conditions.³⁵

Risk Factors

A number of risk factors have been associated with increased mortality in patients with CAP.^33,36 These include increasing age, comorbid conditions (eg, neoplastic disease, immunosuppression, coronary artery disease, congestive heart failure, neurologic disease, diabetes mellitus, and alcohol consumption), radiographic changes (eg, pleural effusions), abnormalities in specific laboratory tests (eg, leukopenia, hyponatremia, hyperglycemia, hypoalbuminemia, hypoxemia, and altered renal or liver function tests), and physical findings (eg, dyspnea, tachypnea, systolic hypotension, chills, altered mental status, hypothermia, and hyperthermia). Higher mortality rates have also been associated with postobstructive pneumonia and infections caused by S aureus, gram-negative bacilli, and anaerobes (eg, aspiration pneumonia).

Risk factors have been identified for infections caused by specific pathogens, including drug-resistant strains.³⁴ Factors associated with DRSP include age greater than 65 years, previous use of a ß-lactamase agent within the previous three months, alcohol dependency, immunosuppression (either from disease-related illnesses or corticosteroid treatment), various other medical comorbidities, and exposure to a child who attends daycare. For enteric gram-negative organisms, the risk factors include recent antimicrobial therapy, nursing home residence, coexistent cardiopulmonary disease, and multiple medical comorbidities. Patients prone to infections involving P aeruginosa exhibit risk factors such as structural lung disease (bronchiectasis), malnutrition, prednisone use greater than 10 mg/day, and broad-spectrum antimicrobial use for greater than 7 days within the past 30 days.

Treatment

The algorithm in Figure 2 (Click here to view Figure 2) outlines the evaluation and treatment of an immunocompetent patient presenting with signs and symptoms of CAP. A careful medical history and physical examination are the initial steps towards making the diagnosis of CAP. A chest radiograph is needed to establish the diagnosis of pneumonia.²⁹ The consensus guidelines from IDSA and ATS differ in their recommendation for routinely performing microbiologic diagnostic tests in all patients.^33,34 Clinicians will need to decide whether a sputum culture with Gram stain, serologic testing for Mycoplasma and Chlamydia species, and a urinary antigen assay for Legionella species are useful. These tests are most likely to be of value in patients with CAP severe enough to require a hospital admission, who are at risk of having an infection cause by a drug-resistant pathogen, or who have recently been treated unsuccessfully with antimicrobial therapy.

Once the diagnosis of CAP is established, the decision whether to hospitalize the patient or not must be determined. To assist in determining if home health care is appropriate, the IDSA has recommended a three-step approach (determine preexisting conditions, calculate a Pneumonia Severity Index, and use sound clinical judgment) to establish if home care is appropriate.³³ Subsequently, the major issue for both outpatient and inpatient management becomes the selection of either culture- and susceptibility-directed therapy (if a pathogen has been identified) or empiric antimicrobial therapy based on the most likely infecting pathogen(s). Initiation of therapy should not be delayed, since early administration (eg, within four hours of presentation) of antibiotics has been associated with improved outcomes.³³ The final steps for both groups include monitoring the efficacy and toxicity of selected therapy, modify treatment as needed, and determine the duration of therapy.

Empirical Antimicrobial Therapy

The following discussion will focus on empiric therapy of CAP in outpatients (Figure 3- Click here to view Figure 3) and patients admitted to either a general medical ward or the ICU (Figure 4- Click here to view Figure 4). The recommendations are based on a recent review that has merged and updated the two previously published guidelines of IDSA and ATS.³⁵ The recommended antimicrobial regimens are considered to be effective against the most likely pathogens associated with the medical comorbidities and/or risk factors of the patient. Obviously, antimicrobial therapy may need to be adjusted in individual patients exposed to other pathogens.

Several other issues must also be considered during the selection of antimicrobial regimens for empiric therapy of CAP.^31,35 These factors include local antimicrobial-susceptibility patterns and incidence of drug-resistant pathogens (especially for S pneumoniae). Considerations about a specific antimicrobial agent include spectrum of activity, pharmacokinetic and pharmacodynamic characteristics, clinical efficacy data in CAP patients, adverse event profile, and cost.

Empirical Antimicrobial Therapy for Outpatients

In mild to moderately ill outpatients who are otherwise healthy and have not recently received treatment with antimicrobial agents, the most likely pathogens associated with CAP are S pneumoniae, M pneumoniae, H influenzae, and C pneumoniae.^31,35 The recommended choice for empiric therapy in this group of outpatients is an extended-spectrum macrolide (clarithromycin or azithromycin); doxycycline would be considered as a second choice. The extended-spectrum macrolides are particularly useful in CAP because of their activity against both S pneumoniae and atypical pathogens. Although erythromycin is considered to be less costly, extended-spectrum macrolides are preferred because of their increased potency against H influenzae, their enhanced gastrointestinal (GI) tolerability, their high intrapulmonary drug concentrations, and their associated improved compliance due to a lower risk of adverse effects and less frequent dosing (Table 2). The IDSA guidelines suggest that extended-spectrum macrolides may be used as monotherapy in patients with comorbidities as long as they have not been treated with antimicrobial therapy within the previous three months.

Doxycycline is a cost-effective alternative to the macrolide agents, and has relatively low toxicity and convenient twice-daily dosing. Disadvantages associated with doxycycline include an increasing risk of resistant S pneumoniae strains (approximately 15%), limited published data regarding clinical efficacy, and photosensitivity.^33,34,36,37 For outpatients with either comorbidities and/or who have received antimicrobial therapy during the past three months, one of four regimens (Figure 3- Click here to view Figure 3) is recommended as empiric therapy: a respiratory fluoroquinolone, telithromycin, an oral ß-lactam plus an extended-spectrum macrolide, or parenteral ceftriaxone plus an oral extended-spectrum macrolide.³³ The most likely pathogens found in this group of outpatients are similar to the other group of outpatients with two major exceptions: there is an increased likelihood of DRSP and enteric gram-negative bacilli. The choice of antimicrobial agents for this group of outpatients should include a broad spectrum of activity that covers DRSP, atypical pathogens, and gram-negative bacilli. In addition, if patients have recently been treated with antimicrobial agents, the selection of the current regimen should be from a different class of antimicrobial agents. Monotherapy with a respiratory fluoroquinolone (eg, levofloxacin, gatifloxacin, gemifloxacin, or moxifloxacin) or combination therapy with an oral ß-lactam plus an extended-spectrum macrolide is the preferred choice of therapy. Extended-release amoxicillin-clavulanate (2000 mg/125 mg every 12 hours) and amoxicillin (1000 mg every 8 hours) are the preferred oral ß-lactams to be combined with a macrolide because of their increased activity against DRSP. Other newer treatment options include telithromycin, which has excellent activity against DRSP and atypical pathogens.^25,33 However, the spectrum of activity for telithromycin is not adequate against gram-negative bacilli, and other treatment regimens must be considered in its place. Finally, in lieu of oral therapy, outpatient services in certain settings may allow the use of parenteral therapy with intravenous (IV) or intramuscular (IM) ceftriaxone plus an oral extended-spectrum macrolide.

Empirical Antimicrobial Therapy for Inpatients

The most likely pathogens for inpatients who are mild to moderately ill and admitted to the general medical ward are S pneumoniae, M pneumoniae, H influenzae, C pneumoniae, and Legionella species (Figure 4- Click here to view Figure 4).^31,35 An initial combination treatment with an IV ß-lactam plus IV azithromycin, and monotherapy with an IV respiratory fluoroquinolone (eg, levofloxacin, gatifloxacin, or moxifloxacin) are the preferred choices for these patients. The parenteral ß-lactams include ceftriaxone, cefotaxime, and ampicillin-sulbactam. Ertapenem may also be considered because of its extended activity for anaerobic and extended-spectrum ß-lactamase producers of Enterobacteriaceae. Ertapenem may be useful in selected patients at risk for these pathogens (eg, elderly patients admitted from nursing homes); however, data regarding clinical experience are limited. Currently, monotherapy with IV azithromycin for inpatients should be limited to patients without risk factors for DRSP or gram-negative organisms. For this group of patients, the recommended dosage regimen of azithromycin is 500 mg once daily for both IV and oral therapy. Finally, consideration of risk factors associated with other pathogens (eg, aspiration pneumonia) also must be considered in selected patients.

In patients with CAP whose illness is severe and requires admission to the ICU, the most likely causative pathogens that need to be taken into account include S pneumoniae, Legionella species, gram-negative bacilli, and S aureus.^31,35 Discounting infections due to Pseudomonas species, the preferred regimens include either a combination of an IV ß-lactam plus IV azithromycin or monotherapy with a parenteral respiratory fluoroquinolone. In addition, a respiratory fluoroquinolone may be considered as part of an initial combination treatment with a ß-lactam.

In ICU patients with risk factors for infection caused by P aeruginosa, initial therapy must include a spectrum of activity that includes antipneumococcal, antipseudomonal, and atypical coverage. Initial therapy directed towards P aeruginosa often includes two effective agents since monotherapy has been associated with a higher risk of treatment failures and development of resistance. The preferred regimens includes combination treatment with an antipseudomonal ß-lactam (eg, piperacillin/tazobactam, cefepime, imipenem, or meropenem) plus an antipseudomonal fluoroquinolone (eg, high-dose ciprofloxacin or levofloxacin). An alternative regimen includes triple drug therapy with an antipseudomonal ß-lactam, an aminoglycoside, and an IV respiratory fluoroquinolone (eg, levofloxacin, gatifloxacin, or moxifloxacin). For patients with ß-lactam hypersensitivity, aztreonam can be substituted in these regimens as an antipseudomonal agent.

Pathogen-Directed Therapy

The algorithms for empiric therapy are useful starting points and should serve as a reminder of the need to modify therapy to pathogen-directed therapy whenever possible.^31,35 Results from microbiological and diagnostic tests are usually available within 24 to 72 hours, and should be used to select antimicrobial therapy for a specific pathogen. Whenever possible, therapy should be with a narrow spectrum agent to minimize the selective pressures for resistance.

Switching from IV to Oral Therapy

The duration of hospitalization has the greatest impact on the cost of treating patients with CAP. Initial antimicrobial therapy for most hospitalized patients is usually with IV agents. Reduced costs and earlier discharge from the hospital can be safely achieved by switching from IV to oral antibiotic therapy in patients who have become hemodynamically stable, show signs of clinical improvement, and are able to maintain an oral intake.³⁶ In addition, some of the typical criteria that a patient must meet before switching the delivery of therapy include fever <37.8^º C for at least eight hours, improved cough and dyspnea, white blood cell count returning to normal range, and adequate oral intake.^34,35 Ideally, the same antibiotic in an oral formulation with adequate bioavailability should replace the IV agent. However, when that is not possible, an oral agent with a similar spectrum of activity should be used to replace the IV therapy.

Most patients can be safely discharged from the hospital after oral therapy has been initiated. The use of appropriate discharge criteria has been associated with decreased costs and readmission rates as well as reduced mortality. The recommended guidelines from IDSA state that no more than one of the following criteria (unless present at baseline) should be present within 24 hours before discharging the patient to home care: temperature >37.8^ºC; pulse >100 beats/minute; respiratory rate >24 breaths/minute; systolic blood pressure <90 mm Hg; blood oxygenation saturation <90%; and inability to maintain oral intake.³³ The use of appropriate discharge criteria has been associated with decreased costs and readmission rates as well as reduced mortality.

Duration of Therapy

Traditionally, the recommended duration of therapy for patients with CAP has been between 7 to 14 days. The ideal duration of antibiotic therapy is unknown, and has not been adequately studied. Recently, the concept of short-course antibiotic therapy (eg, <5 to 7 days) has been introduced for the treatment of upper and lower respiratory tract infections.^26,37,38 The goal of short-course therapy includes rapid eradication of causative pathogens, decrease selection pressure for resistance, less adverse events, improved compliance, and lower costs. Several current studies have demonstrated equivalent efficacy and safety between short-course and traditional duration of antibiotic therapy in patients with CAP. Some experts have recently recommended that patients with CAP should be treated for a minimum of five days, and therapy should not be discontinued until 48 to 72 hours after a clinically stable patient has become afebrile.^33,35 However, not all patients with CAP can be treated with short-course therapy. Longer durations of therapy may be needed for cases involving extrapulmonary infections, S aureus bacteremia, P aeruginosa pneumonia, inadequate initial therapy, and infections caused by less common pathogens.

Prevention of CAP

The mainstay for preventing lower respiratory tract infections is vaccination.^33,34 The two most common and deadly causes of CAP are influenza and pneumococcus infection.^33,34,36 Available vaccines for adults include the 23-valent pneumococcal polysaccharide vaccine, the inactivated trivalent influenza vaccine, and the new live attenuated influenza vaccine. In addition, smoking cessation should be considered in all patients with CAP who smoke.³³ Smoking is one of the major risk factors for both pneumococcal bacteremia and Legionella species infection.

THE ROLE OF THE PHARMACIST

Pharmacists play a key role in the management of patients with lower respiratory tract infections since the majority of these patients are treated in the outpatient or ambulatory care setting. Education of these patients is very important since not all infections require antibiotic therapy. For example, pharmacists may explain to patients that symptoms caused by viruses may not require treatment with an antibiotic whereas symptoms caused by bacteria are likely to be treated with a course of an antibiotic. Patients need to be informed that their cough can typically last up to 10 to 14 days after a visit to their physician's office. Since these patients often search for relief of their cough and chest cold symptoms, pharmacists can assist in selecting over-the-counter products and provide counseling on their appropriate use.

Antibiotics are indicated for bacterial causes of AECB and CAP. Pharmacists are responsible for monitoring the indications for use, pharmacokinetics, efficacy, adverse effects, drug interactions, and costs. In addition, pharmacists must consider the pharmacodynamic relationship between the antibiotic and the microorganism being treated. Risk stratification and treatment guidelines are rational approaches to ensure appropriate empiric antimicrobial therapy in AECB and CAP. Because these guidelines are often being reevaluated and modified, pharmacists will need to provide up-to-date information on the currently recommended dosage regimens and duration of therapy for the effective management of these infections. When possible, pathogen-directed therapy should be initiated to further minimize the selective pressures for resistance. Pharmacists in the inpatient setting can provide a critical role in the implementation of an effective program for switching from IV to oral therapy and can prepare the patient for a safe discharge to the outpatient setting. All of these variables must be incorporated into the individualization of an antibiotic dosage regimen for these patients.

Pharmacists should educate patients about the importance of preventing AECB and CAP. Smoking cessation or reduction can decrease the rate of lung function deterioration, produce symptomatic improvements, and lower the risk of future infections. Pharmacists can provide assistance in the selection of smoking cessation products and provide information about programs and resources available in the community. All patients should be counseled about the benefits of influenza and pneumococcal vaccinations. Pharmacists need to ensure that the goals of prevention and therapy are met for each patient and that patients with increased risk of treatment failure are identified and that the desired outcomes are achieved.

RESISTANCE, COMPLIANCE, AND PHARMACOECONOMIC ISSUES ASSOCIATED WITH THE PRESCRIBING OF ANTIBIOTICS Lower respiratory tract infections (LRTI) have both a large financial as well as clinical impact on employees, employers, and healthcare entities charged with administering care to beneficiaries. With millions of people infected each year and billions of dollars spent fighting these infections, respiratory infections in general represent the most common reason for physician visits and antibiotic prescriptions. Depending on the type of infection, whether or not antibiotics are called for is not always a clear-cut decision. If the diagnosis appears as acute bronchitis, not prescribing an antibiotic is appropriate. In most cases, this disease is self-limiting and in only instances such as a suspected pertussis does an antibiotic treat the underlying offending agent. As with any medical treatment, the judgment of the practitioner weighs in the decision. The information derived from direct-to-consumer (DTC) advertising and the expectation of patients to leave a doctors office with a "cure" in hand versus exposing patients to unnecessary treatments is a common challenge clinicians face every day. Unnecessary treatments not only cost patients and benefit providers monetarily, but they might harm patients and lead to a greater likelihood of bacterial resistance. The notion of appropriate prescribing, in which antimicrobials are used to only treat bacterial infections to cure the patient while avoiding adverse reactions, is paramount. Several large studies show that bacteria, such as S pneumoniae, have widespread resistance to antibiotics such as ß-lactams and macrolides. So not only is there an economic concern for the inappropriate use of antibiotics, but a clinical one as well. Despite the concern for resistance, appropriate past medical history research allows for continued treatment with macrolides. If there is a suspicion of an infection such as AECB or CAP, then the decision to treat for positive clinical outcomes differs from that of acute bronchitis. The use of a diagnostic test to aid in diagnosis occurs very seldom and empirical therapy is recommended in these conditions. The majority of prescriptions written and patients treated for LRTIs are in an outpatient setting, where bacterial susceptibility testing is difficult and treatment failures due to resistance is sparsely documented. In choosing the appropriate therapy, the use of guidelines can aid in choosing an agent with the local patterns of resistance and patient factors providing more tailored therapy. Agencies such as the Centers for Disease Control (CDC) or IDSA can provide a good evidence-based approach to agent selection and treatment. In recent years with developing patterns of resistance to ß-lactams, the newer macrolide and fluoroquinolone antibiotics have added to the arsenal of antibacterials for LRTIs. The current IDSA recommendation for CAP without evidence of recent antibiotic therapy lists macrolides and doxycycline as preferred agents for an outpatient. The macrolides include azithromycin, clarithromycin, or erythromycin. If a patient had no known contraindications to any of these agents, what factors may influence the selection of one of these agents? Erythromycin and doxycycline have been available longer and generically for many years. Additionally, these two agents are both available in once-daily formulations. Although they are more costly than twice-daily or thrice-daily regimens for doxycycline and erythromycin, they are posed for greater use. Several studies have measured compliance patterns for various dosing regimens. Once-daily and twice-daily regimens have similar compliance percentages, with a trend toward once-daily regimens being slightly better. Compliance rates seen with once-daily regimens did not reach 100%, and the reported differences between once-daily and twice-daily regimens were within standard deviations. Medication compliance encompasses patients' behaviors with instructions that often may be misunderstood or not fit into how patients conduct their lives. Additionally, the notion of patients complying with instructions but not adhering to these instructions must also be considered. For instance, if a patient is instructed to take an antibiotic twice a day but takes two doses only three hours apart, the patient may have complied, but not adhered, to the intended 12-hour dosing regimen. Noncompliance may result from adverse reactions, not understanding instructions, or lack of understanding of the importance of therapy. The patient's lifestyle and usual medication-taking behavior cannot be overlooked when determining which regimen provides the more likelihood of compliance. The number of agents used to treat LRTIs continues to grow. Part of this growth is not only in new product development but in the generic market as well. The Drug Price Competition and Patent Act of 1984 began a new era for pharmaceutical manufacturers. This Act, passed in response to escalating drug prices, requires the FDA to make publicly available a list of approved products for substitution. Several key definitions will help clarify the area of product substitution. Pharmaceutical equivalent products provide the same active ingredient, dosage form, and route of administration and have identical strength or concentration when compared to the reference product. Therapeutic equivalent products provide pharmaceutical equivalence along with identical safety and clinical efficacy. Pharmaceutical alternatives contain the same therapeutic moiety but the not the same salt forms, esters, or complexes (ie, hydroxyzine sulfate vs. hydroxyzine pamoate). Bioequivalent products are pharmaceutical equivalent or alternative products without a significant difference in bioavailability. The FDA issues a therapeutic equivalent product code to generic products that they determine are bioequivalent. Products assigned a first letter of an "A" are therapeutically equivalent with a second letter designation referring to particular dosage forms. So an "AB" rated product is equivalent, but a "BP" product is not. When comparing an "AA" to an "AB" rating, the difference is that "AB" rated products had "actual or potential bioequivalence problems" that have been resolved. In order for the FDA to issue a generic manufacturer a rating, the manufacturer must perform a standard bioequivalence study measuring in vitro and in vivo data for their product. The standard pharmacokinetic parameters of Area Under the Curve (AUC) and peak drug concentration (Cmax) are used in the in vivo studies. The pharmacokinetic properties of a product in these studies must fall within a range of 80% to 125%, with the expected mean near 100%. The FDA conducted several surveys of hundreds of bioequivalence studies performed in the 1980s and 1990s. The results showed that the mean difference in AUC and Cmax between brand and generic products for all of the studies was less than 5%. Bioequivalent studies use normal, healthy adults in order to gain acceptance from the FDA. Many patients taking medications are not in ideal health and could have factors that can affect pharmacokinetic properties. If this is the case, they may not be ideal candidates for substituting with a particular generic product. Additionally, medications with a narrow therapeutic window, such as carbamazepine and digoxin, can have a large pharmacodynamic response from a relatively small change in systemic concentration. In these situations, the substitution of a generic product may not achieve clinical results worth the cost savings. Other medications may provide a wider therapeutic window and consequently may have less significant pharmacodynamic outcomes. Because of various issues with generic substitution, the pharmacist and healthcare team must collaborate and decide if the generic substitution makes good clinical and economic sense on a case by case basis. LRTIs are a leading cause of hospitalizations and death. Several studies have shown patients with LRTIs consume twice as many resources and have a higher rate of absenteeism than other employees. The majority of patients with LRTIs are managed as outpatients, which is much less expensive than inpatient care. Additionally, an overwhelming majority of the costs for treating ambulatory patients with an LRTI stems from laboratory, radiography, and medical visit costs, with a vastly smaller expense for medications. Expenditures other than medication costs associated with a hospital stay account for a majority of the expenditures for a hospitalized patient. This places greater emphasis on appropriate antibiotic selection for the outpatient visit to avoid a treatment failure. The cost of a treatment failure is far greater than acquisition cost of any first-line antibiotic and may actually increase hospital stays if a resistant organism is present. Factoring in the cost to a company for healthcare, absenteeism, and disability, patients with LRTIs have more claims and cost roughly twice as much to a benefit provider as do other beneficiaries. The most effective antibiotic for a patient with an LRTI is one that will effectively treat the suspected organism, have assurance of adherence and compliance, and do so with minimal adverse effects. If the treatment for a patient is effective in an outpatient setting, the significant savings compared to inpatient care makes appropriate the choice of an agent that may avoid potential failures. Bibilography Birnbaum HG, Morley M, Leong S, et al. Lower respiratory tract infections: impact on the workplace. Pharmacoeconomics. 2003;21:749-759. Birnbaum HG, Morley M, Greenberg PE, Colice GL. Economic burden of respiratory infections in an employed population. Chest. 2002;122:603-611. Kastrissios H, Blaschke TF. Medication compliance as a feature in drug development. Annu Rev Pharmacol Toxicol. 1997;37:451-475. Klugman KP. Implications for antimicrobial prescribing of strategies based on bacterial eradication. Int J Infect Dis. 2003;7(suppl 1):S27-S31. Mandell LA, Bartlett JG, Dowell SF, et al. Update of practice guidelines for the management of community-acquired pneumonia in immunocompetent adults. Clin Infect Dis. 2003;37:1405-1433. Nicolau D. Clinical and economic implications of antimicrobial resistance for the management of community-acquired respiratory tract infections. J Antimicrob Chemother. 2002;50(suppl S1):61-70.   Author: Marc T. Young, PharmD Graduate Research Associate Pharmacy Care Systems, Harrison School of Pharmacy Auburn University Auburn, Alabama

 REFERENCES