Therapeutic Challenges of Acute Bacterial Exacerbation of Chronic Bronchitis

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1 ...PRESENTATIONS... Therapeutic Challenges of Acute Bacterial Exacerbation of Chronic Bronchitis John Southard, MD, PhD Presentation Summary Determining the difference between colonization and infection is critical to an accurate diagnosis of acute exacerbation of chronic bronchitis (AECB). Chronic bronchitis affects 5.4% of the general population in the United States, and many of these patients carry in their bronchi the most common pathogens implicated in AECB. However, many of these individuals already have minimal respiratory reserves, so the impetus to treat for potential bacterial infection is significant. There is also evidence that repeated attacks of AECB may cause damage to respiratory tissue, which in turn creates an environment favorable to continuing exacerbations. In the short term, antimicrobial therapy can reduce the duration of symptoms, prevent progression to pneumonia, and eliminate the need for hospitalization. Long-term benefits may include an interruption in the cycle of progressive airway damage and a prolongation of the period between exacerbations. Although Haemophilus influenzae is the most frequent cause of AECB, Streptococcus pneumoniae and Moraxella catarrhalis are important pathogens as well. Appropriate antibiotics should have activity against likely causative pathogens, resistance to destruction by ß-lactamase, good sputum and bronchial tissue penetration, high tissue concentration: minimum inhibitory concentration ratio, compliance-enhancing features, and cost effectiveness. Because invasive pneumococcal infections have a high fatality rate in patients with underlying conditions, efforts should be made to ensure those with chronic bronchitis receive pneumococcal vaccinations. Acute exacerbation of chronic bronchitis (AECB) is a disease known both for its indefinite beginnings and for its uncertain therapeutic modalities. It poses particular difficulties for the primary care physician, who must determine if and when treatment for AECB is indicated. Because patients with AECB have bronchitis as an underlying condition, the acute exacerbation represents a progression along a continuum rather than a sudden break from the norm. There is increased dyspnea in already dyspneic patients and increased sputum volume in patients who already have a significant amount of mucus. Many of these patients have chronic obstructive pulmonary disease (COPD), and they VOL. 5, NO. 11, SUP. THE AMERICAN JOURNAL OF MANAGED CARE S677

2 ... PRESENTATIONS... Figure 1. Circle of Bacteria-Mediated Direct Lung Damage and Bacteria-Provoked, Host-Mediated Inflammatory Lung Damage That May Develop During Airway Infection Source: Cole P, Wilson R. Host-microbial relationships in respiratory infection. Chest 1989;95(suppl):217S-221S. Reprinted with permission by the American College of Chest Physicians. often carry the most common pathogens implicated in AECB in their bronchi, making culturing difficult and unreliable. A critical part of the diagnosis involves determining the difference between colonization and infection. Fear of patient failure drives many treatment decisions. Only 50% of AECB cases are caused by infection, 1 and of those 50% only 70% are bacterial in nature. 2 However, by definition these patients are already compromised with minimal respiratory reserve, so the tendency is to treat them empirically and determine the cause later if at all. Any infection, viral or bacterial, can put these individuals over the edge and cause respiratory muscle fatigue and failure. Causes of AECB According to a 1994 survey by the Centers for Disease Control and Prevention, 5.4% of the US general Figure 2. Death Rates Per 100,000 Population Among Adults Age 55 to 65 Years Source: Ball P. Epidemiology and treatment of chronic bronchitis and its exacerbations. Chest 1995;108:43S-52S. Reprinted with permission by the American College of Chest Physicians. S678 THE AMERICAN JOURNAL OF MANAGED CARE AUGUST 1999

3 ... THERAPEUTIC CHALLENGES... population suffers from chronic bronchitis, with the incidence increasing slightly with age to around 6% in those 45 years and older. 3 AECB may be the result of a variety of causes, including thickened secretions and inhalations of allergens or toxic gases. Infectious agents include viruses such as influenza, parainfluenza, respiratory syncytial virus, coronaviruses, and rhinoviruses, as well as a number of bacterial pathogens. 2 An impaired host defense mechanism, acquired as the result of cigarette smoking, subsequent to a viral infection, or inherited (eg, cystic fibrosis), can predispose patients to bronchial infection. 4 Cigarette smoking, either current or past, is a major cause of chronic bronchitis and appears to be common among those with AECB. Equally important, continued cigarette smoking contributes to the escalation of respiratory problems in patients with chronic bronchitis. 5 Subsequent abnormalities in the bronchial system of patients with chronic bronchitis, including impaired mucociliary clearance, obstructed bronchi, and the chronic presence of bacteria in the bronchial epithelium, further contribute to conditions favorable to bacterial infection. 1 Bacterial products, such as pneumolysin and lipopolysaccharide, and chronic inflammation may cause additional damage to respiratory tissue. 1,6 For patients with underlying chronic bronchitis, this sequence of events can set in motion a continuing cycle of acute exacerbations, with many patients experiencing several acute exacerbations each year (Figure 1). 7 Acute bacterial bronchitis is most common in the elderly and in those with compromised immune systems or COPD. 8 It causes considerable morbidity and frequently necessitates hospitalization. 1 Although antimicrobial therapy has improved the prognosis of acute bacterial bronchitis for many, the mortality rate from chronic bronchitis in the industrialized world remains high (Figure 2). 2 Symptoms of acute bacterial exacerbations include increased dyspnea and sputum volume, but sputum purulence is the most important sign in differentiating between chronic bronchitis and an acute exacerbation. However, these symptoms are not diagnostic, and examination of the sputum is necessary to help distinguish between bacterial and viral infection and noninfectious causes (Table 1). 1 Each acute inflammatory episode that occurs in the tracheobronchial tree results in an inflammation of the mucosa. Left untreated or not treated aggressively enough, the mucosa become fibrotic and the airway narrows, resulting in more obstructive pulmonary disease and more respiratory distress on an ongoing basis. 6 Table 1. Differential Diagnosis of Acute Exacerbation of Chronic Bronchitis Diagnosis Inhalation of toxic gases Increased inhalation of allergens Acute viral infection (reevaluate after 5 to 7 days for bacterial infection) Thickened secretions Bacterial infection Sputum Analysis Increased volume, cell concentrations, and percentage of neutrophils Increased volume, cell concentrations, and percentage of eosinophils Swollen bronchial epithelial cells Increased volume and percentage of neutrophils Swollen bronchial epithelial cells Occasional vacuolation of cell cytoplasm or nucleus Absence of increased bacteria Decreased volume Increased cell concentration Sputum grossly thicker, stickier, and more yellowish or green in color Increased volume, cell concentrations, and percentage of neutrophils Increased bacteria on Gram s stain Sputum yellow or green in color Source: Chodosh S. Treatment of acute exacerbations of chronic bronchitis: State of the art. Am J Med 1991;91: Reprinted with permission from Excerpta Medica Inc. VOL. 5, NO. 11, SUP. THE AMERICAN JOURNAL OF MANAGED CARE S679

4 ... PRESENTATIONS... Short-term benefits of antimicrobial therapy include a reduction in the duration of symptoms, avoidance of hospitalization, an earlier return to work, and prevention of progression to pneumonia. 9 In the long term, antibiotic therapy may help prevent progressive airway damage, prolong the period between acute exacerbations, and prevent secondary bacterial colonization and infection after a viral infection. 9 Pathogens Associated With AECB As with other respiratory tract infections, the 3 dominant pathogens remain Haemophilus influenzae, Streptococcus pneumoniae, and Moraxella catarrhalis. 9 H. influenzae is found in approximately 50% of cases of acute bacterial exacerbations, so the prevalence of each of these pathogens differs from that associated with otitis media and sinusitis (Figure 3). 5 S. pneumoniae Figure 3. Etiology of Acute Infective Exacerbation of Chronic Bronchitis Source: Reference 5. and M. catarrhalis constitute roughly the same percentage of isolates cultured from patients with AECB, and Staphylococcus aureus is found in a small percentage of cases. Patients with predisposing lung conditions, such as bronchiectasis secondary to viral infection or cystic fibrosis, may have S. aureus or Pseudomonas aeruginosa as the primary infecting agent. The possibility of multiple pathogens must be considered as well. In a study of patients with chronic bronchitis, Zeckel and associates 10 found that 12% of lower respiratory tract infections were polymicrobial in nature, and 8% involved S. pneumoniae, H. influenzae, or M. catarrhalis. Cigarette smokers may be more likely than nonsmokers to have AECB caused by H. influenzae. The researchers found that whereas H. influenzae was identified as the causative pathogen of AECB in 25% of patients overall, 50% of patients with H. influenzae as a pure or mixed culture were smokers. 10 Because smokers constituted only 35.7% of this cohort, the study demonstrates a correlation between the use of tobacco and the risk of infection with H. influenzae. Nicotine also has been found to stimulate the growth of this pathogen. 11 Mycoplasma pneumoniae is rarely the cause of AECB, 2 although it has been implicated as a cause of community-acquired pneumonia (CAP). 12,13 Table 1 shows the microbiology of AECB. In some patients, especially those who are elderly and institutionalized, oral hygiene plays a role in chronic respiratory illness. The aspiration of oropharyngeal organisms commonly found in dental plaque is postulated to be the mechanism involved. Scannapieco and associates 14 found a strong correlation between poor oral hygiene, as measured by the oral hygiene index, and the incidence of chronic respiratory disease, even after controlling for smoking. By S680 THE AMERICAN JOURNAL OF MANAGED CARE AUGUST 1999

5 stressing proper dental hygiene and monitoring the state of a patient s teeth, a primary care physician in some cases might be able to help prevent the development of chronic respiratory disease. An important consideration is the recent phenomenon of patients who have gram-negative bacilli in the lung that are a cause of AECB and pneumonia. These infections are thought to be linked to increased ph of the gastric juices secondary to histamine 2 (H 2 )-receptor antagonist use, and they result in increased colonization of the oral pharynx and the upper gastrointestinal tract 15 by gram-negative organisms. 16,17 H 2 -receptor antagonists, which are now available over the counter, have come to be a favorite replacement for antacids. It is important to be aware of these possibilities when making empiric choices. In unusual situations, particularly those in which chronic sinusitis is a concomitant illness, anaerobic bacteria must be considered. Bacterial Resistance Inasmuch as H. influenzae is the dominant pathogen in AECB, ß-lactamase production is a pressing concern. Although S. pneumoniae has been recognized as the more dangerous organism, patients with AECB are already compromised, so all infections must be dealt with seriously. Mechanisms of bacterial resistance include modification of target receptors, decreased uptake of the antibiotic either through increased impermeability or increased efflux, and enzyme inactivation of the antibiotic. Resistance may be mediated by plasmid or be chromosomal. 18 Plasmid-mediated resistance mechanisms are transferred very quickly and can move from one species or genus to another. Chromosomally mediated mechanisms are inducible and often arise during the course of treatment. A study by Davies and associates 19 revealed that resistance to azithromycin developed in patients with AECB associated with H. influenzae, with minimum inhibitory concen-... THERAPEUTIC CHALLENGES... Table 2. Percentage of Susceptibility of H. influenzae, M. catarrhalis, and S. pneumoniae to ß-Lactams and Macrolides in Europe and the United States* H. influenzae M. catarrhalis S. pneumoniae Antimicrobial Continent 1995 % 1995 % 1995 % Amoxicillin EU US Amoxicillin/ EU clavulanate US Ampicillin EU US Azithromycin EU US Cefaclor EU US Cefixime EU US Ceftriaxone EU US Cefuroxime EU US Clarithromycin EU US Erythromycin EU US Penicillin EU US *National Committee for Clinical Laboratory Standards breakpoints where available. % = Percentage of change in susceptibility since ; EU = European Union; US = United States; not tested; no breakpoint. Source: Schito GC, Mannelli S, Pesce A, and The Alexander Project Group. Trends in the activity of macrolide and ß-lactam antibiotics and resistance development. J Chemother 1997;9(suppl 3): Reprinted with permission by EIFT srl. VOL. 5, NO. 11, SUP. THE AMERICAN JOURNAL OF MANAGED CARE S681

6 ... PRESENTATIONS... trations (MICs) gradually increasing over the course of therapy. Bacterial resistance is not uniform. Patterns vary internationally and even within countries; some cities have pockets of high resistance, whereas others do not. There has been a considerable effort to track resistance on a worldwide basis since Table 3. Recent International Surveillance Study Results for S. Pneumoniae MICs 90 * Breakpoints Amoxicillin 1 mg/l 1 mg/l 2 mg/l 2 mg/l Amoxicillin/clavulanate 1 mg/l 1 mg/l 2 mg/l 2 mg/l Cefaclor 64 mg/l 64 mg/l 64 mg/l 64 mg/l Cefixime 32 mg/l 16 mg/l 32 mg/l 32 mg/l Ceftriaxone 1 mg/l 1 mg/l 2 mg/l 2 mg/l Cefuroxime 2 mg/l 4 mg/l 8 mg/l 8 mg/l Erythromycin 0.12 mg/l 32 mg/l 32 mg/l 32 mg/l Clarithromycin 0.12 mg/l 32 mg/l 32 mg/l 32 mg/l Azithromycin 0.12 mg/l 32 mg/l 32 mg/l 32 mg/l *Includes United States and European data. Source: Schito GC, Mannelli S, Pesce A, and The Alexander Project Group. Trends in the activity of macrolide and ß-lactam antibiotics and resistance development. J Chemother 1997;9(suppl 3): Reprinted with permission by EIFT srl. Table 4. Characteristics of the Ideal Antimicrobial for Acute Bacterial Exacerbations of Chronic Bronchitis Active against likely target organisms: S. pneumoniae, H. influenzae, M. catarrhalis, and S. aureus Resistant to destruction by or unaffected by ß-lactamase Good sputum and bronchial tissue penetration High tissue concentration:mic ratio High likelihood of compliance with regimen Cost effective MIC = Minimum inhibitory concentration. the inception of the Alexander Project in 1992 (Table 2). 20 The recent international surveillance of S. pneumoniae shows that MICs for 90% of the organisms (MICs 90 ) have increased for most antibiotics over a 4-year period (Table 3). 20 However, there is an urgent need for a clearer picture of both the levels and the extent of bacterial resistance in the United States. S. pneumoniae resistance is not tracked in all states, and this international study involves only a few sites in the United States. Even in states where tracking occurs, the incidence of resistance varies according to the locale. 20 Most of the pathogens isolated also have come from university hospitals rather than from community hospitals; therefore, the samples are skewed and do not reflect the levels of resistance that may be present in the community as a whole. Appropriate Antibiotic Therapy In selecting an appropriate antibiotic, the physician should consider disease-specific factors, such as the likelihood that a resistant organism is causing the infection, and antibioticspecific factors, such as in vitro activity against both gram-negative and gram-positive pathogens. The ideal antibiotic for treating AECB would have the following characteristics: activity against likely causative organisms; resistance to destruction by ß-lactamase; good sputum and bronchial tissue penetration; a high tissue concentration:mic ratio; compliance-enhancing features, such as infrequent dosing and few side effects; and cost effectiveness (Table 4). Amoxicillin/clavulanate is first-line treatment for AECB because it is stable against ß-lactamase and its susceptibility is 100% in H. influenzae and M. catarrhalis and 65.8% to 93.8% in S. pneumoniae The twice-a-day dosing of 875 mg provides adequate time above the MIC in S. pneumoniae, with MIC 90 values ranging from 1 to 4. This dosing regi- S682 THE AMERICAN JOURNAL OF MANAGED CARE AUGUST 1999

7 ... THERAPEUTIC CHALLENGES... men may be more advantageous than the older 3-times-a-day regimen because higher peak levels offer more protection against pathogens with elevated MICs. Twice-a-day dosing is also more easily tolerated and more convenient, which may enhance compliance. Second-generation cephalosporins, such as cefuroxime and cefprozil, and loracarbef (which, although not technically second generation operates in the same way), have proved disappointing as treatment for lower respiratory infections. This is partly the result of variable ß-lactamase stability and partly because of poor tissue penetration. However, the newer thirdgeneration cephalosporins (ie, cefixime and cefpodoxime) are relatively stable to ß-lactamase and are more active against gram-negative bacteria (H. influenzae and M. catarrhalis) than gram-positive bacteria (S. pneumoniae). They have convenient 4-times-daily or twice-a-day dosing. The fluoroquinolones (eg, ciprofloxacin and ofloxacin) are effective alternatives for patients allergic to penicillin. They are not susceptible to ß-lactamase-producing organisms and have good activity against gram-negative bacteria (particularly H. influenzae). 1,2 Their superior penetration into sputum and bronchial mucosa makes them good candidates for the treatment of AECB, and they compare favorably with more traditional agents, such as the ß-lactams. 2 Whereas quinolones have convenient twice-a-day dosing, some inhibit the metabolism of caffeine and theophylline; an interaction that is a problem with some macrolides as well, and which must be taken into consideration. Because of concern about their effects on cartilage development, 24 the use of fluoroquinolones is contraindicated in children. Additional AECB Management Considerations Because of the difficulties in its diagnosis, AECB often must be treated aggressively. In patients with minimal respiratory reserve, each exacerbation robs them of further pulmonary function, and there is a clear correlation between the prognosis and the number of acute exacerbations within a year. 4 The primary care physician also must keep in mind local resistance patterns, as well as the dominant organisms likely to be involved in the infection and the possibility of unusual pathogens. Pneumococcal vaccination holds hope for preventing some future exacerbations and should be a high priority for at-risk patients. Because invasive pneumococcal infections have a high fatality rate in patients with underlying conditions, vaccination against pneumococcal infection is clearly indicated in this group. 25 However, estimates are that only 28% of Americans age 65 years or older the most vulnerable group have been vaccinated against pneumococcal infection. 26 This is one area in which the primary care physician can have a definite impact, and efforts must be made to encourage vaccination of those most susceptible to AECB.... REFERENCES Chodosh S. Treatment of acute exacerbations of chronic bronchitis: State of the art. Am J Med 1991;91(suppl 6A):87S-91S. 2. Ball P. Epidemiology and treatment of chronic bronchitis and its exacerbations. Chest 1995;108:43S-52S. 3. Centers for Disease Control and Prevention. Number of selected chronic conditions per 1,000 persons, by age: United States, Available at: gov/nchswww/fastats/ce94t57.htm. Accessed July 22, Ball P, Harris JM, Lowson D, Tillotson G, Wilson R. Acute infective exacerbations of chronic bronchitis. Q J Med 1995;88: Ball P, Tillotson G, Wilson R. Chemotherapy for chronic bronchitis controversies. Presse Med 1995;24: Wilson R. The pathogenesis and management of bronchial infections: The vicious cir- VOL. 5, NO. 11, SUP. THE AMERICAN JOURNAL OF MANAGED CARE S683

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