Antibiotics for AECB
Causes of AECB, Diagnosis and Treatment of AECB
COPD encompasses a spectrum of chronic inflammatory disorders characterized by cough, sputum production, dyspnea, airflow limitation, and impaired gas exchange. Chronic bronchitis, small-airway obstruction, and emphysema usually occur concurrently. Some patients may have asthma associated with these conditions. Patients with chronic bronchitis and/or emphysema without airflow obstruction or those with asthma whose airway obstruction is completely reversible are excluded from the classification of COPD. COPD includes bronchitis (unspecified and chronic), emphysema, asthma, and AECB
Causes of AECB
Both bacterial products and the chronic inflammation associated with persistent bacterial infection of the airways lead to respiratory tissue damage. For example, as a primary initiator of infection, Haemophilus influenzae releases substances that stimulate mucus production and activate IgA proteases, which further impair local host defenses. Furthermore, H influenzae causes a direct immune reaction in the airways that significantly reduces mucociliary clearance.
These processes allow escalation of bacterial growth, which, in turn, leads to release of inflammatory substances that further exacerbate the cycle of microbial colonization and resultant inflammation and bronchial damage.
H influenzae is isolated in 30% to 70% of all bacterial exacerbations of chronic bronchitis. Streptococcus pneumoniae and Moraxella catarrhalis are the next most common isolates; together they account for another 33% of isolates in AECB.
A meta-analysis of data published between 1983 and 1996 indicates a changing pattern of bacterial incidence in bronchitis. During that period, the incidence of M catarrhalis infection had increased; M catarrhalis was the second most common pathogen, while pneumococci had become significantly less common. The reasons for the shift are unclear; it may be due to increased use of pneumococcal vaccine.
Although Haemophilus parainfluenzae has traditionally been considered part of the normal flora of the nasopharynx in immunocompetent hosts, its role as a pathogen was examined by Hill and colleagues. These investigators isolated H parainfluenzae at mean concentrations of 107 colony-forming units/mL in the sputum of 41% of patients with chronic bronchitis, suggesting that this bacterium's potential pathogenicity should be reevaluated.
Antibiotics in AECB
Results showed that the greater the number of cardinal symptoms present, the better the response to antibiotic therapy compared with placebo. Antibiotic treatment resulted in a higher overall clinical success rate (68% for antibiotics vs 55% for placebo, P =.01) and in fewer treatment failures (10% vs 19%, P =.05) as defined by worsening symptoms requiring either hospitalization or additional antibiotic treatment. Antibiotic benefit was greatest in type 1 and 2 patients.
A study by Allegra and co-authors reported on 300 patients with similar criteria. The clinical response to amoxicillin-clavulanate was 86.5% compared with 50.6% for placebo (P =.0001). These data support the beneficial role of antibiotics in AECB.
It is now widely accepted that the majority of patients with AECB should be treated with an antibiotic. Hence criteria are needed to determine the severity of patients' disease in order to select the appropriate therapy.
The Canadian guidelines targeted therapy for patients with simple chronic bronchitis at H influenzae, M catarrhalis, and S pneumoniae with first-line agents such as an aminopenicillins, tetracycline, or TMP-SMX.
For patients with complicated bronchitis and significant co-morbidity, empiric therapy was based on the likely organisms, including gram-negative bacteria. Currently, these empirically used drugs include broad-spectrum agents such as the fluoroquinolones (for example, ciprofloxacin, levofloxacin), second- and third-generation cephalosporins (for example, cefuroxime, cefixime), beta-lactamase inhibitor combinations, and newer macrolides (for example, clarithromycin, azithromycin).
Patients with uncomplicated, acute bronchitis, which is virtually always viral and rarely causes residual damage, should be managed with fluids, rest, and symptomatic therapy, not with antibiotics. The recommended treatment for exacerbated bronchiectasis -- defined as abnormal, chronic dilation of one or more bronchi -- was a second-line therapy based on the precise bacterial cause as determined by Gram's stain and sputum culture.
The Canadian guidelines must now be revisited in light of new patterns of microbial prevalence and resistance that have emerged since their publication in 1994. Among the antibiotics currently available for AECB, the effectiveness of aminopenicillins is limited by the increasing prevalence of beta-lactamase-producing strains of H influenzae and M catarrhalis. TMP-SMX is an alternative in beta-lactam-allergic patients and in locations where resistance to beta-lactams is prevalent. However, TMP-SMX is essentially inactive against atypical pathogens and although tetracycline is active against H influenzae and M catarrhalis, it has limited activity against PRSP.
Currently, amoxicillin-clavulanate (except for BLNAR strains of H influenzae), cefaclor, cefuroxime axetil, and cefixime are active against H influenzae, M catarrhalis, and penicillin-sensitive S pneumoniae. However, these agents have limited activity against PRSP strains, and both erythromycin and clarithromycin have poor intrinsic activity against H influenzae. Macrolides have been shown to be bacteriostatic, which when combined with poor anti-Haemophilus activity, presents some support of the unpredictable nature of these drugs. Recent evidence of the anti-inflammatory effects of macrolides such as clarithromycin suggests that these may add to the antibacterial capacities of these agents. Although early clinical outcome appears to be initially satisfactory, there is evidence to indicate that patients relapse sooner on clarithromycin therapy than with other agents. The infection-free interval criterion is still somewhat controversial; however, under similar test conditions few antimicrobials achieve as long an exacerbation-free interval as ciprofloxacin.
Fluoroquinolones have excellent activity against gram-negative bacteria, including H influenzae and M catarrhalis. Several anecdotal reports of apparent inconsistent activity of the older fluoroquinolones against S pneumoniae infections have been published. This has provided impetus for the development of the newer quinolones, such as moxifloxacin and gatifloxacin. A review of 37 published clinical trials in more than 3,500 patients, as well as data obtained from Bayer Corporation, revealed that ciprofloxacin performed as well as or better than the standard comparison drugs. In this review, pneumococcal eradication was achieved in more than 86% of patients and the overall clinical cure rate was 94%.
The newer quinolone agents have antimicrobial activity similar to that of ciprofloxacin against gram-negative pathogens but superior activity against gram-positive, atypical, and anaerobic organisms. The clinical efficacy of these compounds has largely been demonstrated to be equivalent to that of commonly prescribed agents.
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