Changes in bronchial inflammation during acute exacerbations of chronic bronchitis.

There are little data describing noncellular changes in bronchial inflammation during exacerbations of chronic bronchitis. The relationship between sputum colour and airway inflammation at presentation has been assessed during an exacerbation in patients with chronic bronchitis and a primary care diagnosis of chronic obstructive pulmonary disease. Sputum myeloperoxidase, neutrophil elastase, leukotriene B4 (LTB4), interleukin-8 (IL-8), sol:serum albumin ratio and serum C-reactive protein were measured in patients presenting with an exacerbation and mucoid (n = 27) or purulent sputum (n = 42). Mucoid exacerbations were associated with little bronchial or systemic inflammation at presentation, and sputum bacteriology was similar to that obtained in the stable state. Purulent exacerbations were associated with marked bronchial and systemic inflammation (p < 0.025 for all features) and positive sputum cultures (90%). Resolution was related to a significant reduction in LTB4 (p < 0.01), but no change in IL-8, suggesting that LTB4 may be more important in neutrophil recruitment in these mild, purulent exacerbations. In the stable state, IL-8 remained higher in patients who had experienced a purulent exacerbation (2p < 0.02). The presented results indicate that exacerbations of chronic bronchitis, defined by sputum colour, differ in the degree of bronchial and systemic inflammation. Purulent exacerbations are related to bacterial infection, and are associated with increased neutrophilic inflammation and increased leukotriene B4 concentrations.     

Epidemiology of chronic bronchitis and acute infective exacerbations of chronic bronchitis

Acute exacerbations of chronic bronchitis (AECBs) are one of the major causes of morbidity and mortality in the United States, resulting in significant cost to the health care system. Epidemiological information on chronic bronchitis is abundant and has been collected in most industrialized countries. The epidemiology of AECB, however, is less forthcoming. The causes of AECB are multifactorial and include environmental pollutants, allergic responses, and viral and bacterial infections. The role of bacterial infection in AECB is controversial but is believed to account for half of AECB. Because the medical and economic implications of treatment failure in these patients are substantial, an aggressive approach to stratify and treat these patients is necessary. Epidemiological data on chronic bronchitis and acute infective exacerbations of chronic bronchitis will allow us to more precisely define the role of bacterial infection in AECB, and this information may help guide antimicrobial therapy.     

Cost-effective therapy for acute exacerbations of chronic bronchitis

Pharmacoeconomic analysis involves the measurement of a ratio determining the extra costs required to achieve an additional unit of clinical benefit. Various techniques including modeling studies, retrospective analysis of databases, "piggy-back" economic analysis of prospective randomized clinical trials, and prospective randomized pharmacoeconomic trials have been developed to aid in economic and health decisions. In acute exacerbations of chronic obstructive pulmonary disease, it is possible to identify a group of patients that are at high risk of treatment failure from routine antimicrobial therapy, hospitalization, respiratory failure, and death. The cost of therapy for this relatively small group of patients is extraordinarily high. Data from a variety of approaches have suggested that aggressive antimicrobial therapy may lead to improved outcomes in these patients.The corollary is that aggressive therapy directed toward patients with either acute bronchitis (mainly a viral infection) or exacerbations of trivial chronic obstructive lung disease leads to emergence of resistance and increased costs.     

Antibiotic therapy in acute exacerbations of chronic bronchitis

Chronic obstructive pulmonary disease (COPD) comprises a spectrum of conditions including chronic bronchitis, emphysema, asthma, and bronchiectasis. It has a prevalence in the United States of 5.1% to 5.4% in the middle-aged to elderly population, with a lower rate in nonsmoking individuals. Moreover, COPD is complicated by frequent and recurring acute exacerbations of chronic bronchitis (AECB). Overall, COPD represents the fourth leading cause of mortality in the United States and is the second leading cause of work disability. This condition is also associated with high morbidity and health care expenditures. Despite the controversy over the need to prescribe antibiotics for patients with AECB, high-risk patients have been identified who will benefit from this therapy.These include, patients with a history of repeated infections (>4 per year), comorbid illnesses (such as diabetes, asthma, coronary heart disease), or marked airway obstruction. Furthermore, a bacterial cause is shown in approximately 50% of AECB episodes, and primarily includes Haemophilus influenzae, Moraxella catarrhalis, and Streptococcus pneumoniae. Additionally, resistance among community-acquired respiratory pathogens in the United States has risen dramatically, with beta-lactamase production evident in 40% of H. influenzae and greater than 95% of M. catarrhalis isolates, and with approximately 10% of pneumococci highly resistant to penicillin and simultaneously resistant to macrolide antibiotics. The criteria used to make choices for antibiotic use in patients with AECB should include knowledge of the frequencies of pathogen resistance and patients' clinical characteristics. An effective antibiotic, however, must be able to rapidly resolve the acute infection with the least patient morbidity and need for hospitalization. Although there remains controversy as to when to initiate antibiotic therapy in patients with AECB, several guidelines have been published.     

Newer oral antimicrobials and newer etiologic agents of acute bronchitis and acute exacerbations of chronic bronchitis

Although the role of antimicrobial therapy in the treatment of chronic bronchitis is unproven, physicians continue to look for microbial etiologies to explain episodes of clinical acute bronchitis and better antimicrobial agents with which to treat these episodes. The newest major pathogen of acute bronchitis is Branhamella catarrhalis, a neisseriae-like organism that has become the third most commonly recognized cause of this disease after Haemophilus influenzae and Streptococcus pneumoniae. Because it produces beta-lactamase, B catarrhalis presents a special problem in drug therapy. A number of newer antimicrobials have been introduced which offer potential in the therapy of acute bronchitis, including the enteric coated erythromycins, several new oral cephalosporins, and a large new class of drugs called the fluorinated quinolones. This report addresses the current level of knowledge on these newer agents and therapies of acute bronchitis.     

Pharmacoeconomic evaluation of acute exacerbations of chronic bronchitis and COPD

BACKGROUND: Although exacerbations are the main cause of medical visits and hospitalizations of patients with chronic bronchitis and COPD, little information is available on the costs of their management. OBJECTIVE: This study attempted to determine the total direct costs derived from the management of exacerbations of chronic bronchitis and COPD in an ambulatory setting. METHOD: A total of 2,414 patients with exacerbated chronic bronchitis and COPD were recruited from 268 general practices located throughout Spain. Patients were followed up for 1 month. RESULTS: A total of 507 patients (21%) relapsed; of these, 161 patients (31.7%) required attention in emergency departments and 84 patients (16.5%) were admitted to the hospital. The total direct mean cost of all exacerbations was $159; patients who were hospitalized generated 58% of the total cost. Cost per failure was $477.50, and failures were responsible for an added mean cost of $100.30/exacerbation. Exacerbations of the 1,130 patients with COPD had a mean cost of $141. Sensitivity analysis showed that a 50% reduction in the failure rate (from 21 to 10.5%) would result in a total cost of exacerbation of $107 (33% reduction). CONCLUSION: Exacerbations of chronic bronchitis and COPD are costly, but the greatest part of costs derives from therapeutic failures, particularly those that end in hospitalization.     

Cefuroxime axetil in acute purulent exacerbations of chronic bronchitis

Summary 51 hospitalised patients with acute purulent exacerbations of chronic bronchitis were treated for ten days with two daily 1 g doses of the orally absorbed pro-drug cefuroxime axetil. However, some patients were still infected withHaemophilus influenzae orBranhamella catarrhalis at follow-up, and sputum purulence remained. Clinical results were excellent or good in 60% of the evaluable patients one week after the end of the treatment. Mean peak serum concentrations averaged 12.8 mg/l with mean peak sputum concentrations of 1.8 mg/l. The MIC₉₀ value forH. influenzae was 4 mg/l. Three patients discontinued cefuroxime because of unwanted gastrointestinal drug effects, and three because of insufficient improvement. These results do not suggest that this compound is indicated for such patients.

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Cefuroxim-Axetil bei akuter eitriger Exazerbation chronischer Bronchitis

Zusammenfassung 51 stationäre Patienten mit akuter eitriger Exazerbation ihrer chronischen Bronchitis erhielten zehn Tage lang eine Behandlung mit zweimal täglich 1 g der oral resorbierbaren Prodrug Cefuroxim-Axetil. Bei der Nachuntersuchung bestand bei einigen Patienten weiterhin eine Infektion mitHaemophilus influenzae oderBranhamella catarrhalis mit eitrigem Sputum. Bei 60% der auswertbaren Patienten wurden die klinischen Ergebnisse eine Woche nach Behandlungsende als ausgezeichnet oder gut beurteilt. Die Serum-Spitzenspiegel der Substanz betrugen im Mittel 12,8 mg/l, die maximalen Wirkstoffspiegel im Sputum lagen im Mittel bei 1,8 mg/l. Der MHK₉₀-Wert fürHaemophilus influenzae betrug 4 mg/l. Gastrointestinale Beschwerden führten bei drei Patienten zum Absetzen von Cefuroxim; bei drei Patienten wurde die Behandlung abgesetzt, da keine ausreichende Besserung eintrat. Aus diesen Ergebnissen ist zu schließen, daß sich diese Verbindung nicht zur Behandlung solcher Patienten eignet.

     

Rufloxacin once daily in acute exacerbations of chronic bronchitis

Summary In this open study the efficacy and tolerability of rufloxacin in a single dose of 400 mg the first day and 200 mg the nine consecutive days was studied in 26 patients with an acute exacerbation of chronic bronchitis. Twenty-two patients were evaluable for efficacy. Four patients stopped treatment prematurely after five days because of clinical cure. At the enrollment visit a pathogen was isolated in the sputum sample in 19 of 22 evaluable patients. The predominant pathogens wereStreptococcus pneumoniae andMoraxella catarrhalis. In 17 of these 19 bacteriologically evaluable patients the initial infecting organism was eradicated from specimens obtained within 48 hours after the end of therapy. There was one case of persistent infection caused byS. pneumoniae (MIC 4 mg/l), one patient had a superinfection withSerratia marcescens (MIC 1 mg/l) susceptible to rufloxacin and therapy was stopped after five days due to clinical failure. One week after the end of therapy, 15 patients remained free from infection whilst one patient experienced reinfection withKlebsiella pneumoniae (MIC 0.5 mg/l). Clinical cure or improvement was observed in 21 of 22 patients. Mild adverse events were reported by two of 26 enrolled patients. In one patient, complaining of headache and dizziness, the adverse events were considered possibly study drug related. No abnormal laboratory findings were reported. Nadir plasma levels of rufloxacin were measured and no accumulation in plasma was observed during treatment. A ten day course of an oral single dose of rufloxacin proved efficacious and was well tolerated in patients with an acute exacerbation of chronic bronchitis. A multicentre, multinational, double-blind study is now in progress to compare the efficacy and tolerability of rufloxacin with amoxycillin in patients with acute exacerbations of chronic bronchitis.

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Rufloxacin bei chronischer Bronchitis

Zusammenfassung In einer offenen Studie wurden 26 Patienten mit akuter Exazerbation einer chronischen Bronchitis mit Rufloxacin in einmal täglicher Applikation von 400 mg am ersten und 200 mg an den weiteren neun Therapietagen behandelt. Die Verträglichkeit der Therapie wurde bei allen, die Wirksamkeit bei 24 Patienten ausgewertet. Wegen frühzeitiger klinischer Heilung beendeten vier Patienten die Behandlung vorzeitig am fünften Tag. Aus den vor der Therapie entnommenen Sputumproben wurde in 19 von 22 Fällen ein Erreger angezüchtet, vorwiegendStreptococcus pneumoniae undMoraxella catarrhalis. 48 Stunden nach Therapieende war bei 17 dieser 19 Patienten der initial isolierte Erreger aus dem Sputum verschwunden. In einem Fall persistierteS. pneumoniae (MHK 4 mg/l), ein Patient hatte eine Superinfektion mit einemin vitro empfindlichenSerratia marcescens-Stamm, sprach aber auf Rufloxacin nicht an, daher wurde das Antibiotikum nach fünf Tagen abgesetzt. Eine Woche nach Therapieende waren 15 Patienten ohne Infektion, in einem Fall war eine Reinfektion durchKlebsiella pneumoniae (MHK 0,5 mg/l) aufgetreten. Bei 21 der 22 Patienten trat eine klinische Heilung oder Besserung ein. Zwei der 26 Patienten berichteten über leichte Nebenwirkungen, die in einem Fall von Kopfschmerzen und Benommenheit als möglicherweise therapiebedingt angesehen wurden. Laborwertveränderungen waren nicht festzustellen. Aus den Meßwerten der Rufloxacin-Talspiegel ergab sich kein Hinweis für eine Kumulation von Rufloxacin im Plasma. Die zehntägige Behandlung mit Rufloxacin in Einmaltagesdosierung erwies sich bei Patienten mit akuter Exazerbation einer chronischen Bronchitis als wirksam und gut verträglich. Eine doppelblind geführte Vergleichsstudie zur Wirksamkeit und Sicherheit von Rufloxacin im Vergleich zu Amoxicillin bei Patienten mit akuter Exazerbation einer chronischen Bronchitis wird derzeit international multizentrisch durchgeführt.

     

Treatment of acute exacerbations of chronic bronchitis: antibiotic therapy

Acute exacerbation of chronic bronchitis (AECB) is a condition associated with increased morbidity and mortality. Bacterial infections are the most frequent cause of exacerbations. The most common bacterial etiologies include Haemophilus influenzae, Moraxella catarrhalis, and Streptococcus pneumonia. The diagnosis of AECB is often based on the clinical presentation, but microbiological assessment, including Gram stain and sputum culture should be done. Antibiotic therapy should be used in patients with the following characteristics: underlying lung disease, frequent exacerbations, and comorbid conditions. Penicillins, erythromycin, beta-lactamase inhibitors, and trimethoprim-sulfamethoxazole have been the preferred antibiotics. However, because of the increasing prevalence of resistance among respiratory pathogens, mainly the production of beta-lactamase by H. influenzae and M. catarrhalis, and the emergence of multidrug-resistant S. pneumonia, new generation macrolides and fluoroquinolones should be the first line of treatment in selected patients. These drugs have increased efficacy and safety.     

Acute exacerbations of chronic bronchitis

Acute exacerbations of chronic bronchitis are one of the major public health challenges. New data suggest that they will remain so for many years. Although the role of bacteria in the initiation and maintenance of bronchial inflammation, both during and between exacerbations, is well recognized, studies of the long-term effects of therapy are few and inadequate, and the nature of the relationship with disease progression is largely unknown. Data are beginning to emerge that firmly link bacterial inflammation and progressive disease with physiological and functional disability. Methods are being developed to provide integrated, uncomplicated and reproducible assessments of health-related quality of life. These may prove fundamental to the proper investigation of new treatment modalities. Among the newer antibacterial agents, fluoroquinolones have received most investigative attention, regrettably usually without providing clinical confirmation of their obvious superiority in vitro and of their pharmacokinetic and related pharmacodynamic properties. New trial designs need to address an integrated outcome analysis, with the assessment of long-term benefit and pharmaco-economic monitoring. More antibacterial agents are available at the millennium than ever before. After 50 years, it would be preferable if we knew a little more about their role in this complex disease.     

Bronchial inflammation in acute bacterial exacerbations of chronic bronchitis: the role of leukotriene B4.

Neutrophils recruited to the airways in chronic obstructive pulmonary disease (COPD) are thought to mediate tissue destruction. Neutrophil recruitment is increased during bacterial exacerbations. The inflammatory process was studied in patients with an acute exacerbation of COPD in order to ascertain the role of leukotriene B4 (LTB4). The sputum of eight subjects with a bacterial exacerbation of COPD was analysed for neutrophil products (myeloperoxidase, elastase) and chemoattractants (interleukin-8 (IL-8) and LTB4). The contribution of LTB4 to the chemotactic activity of the sputum sol phase was determined using the LTB4 receptor antagonist LY293111. The concentrations of the serum acute phase proteins alpha1-proteinase inhibitor, alpha1-antichymotrypsin and C-reactive protein were measured. All patients received appropriate broad-spectrum antibiotic treatment for 7-14 days. Initially, the sputum myeloperoxidase activity was high, indicating neutrophil influx; this was associated with high levels of IL-8 and LTB4. All these concentrations fell with treatment (p<0.01). The chemotactic activity of the sputum was raised on presentation and fell with treatment (p<0.01). LTB4 contributed approximately 30% of the total chemotactic activity on presentation; this diminished with therapy. All acute phase proteins were raised on presentation and fell with therapy (p<0.01). These findings suggest that leukotriene B4 contributes to neutrophil influx into the airway in chronic obstructive pulmonary disease and may influence disease progression.     

Evidence of bacterial infection in acute exacerbations of chronic bronchitis

The frequency with which bacterial infection causes exacerbations of chronic obstructive pulmonary disease (COPD) may depend on the dominant pathology present; patients with chronic bronchitis are more susceptible to bacterial bronchial infections than those at the emphysema or asthma ends of the spectrum. However, impairment in respiratory function may be very important in governing the outcome of an exacerbation. Placebo-controlled trials have provided conflicting evidence of the efficacy of antibiotics in acute exacerbations. Overall, there is a significant benefit, particularly in certain patient groups, defined by symptoms and past history. Haemophilus influenzae, Streptococcus pneumoniae, and Moraxella catarrhalis are the species most commonly isolated during exacerbations, and the same species may colonize the bronchial mucosa when the patient is in a stable state. Evidence is accumulating that bacteria are an independent stimulus of mucus hypersecretion and bronchial inflammation, and that they interact with other stimuli such as viral infection, atmospheric pollution, and tobacco smoke. New approaches are being used to investigate the importance of bacterial infection in patients with COPD.There are several good reasons why new more potent antibiotics might be expected to be superior to older standard compounds in the management of patients with problematic COPD. However, future studies should aim to confirm that bacteriologic superiority translates into improved clinical outcomes, and seek to measure the level of benefit.     

Infection in acute exacerbations of chronic bronchitis: a clinical perspective

Acute exacerbations of chronic bronchitis (AECB) is an important cause of death and morbidity in developed countries and also has significant economic impact. The disease is characterized by increased dyspnoea, sputum volume and sputum purulence; the most commonly associated pathogens are Haemophilus influenzae, Streptococcus pneumoniae and Moraxella catarrhalis. H. influenzae and S. pneumoniae express virulence determinants that directly and indirectly impair mucociliary clearance and incite other consequences that are permissive to microbial persistence. Regarding the use of antibiotics, there is currently a lack of large-scale clinical trials that are sufficiently powerful to provide good evidence-based information. Nonetheless, antimicrobial chemotherapy has repeatedly been shown to confer benefit in patients with moderately severe features of AECB. Simple clinical criteria can be used to identify patients in whom there is a higher likelihood of treatment failure or mortality during AECB. These include significant cardiopulmonary co-morbidity, frequent exacerbations, advanced decline in lung function, malnutrition or other generalized debility, advanced age (>70 years) and concurrent treatment with corticosteroids. In such patients, an aggressive antimicrobial approach to AECB may be warranted in order to prevent clinical failure or representation. From a clinical perspective, appropriate drugs include those that are stable to beta-lactamases, are bactericidal against causative pathogens, penetrate diseased lung tissue in high concentrations and have a good safety profile.