Introduction

Bruce K. Rubin, MEngr, MD, FACP(C), Professor and Vice-Chair for Research, Department of Pediatrics Acting Section Chief, Pediatric Pulmonology, Allergy, and Immunology Professor of Medicine, Physiology and Pharmacology, Wake Forest University School of Medicine, Winston-Salem, North Carolina; Adjunct Professor of Chemistry, University of North Carolina, Greensboro

Erythromycin was first isolated in the 1950s from a Phillipine soil sample, and the derivatives of erythromycin A, called macrolide antibiotics, have since been used as effective antibacterial agents. It has long been suspected that the macrolides have immunomodulatory activity as demonstrated by their early use as adjunctive therapy for asthma and their astounding effectiveness for the therapy of diffuse panbronchiolitis. In-vitro, the 14-membered derivatives such as clarithromycin, decrease neutrophil oxidative burst and proinflammatory cytokine generation and release, and may affect neutrophil chemotaxis. Recent studies also suggest an epithelial cell membrane 'stabilization' effect. Macrolides can decrease mucus hypersecretion both in-vitro and in-vivo.

It is now clear that the macrolides, the 15-membered azalides, and perhaps the ketolides, have a broad range of biological response modifying effects on inflammation, tumour cells, airway secretions, and host defences. The clinical uses of macrolides as biological response modifiers have also been studied for the therapy of a range of diseases, including bronchiectasis, sinus disease, cystic fibrosis, Pneumocystis carinii pneumonia, asthma, and inflammatory disorders. The mechanism(s) for the immunomodulatory effects of the macrolides are not clear. However, these effects seem to be greatest with the 14- and 15-membered derivatives of erythromycin A and least with the 16-membered macrolide agents. As many of these reported studies conducted are small and of short duration, additional research is needed to answer some of the unknowns in this area. There are three main questions. What are the mechanism(s) of action for these immunomodulatory effects? What is the optimal dosage and duration of use for the treatment of chronic inflammatory diseases? Are there other chronic inflammatory diseases that would benefit from macrolide therapy as biological response modifiers? Additional, larger, well-controlled studies will assist in developing safe and appropriate clinical recommendations for treatment and elucidating the mechanism of action for these effects.

Prevalence of COPD

Chronic obstructive pulmonary disease (COPD) and other chronic lung conditions pose a therapeutic challenge that continues to grow in scope. More than 14 million Americans have COPD, which accounts for more than 100,000 deaths a year, making COPD the fourth leading cause of death in North America [Am J Respir Crit Care Med, 1995, 152(suppl):S78-S120; Mon Vital Stat Rep, 1996, 45(suppl):23]. COPD-related mortality has increased substantially over the past two decades, primarily due to cigarette smoking, especially among white women and black men (Clinical Epidemiology of Chronic Obstructive Pulmonary Disease. New York: Marcel Dekker, 1990:23-43; Principles and Practice of Pulmonary Rehabilitation. Philadelphia: WB Saunders Co, 1993:10-17). Currently, COPD is the only common cause of mortality that continues to increase in prevelance (N Engl J Med, 2000, 343:269-280).

COPD encompasses a spectrum of inflammatory disorders characterized by cough, sputum production, dyspnea, airflow limitation, and impaired gas exchange. An estimated 90 percent of all COPD cases fall into the diagnostic category of chronic bronchitis (Am J Respir Crit Care Med, 1995, 152(suppl):S78-S120). The incidence of chronic bronchitis continues to increase, especially among individuals ages 65 and older (Morbidity and Mortality: 1996 Chartbook on Cardiovascular, Lung, and Blood Diseases:52). COPD encompasses chronic bronchitis, emphysema, and acute exacerbations of chronic bronchitis (ICD-9-CM Coding Handbook, 1989).

COPD results in more than 14 million physician office visits and 500,000 hospitalizations each year (Morbidity and Mortality: 1996 Chartbook on Cardiovascular, Lung, and Blood Diseases: 52). Major risk factors for COPD include smoking, exposure to tobacco smoke, exposure to domestic and occupational pollutants, and a history of recurrent respiratory tract infections, especially during infancy (Am Rev Respir Dis, 1996, 94:709-720; Clin Chest Med, 1990, 11:375-387).

Acute exacerbations of chronic bronchitis (AECB) affect five to six percent of Americans each year (DHHS, 1999), primarily affecting elderly patients, immunocompromised individuals, and those with COPD. Bacterial pathogens are implicated in at least half of AECB. The most commonly isolated pathogens are Hemophilus influenzae, H. parainfluenzae, Streptococcus pneumoniae, and Moraxella catarrhalis (Chest, 1995, 108(suppl 2):43S-52S; Postgrad Med, 1994, 96:75-76, 79-82, 87-89). Macrolide antibiotics have emerged as an intriguing therapeutic option for AECB and other manifestations of COPD. Aside from their antimicrobial activity, at least some macrolides have demonstrated anti-inflammatory and mucoregulatory properties, both of which might be of benefit in treating chronic lung disorders. Although several antibiotics are indicated for the treatment of AECB, current clinical design required by the FDA does not differentiate these approved drugs with regard to clinical efficacy.

Current Trends in Therapy

A review of recent trends in COPD hospitalizations in the Veterans' Affairs (VA) system documented an increasing rate of hospitalization (Chest 2000, 118(suppl 4):184S). Between 1991 and 1998, total hospitalization decreased by 36 percent nationally, reported David Dedrick, MD, a pulmonary and critical care medicine specialist at the University of New Mexico. However, hospitalizations for COPD increased 14.3 percent nationally, 13.3 percent for the Western Region (which includes New Mexico), and 104 percent for Albuquerque VA Hospital.

Antibiotic Therapy in Emergency Departments

Initial findings from an ongoing US study suggest underuse of antibiotics in the treatment of older patients who present to emergency departments for evaluation and treatment of obstructive airway disease (Chest 2000, 118(suppl 4):135S). The observation emerged from an analysis of data from the MARC-7 prospective cohort study of patients presenting to 19 emergency departments (EDs) in North America. The study is limited to individuals ages 55 and older, who have physician-diagnosed obstructive airway disease, including asthma, COPD, chronic bronchitis, and emphysema.

The initial 334 subjects consisted of 98 patients with asthma, 104 with asthma and COPD, and 131 with COPD only, according to Sandra Adams, MD, a pulmonary and critical care medicine specialist at the University of Texas at San Antonio. Overall, antibiotic use in the ED was low, but patients with COPD were most likely to receive prescriptions (39 percent), compared to patients with both asthma and COPD or asthma alone (20 percent each).

Antibiotic therapy in the ED was associated with the presence of comorbid conditions, such as pneumonia (37 percent vs six percent, p < 0.001). Patients who received antibiotics were more likely to be admitted to the hospital (89 percent vs 47 percent, p < 0.001), although the degree of dyspnea was similar between patients who received antibiotics and those who did not. Among patients who were on antibiotics at discharge, 89 percent did not have pneumonia. Azithromycin (Zithromax®) and clarithromycin (Biaxin®) were the most commonly prescribed antibiotics at discharge. Patients who were on antibiotics at discharge were less likely to report that their symptoms were the same or worse, as compared to patients who did not receive antibiotics (nine percent vs 22 percent, p = 0.08).

Dr. Adams and her co-investigators concluded that these data suggest underuse of antibiotics in the management of obstructive airway disease in patients who present to emergency departments.

Evaluation of Risk Factors for Acute Bacterial Exacerbations in COPD Patients

Preliminary findings from an ongoing Italian study suggest that specific clinical and demographic parameters might be useful for predicting which COPD patients will have AECB (Chest 2000, 118(suppl 4):242S). Salvatore Lo Cicero, MD, a pulmonologist at Niguarda Hospital in Milan, presented data from a study involving 1,063 stable COPD patients. The presentation focused on characteristics of 125 patients who had AECB during the first six months of follow-up, as compared to patients who did not have exacerbations.

The preliminary analysis showed a significant association between the risk for exacerbation and a patient's baseline score on the Canadian COPD guidelines (Odds Ratio 10, p < 0.001), but not with the American Thoracic Society or European Respiratory Society guidelines-which focus more on degree of obstruction. Several individual measurements identified by the Canadian guidelines were significantly associated with an increased risk of exacerbation: cardiac comorbidity (p < 0.007), number of exacerbations in the previous year (p < 0.001), COPD duration (p < 0.001), sputum volume (p < 0.004), cigarette smoking (p < 0.005), and severity of dyspnea (p < 0.004). Data on all 1,063 patients should be available in time for the American Thoracic Society meeting (May 18-23, 2001), at which time more definitive statements about the prognostic value of specific clinical measurements might be possible.

Specific Assessments for Determining Outcome of Therapy

Investigators in a multicenter clinical trial evaluated the use of specific parameters in patients > 40 years of age with a diagnosis of COPD and acute symptoms based on Anthonesin criteria as entry criteria for clinical trials (Chest 2000, 118(suppl 4):190S). Secondly, they assessed the feasibility of using exercise tolerance as a clinical endpoint. Current US Food and Drug Administration guidelines for clinical trials for acute exacerbation of chronic bronchitis define chronic bronchitis as cough and sputum production on most days during three consecutive months for more than two years. The authors concluded that having better defined parameters for trial inclusion would help distinguish patients and identify the most useful therapies.

The trial included 288 patients who had presumptive AECB and Anthonesin type I symptom criteria of increased dyspnea, increased sputum production, a Gram stain consistent with lower respiratory tract infection, and a medical history or pulmonary function tests giving evidence of COPD. The patients were randomized to receive clarithromycin (Biaxin®) XL 1 gm QD for seven days or amoxicillin/clavulanate potassium (Augmentin®) 875 mg BID for ten days. As part of the evaluation process, patients were asked to perform a six-minute walk at study entry, at the end of assigned treatment, and at a test-of-cure office visit approximately two weeks after completing therapy. These investigators concluded that outcomes other than those specified by the FDA for clinical trials might be used to assess the effect of treatments for COPD. Other measurements such as exercise testing and patients' self-assessment of how they feel after treatment could be especially useful for monitoring response to therapy in clinical practice.

The overall clinical cure rate was 86 percent at the test-of-cure visit and did not differ between the two treatment groups. Similarly, patients in both treatment groups demonstrated improvement in walking distance and dyspnea associated with walking from entry to the test-of-cure visit. However, there was a large degree of intersubject variability, and these changes were not statistically significant. Clarithromycin was better tolerated, as significantly fewer premature discontinuations (three percent vs 12 percent, p = 0.005) occurred in patients treated with clarithromycin. Patient-assessed severity of adverse events also was significantly lower in the clarithromycin cohort, when assessed as all events (p = 0.016) or drug related gastrointestinal events (p = 0.0387). Moreover, 80 percent of clarithromycin patients reported feeling "good" or "excellent and very good" at the end of therapy, compared to 75 percent of amoxicillin/clavulanate potassium patients (p = 0.041).

Mucoregulatory

Among available antibiotic agents, macrolides may offer advantages that distinguish them from other antibiotics, according to Bruce K. Rubin, MEngr, MD, FRCP(C). Dr. Rubin noted that macrolides have demonstrated mucoregulatory activities that have the effect of decreasing mucus secretion by inflamed airway tissue (J Allergy Clin Immunol, 1986, 77:330-334; J Allergy Clin Immunol, 1991, 87:1050-1055; Antimicrob Agents Chemo, 1995, 39:1688-1690; J Thoracic Dis, 1991, 29:72-83). Notably, macrolides do not inhibit mucus secretion in non-inflamed airway tissue. The mucoregulatory effects are most pronounced in the 14-member macrolide agents, which include clarithromycin (Biaxin®) and erythromycin.

In an earlier presentation at the European Congress on Chemotherapy, Dr. Rubin reviewed other non-antibiotic properties of macrolides. Of particular relevance to chronic lung disease, macrolides have been shown to have anti-inflammatory and immunomodulatory effects (Curr Opin Investigational Drugs, 2000). The immunomodulatory effects have led to clinical evaluation of macrolides in conditions such as corticosteroid-dependent asthma (Mark Gotfried, et al. Placebo-Controlled Trial Evaluating the Efficacy of Clarithromycin in Subjects with Cortiosteroid-Dependent Asthma, in press), bronchiectasis, sinus disease, and cystic fibrosis. The anti-inflammatory effects of macrolides appear related to the agent's ability to inhibit pro-inflammatory cytokines and reactive oxygen species.

Though intriguing, the non-antibiotic effects of macrolide antibiotics remain unclear from a mechanistic standpoint. On-going studies aimed at elucidating the mechanisms of these effects hold substantial importance for the application of macrolides in chronic lung diseases, according to Dr. Rubin.