Macrolide effects on the prevention of COPD exacerbations

Prospective randomised study in Japan

Suzuki et al. [49] were the first to perform a prospective study on the clinical benefits that erythromycin has in preventing COPD exacerbations (table 1). The authors performed a prospective, randomised, controlled (but not blinded) trial. A total of 109 patients with COPD were enrolled and randomly assigned to erythromycin therapy or no active treatment. The mean forced expiratory volume in 1 s (FEV₁) values were 1.30 L·s⁻¹ in the control group and 1.47 L·s⁻¹ in the erythromycin group. COPD patients who exhibited bronchiectasis and DPB complications were excluded from the study. The patients in the erythromycin group received erythromycin 200–400 mg·day⁻¹ and the patients in the control group received riboflavin in addition to sustained-release theophylline and inhaled anti-cholinergic agents. The observation period was 12 months. The authors did not examine the bacteria in the sputum in this study. The mean number of exacerbations and the mean number of common colds in the patients in the erythromycin group were lower than those in the control group. Furthermore, more patients were hospitalised due to exacerbations in the control group than in the erythromycin group. These findings suggest that erythromycin has beneficial clinical effects in moderate-to-severe COPD patients with frequent exacerbations due to upper respiratory tract infections. One patient in the erythromycin group had anorexia and diarrhoea and was excluded from the study, whereas the rest of the patients in the erythromycin group did not have any apparent adverse effects from erythromycin therapy during the study period. Based on these findings, the authors concluded that erythromycin therapy has beneficial effects on the prevention of COPD exacerbations. However, the authors also concluded that this intervention should be restricted to patients who are at high risk for COPD exacerbations because of the potential risk of the emergence of erythromycin-resistant pathogens.

Multicentre retrospective study in Japan

Because the prospective study by Suzuki et al. [49] was performed in the hospitals within one prefecture in Japan, our group performed a multicentre study in Japan [50]. We analysed the records of 123 patients in seven Japanese university hospitals and one Japanese general hospital. Of this group, 45 patients received macrolide therapy (macrolide group) and 78 patients did not (control group). The proportion of macrolide-receiving patients with symptoms of sputum (84%, p<0.03) was larger than that in the control group (68%). The macrolide-receiving patients were distributed among the Global Initiative for Chronic Obstructive Lung Disease (GOLD) classification stages as follows: GOLD stage I, 9%; GOLD stage II, 67%; GOLD stage III, 18%; and GOLD stage IV 7%. The severity of the GOLD stages in the macrolide group did not differ from the stage severity in the control group. The mean observation period was 42.9 months. The COPD patients participating in this study were treated with inhaled anti-cholinergic agents, long-acting β₂-agonists and sustained-release theophylline or inhaled steroids. The patients in the macrolide group received daily clarithromycin (200–800 mg·day⁻¹) or erythromycin (200–1,200 mg·day⁻¹) for the observation period. A total of 41 patients were treated with clarithromycin or erythromycin alone, and another four patients were treated with clarithromycin and erythromycin at different times. The number of patients with an exacerbation frequency of ≥1.5 times per year was lower in the macrolide group than in the control group. Likewise, the number of patients with a hospitalisation frequency of ≥0.75 times per year was lower in the macrolide group than in the control group. The patients did not have any apparent adverse effects from erythromycin or clarithromycin treatment. This retrospective multicentre clinical study suggested that macrolide treatment may reduce the frequency of exacerbations and hospitalisation due to the exacerbations in Japanese patients with moderate-to-severe COPD who exhibit frequent exacerbations and hospitalisation and complained of sputum.

Prospective, randomised, double-blind, placebo-controlled study

Based on the report by Suzuki et al. [49], Seemungal et al. [51] designed and performed a randomised, double-blind, placebo-controlled study to examine the effects of long-term erythromycin therapy on the prevention of COPD exacerbations. The authors randomised 109 outpatients and observed the number of exacerbations for 12 months. Patients were included in the study if they had moderate-to-severe COPD with FEV₁ between 30% and 70% predicted. The mean FEV₁ and FEV₁ % predicted values of the enrolled patients were 1.32 L·s⁻¹ and 50%, respectively. Of these, 38 patients had three or more exacerbations in the year prior to recruitment. The patients received inhaled steroids (78%), long-acting β₂-agonists (63%), long-acting anti-cholinergic agents (33%) or theophylline (11%). Furthermore, 53 patients in the erythromycin group received erythromycin (250 mg twice daily). There was a total of 206 moderate to severe exacerbations in 109 of the patients who were enrolled, with 125 exacerbations occurring in the 56 patients in the placebo group. The frequency of moderate to severe exacerbations in the erythromycin group was lower than that in the placebo group. The duration of exacerbations in the erythromycin group was shorter than that in the placebo group, and the time to first exacerbation was longer for the erythromycin group than for the placebo group. There was no significant difference in adverse effects between the erythromycin and placebo groups. The frequency of adverse effects was low in both groups. In some cases, more than one adverse effect occurred in the same patient; e.g. an upper gastrointestinal symptom occurred in a patient who also had tinnitus.

There was no difference in the microorganism detection rate in the spontaneously produced sputum of the two study groups at any of the follow-up time-points over the 1-yr study period. Of the samples taken during stable conditions, 27% tested positive for Haemophilus influenzae, as did 40% of the samples taken during an exacerbation. The distribution for Streptococcus pneumoniae was 7% during stable conditions and 10% during exacerbation. Furthermore, pathogens were detected in 17 out of the 43 sputum samples at the 12-month follow-up visit and included H. influenzae (placebo group n=3, macrolide group n=1), S. pneumoniae (placebo group n=2, macrolide group n=1) and Moraxella catarrhalis (placebo group n=2). Sensitivity tests showed that all four of the H. influenzae samples were resistant to erythromycin and one S. pneumoniae sample from the macrolide group was also resistant to erythromycin. Based on the findings of the sensitivity test, the authors suggested that there were no differences between the macrolide and placebo groups in terms of the bacterial flora in the sputum [51]. The authors concluded that macrolide therapy may be useful in decreasing the excessive disease burden in patients with COPD. Macrolide therapy may have clinical benefits in moderate-to-severe COPD patients with frequent exacerbations.

He et al. [52] performed a randomised, placebo-controlled, double-blind erythromycin trial for a 6-month period. In this study, 36 COPD patients were randomised to treatment with oral erythromycin (n=18, 125 mg three times per day) or placebo (n=18) daily. A total of 31 patients completed the study (16 patients in the erythromycin group and 15 patients in the placebo group). The mean FEV₁ value was 1.1 L·s⁻¹ in both groups, and the FEV₁ % predicted value was 42% in the placebo group and 44% in the erythromycin group. These values suggest that primarily severe COPD patients were enrolled in the study. There were a total of 31 moderate-severe exacerbations over the 6-month treatment period, of which 20 occurred in the placebo group and 11 in the erythromycin group. Erythromycin therapy reduced the mean exacerbation rate and delayed the time to the first exacerbation. The neutrophil counts and neutrophil elastase levels in the sputum were decreased in the patients in the erythromycin group. Two patients discontinued their participation in the study. One patient had abdominal pain after erythromycin treatment, and another experienced left heart failure. A bacterial examination test showed that there was no difference in the detection rates for the three main microorganisms (S. pneumoniae, H. influenzae and M. catarrhalis) between the two groups at baseline or after 6 months of treatment. The three main pathogens that were detected at the 6-month time-point were S. pneumoniae (placebo group n=3, erythromycin group n=2), H. influenzae (placebo group n=2, erythromycin group n=2) and M. catarrhalis (placebo group n=2, erythromycin group n=1). The authors concluded that erythromycin treatment in COPD patients can reduce airway inflammation and decrease exacerbations, and may therefore be useful in the management of COPD. Erythromycin therapy may reduce the frequency of exacerbations and airway inflammation in severe COPD patients who experience frequent exacerbations.

Banerjee et al. [13] performed a controlled study in 67 patients with COPD. The patients were randomised to 3 months of clarithromycin (500 mg daily) or placebo and were observed for 3 months. Overall, 26 patients receiving clarithromycin and 34 receiving placebo completed the trial. The mean FEV₁ value was 44% pred in the placebo group and 43% pred in the clarithromycin group. These values suggest that primarily severe GOLD stage COPD patients were enrolled in the study. One patient from the clarithromycin group had gastrointestinal symptoms and withdrew from the study. The pathogen growth rate in the sputum of the clarithromycin group was similar before treatment (55%) and after 3 months of treatment (58%). However, the frequency of exacerbations in the clarithromycin group (n=5) did not differ from that of the control group (n=2). The exacerbation frequency was smaller in this study than in others [49–53]. Macrolide therapy may not be necessary in patients who do not have frequent exacerbations.

Randomised trial investigating the effects of azithromycin

To examine the effects that macrolide therapy has on COPD exacerbations, Albert et al. [53] performed a prospective, parallel-group, placebo-controlled study, for which 1,577 subjects were screened. Moderate-to-very severe GOLD stage COPD patients were enrolled in this study. None of the COPD patients were in mild GOLD stage. The mean FEV₁ value was 1.1 L·s⁻¹ in both the placebo and azithromycin groups, and the mean FEV₁ % predicted value was 40% in the placebo group and 39% in the azithromycin group. The patients were either using continuous supplemental oxygen or had received systemic glucocorticoids within the previous year [53]. The patients had visited an emergency room or had been hospitalised for an acute COPD exacerbation, but had not experienced an acute COPD exacerbation for at least 4 weeks before enrolment [53]. A total of 1,142 (72%) patients were randomly assigned to receive 250 mg azithromycin (n=570) or placebo (n=572) daily for 1 yr (in addition to their usual care). In addition to azithromycin or placebo, the patients received inhaled steroids (76%), long-acting β₂-agonists (73%), long-acting anti-cholinergic agents (62%) or no medication (9%) as their usual care. The time to the first exacerbation was longer in the azithromycin group than the placebo group, and the COPD exacerbation frequency in the azithromycin group was lower than that in the placebo group. The rate of COPD exacerbations per patient per year was 1.48 in the azithromycin group and 1.83 in the placebo group, and the exacerbation rates in this study were higher than those in the other previously reported [49, 50]. The total St George's Respiratory Questionnaire scores decreased in the azithromycin group, showing an improvement in patient QoL.

No significant differences were observed in the frequency of serious adverse events or adverse events leading to the discontinuation of the study drug. However, hearing decrements were more common in the azithromycin group (n=142, 25%) than in the placebo group (n=110, 20%; p=0.04). Although all of these COPD patients should have had their study drug discontinued, the drug was discontinued in only 61 (76%) patients in the azithromycin group and 37 (82%) in the placebo group, owing to protocol errors.

At the time of enrolment, the rate of selected respiratory pathogen colonisation in the nasopharyngeal swabs from the azithromycin group (14%) did not differ from that in the placebo group (15%). However, more patients in the placebo group (31%) than the azithromycin group (12%) became colonised during the course of the study. Susceptibility testing revealed that the prevalence of respiratory pathogen resistance to macrolides in the azithromycin group (52%) did not differ from that in the placebo group (57%, p=0.64) at the time of enrolment. In contrast, the test investigating the pathogens from the COPD patients who were not colonised at the time of enrolment but became colonised during the course of the study revealed that the incidence of resistance to macrolides was higher (81%) in the azithromycin group than the placebo group (41%, p<0.001). Thus, COPD patients receiving azithromycin were less likely to become colonised with respiratory pathogens but were more likely to become colonised with macrolide-resistant organisms [53].

Based on these findings, the authors concluded that azithromycin treatment decreased COPD exacerbations and improved QoL, but caused hearing decrements in a small percentage of subjects [53]. This study suggested that treatment with azithromycin has clinical benefits in COPD patients with severe conditions.

Studies using other designs

The efficacy of treatment with 500 mg of azithromycin 3 days per week was evaluated for 6 months in a multicentre, randomised, uncontrolled pilot study of tracheostomised COPD patients [54]. 10 (46%) patients received long-term oxygen therapy. An average number of exacerbations in the previous year was 3.1 (standard care group) and 3.0 (azithromycin group). These values suggest the severe conditions of the patients who were enrolled. A total of 22 patients were randomised, and the cumulative number of exacerbations and hospitalisations was lower for the patients in the azithromycin group than the patients in the standard care group. Azithromycin also improved the patients’ QoL in comparison to standard care. No serious adverse events were reported in the azithromycin group. Four patients experienced mild adverse events (diarrhoea, n=3; stomach ache, n= 3). A total of six of the 11 patients in the azithromycin group and five of the 11 patients in the standard care group were colonised with P. aeruginosa at baseline. Two of the azithromycin-treated patients who were initially colonised with P. aeruginosa exhibited reduced colony counts after 3 months of treatment, and the microorganism was eradicated in one patient. In contrast, P. aeruginosa became resistant to ceftazidime and an erythromycin-resistant S. pneumoniae strain was identified in one patient after 6 months of treatment with azithromycin. The authors concluded that long-term azithromycin treatment seems to be safe and effective in severe COPD outpatients with tracheostomy in reducing exacerbations and hospitalisations, as well as in improving QoL.

Gomez et al. [56] examined the effects of azithromycin in 54 COPD patients in a prospective, randomised study. The patients were treated with 500 mg azithromycin daily for 3 days every 21 days during the winter months [56] and were compared to the control group of patients who did not receive treatment. The authors reported that the frequency of acute infectious episodes and hospitalisations was lower in the azithromycin group than in the control group.

Macrolide effects on bronchiectasis

The presence of bronchiectasis is suggested to be important for the pathogenesis of COPD exacerbations [57]. A recent report demonstrated that >50% of COPD patients were shown to have bronchiectasis with severe airflow obstruction and at least one hospitalisation for COPD exacerbation in the previous year [58]. Macrolide therapy improves sputum purulence, airway hypersensitivity [59], lung function and sputum volume [27, 60–63], and symptom scores in patients with bronchiectasis, in addition to reducing the frequency of exacerbations [63, 64].

Treatment with clarithromycin or erythromycin did not change the total amount of bacteria, the bacterial flora or the pathogenic densities in the sputum of patients with bronchiectasis [27, 61]. Likewise, a recent study by Serisier and Martin. [65] demonstrated that 12 months of erythromycin therapy reduced the frequency of exacerbations in patients with bronchiectasis, and that neither new respiratory pathogens nor erythromycin resistant organisms were detected in the sputum during the study.

These findings suggest the possibility that macrolides may have clinical benefits in COPD patients with bronchiectasis, although small numbers of patients were studied.

Anti-inflammatory effects of macrolides

Kadota et al. [14] demonstrated that the high percentage of neutrophils in the bronchoalveolar lavage fluid from patients with DPB decreased after erythromycin treatment. The previously elevated neutrophil chemotactic activities were also reduced after erythromycin treatment (table 2) [14, 15].

Takizawa et al. [16] and Desaki et al. [18] demonstrated that macrolides have effects on bronchial epithelial cells, including suppressing mRNA levels and the release of IL-8 through the activation of nuclear factor-κB and activator protein-1 [18]. The anti-inflammatory effects of macrolide antibiotics were also demonstrated in human peripheral blood monocytes and polymorphonuclear neutrophils [15, 100, 102].

Several other macrolide-mediated anti-inflammatory effects have also been reported in the sputum of patients with COPD, including decreases in the total cell counts, neutrophil chemotaxis, and the levels of IL-8 and tumour necrosis factor (TNF)-α [13, 19].

Inhibitory effects on mucus secretion

Tamaoki et al. [27] conducted a parallel, double-blind, placebo-controlled study to determine the effects that long-term clarithromycin administration has on the amount of sputum in patients with clinical conditions that are associated with excessive airway secretions. A total of 31 patients were divided into two groups: a clarithromycin group (100 mg twice a day) and a placebo group, in which 16 patients had chronic bronchitis and seven patients had bronchiectasis. The authors reported that treatment with clarithromycin decreased sputum production [27]. Tagaya et al. [62] also demonstrated that treatment with clarithromycin decreased the sputum volume in 16 patients with chronic bronchitis (n=5) or bronchiectasis (n=11).

Shimizu et al. [28] examined the effects that macrolide antibiotics have on mucus hypersecretion in vivo, reporting that clarithromycin inhibited ovalbumin (OVA)- and lipopolysaccharide (LPS)-induced mucus production induced by the intranasal instillation of OVA in OVA-sensitised rats and intranasal LPS instillation.

In vitro studies have demonstrated that macrolide antibiotics such as erythromycin [28, 29], clarithromycin [28] and azithromycin [30] have inhibitory effects on mucin or MUC5AC production or secretion after stimulation with TNF-α [28], RV infection [29] or extract of H. influenzae [30] in airway epithelial cells.

Inhibitory effects on bacterial virulence and biofilms

Anderson et al. [109] demonstrated that clarithromycin reduces the production of pneumolysin, a key virulence factor in the infection of S. pneumoniae. Macrolides reduce the production of pro-inflammatory cytokines, soluble intercellular adhesion molecule (ICAM)-1 and mucin in cells such as airway epithelial cells in response to endotoxin and extract of H. influenzae [15, 30, 108, 110]. Azithromycin also maintains the integrity of airway epithelial cells during P. aeruginosa infection [111]. These findings suggest that macrolides may inhibit virulence factor production and the inflammation caused by the bacteria that induce COPD exacerbations. Furthermore, clarithromycin inhibits the twitching motility of P. aeruginosa [33], and azithromycin inhibits the quorum-sensing circuitry of P. aeruginosa, which relates to virulence factor production [32, 107]. In addition, incubating P. aeruginosa with clarithromycin altered the structure and architecture of the biofilm [33]. These findings suggest that macrolides may modulate the virulence of bacteria at the early and late stages of COPD (table 2).

Inhibitory effects on virus infection

Sato et al. [20] and Tsurita et al. [21] reported that erythromycin and clarithromycin increased the survival rate of mice infected with a lethal dose of influenza virus. They also suggested that the reduction in lung injury and the severity of pneumonia were associated with the reduced production of nitric oxide, reactive oxygen species and interferon (IFN)-γ [20] and the elevated IL-12 levels [21] induced by erythromycin and clarithromycin. Kido et al. [23] and Miyamoto et al. [24] also demonstrated that clarithromycin suppresses the growth of the influenza virus and its release in mouse airways and epithelial cells, respectively. Furthermore, Yamaya et al. [26] reported that clarithromycin decreased the release of viruses and cytokines into supernatant fluids in human tracheal epithelial cells that were infected with seasonal type A influenza (H3N2) by reducing the expression of the viral receptor and inhibiting viral RNA entry.

Suzuki et al. [22] showed that erythromycin inhibited RV infection by reducing the levels of ICAM-1, an RV receptor, and/or by blocking RV RNA entry and that erythromycin reduces the production of pro-inflammatory cytokines in the human tracheal epithelial cells. Gielen et al. [112] showed that IFNs were induced in human bronchial epithelial cells when the cells were pre-treated with azithromycin and infected with RV and that this effect may relate to the shorter duration of exacerbations in COPD patients who are treated with macrolides. Asada et al. [25] have also reported that macrolides have inhibitory effects on RSV virus infection in human airway epithelial cells.

These anti-viral and anti-inflammatory effects of macrolides may be associated with the inhibition of viral infection-induced COPD exacerbations, although there is no evidence that macrolides reduce the frequency of viral infection in COPD exacerbations.

Summary of the possible mechanisms by which macrolides exert clinical benefits on COPD exacerbations

As described above and in other reports, macrolides have been found to have various functions other than antimicrobial effects, including anti-inflammatory effects [13–19], reduced mucus secretion [27–30], inhibitory effects on bacterial virulence and biofilm formation [15, 30, 32, 33, 107, 108, 110, 111], enhanced production of antimicrobial peptides and human β-defensins [31], and anti-viral effects [20–26, 112]. The physiological functions of macrolides, including those reported by other authors [17, 99, 101–106], are shown in figure 1 and table 2. Previous studies have suggested that the clinical effects that erythromycin has on DPB are associated with immunomodulatory and physiological activities other than antimicrobial effects [36]. Based on these findings, the clinical benefits that macrolides have on the prevention of COPD exacerbations are also considered to be mediated by these immunomodulatory and other physiological activities [49].