Dr. Harry Shwachman, 1950
Macrolides have been known for their antimicrobial actions since 1952 [
They are considered safe and easily tolerable. Their main side effects are nausea, vomiting, diarrhea, and abdominal pain, which become more evident when erythromycin is used in place of the other macrolides [
Mounting evidence suggests that macrolide antibiotics have both anti-inflammatory and immune-modulatory properties and are thus beneficial to chronic pulmonary diseases such as diffuse panbronchiolitis, cystic fibrosis, asthma, and bronchiectasis. These properties were suspected upon the realization that erythromycin decreased the need for corticosteroids in asthma treatment [
It must be pointed out that immunemodulation is the suppression of inflammation and immune hyperactivation without causing immune depression (immunsuppression) [
The anti-inflammatory effects of macrolides were initially proved on patients with diffuse panbronchiolitis (DPB) [
Historically, DPB used to evolve into respiratory insufficiency and death in half of the patients within five years after diagnosis. After infection by
Kudoh [
A retrospective study carried out by the Research Group of the Ministry of Health, Labor, and Welfare of Japan showed a pronounced improvement in survival rate after long-term use of macrolides at low doses. The 5-year survival rate before the treatment with macrolides was 63% in the 1970s, and 72% between 1980 and 1984. After the introduction of erythromycin in 1985, this rate increased to 92% (
Since then, erythromycin has been the recommended choice of treatment upon diagnosis [
The benefits of macrolides in the treatment of cystic fibrosis are plain to see [
The use of macrolides has been investigated in asthma treatment [
Bronchiectasis is a chronic pulmonary disease with a diverse etiology, characterized by recurrent respiratory infection and chronic inflammation, leading to the destruction of the airways and pulmonary parenchyma.
The treatment of bronchiectasis is currently based on the treatment of the underlying cause, on the prevention and control of respiratory infections, as well as on respiratory physiotherapy, and on surgical corrections, in more severe cases [
Since 1997, several studies based on the knowledge acquired for the treatment of DPB have sought to learn more about the role of macrolides in bronchiectasis.
For the bibliographical research carried out until June 2011 with the use of the Medline database, we used the key words “macrolides” and “bronchiectasis”, seeking original papers and reviews. We found seven clinical studies that evaluated the action of macrolides on patients with bronchiectasis. Only two studies were randomized, placebo-controlled, and double blind (Table
Macrolides in noncystic fibrosis bronchiectasis.
Study | Study design | Macrolide | Age (years) | End-point | |
---|---|---|---|---|---|
Koh et al. [ | Randomized, double-blind, placebo-controlled | 25 | Roxithromycin 4 mg/kg twice daily for 12 weeks | 13.1 ± 2.6 | (i) Reduction of sputum purulence ( |
Tsang et al. [ | Randomized, double-blind, placebo-controlled | 21 | Erythromycin 500 mg twice daily for 8 weeks | 50 ± 15 | (i) FEV1 and FVC improvement ( |
Davies and Wilson [ | Prospective open-label | 39 | Azithromycin 250 mg, thrice weekly for 4 months | 51.9 ± 16.1 | (i) Reduction of clinical exacerbations with the use of oral and intravenous antibiotics ( |
Cymbala et al. [ | Randomized, open-label, crossover | 11 | Azithromycin 500 mg twice weekly for 6 months | — | (i) Reduction in pulmonary exacerbations |
Yalcin et al. [ | Randomized, controlled | 34 | Clarithromycin 15 mg/kg/day for 3 months | 13.1 ± 2.7 | (i) Reduction in bronchial inflammation ( |
Anwar et al. [ | Prospective open-label | 56 | Azithromycin 250 mg, thrice weekly for at least 3 months | 63 (±12.9) | (i) Reduction in pulmonary exacerbations ( |
Serisier et al. [ | Prospective open-label | 21 | Erythromycin 250 mg/day for 12 months | 62.5 (±11) | (i) Reduction in pulmonary exacerbations ( |
FEV1: forced expiratory volume in one second; FEF25–75%: maximal midexpiratory flow; FVC: forced vital capacity.
Koh et al. in a randomized, double-blind, placebo-controlled study with children at a mean age of 13.1 years (±2.6) with increased previous airway reactivity, using roxithromycin 4 mg/Kg twice a day for 12 weeks, evidenced a reduction in airway reactivity after the methacholine challenge test, in addition to an improvement in sputum purulence. However, it did not show any difference in sputum cellularity nor pulmonary function improvement when evaluating FEV1. The authors did not identify the roxithromycin mechanism of action in reducing the airway reactivity, but inferred anti-inflammatory or antimicrobial mechanisms. However, no conclusion was achieved, and the authors could not demonstrate the correlation between their findings and the clinical improvement [
Tsang et al. [
Davies and Wilson in an attempt to reduce pulmonary exacerbation frequency in patients with noncystic fibrosis bronchiectasis, evaluated the pulmonary function and sputum features of 39 adults with a mean age of 51.9 years (±16.1), after treatment with azithromycin 500 mg once daily for 6 days, 250 mg once daily for 6 days, then 250 mg on Monday, Wednesday, and Friday for at least 4 months, and on average for 20 months. All patients had had at least four pulmonary exacerbations in the previous year. A total of 33 patients completed the 4 months of treatment and presented lower pulmonary exacerbation frequency with reduced need for oral (
Cymbala et al. [
Yalcin et al., in a randomized and controlled study, evaluated 34 children aged between 7 and 18 (mean age 13.1 ± 2.7) with noncystic fibrosis bronchiectasis, after 3 months using clarithromycin at a dose of 15 mg/Kg/day. The control group was given supportive therapy only, whereas the study group received supportive therapy and clarithromycin. The presence of inflammatory mediators (IL8, TNF
Anwar et al. described the use of azithromycin 250 mg three times a week in 56 adults (mean age 63 ± 12.9 years) with noncystic fibrosis bronchiectasis for at least 3 months, on an average of 9.1 months, in a prospective open study. This study compared the exacerbation frequency, the self-reported volume, and the microbiology of the sputum, as well as pulmonary function. The results obtained were compared to each patient’s data obtained 6 months before the intervention. Pulmonary function was evaluated in 29 patients. The study evidenced a marked reduction in pulmonary exacerbation frequency (
Serisier and Martin in a prospective, open, noncontrolled study evaluated the exacerbation frequency and the use of Erythromycin in 21 patients aged 62.5 years (±11) on average, after the use of erythromycin 250 mg/day for 12 months. A comparison was made to each patient’s individual data obtained prior to the 12-month time frame of the study. A reduction in the number of exacerbations (
Recent British guidelines on nonfibrocystic bronchiectasis acknowledge the macrolides’ possible immunemodulating effects and suggest that they may have a disease-modifying activity, while emphasizing the need for further studies on the subject before [
To date, there is a paucity of data exploring the mechanisms of action of macrolides in bronchiectasic patients as its clinical effectiveness has only been recently shown. Most of the data in this issue have been extrapolated from other chronic lung disease and animal or cell models or in vitro systems [
Diseases characterized by chronic airway inflammation, such as diffuse panbronchiolitis, asthma, chronic obstructive pulmonary disease (COPD), cystic fibrosis, and bronchiectasis, often bring with them mucus hypersecretion, bronchial hyperactivity, and chronic inflammation [
The authors suggest that the effect of macrolides on the improvement of chronic inflammatory conditions surpasses its antimicrobial effects, considering that in all the studies these drugs were administered in low doses, in which they would not present bactericidal or bacteriostatic effect [
It is believed that macrolides exert anti-inflammatory and immunomodulatory effects through the following mechanisms [
Studies suggest that macrolides reduce expectoration by inhibiting the synthesis of mucus proteins, such as mucin, by modulating gene expression, and by inhibiting chloride channels in the epithelial cells. It is believed that they act in the mucociliary clearance and mucus viscosity, although these findings have yet to be explained [
Gram-negative bacteria such as
Chronic inflammation is characterized by the recruitment of neutrophils with the release of lysosomal enzymes and the generation of reactive oxygen compounds, resulting in tissue damage. Macrolides reduce the quantity of neutrophils in the inflammation site by decreasing molecular adhesion (E-selectin, ICAM-1), integrins (CD11b/CD18), cytokines involved with chemotaxis (IL-8, IL-6, IL4, IL5), and TNF
Macrolides modulate phagocytosis indirectly reducing neutrophil survival by accelerating their apoptosis. They suppress the secretion of epithelial-derived neutrophil survival factors, as GM-CSF (granulocyte-macrophage colony-stimulating factor).
Initially, macrolides improve the host’s defense through neutrophil stimulation, production of proinflammatory cytokines and mediators such as IL-1, IL-2, IL6, and GM-CSF, and production of nitric oxide in order to contain the infection [
Despite the small number of studies shedding light on the anti-inflammatory and immunomodulatory mechanisms of the macrolides, there is strong evidence providing support to the benefit of using this type of drug for the long term and in low doses to treat chronic inflammatory diseases, including noncystic fibrosis bronchiectasis.
The anti-inflammatory properties of macrolides are consolidated. The mechanisms of action, however, are still being investigated.
Future studies are necessary to determine the benefits of macrolides in the many inflammatory diseases of the airways, as well as the ideal dosage and duration of the treatment, not to mention the impact of the development of bacterial resistance.