**7.5. Macrolide antibiotics**

Antibiotic prevention of exacerbations is a highly researched topic in COPD. The most promising class of antibiotics appear to be macrolides. In various chronic lung diseases they seem to have an immune modulatory function.

#### *7.5.1. Proposed working mechanism*

Much *in vivo* and *in vitro* research has been performed with macrolide antibiotics. The effects of macrolides can be divided in antimicrobial effects and immune modulatory effects. Macrolides bind to the 50S subunit of the bacterial ribosome and inhibit bacterial protein synthesis [94]. Most macrolides have a uniform degree of activity; their antimicrobial spectrum extends from Gram-positive bacteria to a limited activity against Gram-negative bacteria [95]. Of the macrolides, azithromycin displays superior activity against Gram-negative organisms, such as *H. influenzae* [94]. Compared to other macrolides as erythromycin and clarithromycin, azithromycin also has better uptake in peripheral blood polymorphonuclear neutrophils (PMN) with slower release [96, 97], better tissue uptake and tissue concentrations are higher long after the last administered dose [98, 99]. *Pseudomonas aeruginosa* is a Gram-negative rod which has intrinsic resistance for macrolides but has nonetheless been extensively studied in combination with macrolides. Studies have shown that macrolides influence the virulence of not only *P. aeruginosa* [100-102] but also other microorganisms, like *Proteus mirabilis* [103]*, Salmonella enterica* [104]*, Staphylococcus epidermidis*[105] and *H. influenzae*[106]. Macrolides alter the biofilm around bacteria [105-107], in *P. aeruginosa* this may facilitate phagocytosis by PMN [101]. It is also suggested that macrolides block quorum sensing [108, 109] in *P. aeruginosa*, reduce flagellin synthesis and expression [103, 104] and reduce production of bacterial exoenzymes [100]. In murine models and in in vitro studies macrolides have shown to influence respiratory viral infections. In one study therapy with erythromycin increased survival rates in mice infected with lethal doses of influenza virus [110]. This effect might be exerted through the inhibitory action of erythromycin against virus-induced inflammatory responses in the lung. The production of interferon-gamma (IFN-γ) in the lungs was signifi‐ cantly decreased by the administration of erythromycin to the infected mice. Two in vitro studies researching the effect of erythromycin and clarithromycin in human tracheal cells infected with rhinovirus and influenza A virus, also showed that macrolides decrease the production of pro-inflammatory cytokines and inhibited activation of nuclear factor-κB (a regulating factor in transcription of DNA in response to cellular stress) [111, 112]. These antiviral effects of macrolides have not yet been proven in patients, although there is evidence that macrolides may prevent common colds which are mostly of viral aetiology [113]. Macro‐ lides support the airway innate immune system by maintaining airway epithelial integrity [114, 115]. In vitro [116] and in vivo [117] studies show that macrolides improve alveolar macrophage phagocytosis function. Macrolide therapy stimulates the prolonged degranula‐ tion of neutrophils (suggesting anti-inflammatory activity in non-infective inflammation), decreases long term oxidative burst and can decrease the release of pro-inflammatory cyto‐ kines (such as IL-6 and IL-8) in healthy individuals [118]. In vitro it is observed that macrolides decrease the release of IL-1β, IL-6 and tumor necrosis factor-alpha (TNF-α) in sputum cells of patients with COPD [119]. Azithromycin exerts direct inhibitory effects on mucus secretion from airway epithelial cells in vitro and in vivo [120].

#### *7.5.2. Success of macrolides in chronic lung diseases*

**7.4. Phosphodiesterase inhibitors**

86 Oncogenesis, Inflammatory and Parasitic Tropical Diseases of the Lung

AECOPD.

**7.5. Macrolide antibiotics**

*7.5.1. Proposed working mechanism*

seem to have an immune modulatory function.

Currently, two phosphodiesterase inhibitors are available for the treatment of COPD: theo‐ phylline and roflumilast. Theophylline is a xanthine derivative which acts as a non-selective phosphodiesterase inhibitor. It has bronchodilator effects, improves symptoms and there is evidence that it can reduce exacerbations [89-91]. It is a drug which needs therapeutic window monitoring. It can interact with many drugs and can have toxic side effects which may be potentially dangerous, like cardiac arrhythmia. Therapy with theophyllines is not recom‐ mended if LABAs are available but can be used as add-on therapy [8]. Roflumilast is a selective phosphodiesterase-4 inhibitor. It increases prebronchodilator FEV1 and can reduce exacerba‐ tions in a selected group of patients with COPD [92, 93]. In all trials patients in the roflumilast group experienced more side effects in comparison to patients in the placebo groups. The side effects were mostly gastro-intestinal related (nausea, diarrhoea, weight loss) and headache. These adverse events were associated with increased patient withdrawal in the roflumilast groups. The design of the trials limits the generalizability of these results. The included COPD patients were required to have symptoms of chronic bronchitis and AECOPD in the past. More investigation is needed to determine the exact place of this medication in the treatment of

Antibiotic prevention of exacerbations is a highly researched topic in COPD. The most promising class of antibiotics appear to be macrolides. In various chronic lung diseases they

Much *in vivo* and *in vitro* research has been performed with macrolide antibiotics. The effects of macrolides can be divided in antimicrobial effects and immune modulatory effects. Macrolides bind to the 50S subunit of the bacterial ribosome and inhibit bacterial protein synthesis [94]. Most macrolides have a uniform degree of activity; their antimicrobial spectrum extends from Gram-positive bacteria to a limited activity against Gram-negative bacteria [95]. Of the macrolides, azithromycin displays superior activity against Gram-negative organisms, such as *H. influenzae* [94]. Compared to other macrolides as erythromycin and clarithromycin, azithromycin also has better uptake in peripheral blood polymorphonuclear neutrophils (PMN) with slower release [96, 97], better tissue uptake and tissue concentrations are higher long after the last administered dose [98, 99]. *Pseudomonas aeruginosa* is a Gram-negative rod which has intrinsic resistance for macrolides but has nonetheless been extensively studied in combination with macrolides. Studies have shown that macrolides influence the virulence of not only *P. aeruginosa* [100-102] but also other microorganisms, like *Proteus mirabilis* [103]*, Salmonella enterica* [104]*, Staphylococcus epidermidis*[105] and *H. influenzae*[106]. Macrolides alter the biofilm around bacteria [105-107], in *P. aeruginosa* this may facilitate phagocytosis by PMN [101]. It is also suggested that macrolides block quorum sensing [108, 109] in *P. aeruginosa*, reduce flagellin synthesis and expression [103, 104] and reduce production of bacterial exoenzymes [100]. In murine models and in in vitro studies macrolides have shown to

Diffuse panbronchiolitis is a progressive inflammatory disorder of the airways found almost exclusively in Japan. Clinically it is characterized by chronic cough, excessive sputum pro‐ duction, exertional breathlessness, chronic sinusitis and Pseudomonas colonization [121]. Untreated, the prognosis of diffuse panbronchiolitis is poor, with progressive deterioration of lung function, the development of diffuse bronchiectasis and death caused by respiratory failure. The introduction of long-term macrolide therapy has resulted in dramatic improve‐ ments in survival, with 5-year survival rates increasing from 63 to 92% [121, 122]. Significant symptom reduction and improved pulmonary function have also been achieved [123-126]. Also in patients with cystic fibrosis (CF) who are colonized with *P. aeruginosa*, macrolide therapy had led to improvement in FEV1 and forced vital capacity (FVC), a reduction in exacerbation rate, a reduction in hospital days and days of intravenous antibiotic use, delaying time until the first exacerbation and reducing number of additional courses of antibiotics [127-132]. A Cochrane review of macrolide therapy concluded that treatment with azithro‐ mycin had a small but significant effect on pulmonary function in patients with cystic fibrosis [133]. In a in New Zealand performed randomized controlled trial in non-CF bronchiectasis, maintenance treatment with 3 times a week 500 mg azithromycin showed a reduction in exacerbations [134] though no effects were seen in quality of life and lung function. In a Dutch study where a treatment scheme was given with daily 250 mg azithromycin, the reduction in exacerbations was accompanied by an improved quality of life assessed by St George's Respiratory Questionnaire (SGRQ) and an increase in lung function [135]. As for COPD there have been few researches concerning macrolides in preventing AECOPD. One published study has examined the effect of clarithromycin treatment in COPD [136]. This was a prospective double-blind randomized controlled trial of 67 patients with moderately severe COPD. The effects of 3 months' clarithromycin therapy on health status, exacerbation rate and sputum bacterial numbers were measured. Overall, no significant benefit was seen in any measure. However, significant improvements in both the SGRQ symptom score and 36-item short-form health survey (SF-36) physical function score were seen. A Japanese study performed in 1997 investigated the effect of long-term erythromycin therapy on common colds in patients with COPD [113]. It was a prospective, randomized, controlled but not blinded study. Patients who received erythromycin therapy had less common colds and less subsequent AECOPD compared to patients in the control group. In 2006, another study had been performed in the UK to investigate the influence of erythromycin on exacerbation of COPD [137]. Unfortunately, the total number of patients needed for inclusion was not reached. Although the study showed a significant reduction in number of exacerbations in COPD patients who received 1 year daily erythromycin, the reached conclusions should be carefully interpreted. The most recent study published concerning long term macrolide therapy in COPD was performed in the USA with over 1,000 patients. It showed a reduction in time to first exacerbation and a reduced risk for exacerbations in patients receiving daily azithromycin during 1 year [138]. The study partici‐ pants were patients who had at least 1 treated exacerbation in the previous year or who were on continuous supplemental oxygen or had an emergency department (ED) visit or hospital admission for an exacerbation COPD. The applicability of these results is somewhat difficult. The results of the study could suggest that long term azithromycin can be given to many COPD patients, even to those who are not actually frequent exacerbators. The place of azithromycin in the prevention of COPD exacerbations is a topic which needs further research.

**Author details**

, R.S. Djamin1

spir Med, (2004). , 99-107.

Care Med, (2007). , 532-555.

(1996). Pt 1): , 959-967.

Health Organization. , 146.

Obstructive Lung Disease. , 78.

Lancet, (2009). , 733-743.

a longitudinal study. Lung, (2010). , 321-329.

tiative. Int J Tuberc Lung Dis, (2008). , 703-708.

1418-1422.

, H.C. Hoogsteden2

1 Department of Respiratory Medicine, Amphia Ziekenhuis, Breda, The Netherlands

2 Department of Respiratory Medicine, Erasmus Medical Centre, Rotterdam, The Netherlands

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, J.G.J.V. Aerts1,2 and M.M. van der Eerden2

Acute Exacerbations of Chronic Obstructive Pulmonary Disease

http://dx.doi.org/10.5772/54867

89

S. Uzun1

**References**

#### *7.5.3. Antimicrobial resistance*

Giving long term antibiotic treatment to a patient may have consequences; the development of antimicrobial resistance is by far the most important one. Several researches have shown that the erm(B) and mef genes are mostly responsible for macrolide resistance in streptococci bacteria [139-142]. This resistance can develop even when short term therapy with macrolides is given [141]. The participants receiving azithromycin in the USA study, where a 1-year therapy was administered, were less likely to be colonized with respiratory pathogens but more likely to become colonized with macrolide resistant pathogens [138]. In the UK study in patients with COPD the researchers found there were no significant changes in resistance of sputum pathogens (*H. influenzae, S. pneumoniae, M. catarrhalis*) after 1 year of daily erythro‐ mycin [137]. In a Dutch study investigating antibiotic treatment before cardiovascular surgery 300 patients were treated with 2 weeks of clarithromycin. A significant rise in macrolide resistance in oropharyngeal flora was observed and this resistance continued to exist for at least 8 weeks [140]. Since macrolide resistance in pneumococci is already a known problem [141, 143, 144] it is of great importance to prevent the development of resistance in other microorganisms.
