Review
Macrolides beyond the conventional antimicrobials: a class of potent immunomodulators

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Abstract

The historical change in the natural course of diffuse panbronchiolitis (DPB), a fatal disorder of the airways, following the introduction of erythromycin in its treatment has focused attention of researchers on the anti-inflammatory properties of macrolides. Chronic inflammation of the airways accompanied by infiltration by neutrophils and overproduction of mucus and pro-inflammatory cytokines is observed in bronchial asthma, cystic fibrosis (CF), DPB, chronic obstructive pulmonary disease (COPD) and bronchiectasis. The airways of these patients are often colonised by mucoid Pseudomonas aeruginosa attached to epithelium by a biofilm. Bacteria intercommunicate for biofilm formation by a system of lactones known as quorum sensing. Macrolides inhibit mobility and quorum sensing of P. aeruginosa; they also decrease production of mucus by epithelial cells and biosynthesis of pro-inflammatory cytokines from monocytes and epithelial cells by inhibiting nuclear factor-κB. Large, randomised clinical trials for the management of these disorders with macrolides are not available, with the sole exception of four trials denoting benefit following long-term administration of azithromycin in patients with CF. That benefit is consistent with an increase in forced expiratory volume in 1 s (FEV1) and a decrease in the rate of bacterial exacerbations. Studies with small numbers of patients with COPD revealed attenuation of the inflammatory reaction by macrolides. Experimental studies of Gram-negative sepsis have shown considerable attenuation of the systemic inflammatory response following intravenous administration of clarithromycin. Results of the effects of clarithromycin in patients with ventilator-associated pneumonia and sepsis in a large, randomised study of 200 patients are awaited.

Introduction

Macrolides are an old class of antimicrobials with an antimicrobial spectrum against mainly Gram-positive cocci and atypical pathogens. However, there is an accumulating body of evidence over the last few years that part of the activity of macrolides is not mediated through their traditional antimicrobial effect. This belief was created by the use of macrolides for the management of diffuse panbronchiolitis (DPB). DPB is a chronic devastating disorder solely presenting in Eastern Asian populations. The disorder is characterised by chronic inflammatory infiltration of the bronchi accompanied by chronic respiratory failure and cor pulmonale. The 5-year survival rate was <50% until 1979 when erythromycin was introduced as the main treatment, leading to considerable prolongation of survival and subsequent reduction of the death rate [1]. These patients have airway colonisation by Pseudomonas aeruginosa, which often leads to repeated cycles of exacerbation and remission. Pseudomonas aeruginosa does not belong to the antimicrobial spectrum of macrolides, raising numerous questions about the mechanism of action in DPB.

The anti-inflammatory action of macrolides is the most probable explanation for this phenomenon [2]. This belief is further reinforced by clinical data showing that the outcome of pneumococcal infections is favourable when macrolides are included in the treatment regimen. More precisely, retrospective analysis of cases of bacteraemia caused by Streptococcus pneumoniae revealed that addition of a macrolide to a β-lactam decreased the relative risk of death by 2.5-fold [3]. In the same context, a retrospective analysis of a Spanish series of patients with pneumococcal pneumonia showed lower mortality among those treated with a combination of a β-lactam and a macrolide compares with β-lactam monotherapy [4]. These observations have focused the attention of researchers to probable interactions of macrolides with the host immune system.

Despite increased knowledge about the non-antimicrobial activity of macrolides, clinical data are either missing or are restricted to studies with a limited number of patients. The present review discusses the significance of the non-antimicrobial activity of macrolides for the management of human disease. It is divided into three parts: in the first part, the effect of macrolides on cells of the immune system is analysed; in the next two parts, clinical data regarding the immunomodulatory role of macrolides for human disease are presented, with special emphasis on diseases of the lower respiratory tract.

Section snippets

What is the anti-inflammatory mode of action of macrolides?

Although DPB is an entity uncommon in Western societies, it has been used as a prototype of chronic inflammation of the airways, with particular attention on the role of colonisation by P. aeruginosa as a factor eliciting exacerbations. As a consequence, it is hypothesised that a favourable outcome following macrolide treatment is probably connected to an effect on the host–bacteria interaction.

Role of macrolides for the management of chronic inflammatory disorders of the lower respiratory tract

The clinical significance of the above-mentioned in vitro anti-inflammatory effects of macrolides is mainly dependent on their pharmacokinetics with special emphasis on their penetration to epithelial lining fluid (ELF) and alveolar macrophages. This is the salient factor determining the probability of macrolides behaving as immunomodulators for chronic disorders of the lower respiratory tract. Concentrations of clarithromycin in ELF following a single oral dose of 500 mg range between 15 μg/mL

Do macrolides have any role for the management of acute inflammatory conditions?

The data already analysed implicate a direct anti-inflammatory effect of macrolides for chronic inflammatory disorders of the airways. According to these data, macrolides should be administered as long-term therapy. The question arising is whether macrolides could be administered for the management of acute inflammatory disorders. The prototype of these conditions is systemic inflammatory response syndrome in the setting of an acute infection, i.e. sepsis. Available data for a possible role of

Conclusions

The above review of all recent data in the literature clearly describes macrolides as agents that, far beyond their traditional antimicrobial properties, possess a considerable anti-inflammatory effect (Fig. 1). Their exact role in everyday clinical practice for the therapy of chronic respiratory inflammatory conditions depends on results of large randomised clinical trials. With the sole exception of four trials disclosing considerable benefit from the long-term administration of azithromycin

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