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Role of long term antibiotics in chronic respiratory diseases

Open ArchivePublished:March 25, 2013DOI:https://doi.org/10.1016/j.rmed.2013.02.009

      Summary

      Antibiotics are commonly used in the management of respiratory disorders such as cystic fibrosis (CF), non-CF bronchiectasis, asthma and COPD. In those conditions long-term antibiotics can be delivered as nebulised aerosols or administered orally. In CF, nebulised colomycin or tobramycin improve lung function, reduce number of exacerbations and improve quality of life (QoL). Oral antibiotics, such as macrolides, have acquired wide use not only as anti-microbial agents but also due to their anti-inflammatory and pro-kinetic properties. In CF, macrolides such as azithromycin have been shown to improve the lung function and reduce frequency of infective exacerbations. Similarly macrolides have been shown to have some benefits in COPD including reduction in a number of exacerbations. In asthma, macrolides have been reported to improve some subjective parameters, bronchial hyperresponsiveness and airway inflammation; however have no benefits on lung function or overall asthma control. Macrolides have also been used with beneficial effects in less common disorders such as diffuse panbronchiolitis or post-transplant bronchiolitis obliterans syndrome. In this review we describe our current knowledge the use of long-term antibiotics in conditions such as CF, non-CF bronchiectasis, asthma and COPD together with up-to-date clinical and scientific evidence to support our understanding of the use of antibiotics in those conditions.

      Keywords

      Introduction

      Respiratory diseases are commonly associated with significant morbidity and mortality, affecting patients' quality of life (QoL) and leading to associated increased costs to the health services. Therefore therapeutic anti-bacterial and anti-inflammatory modalities that may reduce the frequency of exacerbations, the need for hospitalisation and resulting improvement in patients QOL may have important health economic implications. In recent years there has been an improvement in our understanding of managing respiratory conditions using anti-bacterial and/or anti-inflammatory agents. Control of infective exacerbations and thereby the inflammation with oral or aerosol preparations of antibiotics has been shown to have beneficial effects in many of respiratory disorders. This review aims to examine the studies on long-term antibiotic use in management of respiratory diseases, to identify evidence supporting their role and to discuss their potential clinical benefits and limitations.

      Role for macrolides

      Macrolide antibiotics belong to an expansive family of compounds that are characterized by the presence of a macrocyclic lactone ring.
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      The immunomodulatory properties of macrolides is related to the lactone ring which is seen with the 14 (erythromycin, clarithromycin and roxithromycin) and the 15 (azithromycin) member macrolides.
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      Though the precise mechanism of action of macrolides is unknown it has been proposed that macrolides can: attenuate mucous hypersecretion; reduce production of pro-inflammatory cytokines which can lead to a reduction in accumulation and proliferation of neutrophils in the mucosal epithelium; and a suppressive effect on lymphocytic activity.
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      Macrolides for diffuse panbronchiolitis.
      In human and animal models macrolides suppress the production of cytokines such as interleukin (IL)-5, IL-8, IL-6, IL-1β, IL-10, tumour necrosis factor (TNF)-α and granulocyte-monocyte colony stimulating factor (GM-CSF); inhibit neutrophil adhesion to epithelial cells; the respiratory burst of neutrophils; and the mucous secretion from airways.
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      Azithromycin, clarithromycin and telithromycin inhibit MUC5AC induction by Chlamydophila pneumoniae in airway epithelial cells.
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      Effect of clarithromycin on cytokines and chemokines in children with an acute exacerbation of recurrent wheezing: a double-blind, randomized, placebo-controlled trial.
      Macrolides also inhibit RNA-dependent protein synthesis and binding to the bacterial ribosomal subunits. Moreover, macrolides attenuate lipopolysaccharide-induced MUC5AC gene expression and clarithromycin in particular significantly reduces the MUC5AC expression at both the mRNA and protein levels.
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      Clarithromycin inhibits overproduction of muc5ac core protein in murine model of diffuse panbronchiolitis.
      It has also been reported that in COPD patients, macrolides improve macrophage phagocytosis of apoptotic airways epithelial cells, reduce systemic inflammation and induced increased expression of macrophage mannose receptors.
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      Low-dose azithromycin improves phagocytosis of bacteria by both alveolar and monocyte-derived macrophages in chronic obstructive pulmonary disease subjects.
      Hence the dual action of enhanced clearance of apoptotic cells and bacteria may diminish the secondary necrosis and production of inflammatory mediators.
      In patients infected with Pseudomonas (P.) aeruginosa macrolides have effects on biofilm development. Biofilm formation and virulence factors in P. aeruginosa are controlled by a system of bacterial intercommunication, known as quorum sensing. This system comprises genes encoding transcriptional activators, namely lasR and rhlR and macrolides inhibit the transcription of several of these genes.
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      Macrolides can affect bacterial adherence of pathogens like P. aeruginosa
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      Macrolide antibiotics and cystic fibrosis.
      and consequently there has been an increasing interest in the use of macrolides in patients colonised with pseudomonas. Macrolides have also been proposed to have pro-kinetic activity on the gastrointestinal tract hence reducing gastro-oesophageal reflux and micro-aspiration which are common phenomena in pulmonary conditions.
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      Impact of gastro-oesophageal reflux disease symptoms on COPD exacerbation.
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      Gastro-oesophageal reflux and aspiration of gastric contents in adult patients with cystic fibrosis.
      • Mertens V.
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      • Farre R.
      • Vanaudenaerde B.
      • Vos R.
      • et al.
      Azithromycin reduces gastroesophageal reflux and aspiration in lung transplant recipients.
      Additionally, macrolides have been reported to have anti-proliferative actions and slow both bronchial epithelial cell proliferation and fibroblast migration.
      • Kohyama T.
      • Yamauchi Y.
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      • Kato J.
      • et al.
      Clarithromycin inhibits fibroblast migration.
      • Shinkai M.
      • Tamaoki J.
      • Kobayashi H.
      • Kanoh S.
      • Motoyoshi K.
      • Kute T.
      • et al.
      Clarithromycin delays progression of bronchial epithelial cells from G1 phase to S phase and delays cell growth via extracellular signal-regulated protein kinase suppression.
      Despite the numerous positive outcomes macrolides possess, more recently, there have been reports in murine models
      • Renna M.
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      • Shang S.
      • Tamayo M.H.
      • Hegyi K.
      • et al.
      Azithromycin blocks autophagy and may predispose cystic fibrosis patients to mycobacterial infection.
      and CF patients
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      • Macheras E.
      • Ravilly S.
      • et al.
      Multicenter study of prevalence of nontuberculous mycobacteria in patients with cystic fibrosis in france.
      • Esther Jr., C.R.
      • Esserman D.A.
      • Gilligan P.
      • Kerr A.
      • Noone P.G.
      Chronic Mycobacterium abscessus infection and lung function decline in cystic fibrosis.
      that long-term macrolides may be associated with the development of non-tuberculous mycobactria (NTM) infections by blocking the autophagosomal clearance of human macrophages by preventing lysosomal acidification, hence impairing autophagic and phagosomal degradation. Hence macrolide therapy may predispose NTM infections by hampering intracellular mycobacterial killing in macrophages.

      Role for nebulised antibiotics

      Antibiotics delivered directly to the airways by nebulisation have been shown to be very effective in managing pulmonary complications of cystic fibrosis (CF).
      • Cystic Fibrosis Foundation Trust
      Antibiotic treatment for cystic fibrosis: report of the UK Cystic Fibrosis Trust Antibiotic Working Group.
      The benefits of inhaled antibiotics are related to the local delivery of the drug to the lung resulting in much higher sputum concentrations compared with that of intravenous or oral agents. In addition, nebulised antibiotics seem to have a lower side effect profile and toxicity. In the context of inhaled antibiotics therapies, it is important to highlight, the role of the inhalation devices as they determine optimal particle size and the lung deposition of the medication.
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      • et al.
      A widely available method for the assessment of aerosol delivery in cystic fibrosis.
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      Inhaled medication and inhalation devices for lung disease in patients with cystic fibrosis: a European consensus.
      Besides the anti-microbial features of antibiotics, their bioavailability as well as the profile of the adverse effects should also be taken into account. A potential problem associated with the long-term use of nebulised antibiotics is related to patients' adequate adherence with their medications.
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      • Duff A.
      • Quinn J.
      • Conway S.
      • Conner M.
      Adherence to nebulised antibiotics in cystic fibrosis.
      Despite some limitations, inhaled antibiotics have been shown to be beneficial in CF patients, especially those with chronic colonisation with P. aeruginosa.

      Asthma

      There is a reasonable body of evidence indicating attenuation of corticosteroid requirements with the use of macrolides in stable corticosteroid-dependent asthma patients. It has been proposed that the anti-inflammatory mechanism of macrolides is due to the inhibition of the cytochrome P450 system (CYP3A4).
      • Rollins D.R.
      • Beuther D.A.
      • Martin R.J.
      Update on infection and antibiotics in asthma.
      Erythromycin, clarithromycin and troleandomycin have been reported to reduce methylpredinsolone clearance in asthmatics
      • Fost D.A.
      • Leung D.Y.
      • Martin R.J.
      • Brown E.E.
      • Szefler S.J.
      • Spahn J.D.
      Inhibition of methylprednisolone elimination in the presence of clarithromycin therapy.
      • Spahn J.D.
      • Fost D.A.
      • Covar R.
      • Martin R.J.
      • Brown E.E.
      • Szefler S.J.
      • et al.
      Clarithromycin potentiates glucocorticoid responsiveness in patients with asthma: results of a pilot study.
      • Jaffe A.
      • Bush A.
      Anti-inflammatory effects of macrolides in lung disease.
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      • Ellis E.F.
      • Spector S.L.
      • Green A.W.
      • Jusko W.J.
      The effect of troleandomycin on methylprednisolone elimination.
      besides independently manifesting anti-inflammatory activity to those of corticosteroids and theophyllines. Roxithromycin and azithromycin do not inhibit the cytochrome P450 system, but still are effective in reducing bronchial hyperresponsiveness (BHR).
      • Ekici A.
      • Ekici M.
      • Erdemoglu A.K.
      Effect of azithromycin on the severity of bronchial hyperresponsiveness in patients with mild asthma.
      • Shimizu T.
      • Kato M.
      • Mochizuki H.
      • Tokuyama K.
      • Morikawa A.
      • Kuroume T.
      Roxithromycin reduces the degree of bronchial hyperresponsiveness in children with asthma.
      Moreover macrolides by inhibiting IL-6 and IL-8 may possibly lead to improvements in FEV1 in asthmatics.
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      • Holgate S.T.
      Role of tumor necrosis factor alpha in asthma.
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      • Davies D.E.
      • Holgate S.T.
      Sputum IL-6 concentrations in severe asthma and its relationship with FEV1.
      Several case series' and open-labelled studies using macrolides have been conducted in asthmatic patients with positive outcomes.
      • Richeldi L.
      • Ferrara G.
      • Fabbri L.M.
      • Lasserson T.J.
      • Gibson P.G.
      Macrolides for chronic asthma.
      • Fost D.A.
      • Leung D.Y.
      • Martin R.J.
      • Brown E.E.
      • Szefler S.J.
      • Spahn J.D.
      Inhibition of methylprednisolone elimination in the presence of clarithromycin therapy.
      • Spahn J.D.
      • Fost D.A.
      • Covar R.
      • Martin R.J.
      • Brown E.E.
      • Szefler S.J.
      • et al.
      Clarithromycin potentiates glucocorticoid responsiveness in patients with asthma: results of a pilot study.
      • Szefler S.J.
      • Rose J.Q.
      • Ellis E.F.
      • Spector S.L.
      • Green A.W.
      • Jusko W.J.
      The effect of troleandomycin on methylprednisolone elimination.
      • Ekici A.
      • Ekici M.
      • Erdemoglu A.K.
      Effect of azithromycin on the severity of bronchial hyperresponsiveness in patients with mild asthma.
      • Shimizu T.
      • Kato M.
      • Mochizuki H.
      • Tokuyama K.
      • Morikawa A.
      • Kuroume T.
      Roxithromycin reduces the degree of bronchial hyperresponsiveness in children with asthma.
      • Itkin I.H.
      • Menzel M.L.
      The use of macrolide antibiotic substances in the treatment of asthma.
      • Spector S.L.
      • Katz F.H.
      • Farr R.S.
      Troleandromycin: effectiveness in steroid-dependent asthma and bronchitis.
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      • Brenner M.
      • Sanks R.
      • Szefler S.J.
      Effect of low-dose troleandomycin on glucocorticoid pharmacokinetics and airway hyperresponsiveness in severely asthmatic children.
      In 2005, a Cochrane review assessed the use of macrolides in asthma.
      • Richeldi L.
      • Ferrara G.
      • Fabbri L.M.
      • Lasserson T.J.
      • Gibson P.G.
      Macrolides for chronic asthma.
      Seven studies with a total of 416 asthma patients were considered based on an inclusion criteria of (summarised in Table 1): the studies being double-blind placebo-controlled (DBPC); ≥4 weeks of treatment in patients with varying severity of asthma (clarithromycin – 3 studies, roxithromycin – 2 studies; troleandomycin – 2 studies); evaluation of asthma symptoms and at least one measure of lung function (FEV1, FVC and/or PEF).
      • Amayasu H.
      • Yoshida S.
      • Ebana S.
      • Yamamoto Y.
      • Nishikawa T.
      • Shoji T.
      • et al.
      Clarithromycin suppresses bronchial hyperresponsiveness associated with eosinophilic inflammation in patients with asthma.
      • Black P.N.
      • Blasi F.
      • Jenkins C.R.
      • Scicchitano R.
      • Mills G.D.
      • Rubinfeld A.R.
      • et al.
      Trial of roxithromycin in subjects with asthma and serological evidence of infection with Chlamydia pneumoniae.
      • Kamada A.K.
      • Hill M.R.
      • Ikle D.N.
      • Brenner A.M.
      • Szefler S.J.
      Efficacy and safety of low-dose troleandomycin therapy in children with severe, steroid-requiring asthma.
      • Kostadima E.
      • Tsiodras S.
      • Alexopoulos E.I.
      • Kaditis A.G.
      • Mavrou I.
      • Georgatou N.
      • et al.
      Clarithromycin reduces the severity of bronchial hyperresponsiveness in patients with asthma.
      • Kraft M.
      • Cassell G.H.
      • Pak J.
      • Martin R.J.
      Mycoplasma pneumoniae and Chlamydia pneumoniae in asthma: effect of clarithromycin.
      • Nelson H.S.
      • Hamilos D.L.
      • Corsello P.R.
      • Levesque N.V.
      • Buchmeier A.D.
      • Bucher B.L.
      A double-blind study of troleandomycin and methylprednisolone in asthmatic subjects who require daily corticosteroids.
      • Shoji T.
      • Yoshida S.
      • Sakamoto H.
      • Hasegawa H.
      • Nakagawa H.
      • Amayasu H.
      Anti-inflammatory effect of roxithromycin in patients with aspirin-intolerant asthma.
      There were no significant differences in forced expiratory volume in 1 s (FEV1), and difference between forced vital capacity (FVC) and corticosteroid usage in the studies. However, significant improvements in favour of macrolides in symptom control, BHR, attenuation in eosinophilic inflammation and good drug tolerability. Despite the positive outcomes, caution in the interpretation is vital as the studies include small numbers, different macrolides assessed, a variety in severities of asthma and chronic infection with Chlamydia (C.) pneumonia, as well as diverse range outcome measures.
      Table 1Summary of the studies of macrolides in asthma (Modified from Richeldi et al.
      • Richeldi L.
      • Ferrara G.
      • Fabbri L.M.
      • Lasserson T.J.
      • Gibson P.G.
      Macrolides for chronic asthma.
      ).
      Study (Reference)Study designNumber of subjectsDuration of studyAntibioticOutcomes
      Amayasu et al.
      • Amayasu H.
      • Yoshida S.
      • Ebana S.
      • Yamamoto Y.
      • Nishikawa T.
      • Shoji T.
      • et al.
      Clarithromycin suppresses bronchial hyperresponsiveness associated with eosinophilic inflammation in patients with asthma.
      Randomised DBPC Crossover study17 adult subjects with mild-to-moderate atopic asthma8 weeksCRM
      • -
        Improvement in patients' symptoms and Methacholine PC20 in favour of CRM -No change in FEV1 and FVC between Gps
      • -
        Reduction in blood and sputum eosinophil counts, and sputum ECP
      • -
        No serious adverse events
      Black et al.
      • Black P.N.
      • Blasi F.
      • Jenkins C.R.
      • Scicchitano R.
      • Mills G.D.
      • Rubinfeld A.R.
      • et al.
      Trial of roxithromycin in subjects with asthma and serological evidence of infection with Chlamydia pneumoniae.
      Randomised DBPC219 asthmatic subjects with serological evidence of C. pneumoniae infection as demonstrated by IgG and IgA antibody titres6 weeksRXM
      • -
        Improvements in morning and evening PEF in favour of RXM
      • -
        No significant changes symptom scores, AQLQ or Chlamydia antibody titres between Gps
      • -
        No serious adverse events
      Kamada et al.
      • Kamada A.K.
      • Hill M.R.
      • Ikle D.N.
      • Brenner A.M.
      • Szefler S.J.
      Efficacy and safety of low-dose troleandomycin therapy in children with severe, steroid-requiring asthma.
      Randomised DBPC Gp A: TDM + MP; Gp B: TDM + prednisolone; Gp C: placebo + MP19 children (6–17 yrs) with OCS-dependent asthma (OCS tapering study)12 weeksTDM
      • -
        Improvements in all Gps in OCS reduction compared to baseline (and between Gp A and Gp C)
      • -
        Significant improvement in Gp A in symptom scores
      • -
        Non-significant reduction in pulmonary function in all Gps (except for significant attenuation in FEV1 and FEF25-75 in Gp B)
      • -
        Significant reduction in Methacholine PC20 in Gp A
      • -
        No serious adverse events
      Kostadima et al.
      • Kostadima E.
      • Tsiodras S.
      • Alexopoulos E.I.
      • Kaditis A.G.
      • Mavrou I.
      • Georgatou N.
      • et al.
      Clarithromycin reduces the severity of bronchial hyperresponsiveness in patients with asthma.
      Randomised DBPC of Gp A: CRM b.i.d.; Gp B: CRM t.i.d.; Gp C: placebo75 adult subjects with mild persistent asthma8 weeksCRM
      • -
        Significant improvement in FEV1 in Gp B
      • -
        Significant improvement in Methacholine PD20 in Gps A and B
      • -
        No changes in cortisol levels (in the 40 subjects that were assessed compared to baseline)
      Kraft et al.
      • Kraft M.
      • Cassell G.H.
      • Pak J.
      • Martin R.J.
      Mycoplasma pneumoniae and Chlamydia pneumoniae in asthma: effect of clarithromycin.
      Randomised DBPC55 adult subjects with moderate persistent asthma (31 with evidence of C. pneumoniae or M. pneumoniae infection)6 weeksCRM
      • -
        No change in FEV1 between Gps
      • -
        No significant difference in IL-2, IL-4, IL-5, IL-12 and TNF-α airway biopsies and BAL between PCR + ve and PCR –ve subjects
      • Subgroup analysis of PCR + ve and –ve for C. pneumomiae or M. Pneumoniae receiving CRM or placebo:
      • -
        Significant increase in FEV1 in PCR + ve subjects receiving CRM (not in PCR –ve or PCR + ve subjects receiving placebo)
      • -
        Significant reduction in IL-5, IL-12 and TNF-α in BAL in PCR + ve receiving CRM and only the latter 2 mediators in PCR –ve receiving CRM
      • Significant reduction in TNF-α in airway biopsies in PCR + ve and –ve receiving CRM
      Nelson et al.
      • Nelson H.S.
      • Hamilos D.L.
      • Corsello P.R.
      • Levesque N.V.
      • Buchmeier A.D.
      • Bucher B.L.
      A double-blind study of troleandomycin and methylprednisolone in asthmatic subjects who require daily corticosteroids.
      Randomised DBPC of TDM + MP vs. placebo + MP75 adult asthmatic subjects with severe persistent asthma (OCS tapering study)52 weeks (single blind for 52 weeks for 57 subjects [TDM n = 30; Placebo n = 27]TDM
      • -
        Significant reduction in hospitalisation, OCS for exacerbations, OCS tapering and dual- photon densitometry of lumbar spine in both Gps at 52 and 104 weeks compared to baseline (but not between Gps)
      • -
        Significant increase in blood eosinophil count and 60 min stimulated cortisol levels at 52 weeks in both Gps
      • -
        Significant reduction in mean IgG level in the TDM compared to placebo at 52 weeks
      • -
        Significant increase in mean fasting blood sugar (at 104 weeks) and cholesterol levels (at 52 and 104 weeks) in the TDM Gp than placebo
      • -
        No significant improvement in Methacholine PC20 between Gps
      Shoji et al.
      • Shoji T.
      • Yoshida S.
      • Sakamoto H.
      • Hasegawa H.
      • Nakagawa H.
      • Amayasu H.
      Anti-inflammatory effect of roxithromycin in patients with aspirin-intolerant asthma.
      Randomised DBPC Crossover study14 adult subjects with aspirin-intolerant mild/moderate asthma8 weeksRXM
      • -
        Significant reduction in symptom score with RXM compared to placebo
      • -
        No significant differences between both in pulmonary function, sulpyrine PC20 and leukotriene E4 urinary elimination.
      • -
        Significant reduction with RXM in mean ECP and eosinophil count in serum and sputum compared to placebo
      • -
        No serious adverse events
      Abbreviations: DBPC – Double-blind, placebo-controlled study; CRM – Clarithromycin; PC20 – Provocation concentration causing a 20% reduction in FEV1; Gp – Group; FEV1 – Forced expiratory volume in 1 s; FVC – Forced vital capacity; ECP – Eosinophilic cationic protein; RXM – Roxithromycin; C. pneumomiaeChlamydia pneumoniae; Ig – Immunoglobulin; flow; PEF – Peak expiratory flow; AQLQ – Asthma-related quality of life; TDM – Troleandomycin; MP – Methylprednisolone; yrs – years; OCS – Oral corticosteroids; FEF25–75 – Forced expiratory flow 25%–75%; b.i.d – Twice daily; t.i.d. – thrice daily; PD20 – Provocation dose causing a 20% reduction in FEV1; M. pneumoniaeMycoplasma pneumoniae; IL – Interleukin; TNF-α – Tumour necrosis factor alpha; PCR – Polymerase chain reaction; +ve – Positive; –ve – Negative; vs. – versus.
      Following this review, a number of new studies have been published in the literature using clarithromycin and azithromycin. A trial on patients with severe refractory asthma
      • Simpson J.L.
      • Powell H.
      • Boyle M.J.
      • Scott R.J.
      • Gibson P.G.
      Clarithromycin targets neutrophilic airway inflammation in refractory asthma.
      reported significant improvements in the clarithromycin-treated group compared to placebo in Juniper's Asthma-related Quality of Life Questionnaire (AQLQ) scores,
      • Juniper E.F.
      • Guyatt G.H.
      • Ferrie P.J.
      • Griffith L.E.
      Measuring quality of life in asthma.
      and reduction in sputum IL-8 and neutrophils, and self-reported wheezing; particularly in the subgroup of patients with non-eosinophilic (sputum) asthma but there was no improvements in FEV1, hypertonic saline challenge or sputum eosinophil counts. Piacentini et al. conducted an 8 week trial on the efficacy of azithromycin versus placebo on lung function, BHR and airway inflammation in 16 asthmatic children
      • Piacentini G.L.
      • Peroni D.G.
      • Bodini A.
      • Pigozzi R.
      • Costella S.
      • Loiacono A.
      • et al.
      Azithromycin reduces bronchial hyperresponsiveness and neutrophilic airway inflammation in asthmatic children: a preliminary report.
      and reported significant reduction in hypertonic saline-induced BHR and sputum neutrophilia in favour of the azithromycin-treated children compared to placebo, but no changes in FEV1 between both groups. In another randomised placebo-controlled, blinded, allocation-concealed parallel group clinical trial in 45 adults with stable, persistent asthma, it was observed that there were significant improvements in azithromycin-treated (compared to placebo) subjects in asthma symptoms and rescue inhaler use during treatment that persisted at 3 months after treatment, but not in the AQLQ.
      • Hahn D.L.
      • Plane M.B.
      • Mahdi O.S.
      • Byrne G.I.
      Secondary outcomes of a pilot randomized trial of azithromycin treatment for asthma.
      Of note, in the azithromycin-treated subjects the overall asthma symptom improvement was higher in the subgroup of patients with high immunoglobin (Ig) A to Chlamydia pnuemoniae than in the lower IgA (28% vs. 12%), but not significant. Moreover, there was a positive and significant association between anti-Chlamydial IgA, but not anti-Chlamydial IgG, with asthma symptom changes at 6 months. Hence, it was proposed that the anti-Chlamydial IgA could help with 6-month asthma prognosis, as measured by an overall asthma symptom scale. From the various studies, we can see that there may be a possible role for macrolides in chronic asthma; however their routine use is not clearly justified based on current evidence.

      Chronic Obstructive Pulmonary Disease (COPD)

      Exacerbations of Chronic Obstructive Pulmonary Disease (COPD) impair health status, accelerate the progression of the disease and are associated with significant early mortality.
      • Price L.C.
      • Lowe D.
      • Hosker H.S.
      • Anstey K.
      • Pearson M.G.
      • Roberts C.M.
      UK National COPD Audit 2003: impact of hospital resources and organisation of care on patient outcome following admission for acute COPD exacerbation.
      The frequency and severity of exacerbations is associated with long-term mortality independent of co-morbidities, FEV1, age and body mass index (BMI).
      • Soler-Cataluna J.J.
      • Martinez-Garcia M.A.
      • Roman Sanchez P.
      • Salcedo E.
      • Navarro M.
      • Ochando R.
      Severe acute exacerbations and mortality in patients with chronic obstructive pulmonary disease.
      Airway inflammation plays a key role in the pathogenesis of COPD and a variety of microbial organisms promote the inflammatory process precipitating an acute exacerbation. Given the role of inflammation and infections in COPD the use of long-term antibiotics may offer a distinctive benefit to control this disease.
      • Martinez F.J.
      • Curtis J.L.
      • Albert R.
      Role of macrolide therapy in chronic obstructive pulmonary disease.
      One of the earliest studies by Gomez and colleagues observed a statistically significant reduction in the number of acute infectious episodes and hospital admissions in azithromycin-treated versus placebo following a 3-day prophylactic treatment course every 21 days during the winter months.
      • Gomez J.
      • Banos V.
      • Simarro E.
      • Lorenzo Cruz M.
      • Ruiz Gomez J.
      • Latour J.
      • et al.
      Prospective, comparative study (1994–1998) of the influence of short-term prophylactic treatment with azithromycin on patients with advanced COPD.
      The important trials are summarised in Table 2.
      • Albert R.K.
      • Connett J.
      • Bailey W.C.
      • Casaburi R.
      • Cooper Jr., J.A.
      • Criner G.J.
      • et al.
      Azithromycin for prevention of exacerbations of COPD.
      • Banerjee D.
      • Khair O.A.
      • Honeybourne D.
      The effect of oral clarithromycin on health status and sputum bacteriology in stable COPD.
      • Marcon S.S.
      • Rossini A.F.
      • Aceti E.L.
      Nursing assistance by a home care team after the death of the patient.
      • He Z.Y.
      • Ou L.M.
      • Zhang J.Q.
      • Bai J.
      • Liu G.N.
      • Li M.H.
      • et al.
      Effect of 6 months of erythromycin treatment on inflammatory cells in induced sputum and exacerbations in chronic obstructive pulmonary disease.
      • Seemungal T.A.
      • Wilkinson T.M.
      • Hurst J.R.
      • Perera W.R.
      • Sapsford R.J.
      • Wedzicha J.A.
      Long-term erythromycin therapy is associated with decreased chronic obstructive pulmonary disease exacerbations.
      • Sethi S.
      • Jones P.W.
      • Theron M.S.
      • Miravitlles M.
      • Rubinstein E.
      • Wedzicha J.A.
      • et al.
      Pulsed moxifloxacin for the prevention of exacerbations of chronic obstructive pulmonary disease: a randomized controlled trial.
      The first prospective study investigating the efficacy of long-term macrolide therapy in patients with stable COPD was an open-label, randomized trial of erythromycin (200–400 mg/d) for 12 months in 109 patients with COPD. Thirty patients (56%) compared to six patients (11%) in the control group and erythromycin group respectively had one or more exacerbations. Although this trial was noteworthy, it was unblinded. However, not all the initial trials were supportive of a role for long-term antibiotics. Banerjee et al. examined the role of 3-months oral clarithromycin or placebo once-daily in 67 patients with moderate-to-severe COPD. The authors concluded that treatment of stable COPD with clarithromycin yielded no clinical advantage and did not improve health status, sputum bacterial numbers, or prevent infective exacerbations.
      • Banerjee D.
      • Khair O.A.
      • Honeybourne D.
      The effect of oral clarithromycin on health status and sputum bacteriology in stable COPD.
      However, the short duration (3 months) of the antibiotic could have had a bearing on the results. Seemungal and colleagues in a randomized, DPBC study of 109 patients administered erythromycin 250 mg twice daily to patients with moderate COPD (80% of patients on inhaled corticosteroids) over 12 months.
      • Seemungal T.A.
      • Wilkinson T.M.
      • Hurst J.R.
      • Perera W.R.
      • Sapsford R.J.
      • Wedzicha J.A.
      Long-term erythromycin therapy is associated with decreased chronic obstructive pulmonary disease exacerbations.
      They found that erythromycin treatment was associated with a significant reduction in exacerbations compared with placebo, but had no significant impact on FEV1, sputum inflammatory markers, serum inflammatory markers or bacterial flora. The frequency of side effects was low in both arms with no differences between the two arms.
      Table 2Summary of the studies of long term antibiotics in COPD.
      StudyStudy designNumber of subjectsDuration of studyAntibioticOutcomes
      Albert et al.
      • Albert R.K.
      • Connett J.
      • Bailey W.C.
      • Casaburi R.
      • Cooper Jr., J.A.
      • Criner G.J.
      • et al.
      Azithromycin for prevention of exacerbations of COPD.
      Randomised placebo control study157712 monthsAzithromycin250 mg daily
      • -
        Median time for first exacerbation better for azithromycin group
      • -
        Reduced frequency of acute exacerbations
      • -
        Reduced risk of acute exacerbations
      • -
        Improved quality of life
      • -
        Caused hearing decrements in a small percentage
      He et al.
      • He Z.Y.
      • Ou L.M.
      • Zhang J.Q.
      • Bai J.
      • Liu G.N.
      • Li M.H.
      • et al.
      Effect of 6 months of erythromycin treatment on inflammatory cells in induced sputum and exacerbations in chronic obstructive pulmonary disease.
      Randomised DPBC trial366 monthsErythromycin125 mg three times daily
      • -
        lower mean exacerbation rate
      • -
        Delayed time for first exacerbation favouring erythromycin
      • -
        Decreased sputum neutrophils and neutrophil elastase
      Blasi et al.
      • Marcon S.S.
      • Rossini A.F.
      • Aceti E.L.
      Nursing assistance by a home care team after the death of the patient.
      Randomised uncontrolled trial226 monthsAzithromycin 500 mg three times a week
      • -
        Lower cumulative number of exacerbations and hospitalisations-Reduction in the time for first exacerbation-Improved quality of life
      Seemungal et al.
      • Seemungal T.A.
      • Wilkinson T.M.
      • Hurst J.R.
      • Perera W.R.
      • Sapsford R.J.
      • Wedzicha J.A.
      Long-term erythromycin therapy is associated with decreased chronic obstructive pulmonary disease exacerbations.
      Randomised DPBC trial10912 monthsErythromycin250 mg twice daily
      • -
        Reduced rate of exacerbations
      • -
        Shorter duration of exacerbations
      • -
        No difference in terms of stable FEV1, serum CRP, sputum IL-6 or IL-8
      Banerjee et al.
      • Banerjee D.
      • Khair O.A.
      • Honeybourne D.
      The effect of oral clarithromycin on health status and sputum bacteriology in stable COPD.
      Prospective Randomised DPBC trial673 monthsClarithromycin 500 mg once daily
      • -
        No change in health status, exacerbation rate or sputum bacterial numbers
      Sethi et al.
      • Sethi S.
      • Jones P.W.
      • Theron M.S.
      • Miravitlles M.
      • Rubinstein E.
      • Wedzicha J.A.
      • et al.
      Pulsed moxifloxacin for the prevention of exacerbations of chronic obstructive pulmonary disease: a randomized controlled trial.
      Randomised DPBC trial115748 months6 courses of Moxifloxacin 400 mg OD for 5 days
      • -
        Reduction in the exacerbation rates
      • -
        No unexpected adverse events
      The results of the above studies suggest that macrolide therapy may be beneficial in COPD patients preventing acute exacerbations of COPD (AECOPD) and altering the natural course of the disease. Whether this is due to its anti-microbial properties or due to immunomodulation needs to be established. The balance between inflammation and immunomodulation is important in chronic airway diseases and macrolides may have a possible effect on this balance in addition to its anti-microbial effects to reduce AECOPD. That said, a randomised DBPC trial in stable COPD patients with pulsed moxifloxacin (moxifloxacin 400 mg/day) (N = 573) or placebo (N = 584) once daily for 5 days and treatment repeated every 8 weeks for a total of 6 courses found that at 48 weeks the odds ratio (OR) for suffering an exacerbation was reduced by 20% in the intention-to-treat group.
      • Sethi S.
      • Jones P.W.
      • Theron M.S.
      • Miravitlles M.
      • Rubinstein E.
      • Wedzicha J.A.
      • et al.
      Pulsed moxifloxacin for the prevention of exacerbations of chronic obstructive pulmonary disease: a randomized controlled trial.
      No changes in the overall health status, rates of hospitalization or mortality, or attenuation of lung function decline were noted. Subgroup analyses demonstrated that the reduction in exacerbations with moxifloxacin was seen in COPD of all severity categories, supporting a role for quinolones in preventing exacerbations.
      Recently, Albert and colleagues conducted a multicenter randomised trial of 1142 patients at risk of AECOPD to receive 250 mg daily of azithromycin (n = 570) or placebo (n = 572) for a year in addition to usual care.
      • Albert R.K.
      • Connett J.
      • Bailey W.C.
      • Casaburi R.
      • Cooper Jr., J.A.
      • Criner G.J.
      • et al.
      Azithromycin for prevention of exacerbations of COPD.
      The primary outcome i.e. time to first exacerbation was significantly increased in the azithromycin group when compared to placebo (226 days vs. 174 days). The hazard ratio for having an acute exacerbation per patient year was 0.74 in the azithromycin group. Although there was no significant reduction in the hospitalisation rates, urgent care visits or mortality between the two groups, azithromycin treatment improved the QoL measures and had similar frequency of serious adverse events in both groups except for hearing loss and colonisation with macrolide-resistant organisms. While there was a question on the role of long-term antibiotics in stable COPD to prevent exacerbations, the trial by Albert et al. has provided support for the long-term use of azithromycin to reduce exacerbations. It is still unclear whether this beneficial effect is due to the anti-bacterial properties or to the immunomodulatory effects of macrolides. Furthermore, the likely development of resistance to antibiotics in the long-run and the role for azithromycin on a once, twice or thrice weekly regimen, given the extremely long tissue persistence of the drug needs to be explored. Therefore, adverse effects of macrolides such as hearing loss, effects on QTc and interactions with other agents need to be taken into account and balanced against possible benefits in individual patients. In addition, patients need ongoing assessments for potential benefits of long term therapy with macrolides and at the same time be aware of potential adverse effects. Although, there have been no studies or guidelines recommended how long one should administer macrolides to assess the efficacy of macrolides, we suggest a trial of 3–6 months in the first instance, followed by regular reviews on benefit vs adverse events.

      Cystic fibrosis (CF)

      CF is one of the most common genetic disorders
      • Rowe S.M.
      • Miller S.
      • Sorscher E.J.
      Cystic fibrosis.
      • O'Sullivan B.P.
      • Freedman S.D.
      Cystic fibrosis.
      • Rommens J.M.
      • Iannuzzi M.C.
      • Kerem B.
      • Drumm M.L.
      • Melmer G.
      • Dean M.
      • et al.
      Identification of the cystic fibrosis gene: chromosome walking and jumping.
      in which the main defect relates to the malfunction in the CF trans-membrane conductance regulator (CFTR). This defect in turn results in chronic respiratory infections which remain the main cause of morbidity and mortality in CF.
      • Welsh M.J.
      Targeting the basic defect in cystic fibrosis.
      • Bilton D.
      • Canny G.
      • Conway S.
      • Dumcius S.
      • Hjelte L.
      • Proesmans M.
      • et al.
      Pulmonary exacerbation: towards a definition for use in clinical trials. Report from the EuroCareCF Working Group on outcome parameters in clinical trials.
      • Clifton I.J.
      • Kastelik J.A.
      • Peckham D.G.
      • Hale A.
      • Denton M.
      • Etherington C.
      • et al.
      Ten years of viral and non-bacterial serology in adults with cystic fibrosis.
      • Boucher R.C.
      New concepts of the pathogenesis of cystic fibrosis lung disease.
      In early CF, Staphylococcus (S.) aureus and Haemophilus (H.) influenzae remain the main pathogens.
      • Cystic Fibrosis Foundation Trust
      Antibiotic treatment for cystic fibrosis: report of the UK Cystic Fibrosis Trust Antibiotic Working Group.
      • Rowe S.M.
      • Miller S.
      • Sorscher E.J.
      Cystic fibrosis.
      However, overall the most commonly isolated pathogen in CF is P aeruginosa. Recently, pathogens such as Burkholderia (B.) cepacia and Stenotrophomonas (S.) maltophilia have been reported in CF with increasing frequency.
      • Cystic Fibrosis Foundation Trust
      Antibiotic treatment for cystic fibrosis: report of the UK Cystic Fibrosis Trust Antibiotic Working Group.
      • Rowe S.M.
      • Miller S.
      • Sorscher E.J.
      Cystic fibrosis.
      Antibiotics in CF are used to manage exacerbations as well as to prevent, eradicate and control respiratory infections, hence potentially improving survival.
      • Cystic Fibrosis Foundation Trust
      Antibiotic treatment for cystic fibrosis: report of the UK Cystic Fibrosis Trust Antibiotic Working Group.
      Flucloxacillin, which has shown to reduce the incidence of infection with S. aureus, has acquired long term use in young children with CF aged up to 3 years.
      • Smyth A.
      • Walters S.
      Prophylactic antibiotics for cystic fibrosis.
      Similarly, other oral agents in particular macrolides have been shown to be beneficial in CF (Table 3).
      • Jaffe A.
      • Francis J.
      • Rosenthal M.
      • Bush A.
      Long-term azithromycin may improve lung function in children with cystic fibrosis.
      • Wolter J.
      • Seeney S.
      • Bell S.
      • Bowler S.
      • Masel P.
      • McCormack J.
      Effect of long term treatment with azithromycin on disease parameters in cystic fibrosis: a randomised trial.
      • Saiman L.
      • Marshall B.C.
      • Mayer-Hamblett N.
      • Burns J.L.
      • Quittner A.L.
      • Cibene D.A.
      • et al.
      Azithromycin in patients with cystic fibrosis chronically infected with Pseudomonas aeruginosa: a randomized controlled trial.
      • Nguyen D.
      • Emond M.J.
      • Mayer-Hamblett N.
      • Saiman L.
      • Marshall B.C.
      • Burns J.L.
      Clinical response to azithromycin in cystic fibrosis correlates with in vitro effects on Pseudomonas aeruginosa phenotypes.
      • Clement A.
      • Tamalet A.
      • Leroux E.
      • Ravilly S.
      • Fauroux B.
      • Jais J.P.
      Long term effects of azithromycin in patients with cystic fibrosis: a double blind, placebo controlled trial.
      • Southern K.W.
      • Barker P.M.
      • Solis A.
      Macrolide antibiotics for cystic fibrosis.
      • McCormack J.
      • Bell S.
      • Senini S.
      • Walmsley K.
      • Patel K.
      • Wainwright C.
      • et al.
      Daily versus weekly azithromycin in cystic fibrosis patients.
      • Pirzada O.M.
      • McGaw J.
      • Taylor C.J.
      • Everard M.L.
      Improved lung function and body mass index associated with long-term use of macrolide antibiotics.
      • Hansen C.R.
      • Pressler T.
      • Koch C.
      • Hoiby N.
      Long-term azitromycin treatment of cystic fibrosis patients with chronic Pseudomonas aeruginosa infection; an observational cohort study.
      A number of studies have shown that the long-term use of azithromycin in CF patients resulted in improved lung function, reduction in a number of infective exacerbations and the use of antibiotics.
      • Jaffe A.
      • Francis J.
      • Rosenthal M.
      • Bush A.
      Long-term azithromycin may improve lung function in children with cystic fibrosis.
      • Wolter J.
      • Seeney S.
      • Bell S.
      • Bowler S.
      • Masel P.
      • McCormack J.
      Effect of long term treatment with azithromycin on disease parameters in cystic fibrosis: a randomised trial.
      • Saiman L.
      • Marshall B.C.
      • Mayer-Hamblett N.
      • Burns J.L.
      • Quittner A.L.
      • Cibene D.A.
      • et al.
      Azithromycin in patients with cystic fibrosis chronically infected with Pseudomonas aeruginosa: a randomized controlled trial.
      • Nguyen D.
      • Emond M.J.
      • Mayer-Hamblett N.
      • Saiman L.
      • Marshall B.C.
      • Burns J.L.
      Clinical response to azithromycin in cystic fibrosis correlates with in vitro effects on Pseudomonas aeruginosa phenotypes.
      • Clement A.
      • Tamalet A.
      • Leroux E.
      • Ravilly S.
      • Fauroux B.
      • Jais J.P.
      Long term effects of azithromycin in patients with cystic fibrosis: a double blind, placebo controlled trial.
      • Southern K.W.
      • Barker P.M.
      • Solis A.
      Macrolide antibiotics for cystic fibrosis.
      • McCormack J.
      • Bell S.
      • Senini S.
      • Walmsley K.
      • Patel K.
      • Wainwright C.
      • et al.
      Daily versus weekly azithromycin in cystic fibrosis patients.
      • Pirzada O.M.
      • McGaw J.
      • Taylor C.J.
      • Everard M.L.
      Improved lung function and body mass index associated with long-term use of macrolide antibiotics.
      • Hansen C.R.
      • Pressler T.
      • Koch C.
      • Hoiby N.
      Long-term azitromycin treatment of cystic fibrosis patients with chronic Pseudomonas aeruginosa infection; an observational cohort study.
      • Kabra S.K.
      • Pawaiya R.
      • Lodha R.
      • Kapil A.
      • Kabra M.
      • Vani A.S.
      • et al.
      Long-term daily high and low doses of azithromycin in children with cystic fibrosis: a randomized controlled trial.
      • Kastelik J.A.
      • Peckham D.G.
      • Conway S.
      Azithromycin in cystic fibrosis.
      For example, Wolter et al. reported that in adults with CF, azithromycin improved QoL, reduced both the number of respiratory exacerbations, and the rate of decline in the lung function.
      • Wolter J.
      • Seeney S.
      • Bell S.
      • Bowler S.
      • Masel P.
      • McCormack J.
      Effect of long term treatment with azithromycin on disease parameters in cystic fibrosis: a randomised trial.
      Similar outcomes were reported by Saiman and colleagues with oral azithromycin in CF patients chronically infected with P. aeruginosa.
      • Saiman L.
      • Marshall B.C.
      • Mayer-Hamblett N.
      • Burns J.L.
      • Quittner A.L.
      • Cibene D.A.
      • et al.
      Azithromycin in patients with cystic fibrosis chronically infected with Pseudomonas aeruginosa: a randomized controlled trial.
      Although the exact mode of action of macrolides in CF is not fully understood, the benefits are mainly observed in patients colonised with P. aeruginosa. However, some also reported the benefit of long-term macrolides in CF patients even prior to P. aeruginosa infection.
      • Clement A.
      • Tamalet A.
      • Leroux E.
      • Ravilly S.
      • Fauroux B.
      • Jais J.P.
      Long term effects of azithromycin in patients with cystic fibrosis: a double blind, placebo controlled trial.
      Chronic colonisation with P. aeruginosa is one of the main predictors of morbidity and mortality in CF,
      • Emerson J.
      • Rosenfeld M.
      • McNamara S.
      • Ramsey B.
      • Gibson R.L.
      Pseudomonas aeruginosa and other predictors of mortality and morbidity in young children with cystic fibrosis.
      hence the need to control this infection.
      Table 3Summary of the studies of long term antibiotics in cystic fibrosis.
      StudyStudy designNumber of subjectsDuration

      of study
      Antibiotic usedOutcomes
      Saiman et al.
      • Saiman L.
      • Marshall B.C.
      • Mayer-Hamblett N.
      • Burns J.L.
      • Quittner A.L.
      • Cibene D.A.
      • et al.
      Azithromycin in patients with cystic fibrosis chronically infected with Pseudomonas aeruginosa: a randomized controlled trial.
      Randomised Placebo controlled185(87 treatment group)6 monthsAzithromycinImproved FEV1, reduced number of exacerbations,
      Wolter et al.
      • Wolter J.
      • Seeney S.
      • Bell S.
      • Bowler S.
      • Masel P.
      • McCormack J.
      Effect of long term treatment with azithromycin on disease parameters in cystic fibrosis: a randomised trial.
      Randomised placebo controlled60 adult CF patients3 monthsAzithromycinNo decline in FEV1, fewer courses of IV antibiotics, decline in C reactive protein, improvement in QOL
      Kabra et al.
      • Kabra S.K.
      • Pawaiya R.
      • Lodha R.
      • Kapil A.
      • Kabra M.
      • Vani A.S.
      • et al.
      Long-term daily high and low doses of azithromycin in children with cystic fibrosis: a randomized controlled trial.
      Randomised controlled56 children12 monthsAzithromycin low dose 5 mg/kg/day compared with high dose 15 mg/kg/dayNo difference in clinical score, FEV1 and pulmonary exacerbation rates between the two groups
      Hodson et al.
      • Hodson M.E.
      • Gallagher C.G.
      • Govan J.R.
      A randomised clinical trial of nebulised tobramycin or colistin in cystic fibrosis.
      Randomised controlled1154 weeksNebulised colomycin compared with nebulised tobramycinBoth treatments reduced bacterial load. Nebulised tobramycin improved lung function in CF patients chronically colonised with P. aeruginosa
      Ramsey et al.
      • Ramsey B.W.
      • Pepe M.S.
      • Quan J.M.
      • Otto K.L.
      • Montgomery A.B.
      • Williams-Warren J.
      • et al.
      Intermittent administration of inhaled tobramycin in patients with cystic fibrosis. Cystic Fibrosis Inhaled Tobramycin Study Group.
      Randomised placebo controlled52024 weeksNebulised tobramycinImprovement in pulmonary function, decrease in the density of P. aeruginosa in sputum, decreased risk of hospitalization
      McCoy et al.
      • McCoy K.S.
      • Quittner A.L.
      • Oermann C.M.
      • Gibson R.L.
      • Retsch-Bogart G.Z.
      • Montgomery A.B.
      Inhaled aztreonam lysine for chronic airway Pseudomonas aeruginosa in cystic fibrosis.
      Randomised controlled21128 daysInhaled aztreonam solutionImprovement in pulmonary function and respiratory symptoms
      Retsch-Bogart et al.
      • Retsch-Bogart G.Z.
      • Quittner A.L.
      • Gibson R.L.
      • Oermann C.M.
      • McCoy K.S.
      • Montgomery A.B.
      • et al.
      Efficacy and safety of inhaled aztreonam lysine for airway pseudomonas in cystic fibrosis.
      Randomised placebo controlled16428 daysInhaled aztreonam solutionImprovement in pulmonary function and respiratory symptoms
      Oermann et al.
      • Oermann C.M.
      • Retsch-Bogart G.Z.
      • Quittner A.L.
      • Gibson R.L.
      • McCoy K.S.
      • Montgomery A.B.
      • et al.
      An 18-month study of the safety and efficacy of repeated courses of inhaled aztreonam lysine in cystic fibrosis.
      Open label27418 mothsInhaled aztreonam solutionClinical benefits in pulmonary function, health-related quality of life, and weight
      Ledson et al.
      • Ledson M.J.
      • Gallagher M.J.
      • Robinson M.
      • Cowperthwaite C.
      • Williets T.
      • Hart C.A.
      • et al.
      A randomized double-blinded placebo-controlled crossover trial of nebulized taurolidine in adult cystic fibrosis patients infected with Burkholderia cepacia.
      Randomised double blinded cross over204 weeksInhaled taurolidineNo change in B. cepacia colony count or spirometry, nor symptom score
      Frederiksen et al.
      • Frederiksen B.
      • Koch C.
      • Hoiby N.
      Antibiotic treatment of initial colonization with Pseudomonas aeruginosa postpones chronic infection and prevents deterioration of pulmonary function in cystic fibrosis.
      Comparison with historical control48 patients compared with 43 control44 mothsInhalation of colistin and oral ciprofloxacin16% of the treated patients developed chronic P. aeruginosa infection compared with 72% of the control patients (P < 0.005), improvement in lung function
      Gibson et al.
      • Gibson R.L.
      • Emerson J.
      • McNamara S.
      • Burns J.L.
      • Rosenfeld M.
      • Yunker A.
      • et al.
      Significant microbiological effect of inhaled tobramycin in young children with cystic fibrosis.
      Randomised double blind2128 daysInhaled tobramycinReduction in P. aeruginosa density
      Geller et al.
      • Geller D.E.
      • Flume P.A.
      • Staab D.
      • Fischer R.
      • Loutit J.S.
      • Conrad D.J.
      Levofloxacin inhalation solution (MP-376) in patients with cystic fibrosis with Pseudomonas aeruginosa.
      Randomised placebo controlled15128 daysInhaled ciprofloxacinReduction in P. aeruginosa density, improvement in pulmonary function (FEV1), reduction in need for anti-pseudomonal antibiotics
      Numerous antibiotics have been tested for aerosolized use in CF, including tobramycin, colomycin, gentamicin, aztreonam and taurolidine and some of them have acquired clinical use in CF.
      • Frederiksen B.
      • Koch C.
      • Hoiby N.
      Antibiotic treatment of initial colonization with Pseudomonas aeruginosa postpones chronic infection and prevents deterioration of pulmonary function in cystic fibrosis.
      • Valerius N.H.
      • Koch C.
      • Hoiby N.
      Prevention of chronic Pseudomonas aeruginosa colonisation in cystic fibrosis by early treatment.
      • Hodson M.E.
      • Gallagher C.G.
      • Govan J.R.
      A randomised clinical trial of nebulised tobramycin or colistin in cystic fibrosis.
      • Ramsey B.W.
      • Pepe M.S.
      • Quan J.M.
      • Otto K.L.
      • Montgomery A.B.
      • Williams-Warren J.
      • et al.
      Intermittent administration of inhaled tobramycin in patients with cystic fibrosis. Cystic Fibrosis Inhaled Tobramycin Study Group.
      • Littlewood J.M.
      • Miller M.G.
      • Ghoneim A.T.
      • Ramsden C.H.
      Nebulised colomycin for early pseudomonas colonisation in cystic fibrosis.
      • Crowther Labiris N.R.
      • Holbrook A.M.
      • Chrystyn H.
      • Macleod S.M.
      • Newhouse M.T.
      Dry powder versus intravenous and nebulized gentamicin in cystic fibrosis and bronchiectasis. A pilot study.
      • Gibson R.L.
      • Retsch-Bogart G.Z.
      • Oermann C.
      • Milla C.
      • Pilewski J.
      • Daines C.
      • et al.
      Microbiology, safety, and pharmacokinetics of aztreonam lysinate for inhalation in patients with cystic fibrosis.
      • Ledson M.J.
      • Gallagher M.J.
      • Robinson M.
      • Cowperthwaite C.
      • Williets T.
      • Hart C.A.
      • et al.
      A randomized double-blinded placebo-controlled crossover trial of nebulized taurolidine in adult cystic fibrosis patients infected with Burkholderia cepacia.
      Nebulised antibiotics in CF have been used to manage acute respiratory exacerbations as well as chronic therapy to stabilise lung function and prevent chronic colonisation with P. aeruginosa. For example, studies have shown that treatment with nebulised colomycin can lead to effective eradication of colonisation of P. aeruginosa.
      • Frederiksen B.
      • Koch C.
      • Hoiby N.
      Antibiotic treatment of initial colonization with Pseudomonas aeruginosa postpones chronic infection and prevents deterioration of pulmonary function in cystic fibrosis.
      • Valerius N.H.
      • Koch C.
      • Hoiby N.
      Prevention of chronic Pseudomonas aeruginosa colonisation in cystic fibrosis by early treatment.
      In fact, three months thrice daily regime of nebulised colistin showed that after 3.5 years only 16% of treated patients had developed chronic P. aeruginosa infection compared to 72% of untreated historical controls.
      • Frederiksen B.
      • Koch C.
      • Hoiby N.
      Antibiotic treatment of initial colonization with Pseudomonas aeruginosa postpones chronic infection and prevents deterioration of pulmonary function in cystic fibrosis.
      Similarly, studies revealed that in CF patients inhaled tobramycin resulted in effective eradication of early infection with P. aeruginosa.
      • Gibson R.L.
      • Emerson J.
      • McNamara S.
      • Burns J.L.
      • Rosenfeld M.
      • Yunker A.
      • et al.
      Significant microbiological effect of inhaled tobramycin in young children with cystic fibrosis.
      Moreover, long-term intermittent administration of inhaled tobramycin has been well tolerated and resulted in improved lung function and decreased density of P. aeruginosa in the sputum as well as reducing the risk of hospitalization.
      • Ramsey B.W.
      • Pepe M.S.
      • Quan J.M.
      • Otto K.L.
      • Montgomery A.B.
      • Williams-Warren J.
      • et al.
      Intermittent administration of inhaled tobramycin in patients with cystic fibrosis. Cystic Fibrosis Inhaled Tobramycin Study Group.
      • Burns J.L.
      • Van Dalfsen J.M.
      • Shawar R.M.
      • Otto K.L.
      • Garber R.L.
      • Quan J.M.
      • et al.
      Effect of chronic intermittent administration of inhaled tobramycin on respiratory microbial flora in patients with cystic fibrosis.
      Similar observations have been reported with nebulised tobramycin and colomycin in CF patients colonised with P. aeruginosa by others
      • Hodson M.E.
      • Gallagher C.G.
      • Govan J.R.
      A randomised clinical trial of nebulised tobramycin or colistin in cystic fibrosis.
      ; hence both of these agents are being regularly used in clinical practice. A recent Cochrane review on long term inhaled antibiotics in CF has concluded that inhaled antibiotic treatment probably improves lung function and reduces exacerbation rate, but a pooled estimate of the level of benefit was not possible. The best evidence was for inhaled tobramycin.
      • Ryan G.
      • Singh M.
      • Dwan K.
      Inhaled antibiotics for long-term therapy in cystic fibrosis.
      Amongst the new inhalation antibiotics approved for the use in CF patients with P. aeruginosa colonisation is a monobactam formulation, aztreonam lysinate.
      • Gibson R.L.
      • Retsch-Bogart G.Z.
      • Oermann C.
      • Milla C.
      • Pilewski J.
      • Daines C.
      • et al.
      Microbiology, safety, and pharmacokinetics of aztreonam lysinate for inhalation in patients with cystic fibrosis.
      • Daddario M.K.
      • Hagerman J.K.
      • Klepser M.E.
      Clinical perspective on aztreonam lysine for inhalation in patients with cystic fibrosis.
      The use of inhaled aztreonam in CF patients with P. aeruginosa colonisation resulted in reduction of bacterial burden, preservation of lung function, and improvement in symptoms associated with disease.
      • McCoy K.S.
      • Quittner A.L.
      • Oermann C.M.
      • Gibson R.L.
      • Retsch-Bogart G.Z.
      • Montgomery A.B.
      Inhaled aztreonam lysine for chronic airway Pseudomonas aeruginosa in cystic fibrosis.
      • Retsch-Bogart G.Z.
      • Quittner A.L.
      • Gibson R.L.
      • Oermann C.M.
      • McCoy K.S.
      • Montgomery A.B.
      • et al.
      Efficacy and safety of inhaled aztreonam lysine for airway pseudomonas in cystic fibrosis.
      • Oermann C.M.
      • Retsch-Bogart G.Z.
      • Quittner A.L.
      • Gibson R.L.
      • McCoy K.S.
      • Montgomery A.B.
      • et al.
      An 18-month study of the safety and efficacy of repeated courses of inhaled aztreonam lysine in cystic fibrosis.
      McCoy and colleagues observed that 28-days of nebulised aztreonam compared with the placebo in CF patients on nebulised tobramycin improved lung function, respiratory symptoms and reduced sputum density of P. aeruginosa.
      • McCoy K.S.
      • Quittner A.L.
      • Oermann C.M.
      • Gibson R.L.
      • Retsch-Bogart G.Z.
      • Montgomery A.B.
      Inhaled aztreonam lysine for chronic airway Pseudomonas aeruginosa in cystic fibrosis.
      Similar observations were noted in an 18-month study with nebulised aztreonam besides being well tolerated.
      • Oermann C.M.
      • Retsch-Bogart G.Z.
      • Quittner A.L.
      • Gibson R.L.
      • McCoy K.S.
      • Montgomery A.B.
      • et al.
      An 18-month study of the safety and efficacy of repeated courses of inhaled aztreonam lysine in cystic fibrosis.
      Another novel inhaled antibiotic tested in CF patients with chronic P. aeruginosa includes an aerosol formulation of levofloxacin (MP-376, Aeroquin).
      • Geller D.E.
      • Flume P.A.
      • Staab D.
      • Fischer R.
      • Loutit J.S.
      • Conrad D.J.
      Levofloxacin inhalation solution (MP-376) in patients with cystic fibrosis with Pseudomonas aeruginosa.
      This new preparation of inhaled levofloxacin resulted in improved lung function and reduction in antibiotics use. Geller et al. observed that in CF patients colonised with P. aeruginosa nebulised levofloxacin was well tolerated, improved FEV1 by 8.7% and reduced sputum P. aeruginosa density.
      • Geller D.E.
      • Flume P.A.
      • Staab D.
      • Fischer R.
      • Loutit J.S.
      • Conrad D.J.
      Levofloxacin inhalation solution (MP-376) in patients with cystic fibrosis with Pseudomonas aeruginosa.
      There have also been attempts to use nebulised antibiotics to treat CF patients colonised with B. cepacia as those patients have an increased morbidity and mortality. Taurolidine is an antibiotic with a broad spectrum of activity against gram negative and positive bacteria as well as being an anti-endotoxin. Ledson and colleagues assessed the effects of inhaled taurolidine in CF patients infected with B. cepacia.
      • Ledson M.J.
      • Gallagher M.J.
      • Robinson M.
      • Cowperthwaite C.
      • Williets T.
      • Hart C.A.
      • et al.
      A randomized double-blinded placebo-controlled crossover trial of nebulized taurolidine in adult cystic fibrosis patients infected with Burkholderia cepacia.
      Although Taurolidine was well tolerated it did not affect the B. cepacia colony count or other outcomes assessed. Inhaled formulations of ciprofloxacin have shown promise in patients with non-CF bronchiectasis
      • Bilton D.
      • Serisier D.J.
      • De Soyza A.T.
      • Wolfe R.
      • Bruinenberg P.
      Multicenter, randomized, double-blind, placebo-controlled study (ORBIT 1) to evaluate the efficacy, safety, and tolerability of once daily ciprofloxacin for inhalation in the management of Pseudomonas aeruginosa infections in patients with non-cystic fibrosis bronchiectasis.
      and will be of interest to see whether similar effects will be seen in CF. Overall the use of inhaled antibiotics in CF has been widely accepted. The main role of inhaled antibiotics in CF has been in patients with chronic colonisation with P. aeruginosa, however there are potential new agents currently being assessed which may acquire clinical use in the future.

      Non-CF bronchiectasis

      Long-term antibiotics in bronchiectasis reduces exacerbations, improves symptoms and QoL by reducing bacterial load and airway inflammation.
      BTS statement on criteria for specialist referral, admission, discharge and follow-up for adults with respiratory disease.
      The early evidence for long-term antibiotics in bronchiectasis stems from the MRC multi-centre study where 122 patients with bronchiectasis were allocated to penicillin (n = 38), oxytetracycline (n = 44) and placebo (n = 40). After a year, in the oxytetracycline group there was a 64% reduction in sputum volume, had fewer days off work; fewer days confined to bed and reduced episodes of fever. Unfortunately, no formal statistical analyses were performed.
      PROLONGED antibiotic treatment of severe bronchiectasis; a report by a subcommittee of the Antibiotics Clinical Trials (non-tuberculous) Committee of the Medical Research Council.
      Currie et al. in a randomised placebo controlled trial evaluated the effect of high-dose amoxicillin (3 gm twice daily) in 38 patients with bronchiectasis.
      • Currie D.C.
      • Garbett N.D.
      • Chan K.L.
      • Higgs E.
      • Todd H.
      • Chadwick M.V.
      • et al.
      Double-blind randomized study of prolonged higher-dose oral amoxycillin in purulent bronchiectasis.
      The frequency of exacerbations during the study treatment phase was similar in both groups, but they were less severe than before study treatment in the amoxicillin group. There was a greater reduction in purulent sputum volume between exacerbations during the study treatment in the amoxicillin group compared to placebo. Independent assessment of the overall response based on patients' diary cards showed that a higher proportion improved in the amoxicillin-treated (11 of 17) compared to placebo (4 of 19). Adverse events experienced by patients were minor and there was no change in the bacterial flora based on sputum and stool cultures. More recently a New Zealand group conducted a DBPC study to evaluate the role of azithromycin in reducing frequency of exacerbations, improvement in lung function and health-related QoL in 141 (71 azithromycin; 70 placebo) patients with non-CF bronchiectasis for 6 months.
      • Wong C.
      • Jayaram L.
      • Karalus N.
      • Eaton T.
      • Tong C.
      • Hockey H.
      • et al.
      Azithromycin for prevention of exacerbations in non-cystic fibrosis bronchiectasis (EMBRACE): a randomised, double-blind, placebo-controlled trial.
      They reported a significant reduction in the rate of exacerbations but no differences in the other parameters assessed.
      Studies in non-CF bronchiectasis include both oral and nebulised antibiotics and are summarised in Table 4.
      • Currie D.C.
      • Garbett N.D.
      • Chan K.L.
      • Higgs E.
      • Todd H.
      • Chadwick M.V.
      • et al.
      Double-blind randomized study of prolonged higher-dose oral amoxycillin in purulent bronchiectasis.
      • Davies G.
      • Wilson R.
      Prophylactic antibiotic treatment of bronchiectasis with azithromycin.
      • Drobnic M.E.
      • Sune P.
      • Montoro J.B.
      • Ferrer A.
      • Orriols R.
      Inhaled tobramycin in non-cystic fibrosis patients with bronchiectasis and chronic bronchial infection with Pseudomonas aeruginosa.
      • Murray M.P.
      • Govan J.R.
      • Doherty C.J.
      • Simpson A.J.
      • Wilkinson T.S.
      • Chalmers J.D.
      • et al.
      A randomized controlled trial of nebulized gentamicin in non-cystic fibrosis bronchiectasis.
      • Orriols R.
      • Roig J.
      • Ferrer J.
      • Sampol G.
      • Rosell A.
      • Ferrer A.
      • et al.
      Inhaled antibiotic therapy in non-cystic fibrosis patients with bronchiectasis and chronic bronchial infection by Pseudomonas aeruginosa.
      • Yalcin E.
      • Kiper N.
      • Ozcelik U.
      • Dogru D.
      • Firat P.
      • Sahin A.
      • et al.
      Effects of claritromycin on inflammatory parameters and clinical conditions in children with bronchiectasis.
      Davies and colleagues in an open-labelled prospective trial evaluated the role of azithromycin 250 mg thrice/wk for 4 months in 39 bronchiectasis patients.
      • Davies G.
      • Wilson R.
      Prophylactic antibiotic treatment of bronchiectasis with azithromycin.
      All the patients had more than 4 documented exacerbations during the previous 12 months. There was a reduction in exacerbations warranting oral and intravenous antibiotics, and an improvement in TLCO. Yalcin and colleagues examined the effects of clarithromycin on inflammatory markers (IL-8, TNF-alpha, IL-10 levels and cell profiles in bronchoalveolar lavage (BAL) fluid, pulmonary function and sputum production in children with non-CF bronchiectasis in a randomised DBPC trial.
      • Yalcin E.
      • Kiper N.
      • Ozcelik U.
      • Dogru D.
      • Firat P.
      • Sahin A.
      • et al.
      Effects of claritromycin on inflammatory parameters and clinical conditions in children with bronchiectasis.
      Following 3 months of treatment compared to placebo, the clarithromycin-treated subjects showed a significant decrease in IL-8 levels, total cell count, neutrophil ratios in BAL fluid and daily sputum production, but no significant differences in pulmonary function test parameters. Barker and colleagues examined the microbiological efficacy and safety of nebulised tobramycin twice daily for 4 weeks in 74 patients with bronchiectasis and P. aeruginosa in a randomised DBPC trial (n = 37 in each group).
      • Barker A.F.
      • Couch L.
      • Fiel S.B.
      • Gotfried M.H.
      • Ilowite J.
      • Meyer K.C.
      • et al.
      Tobramycin solution for inhalation reduces sputum Pseudomonas aeruginosa density in bronchiectasis.
      At Week-4, the treatment group had a mean decrease in P. aeruginosa density of 4.54 log10 colony-forming units/g sputum (p < 0.01). At Week-6, P. aeruginosawas eradicated in 35% in the treatment group but was detected in all placebo patients. No differences in lung function were reported. This study supported a role for nebulised antibiotics in bronchiectasis, albeit for a 4-week duration.
      Table 4Summary of the studies of long term antibiotics in Non-CF bronchiectasis.
      StudyStudy designNumber of subjectsDuration of studyAntibioticOutcomes
      Murray et al.
      • Murray M.P.
      • Govan J.R.
      • Doherty C.J.
      • Simpson A.J.
      • Wilkinson T.S.
      • Chalmers J.D.
      • et al.
      A randomized controlled trial of nebulized gentamicin in non-cystic fibrosis bronchiectasis.
      Randomised placebo controlled trial6512 monthsNeb gentamicin 80 mg twice daily
      • -
        Reduction in bacterial load
      • -
        Decrease in number of exacerbations
      • -
        Significant prolongation for time to first exacerbation
      • -
        Bronchospasm observed in 21.9% (Vs 6% in placebo)
      Orriols et al.
      • Orriols R.
      • Roig J.
      • Ferrer J.
      • Sampol G.
      • Rosell A.
      • Ferrer A.
      • et al.
      Inhaled antibiotic therapy in non-cystic fibrosis patients with bronchiectasis and chronic bronchial infection by Pseudomonas aeruginosa.
      Open labelled study1712 monthsNeb ceftazidime 1 gm bd & Neb tobramycin 100 mg bd or placebo
      • -
        Reduced number of admissions & in-patient stays
      • -
        No difference in the use of oral antibiotics
      • -
        No changes in lung function
      Drobnic et al.
      • Drobnic M.E.
      • Sune P.
      • Montoro J.B.
      • Ferrer A.
      • Orriols R.
      Inhaled tobramycin in non-cystic fibrosis patients with bronchiectasis and chronic bronchial infection with Pseudomonas aeruginosa.
      Double blind placebo controlled crossover trial306 monthsNebulised tobramycin 300 mg twice daily
      • -
        Reduction in the number of admissions
      • -
        Reduction in hospital stays
      • -
        Reduction in pseudomonas density in sputum
      • -
        No difference in number of exacerbations or QOL
      Yalcin et al.
      • Yalcin E.
      • Kiper N.
      • Ozcelik U.
      • Dogru D.
      • Firat P.
      • Sahin A.
      • et al.
      Effects of claritromycin on inflammatory parameters and clinical conditions in children with bronchiectasis.
      Randomised placebo controlled34 (children)3 monthsClarithromycin 15 mg/kg
      • -
        Reduction in sputum volume
      • -
        Improvement in maximal mid-expiratory flow
      • -
        No change in FEV1
      Davies et al.
      • Davies G.
      • Wilson R.
      Prophylactic antibiotic treatment of bronchiectasis with azithromycin.
      Prospective open labelled3910 monthsAzithromycin 250 mg three times weekly
      • -
        Decreased exacerbation frequency
      • -
        Decreased need for IV antibiotics
      • -
        Improvement in symptoms and TLCO
      Currie et al.
      • Currie D.C.
      • Garbett N.D.
      • Chan K.L.
      • Higgs E.
      • Todd H.
      • Chadwick M.V.
      • et al.
      Double-blind randomized study of prolonged higher-dose oral amoxycillin in purulent bronchiectasis.
      Randomised placebo controlled3832 weeksAmoxicillin 39 twice daily
      • -
        Similar frequency of exacerbations but less severe in the amoxicillin group
      • -
        Greater reduction in sputum purulence
      • -
        Less time confined to bed and away from work
      In a trial involving 30 bronchiectatic patients with nebulised tobramycin for 6 months with
      • Drobnic M.E.
      • Sune P.
      • Montoro J.B.
      • Ferrer A.
      • Orriols R.
      Inhaled tobramycin in non-cystic fibrosis patients with bronchiectasis and chronic bronchial infection with Pseudomonas aeruginosa.
      there was a reduction in hospital admissions and in-patient days during treatment phase and a decrease in P. aeruginosa density up to 3 months of stopping tobramycin. However, there was no difference in exacerbations, antibiotic use, lung function or QoL between the treatment periods. Another trial involving nebulised ceftazidime and tobramycin twice daily in patients with bronchiectasis concluded that the treatment group had less admissions and in-patient days, but there was no difference in the lung function or use of oral antibiotics use between groups.
      • Orriols R.
      • Roig J.
      • Ferrer J.
      • Sampol G.
      • Rosell A.
      • Ferrer A.
      • et al.
      Inhaled antibiotic therapy in non-cystic fibrosis patients with bronchiectasis and chronic bronchial infection by Pseudomonas aeruginosa.
      More recently, a study from Edinburgh randomised sixty-five patients to either twice daily nebulised gentamicin, or 0.9% saline, for 12 months.
      • Murray M.P.
      • Govan J.R.
      • Doherty C.J.
      • Simpson A.J.
      • Wilkinson T.S.
      • Chalmers J.D.
      • et al.
      A randomized controlled trial of nebulized gentamicin in non-cystic fibrosis bronchiectasis.
      At 12 months the treatment group had reduced sputum bacterial density with 30.8% eradication in those infected with P. aeruginosa and 92.8% eradication in those infected with other pathogens; less sputum purulence; greater exercise capacity and fewer exacerbations with increased time to first exacerbation. No differences were seen in 24-h sputum volume and lung function parameters. Of note, P. aeruginosa isolates developed resistance to gentamicin. Recently, the ORBIT 1 study evaluated the efficacy, safety, and tolerability of once daily inhaled ciprofloxacin in the management of P. aeruginosa infections in patients with non-CF bronchiectasis.
      • Bilton D.
      • Serisier D.J.
      • De Soyza A.T.
      • Wolfe R.
      • Bruinenberg P.
      Multicenter, randomized, double-blind, placebo-controlled study (ORBIT 1) to evaluate the efficacy, safety, and tolerability of once daily ciprofloxacin for inhalation in the management of Pseudomonas aeruginosa infections in patients with non-cystic fibrosis bronchiectasis.
      The data revealed that at 28 days nebulised ciprofloxacin reduced P. aeruginosa density and improved QoL. Murray et al. conducted a 1-year randomised placebo controlled study assessing the efficacy of nebulised gentamicin compared to placebo in a number of sputum, objective, subjective and exacerbations parameters.
      • Murray M.P.
      • Govan J.R.
      • Doherty C.J.
      • Simpson A.J.
      • Wilkinson T.S.
      • Chalmers J.D.
      • et al.
      A randomized controlled trial of nebulized gentamicin in non-cystic fibrosis bronchiectasis.
      They reported substantial improvements sputum bacterial density with over 30% having eradicated P. aeruginosa and over 90% eradicating other pathogens, sputum purulence, fewer exacerbations and delay to first exacerbations, improved exercise capacity as well as improvement in subjective parameters of cough and QoL. Moreover there were no P. aeroginosa isolates developing resistance to gentamicin. Of note, there were no improvement sin 24-h sputum volume and various assessments of lung function.
      There is consistent evidence that long-term antibiotics either oral or nebulised improves QoL, decreases exacerbation frequency and reduces the bacterial load. Unlike the CF experience, there does not seem to be an improvement of pulmonary function after treatment with nebulised antibiotics. In practice, the prescription of long-term antibiotics should be considered for patients exacerbating at least 3 times/yr and in patients with fewer exacerbations but with greater morbidity.
      • Pasteur M.C.
      • Bilton D.
      • Hill A.T.
      British Thoracic Society guideline for non-CF bronchiectasis.
      There may also be a lower threshold for starting long-term antibiotics in patients with primary or secondary immunodeficiency. Antibiotic choices should be based on sputum microbiology and careful monitoring needs to be in place regarding microbial resistance and adverse events.

      Diffuse panbronchiolitis (DPB)

      DPB is a chronic respiratory condition of unknown aetiology, almost exclusively described in the Far East (mainly Japan, but also Korea and China), characterised by chronic inflammation of the respiratory tract with progressive destruction of the lung parenchyma.
      • Homma H.
      • Yamanaka A.
      • Tanimoto S.
      • Tamura M.
      • Chijimatsu Y.
      • Kira S.
      • et al.
      Diffuse panbronchiolitis. A disease of the transitional zone of the lung.
      • Ding K.
      • Liu M.B.
      • Wu J.L.
      • Ma H.Q.
      • Fang X.Y.
      • Miao G.B.
      • et al.
      Diffuse panbronchiolitis in China: analysis of 45 cases.
      • Izumi T.
      Diffuse panbronchiolitis.
      Up to the early 1980s DPB was a fatal condition, however with the use of long-term macrolides it is now a very treatable condition with its 5-year prognosis increasing from 63% in the 1970s to about 90% in the late 1990s.
      • Kudoh S.
      • Azuma A.
      • Yamamoto M.
      • Izumi T.
      • Ando M.
      Improvement of survival in patients with diffuse panbronchiolitis treated with low-dose erythromycin.
      Initially, case reports and series' using low-dose erythromycin
      • Kudoh S.
      • Azuma A.
      • Yamamoto M.
      • Izumi T.
      • Ando M.
      Improvement of survival in patients with diffuse panbronchiolitis treated with low-dose erythromycin.
      • Kudoh S.
      • Uetake T.
      • Hagiwara K.
      • Hirayama M.
      • Hus L.H.
      • Kimura H.
      • et al.
      Clinical effects of low-dose long-term erythromycin chemotherapy on diffuse panbronchiolitis.
      reported clinical and radiological improvements in patients with DPB, but recent reports have also reported similar positive findings with clarithromycin, roxithromycin and azithromycin (Table 5).
      • Tamaoki J.
      • Takeyama K.
      • Tagaya E.
      • Konno K.
      Effect of clarithromycin on sputum production and its rheological properties in chronic respiratory tract infections.
      • Kadota J.
      • Mukae H.
      • Ishii H.
      • Nagata T.
      • Kaida H.
      • Tomono K.
      • et al.
      Long-term efficacy and safety of clarithromycin treatment in patients with diffuse panbronchiolitis.
      • Nakamura H.
      • Fujishima S.
      • Inoue T.
      • Ohkubo Y.
      • Soejima K.
      • Waki Y.
      • et al.
      Clinical and immunoregulatory effects of roxithromycin therapy for chronic respiratory tract infection.
      • Kobayashi H.
      • Takeda H.
      • Sakayori S.
      • Kawakami Y.
      • Otsuka Y.
      • Tamura M.
      • et al.
      Study on azithromycin in treatment of diffuse panbronchiolitis.
      A recent Cochrane review reported that, of the many studies assessed only one was identified to have adequate quality.
      • Yang M.
      • Dong B.R.
      • Lu J.
      • Lin X.
      • Wu H.M.
      Macrolides for diffuse panbronchiolitis.
      In this study of 19 subjects with DPB, 12 were randomly assigned to receive low-dose erythromycin and rest no treatment.
      • Akira M.
      • Higashihara T.
      • Sakatani M.
      • Hara H.
      Diffuse panbronchiolitis: follow-up CT examination.
      It was observed that compared to the pre-treatment CT scan, there were marked improvements in the interval CT scan in all subjects following treatment with the erythromycin. Of note, 71.4% of the control group subjects had worsening of their interval scan. This study had a number of methodological errors with no fixed times of treatments, interval scans, and mention of adverse events besides the small cohort of subjects. Despite the lack of large RCTs to confirm the efficacy and safety of macrolides in DPB, the Ministry of Health and Welfare of Japan have implemented the use of macrolides in its treatment on diagnosis for 6-months based on the observational studies and expert opinion.
      Table 5Summary of the studies of macrolides in diffuse panbronchiolitis.
      StudyStudy designNumber of subjectsDuration of studyAntibiotic usedOutcomes
      Akira et al.
      • Akira M.
      • Higashihara T.
      • Sakatani M.
      • Hara H.
      Diffuse panbronchiolitis: follow-up CT examination.
      Observational RCT of efficacy of macrolide treatment19 subjects (12 active treatment and 7 no treatment)Not specifiedErythromycin
      • -
        CT scans showed a reduction in number and size of centrilobular and branched linear airways of high attenuation in all subjects.
      • -
        No change to airway dilatation or peripheral areas of lung attenuation. In the untreated group progression of disease was noted in 71.4% of subjects.
      Kudoh et al.
      • Kudoh S.
      • Azuma A.
      • Yamamoto M.
      • Izumi T.
      • Ando M.
      Improvement of survival in patients with diffuse panbronchiolitis treated with low-dose erythromycin.
      Retrospective observational survival study based on year of diagnosis498 subjects(Gp A: 1970–79 [only std ABx avail} [n = 190]; Gp B: 1980–84 [quinolones avail][n = 221]; Gp C: 1985–90 (Erythromycin avail} [n = 87])N/AErythromycin
      • -
        Survival rate of Gp C was significantly higher than Gps A and B.
      • -
        Of the 87 in Gp C 5/24 died in patients not receiving ERM compared to 3/63 from ERM treated.
      • -
        Efficacy of ERM increased survival in older compared to younger subjects.
      Yamamoto et al.
      • Yamamoto M.
      • Kondo A.
      • Tamura M.
      • Izumi T.
      • Ina Y.
      • Noda M.
      Long-term therapeutic effects of erythromycin and newquinolone antibacterial agents on diffuse panbronchiolitis.
      Retrospective observational study comparing quinolone vs. macrolide101 subjectsN/AErythromycin
      • Significant improvements in favour of ERM in:
      • -
        Exertional dyspnoea
      • -
        CXR findings, PaO2
      • -
        ESR, titre of cold agglutination
      • -
        Amount of sputum in favour of ERM
      Kobayashi et al.
      • Kobayashi H.
      • Takeda H.
      • Sakayori S.
      • Kawakami Y.
      • Otsuka Y.
      • Tamura M.
      • et al.
      Study on azithromycin in treatment of diffuse panbronchiolitis.
      Open-labelled study of efficacy and safety60 subjects (efficacy data on 52 and safety data on 55)12 weeksAzithromycin
      • -
        Efficacy rate was 86.6% (44/52)
      • -
        Sputum reduction 65.2% (30/46)
      • -
        Reduction in exertional dyspnoea 50% (23/46)
      • -
        Improvement in FEV1, cold agglutination and CRP in smaller numbers of subjects.
      • -
        Eradication of sputum organisms 39.5% (15/38)
      Kadota et al.
      • Kadota J.
      • Mukae H.
      • Ishii H.
      • Nagata T.
      • Kaida H.
      • Tomono K.
      • et al.
      Long-term efficacy and safety of clarithromycin treatment in patients with diffuse panbronchiolitis.
      Prospective open-labelled study10 subjects4 yearsClarithromycin
      • -
        FEV1 and FVC improved within 6 months in most subjects.
      • -
        PaO2 at rest improved in 3–6 months.
      • -
        Improvement in the comprehensive improvement score in 6 months (in 9 subjects).
      • -
        Negative sputum cultures in majority of subjects at 6 months.
      • -
        No adverse events with the use of CRM.
      Abbreviations: RCT – Randomised control trial; CT scan – Computed tomography scan; Gp – Group; std – standard; ABx – antibiotics; avail – available; n – number; N/A – Not applicable; vs. – versus; CXR – Chest X-ray; PaO2 – Partial pressure of oxygen in arterial blood; ESR – erythrocyte sedimentation rate; FEV1 – Forced expiratory volume in 1 s; CRP – C-reactive protein; FVC – Forced vital capacity.

      Post-transplant bronchiolitis obliterans syndrome (BOS)

      Obliterative bronchiolitis (OB) is an airway inflammatory process that results in significant long-term morbidity and mortality in post-transplant patients, mainly of the lung, but also of other organs, synonymous with chronic graft rejection.
      • Boehler A.
      • Kesten S.
      • Weder W.
      • Speich R.
      Bronchiolitis obliterans after lung transplantation: a review.
      • Ishii T.
      • Manabe A.
      • Ebihara Y.
      • Ueda T.
      • Yoshino H.
      • Mitsui T.
      • et al.
      Improvement in bronchiolitis obliterans organizing pneumonia in a child after allogeneic bone marrow transplantation by a combination of oral prednisolone and low dose erythromycin.
      • Bando K.
      • Paradis I.L.
      • Similo S.
      • Konishi H.
      • Komatsu K.
      • Zullo T.G.
      • et al.
      Obliterative bronchiolitis after lung and heart-lung transplantation. An analysis of risk factors and management.
      Although OB is thought to be mainly immunologically mediated and is rarely successfully managed with the use of immunosuppressive agents, significant numbers of transplant patients experience concurrent bacterial and non-bacterial infections which may worsen lung inflammation and potentially worsen the chronic rejection. Azithromycin has been examined in several small post-lung transplant studies with potential benefits, but this has been questioned. Four prospective open-labelled studies with azithromycin treatment have been described in the literature, 3 have shown significant improvements in FEV1,
      • Gerhardt S.G.
      • McDyer J.F.
      • Girgis R.E.
      • Conte J.V.
      • Yang S.C.
      • Orens J.B.
      Maintenance azithromycin therapy for bronchiolitis obliterans syndrome: results of a pilot study.
      • Verleden G.M.
      • Dupont L.J.
      Azithromycin therapy for patients with bronchiolitis obliterans syndrome after lung transplantation.
      • Verleden G.M.
      • Vanaudenaerde B.M.
      • Dupont L.J.
      • Van Raemdonck D.E.
      Azithromycin reduces airway neutrophilia and interleukin-8 in patients with bronchiolitis obliterans syndrome.
      but 1 showing no improvement in FEV1.
      • Shitrit D.
      • Bendayan D.
      • Gidon S.
      • Saute M.
      • Bakal I.
      • Kramer M.R.
      Long-term azithromycin use for treatment of bronchiolitis obliterans syndrome in lung transplant recipients.
      Furthermore, 2 retrospective case series' using azithromycin have been conducted, one reporting positive FEV1 improvements beyond 3 months of treatment cessation in a majority of patients,
      • Yates B.
      • Murphy D.M.
      • Forrest I.A.
      • Ward C.
      • Rutherford R.M.
      • Fisher A.J.
      • et al.
      Azithromycin reverses airflow obstruction in established bronchiolitis obliterans syndrome.
      but the other did not.
      • Angel L.F.
      • Levine D.
      • Sanchez J.
      • Levine S.
      Azithromycin in bronchiolitis obliterans: is the evidence strong enough?.
      In the largest prospective study of 14 lung transplant patients receiving azithromycin for 3 months, besides the mean increase in FEV1, it was reported that BAL neutrophils, % neutrophils and IL-8 mRNA ratio decreased significantly but had no impact on IL-17 mRNA ratio.
      • Verleden G.M.
      • Vanaudenaerde B.M.
      • Dupont L.J.
      • Van Raemdonck D.E.
      Azithromycin reduces airway neutrophilia and interleukin-8 in patients with bronchiolitis obliterans syndrome.
      They noted a responder group of 6 patients (increase >10% FEV1) who had a marked reduction in %BAL neutrophilia, IL-8 mRNA and IL-17 mRNA. Moreover, they reported a significantly positive correlation between the initial %BAL neutrophilia and response to treatment. Of note, a BAL neutrophilia of >15% had a positive predictive value of 85% for a significant FEV1 response to azithromycin, and that a BAL neutrophilia <15% had a negative predictive value of 100%.
      • Verleden G.M.
      • Vanaudenaerde B.M.
      • Dupont L.J.
      • Van Raemdonck D.E.
      Azithromycin reduces airway neutrophilia and interleukin-8 in patients with bronchiolitis obliterans syndrome.
      Similar positive and negative predictive values have been reported by another group.
      • Gottlieb J.
      • Szangolies J.
      • Koehnlein T.
      • Golpon H.
      • Simon A.
      • Welte T.
      Long-term azithromycin for bronchiolitis obliterans syndrome after lung transplantation.
      The clinical benefits of azithromycin have been hypothesised to be due to: the pro-kinetic effect diminishing the gastro-oesophageal reflux
      • Gerhardt S.G.
      • McDyer J.F.
      • Girgis R.E.
      • Conte J.V.
      • Yang S.C.
      • Orens J.B.
      Maintenance azithromycin therapy for bronchiolitis obliterans syndrome: results of a pilot study.
      and enzyme inhibition, increasing the plasma concentrations of immunosupressors.
      • Verleden G.M.
      • Dupont L.J.
      Azithromycin therapy for patients with bronchiolitis obliterans syndrome after lung transplantation.
      • Verleden G.M.
      • Vanaudenaerde B.M.
      • Dupont L.J.
      • Van Raemdonck D.E.
      Azithromycin reduces airway neutrophilia and interleukin-8 in patients with bronchiolitis obliterans syndrome.
      • Shitrit D.
      • Bendayan D.
      • Gidon S.
      • Saute M.
      • Bakal I.
      • Kramer M.R.
      Long-term azithromycin use for treatment of bronchiolitis obliterans syndrome in lung transplant recipients.
      • Yates B.
      • Murphy D.M.
      • Forrest I.A.
      • Ward C.
      • Rutherford R.M.
      • Fisher A.J.
      • et al.
      Azithromycin reverses airflow obstruction in established bronchiolitis obliterans syndrome.
      However, these have not been substantiated. The role of C. pneumoniae infection has been implicated in the development of BOS, with donor-recipient serology mismatch (i.e. donor positive/recipient negative) being an independent risk factor for BOS development.
      • Kotsimbos T.C.
      • Snell G.I.
      • Levvey B.
      • Spelman D.W.
      • Fuller A.J.
      • Wesselingh S.L.
      • et al.
      Chlamydia pneumoniae serology in donors and recipients and the risk of bronchiolitis obliterans syndrome after lung transplantation.
      Furthermore, it has been reported that C. pneumoniae infection in lung transplant patients is associated with poor outcome and increased risk of BOS.
      • Glanville A.R.
      • Gencay M.
      • Tamm M.
      • Chhajed P.
      • Plit M.
      • Hopkins P.
      • et al.
      Chlamydia pneumoniae infection after lung transplantation.
      From the available data, azithromycin has been associated with positive outcomes; physicians need to be cautious that this therapy is not viewed as a panacea for treatment of BOS, and that larger clinical trial with long-term follow-up are needed to determine the benefits in all and responding patients.

      Opinions and conclusions

      Different macrolides have variable pharmacokinetic and pharmcodynamic properties such as the long half-life of azithromycin and its higher concentration in sputum,
      • Zuckerman J.M.
      Macrolides and ketolides: azithromycin, clarithromycin, telithromycin.
      • Wilms E.B.
      • Touw D.J.
      • Heijerman H.G.
      Pharmacokinetics of azithromycin in plasma, blood, polymorphonuclear neutrophils and sputum during long-term therapy in patients with cystic fibrosis.
      whereas roxithromycin with its higher anti-inflammatory activity,
      • Scaglione F.
      • Rossoni G.
      Comparative anti-inflammatory effects of roxithromycin, azithromycin and clarithromycin.
      compared to other macrolides. It is also not clear as to whether the actual mechanism of action of macrolides is due to the anti-microbial (deep-seated infection clearance), anti-reflux or anti-inflammatory, and in certain cases anti-fibrotic properties. From this it appears that macrolides may manifest their biological efficacy in a range of respiratory conditions through a number of recognised potential mechanisms or others that still yet to be established. To investigate these mechanisms needs substantial effort and collaboration between clinicians and scientists not only in translational studies, but also on the bench. From the available evidence it should be noted that guidelines recommend the use of macrolides in the management of CF (azithromycin in particular) and panbronchiolitis. In the former, the recommendations are based on well designed DBPC studies and meta-analyses and in the latter by consensus opinion (Japanese health authority). In the remaining conditions discussed in this review the data are not so stringently clear and hence there remains a need for well-conducted studies to establish their efficacy. Lastly, it may be that with the aid of these mechanistic and efficacy-based studies in the future, we may be in a better position to determine a disease-specific macrolide, i.e. ‘tailored treatment’ for the individual patients.
      Aerosolised antibiotics deliver anti-microbial therapy to diseased lungs, hence providing targeted therapy with possibly limited adverse events to patients. Most of the current available data on inhaled antibiotics involve anti-pseudomonal agents which if administered early enough may help with eradication, or in the long-term reduce the risk of recurrent infections especially in CF and non-CF bronchiectasis patients.
      In this review we have highlighted the various respiratory conditions in which long-term antibiotics, oral or nebulised, have been investigated. The data is more robust in CF (nebulised antibiotics and oral azithromycin) compared to non-CF bronchiectasis, panbronchiolitis and COPD, and even less so with asthma and BOOP. The CF model can serve as a foundation to investigate the role of long-term antibiotics, especially nebulised in non-CF bronchiectasis. Identification of the precise mechanism of anti-inflammatory effect of macrolides would encourage development of newer molecules with immunomodulatory effects, hence circumventing the anti-bacterial effects. There appears to be a role for long-term antibiotics, especially macrolides, in a number of chronic inflammatory airway disorders, however there is an urgent need to establish this by performing longer, macrolide-specific, DBPC and bench studies to establish their efficacy, safety and mechanisms of action.

      Conflict of interest statement

      KSB has received honoraria for speaking and financial support to attend meetings from Chiesi, Astra Zeneca, Boehringer, GSK/Allen & Hanburys and Wyeth.JK has no conflict of interest.JBM has received honoraria for speaking and financial support to attend meetings/advisory boards from Wyeth, Chiesi, Pfizer, MSD, Boehringer Ingelheim, Teva, GSK/Allen & Hanburys, Napp, Almirall and Novartis.

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