http://thorax.bmj.com/content/early/2010/10/21/thx.2010.142711.abstract

Thorax doi:10.1136/thx.2010.142711

Chronic cough

Long-term low-dose erythromycin in patients with unexplained chronic cough: a double-blind placebo controlled trial

1. Nadia Yousaf1,

2. William Monteiro1,

3. Debbie Parker1,

4. Sergio Matos2,

5. Surinder Birring3,

6. Ian D Pavord1

+ Author Affiliations

1. 1Institute for Lung Health, Glenfield Hospital, University Hospitals of Leicester NHS Trust, Leicester,

UK

2. 2Institute of Electronics and Telematics Engineering (IEETA), University of Aveiro, Aveiro, Portugal

3. 3Kings College Hospital, Denmark Hill, London, UK

1. Correspondence to Professor Ian D Pavord, Institute for Lung Health, Glenfield Hospital, University Hospitals of

Leicester NHS Trust, Groby Road, Leicester LE3 9QP, UK; ian.pavord@uhl-tr.nhs.uk

Received 14 May 2010

Accepted 5 August 2010

Published Online First 21 October 2010

Abstract

Aims Unexplained chronic cough is a common condition with no satisfactory treatments. Previous work has

suggested that cough may be linked to neutrophilic airway inflammation. This study tested the hypothesis that long-

term low-dose erythromycin reduces the induced sputum neutrophil count and 24 h cough frequency in patients with

unexplained chronic cough.

Methods 30 patients with an unexplained chronic cough lasting more than 8 weeks were randomly assigned to take

250 mg erythromycin once daily (n=15) or placebo (n=15) for 12 weeks in a double-blind parallel group study. Cough

frequency, cough reflex sensitivity and cough severity were assessed at baseline, 6, 12 and 24 weeks. The primary

outcome measure was change in 24 h cough frequency at 12 weeks.

Results There was no difference in the change in cough frequency between the erythromycin and placebo groups at

12 weeks (mean difference in fold change 1.1; 95% CI 0.7 to 1.5; p=0.585) or at other times. There was a statistically

significant between-treatment difference in the change in sputum neutrophils at 12 weeks (−10.2% vs +6.6% with

erythromycin and placebo; mean difference 16.8%; 95% CI 1.6 to 32.1; p=0.03) but not at other times. There was no

difference in the change in other measures of cough between treatments.

Conclusions Treatment with low-dose erythromycin for 12 weeks reduces the induced sputum neutrophil count but

not cough frequency or severity in patients with unexplained chronic cough.

Macrolides• 14-member (clarithromycin,erythromycin, roxithromycin)• 15-member (azithromycin)

Macrolides• Immunomodulatory effects• Decreases length of stay andmortalityG. W. Amsden. Anti-inflammatory effects of macrolides—an underappreciated benefit in thetreatment of community-acquired respiratory tract infections and chronic inflammatorypulmonary conditions? J Antimicrob Chemother 2005 55(1):10-21

Macrolides• Decrease sputum/mucusproduction• suppress the overabundanceof neutrophils (PMNs)• eosinopenic effect• break down and preventfurther development ofbiofilms of P. aeruginosa

G. W. Amsden. Anti-inflammatory effects of macrolides—an underappreciated benefit in thetreatment of community-acquired respiratory tract infections and chronic inflammatorypulmonary conditions? J Antimicrob Chemother 2005 55(1):10-21

Pharmacological Treatment Options for Bronchiectasis: Focus on Antimicrobial and Anti-Inflammatory Agents

Ilowite, Jonathan; Spiegler, Peter; Kessler, Heather

Abstract

Patients with bronchiectasis experience tenacious mucus, recurrent infectious exacerbations, and progressive worsening of symptoms and obstruction over time. Treatment is aimed at trying to break the cycle of infection and progressive airway destruction. Antibacterial treatment is targeted towards likely organisms or tailored to the results of sputum culture. Inhaled antibacterial therapy may offer the advantage of increased local concentration of medication, while minimizing systemic adverse effects; however, to date, studies have been equivocal in this disorder. Macrolides, in addition to their antibacterial properties, have unique anti-inflammatory properties, which may make them useful in this disorder. Other mucoactive and anti-inflammatory agents, such as inhaled corticosteroids, mannitol and hypertonic saline, may also prove useful in this disease, but further studies are needed.

Azithromycin as a Treatment for COPD

After 12 weeks of low-dose azithromycin, COPD patients showed increased alveolar macrophage expression of mannose receptors and increased phagocytosis of apoptotic bronchial epithelium cells.

Chronic obstructive pulmonary disease (COPD) is associated with inflammation and loss of lung integrity. Some investigators have hypothesized that these changes result from dysregulated apoptosis of bronchial epithelial cells and reduced phagocytosis by alveolar macrophages (AMs). Low-dose macrolide antibiotics have been shown to have anti-inflammatory properties, and azithromycin may be particularly useful because of its ability to reach high levels in AMs. One

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proposed mechanism for these macrolide effects involves enhanced expression of collectins and their receptors. Mannose-binding lectin (MBL) — a lung collectin — binds to mannose receptors (MRs) on the surface of AMs and augments phagocytosis.

In a partially industry-funded study involving 11 patients with COPD, researchers in Australia investigated azithromycin’s effectiveness and mechanism of action. In vitro, azithromycin significantly enhanced the percentage of AMs expressing MRs on their surface. Moreover, MBL levels and surface MR expression on AMs in bronchoalveolar lavage (BAL) samples from COPD patients were significantly lower than those in samples from nonsmoking healthy controls (P<0.05). However, after 12 weeks of low-dose azithromycin (250 mg orally for 5 days, then twice weekly), the expression of MRs and the phagocytotic ability of AMs were significantly increased. In addition, the percentage of apoptotic bronchial epithelial cells in BAL samples from COPD patients was significantly decreased.

Comment: The findings from in vitro and ex vivo analyses suggest that low-dose azithromycin can reduce inflammation in patients with COPD by increasing AM phagocytosis of apoptotic bronchial epithelial cells. This effect is not antibacterial but rather is modulated through the innate immune response.

— Neil M. Ampel, MD

Published in Journal Watch Infectious Diseases July 23, 2008

10.1378/chest.123.1.261 CHEST January 2003 vol. 123 no. 1 261-265

Tissue Reparative Effects of Macrolide Antibiotics in Chronic Inflammatory Sinopulmonary Diseases*

1. Kevin W. Garey, PharmD, 2. Anita Alwani, MD, 3. Larry H. Danziger, PharmD and 4. Israel Rubinstein, MD, FCCP

+ Author Affiliations

1. *From the Department of Clinical Sciences and Administration (Dr. Garey), University of Houston College of Pharmacy, Houston, TX; the Departments of Medicine (Drs. Alwani and Rubinstein) and Pharmacy Practice (Dr. Danziger), Colleges of Medicine and Pharmacy, University of Illinois at Chicago, Chicago, and Chicago VA Health Care System, West Side Division, Chicago, IL.

1. Correspondence to: Israel Rubinstein, MD, FCCP, Professor of Medicine, Section of Respiratory and Critical Care Medicine, Department of Medicine (M/C 787), University of Illinois at Chicago, 840 S Wood St, Chicago, IL 60612-7323; e-mail: Irubinst@uic.edu

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AbstractIt is well established that macrolide antibiotics are efficacious in treating sinopulmonary infections in humans. However, a growing body of experimental and clinical evidence indicates that they also express distinct salutary effects that promote and sustain the reparative process in the chronically inflamed upper and lower respiratory tract. Unlike the anti-infective properties, these distinct effects are manifested at lower doses, usually after a relatively prolonged period (weeks) of treatment, and in the absence of an identifiable, viable pathogen. Long-term, low-dose administration of macrolide antibiotics has been used most commonly for sinusitis, diffuse panbronchiolitis, asthma, bronchiectasis, and cystic fibrosis. It is associated with down-regulation of nonspecific host inflammatory response to injury and promotion of tissue repair. Although large-scale trials are lacking, the prolonged use of these drugs has not been associated with emergence of clinically significant bacterial resistance or immunosuppression. Long-term, low-dose administration of 14- and 15-membered ring macrolide antibiotics may represent an important adjunct in the treatment of chronic inflammatory sinopulmonary diseases in humans.

anti -inflammatory

immunomodulatory

macrolide antibiotics

It is well established that macrolide antibiotics, including the semisynthetic derivatives of erythromycin, are clinically useful in treating sinopulmonary infections in humans.123 However, a growing body of experimental and clinical evidence emanating predominantly from Japan indicates that the 14- and 15-membered ring macrolide antibiotics also possess distinct salutary properties that promote and sustain the reparative process in the chronically inflamed upper and lower respiratory tract.45 Unlike the anti-infective properties, these distinct effects are expressed at lower doses, usually after a relatively prolonged period (weeks) of treatment, and in the absence of an identifiable, viable pathogen.4678 Importantly, long-term, low-dose administration of macrolide antibiotics is not associated with increased incidence of adverse events, emergence of clinically relevant bacterial resistance, or immunosuppression.8910

Although the mechanisms underlying the pleiotropic tissue reparative effects of macrolide antibiotics in chronically inflamed sinopulmonary tissues in humans are uncertain, they may be related, in part, to the highly hydrophobic nature of the 14- and 15-membered lactone ring coupled with the hydrophilic nature of both sugar moieties of the cell.3111213 This distinct biophysical feature may form drug micelles and promote avid and preferential interaction of macrolide antibiotics with phospholipids in the plasma and intracellular organellar membranes, including the nucleus, in activated effector cells that sustain uncontrolled, self-perpetuating inflammation in the chronically inflamed sinopulmonary tissue, such as leukocytes, macrophages, epithelial cells, goblet cells, and fibroblasts.3111213 This process may, in turn, alter the biophysical state of the membrane bilayer in effector cells, including fluidity and charge, thereby disrupting the functional integrity of key membrane-associated proteins that regulate key intracellular metabolic and transcriptional pathways involved in the inflammatory cascade, such as reactive oxygen species, nitric oxide, and cytokines.131415

The purpose of this review is to provide a concise account of the tissue reparative effects of macrolide antibiotics in chronic inflammatory sinopulmonary diseases in humans based on published English-language literature. Articles were identified by a MEDLINE search from 1966 to present using the search terms macrolides, anti-inflammatory, and immunomodulatory, and a review of identified bibliographies. A detailed account of the putative cellular and molecular mechanisms underlying these effects is beyond the scope of this article.

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Chronic Inflammatory Sinopulmonary Diseases Chronic Rhinosinusitis and Nasal Polyps

Chronic sinusitis, a common disease of the paranasal sinuses, is characterized by purulent sinus effusion and nasal discharge.16 Neutrophils play an important role in regulating the inflammatory process by secreting various pro-inflammatory cytokines, such as interleukin (IL)-8.17 Fourteen-membered ring macrolide antibiotics, such as erythromycin and clarithromycin, are efficacious in chronic sinusitis.8181920 Patients administered low-dose clarithromycin8 or roxithromycin (not available in the United States)19 displayed improved aeration, and decreased neutrophil and IL-8 levels in the nasal discharge. Suzuki et al21 determined the prognostic factors that influence the efficacy of low-dose macrolide antibiotic therapy. They found that patients without atopy or eosinophilia were more likely to respond to either clarithromycin or roxithromycin. Importantly, maximal effects were not seen until at least 12 weeks of continuous therapy, and the authors hypothesized that even longer treatment may be necessary for maximal effect. In further in vitro studies, cultured nasal epithelial cells from patients with chronic sinusitis secreted less IL-8 in the presence of low concentrations of 14-membered ring macrolides.1920222324

Asthma

Macrolide antibiotics, especially troleandomycin and erythromycin, have been studied since the 1950s and have been shown to decrease corticosteroid requirement in patients with corticosteroid-dependent asthma.252627 For instance, Spector et al28 reported a double-blind, crossover trial comparing troleandomycin to placebo in 74 corticosteroid-dependent patients with severe asthma and chronic bronchitis. Sixty-seven percent of patients had a marked improvement in sputum production, pulmonary function measurements, need for bronchodilators, and subjective evaluations. Much of this effect, however, was attributed to troleandomycin-induced inhibition of methylprednisolone and theophylline metabolism by the hepatic cytochrome P450 complex.29303132

In vitro studies have suggested that macrolide antibiotics have beneficial anti-inflammatory and immunomodulatory effects in patients with asthma who are independent of the corticosteroid metabolism.33 Macrolide antibiotics inhibit lymphocyte proliferation in response to phytohemagglutinin, decrease neutrophil accumulation through decrease chemotactic activity, decreased mucus secretion, and decrease contraction of isolated bronchial tissue.33

Open-label studies with troleandomycin in methyprednisolone-dependent patients with asthma (adults and children) have demonstrated greater reduction in corticosteroid doses than would be predicted by hepatic inhibition of corticosteroid metabolism.273435 Gotfried et al36 showed a significant improvement in pulmonary function test results and quality of life measures in prednisone-dependent patients with asthma administered a 6-week course of clarithromycin without any change in prednisone requirements. In a small case series of patients administered clarithromycin for 1 year, two of three prednisone-dependent patients were able to discontinue prednisone entirely.10

Macrolide antibiotics are efficacious measures in asthmatic patients without corticosteroid dependency by reducing airway hyperreactivity.313738394041 A 10-week course of low-dose erythromycin was associated with a significant decrease in bronchial hyperresponsiveness in asthmatic patients tested by histamine challenge.3839 Similar effects were observed when 12 hospitalized children were treated with roxithromycin.42 Tamaoki et al43 showed that erythromycin, roxithromycin, and clarithromycin attenuated the contractile response of human isolated bronchial strips to electrical field stimulation. They hypothesized that macrolide antibiotics inhibit the cholinergic neuroeffector transmission in human airway smooth muscle.

Another possible explanation for the efficacy of macrolide antibiotics in patients with asthma is the role of chronic infectious diseases, particularly Chlamydia pneumoniae.44 These infectious agents may underlie acute asthma exacerbations and the initiation and maintenance of asthma in previously asymptomatic patients.45 The anti-infective vs tissue reparatory effects of

macrolide antibiotics in asthma will require further controlled studies to unravel these pathways.

Diffuse Panbronchiolitis

Diffuse panbronchiolitis, a noninfectious, inflammatory disease prevalent in Japan, is characterized by chronic inflammation of the respiratory bronchioles, and parabronchial and luminal accumulation of mononuclear inflammatory cells.464748 Persistent accumulation of neutrophils evokes airway damage through the effects of oxidative and proteolytic products. 495051

In addition, there is a significant correlation between neutrophil accumulation and augmented neutrophil chemotactic activity in the BAL fluid of these patients.51

Diffuse panbronchiolitis presents with chronic cough, mucopurulent expectoration, and dyspnea, and is associated with chronic sinusitis in 75% of cases. The chest radiograph and high-resolution CT findings reveal diffuse ill-defined centrilobular nodules with hyperinflated lungs. Bronchiectasis is observed in the most advanced cases.46 Infections with Haemophilus influenzae, Streptococcus pneumoniae, Klebsiella pneumonia, and Staphylococcus aureus are common and are ultimately superceded by infections with Pseudomonas aeruginosa.52 Untreated, the 5-year mortality rate is 50% and the 10-year survival rate is 25%.74648 Kudoh47 reported that long-term, low-dose oral administration of erythromycin was effective in the treatment of diffuse panbronchiolitis. Eighteen patients with diffuse panbronchiolitis were treated for 19 months with significant increases in lung function along with decreased signs and symptoms of disease. Similar effects were observed with roxithromycin, clarithromycin, and azithromycin.4567

Clindamycin, piperacillin, and ampicillin, administered as comparator agents in these trials, were ineffective. Since the initiation of macrolide antibiotic therapy in patients with diffuse panbronchiolitis, the 10-year survival rate has improved > 90%.6752 However, the mechanisms underlying these salutary effects have not yet been elucidated.

Non-Cystic Fibrosis Bronchiectasis and Chronic Bronchitis

Bronchiectasis and chronic bronchitis are characterized by excessive mucus production. 535455 An 8-week pilot study of low-dose erythromycin showed an improvement in lung function and a decrease in sputum volume in patients with bronchiectasis.56 Koh et al57 treated 25 children with bronchiectasis with 12 weeks of low-dose roxithromycin and found an improvement in sputum purulence by 6 weeks and a decrease in airway hyperresponsiveness by inhaled methacholine challenge. In another study, low-dose roxithromycin treatment improved symptoms, pulmonary functions, and radiographic findings of patients with chronic lower respiratory tract inflammation. This was associated with a decrease in IL-8, neutrophil elastase, and complement 5a concentrations in the epithelial lining fluid and resulted in attenuation of neutrophil infiltration.58

Cystic Fibrosis and P aeruginosa Colonization

Nonmucoid P aeruginosa initially invades the airway of patients with cystic fibrosis and subsequently transforms into mucoid strains producing alginate, a major component of the mucoid material.596061 These mucoid strains form a bacterial biofilm by encasing the alginate around them as they adhere to the airway mucosa, thereby enhancing their resistance to the host’s phagocytic activity.626364 Alginate also increases sputum viscosity thus promoting bacterial colonization.

The minimum inhibitory concentration of macrolide antibiotics for most pseudomonal infections is higher than the peak serum concentration achieved after the IV administration of these drugs. 65

Thus, by conventional criteria, P aeruginosa is resistant to macrolide antibiotics. However, Kita et al66 showed that erythromycin exhibited an inhibitory effect on the virulence factors produced by P aeruginosa, such as protease, elastase, and leucocidin. Likewise, 14- and 15-membered ring macrolide antibiotics inhibit alginate production by mucoid P aeruginosa strains, an effect not seen with 16-membered ring macrolide antibiotics.61626364 It is also notable that 14- and 15-

membered ring macrolide antibiotics can facilitate the penetration of bacterial biofilm by ciprofloxacin thus eliminating bacteria inside the biofilm.67

Cryptogenic Organizing Pneumonia

Hotta68 showed that in a small number of patients with cryptogenic organizing pneumonia, daily, low-dose, oral erythromycin for 2 to 3 months is associated with a favorable clinical response along with a significant decrease in IL-8 and neutrophil chemotactic activity in the BAL fluid. These preliminary observations should be corroborated by large-scale studies using well-defined patient populations with idiopathic pulmonary fibrosis.

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ConclusionLong-term, low-dose administration of 14- and 15-membered ring macrolide antibiotics is associated with salutary tissue reparative effects in patients with chronic inflammatory sinopulmonary diseases such as chronic sinusitis, asthma, bronchiectasis, cystic fibrosis, and diffuse panbronchiolitis that are distinct from their anti-infective properties. Overall, these responses are associated with down-regulation of the nonspecific host inflammatory response to injury in these tissues. Importantly, the prolonged use of these drugs is not associated with emergence of clinically significant bacterial resistance or immunosuppression. Large-scale, double-blind, randomized studies are warranted to establish the merit of long-term, low-dose macrolide antibiotic therapy in chronic inflammatory sinopulmonary conditions.

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Footnotes Abbreviation: IL = interleukin

Dr. Garey is on the Speakers’ Bureau for Abbott Laboratories and Aventis Pharmaceuticals. Dr. Danziger is on the Speakers’ Bureau and has received research grants from Abbott Laboratories, Ortho-McNeil Pharmaceuticals, AstraZeneca Pharmaceuticals, and Merck & Co.

Dr. Rubinstein is on the Speakers’ Bureau and has received research grants from Abbott Laboratories, Aventis Pharmaceuticals, GlaxoSmithKline, and Chiron. Financial support for this review was provided by the University of Illinois at Chicago and Abbott Laboratories.

o Received October 16, 2001. o Accepted June 27, 2002.

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66. ↵ Kita, E, Sawaki, M, Oku, D, et al Suppression of virulence factors of Pseudomonas aeruginosa by erythromycin. J Antimicrob Chemother 1991;27,273-284

Abstract / FREE Full Text

67. ↵ Majtan, V., Hybenova, D. Inhibition of Pseudomonas aeruginosa alginate expression by subinhibitory concentrations of antibiotics. Folia Microbiol (Praha) 1996;41,61-64

68. ↵ Hotta, M Neutrophil chemotactic activity in cryptogenic organizing pneumonia and the response to erythromycin. Kurume Med J 1996;43,207-217

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Macrolides for the Treatment of Chronic Sinusitis, Asthma, and COPD*

1. Mark H. Gotfried, MD, FCCP

+ Author Affiliations

1. *From the University of Arizona, Phoenix, AZ.  

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AbstractIn addition to their well-known antimicrobial activity, macrolides possess immunomodulatory properties that may confer beneficial effects to patients with respiratory diseases associated with chronic inflammation. These properties include attenuation of inflammatory responses in the lung, mucoregulatory properties, and effects on bronchial responsiveness. Macrolides increase mucociliary clearance, improve sinusitis symptoms, and decrease nasal secretions and polyp size in patients with sinusitis. They also have been shown to modify the inflammatory response associated with chronic sinusitis. In patients with asthma, macrolides have been reported to reduce airway hyperresponsiveness and improve pulmonary function, and have historically been selected for their “steroid-sparing” effect. Preliminary data from studies of patients with COPD have shown improvements in symptom scores and FEV1 after macrolide treatment. As biological response modifiers, macrolides have the potential to improve the outcomes of patients with inflammatory airway diseases. Large scale, placebo-controlled clinical trials designed to assess long-term efficacy and safety in these diseases are warranted.

anti -inflammatory activity

as thma

clarithromycin

COPD

erythromycin

macrolide s

roxithromycin

sinusitis

The role of macrolide antibiotics for the treatment of upper and lower respiratory tract infections is well-established. Based on a consistent record of efficacy, the newer macrolides, clarithromycin (Biaxin; Abbott Pharmaceuticals; Abbott Park, IL) and azithromycin (Zithromax; Pfizer Pharmaceuticals; New York, NY), are currently recommended by several agencies/medical societies for first-line (or alternative) treatment of community-acquired pneumonia, acute exacerbations of chronic bronchitis, acute bacterial sinusitis, and streptococcal pharyngitis. Perhaps less appreciated is a long-standing and relatively consistent body of literature that suggests that macrolides act as biological response modifiers, attenuating respiratory tract inflammation.

Independent of their potent antimicrobial activity, 14-membered and 15-membered macrolides possess anti-inflammatory properties that may contribute to clinical benefits observed in patients with airway inflammation (Table 1 ).12345 Macrolides can normalize bronchial and nasal mucus secretion and/or properties, and may reduce bronchial hyperresponsiveness and sputum purulence. Macrolides also affect neutrophil migration, the oxidative burst in phagocytes, the

production of proinflammatory cytokines, and eosinophilic inflammation. The clinical impact of these effects in patients with chronic sinusitis, asthma, and COPD is the focus of this article. The results of studies in which patients with chronic sinusitis, asthma, or COPD received a macrolide are summarized.

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Chronic SinusitisChronic sinusitis is one of the most common diseases in the United States, affecting 14% of the population.6 It is a burdensome clinical illness, significantly diminishing quality of life. 78 Between 1990 and 1992, sinusitis-associated symptoms resulted in > 70 million days of restricted activity.9 The economic impact of the disease is also staggering, with health-care expenditures in the United States attributable to sinusitis estimated to be about $5.8 billion annually.10

Nasal congestion, increased quantity and tenacity of secretions, facial pain, and fatigue are common among patients with chronic sinusitis. Hyperplastic changes in the mucosa, hypertrophy, and hypersecretion of the nasal and paranasal sinus mucosa are typical, as is an inflammatory infiltrate containing lymphocytes, plasma cells, neutrophils, and eosinophils.11

Hyperplastic and hypertrophic changes of the nasal mucosa cause narrowing of the drainage route from the paranasal sinuses and sinus cavities, leading to mucosal congestion and edema. Hypersecretion disturbs mucociliary clearance. Obstruction of the sinus ostia creates an increasingly hypoxic environment within the sinus, and leads to inflammation and an ideal culture medium within the sinus cavity.12 Maintaining ostia patency is critical to reversing the cycle of sinusitis.13 As summarized below, there is accumulating evidence that macrolides may alter the natural history of chronic sinusitis, which is characterized by elevated levels of inflammatory mediators (eg, granulocyte macrophage colony-stimulating factor, interleukin [IL]-3, and IL-8).141516 Macrolides may inhibit the vicious cycle of cytokine production, neutrophil recruitment, and impaired mucociliary function at the site of inflammation, thereby interrupting the prolonged inflammation of chronic sinusitis.

Clinical Experience

Clinical reports of macrolide use in patients with chronic sinusitis come primarily from small, open-label case series. Consistent across the studies have been improvements in sinusitis symptoms, shrinkage in the size of nasal polyps, and a decrease in levels of proinflammatory cytokines in nasal secretions. Most of the clinical experiences demonstrating the favorable anti-inflammatory effects of macrolides on patients with chronic sinusitis have been published in the Japanese literature. A summary of articles describing the clinical experience with macrolides in patients with chronic sinusitis is presented in Table 2 .1718192021222324252627

Data from the beginning of the last decade from Kikuchi and coworkers17 from Japan documented improvement of sinusitis signs and symptoms in 50 to 100% of patients who were given macrolide therapy. The investigators treated 26 postoperative patients with persistent sinus symptoms following sinus surgery using erythromycin, 600 mg per day for an average of 7.9 months. Also published in the Japanese literature were the results of studies by Nishi et al 22 and Suzuki et al.27 Following treatment with clarithromycin, 400 mg daily for 4 weeks, significant improvements in mucociliary clearance, volume of secretions, cough frequency, and dyspnea-on-exertion were documented in 32 patients with sinobronchial syndrome.22 Low-dose roxithromycin (Rulid; Albert-Roussel Pharma GmbH; Wiesbaden, Germany) was shown to significantly improve the aeration of all four sinuses and to significantly reduce neutrophil and IL-8 levels in the nasal discharge of 12 patients with chronic sinusitis.27

The first article describing the use of macrolides in patients with chronic sinusitis appeared in the English literature in 1996. Hashiba and Baba20 treated 45 chronic sinusitis patients with clarithromycin, 400 mg daily for 8 to 12 weeks. Improvements in symptoms and rhinoscopic findings were directly related to the duration of macrolide therapy. The investigators noted improvement rates of 5%, 48%, 63%, and 71%, respectively, after 2, 4, 8, and 12 weeks of therapy. After 12 weeks of therapy, 64% of patients had reduced viscosity of nasal secretions,

56% had reduced quantity of nasal secretions, 62% had reduced postnasal drip, and 51% had reduced nasal obstruction. Clinical benefit in patients with chronic sinusitis also was observed following long-term administration of roxithromycin, 150 mg daily.26

The following year, Rubin and associates21 reported on the results of a study in which the nasal mucus properties in 10 healthy volunteers were compared to those in 10 patients with purulent rhinitis before and after treatment with clarithromycin, 500 mg twice daily for 2 weeks. Before the initiation of therapy with the macrolide, secretions from those patients with rhinitis had statistically significantly decreased wetability and sneeze clearability, and had statistically significantly increased the percentage of solids and cohesion, compared to those in secretions from the healthy subjects. After clarithromycin therapy, the secretions from the healthy adults without nasal symptoms were similar, based on rheology, hydration, cohesion, and transportability, to that of rhinitis patients. The secretion volume decreased by > 10-fold (p < 0.01), and mucociliary transportability increased by 30% (p = 0.005). Secretory response to methacholine was not affected by clarithromycin, suggesting that the effect of the macrolide on mucus properties was based on the modulation of inflammation.

In a prospective, open-label study conducted at a single center in the United States, 25 patients (mean age, 45 years) with chronic sinusitis were treated with clarithromycin, 500 mg twice daily for 14 days.24 The diagnosis of chronic sinusitis was established based on history, physical examination findings, and the results of an ear-nose-throat evaluation and CT scan. Biopsy specimens of the maxillary sinus mucosa were obtained prior to the initiation of macrolide therapy and 7 days after its completion. Statistically significant reductions from baseline were observed for all major markers of sinus mucosal inflammation, including the levels of macrophages (CD68), elastase, IL-6, IL-8, and tumor necrosis factor (TNF)-α, and the activity of eosinophils (EG2). Edema score decreased by 41% (p < 0.001). Improvement in clinical signs and symptoms (ie, sinus pain, sinus headache severity, nasal congestion, nasal discharge, and mucopurulent discharge) was observed at the 1-week and 2-week follow-up visits (Fig 1 ).24 The associated reduction of various markers of sinus inflammation supports the hypothesis that clarithromycin modulates the immune response.

While endoscopic sinus surgery cures many patients with chronic sinusitis, especially those with anatomic narrowing of the drainage route from the sinuses, there is a group of patients who experience persistent symptoms following surgical intervention. Cervin and colleagues19

evaluated the effect of macrolide therapy (erythromycin, 250 mg twice daily, or clarithromycin, 250 mg once daily) on clinical outcome and mucociliary parameters in 17 patients with chronic, persistent sinusitis after sinus surgery. Twelve of these patients responded to macrolide therapy at 3 months and were reassessed after 12 months of treatment. Nonresponders abandoned antibiotic therapy after 3 months. At the 12-month follow-up visit, an improvement in the mucociliary transit time was observed (p < 0.05), without a statistically significant change in ciliary beat frequency. Statistically significant improvements also were seen in endoscopic nasal examination scoring (p < 0.01) as well as in nasal congestion, sticky secretions, and runny nose at both 3 and 12 months based on visual analog scale scoring (p < 0.01 each). Patients also experienced fewer headaches (p < 0.05).

Patients with chronic sinusitis often develop nasal polyps, which are either neutrophil-dominant (ie, containing abundant proinflammatory cytokines such as IL-8) or eosinophil-dominant. The 14-membered macrolides (eg, erythromycin, clarithromycin, and roxithromycin), and less so the 16-membered macrolides (eg, josamycin [Yamanouchi Pharmaceutical Co; Tokyo, Japan]), inhibited IL-8 secretion from cultures of human nasal epithelial cells harvested from the nasal polyps of patients with chronic sinusitis.28

Yamada and coworkers23 evaluated the effect of macrolide therapy on the size of nasal polyps and IL-8 levels in the nasal lavage fluid of 20 patients (age range, 24 to 84 years; mean age, 57 years) with chronic paranasal rhinosinusitis. All patients had experienced > 1 year of congestion, rhinorrhea, postnasal drip, olfactory disturbance, and/or discomfort in the regions of the sinuses. During macrolide treatment (clarithromycin, 400 mg daily for 8 to 12 weeks), patients had a significant decrease in levels of IL-8, a critical cytokine in the pathogenesis of chronic rhinosinusitis. Clinical response correlated significantly with decreased IL-8 levels. In the group of

patients in whom polyps were reduced in size during macrolide therapy, IL-8 levels were significantly higher at baseline (231.2 vs 88.1 pg/mL, respectively [among those whose polyps showed no change in size; p < 0.005]) and decreased by more than fivefold (p < 0.05). In contrast, there was no difference in IL-8 levels before and after macrolide therapy in the patients in whom polyps did not change in size.

Similar findings were reported by Ichimura et al,25 who treated 20 patients with nasal polyps associated with chronic sinusitis with roxithromycin, 150 mg once a day for 8 weeks. At the completion of macrolide treatment, a reduction in the size of nasal polyps was observed in more than half of the treated patients. The investigators theorized that the shrinkage of nasal polyps by macrolides is related to the suppression of cytokine production by inflammatory cells in the paranasal sinus epithelium.

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Asthma Affecting about 5% of the population,29 asthma is associated with increased risks of long-term morbidity and mortality. Exposure to allergens and airway irritants (eg, tobacco smoke and air pollutants) has been proposed as causes for increased prevalence and morbidity of asthma.29 In 1999, asthma accounted for about 9.5 million physician office visits and 500,000 hospitalizations in the United States.30 While death due to asthma is relatively uncommon, the age-adjusted annual mortality rate is significantly higher among African Americans than among whites, and was higher among women than men for each ethnic group.30 The annual economic burden of asthma in the United States, including direct and indirect costs, has been estimated at $14 billion.30

Asthma is the prototypical inflammatory disease of the lower airways. Persistent airway inflammation, a cardinal feature of asthma, produces airway hyperresponsiveness and recurrent episodes of airway obstruction. Given the role of airway inflammation, the prompt initiation of an anti-inflammatory agent (ie, inhaled or oral corticosteroids) is the mainstay of therapy.29 According to data published over the last several years, macrolide therapy improves the signs and symptoms of asthma, likely as a result of their anti-inflammatory properties.

Clinical Experience

The initial experience with macrolides in treating asthma dates back > 40 years.31 Since then, reductions in steroid use by > 50% in steroid-dependent asthmatic patients,3233343536 airway hyperresponsiveness,34 and hospital admissions,353738 as well as improved spirometry test results (eg, FEV1 and FVC)323338 and asthma control3738 have been documented in numerous trials subsequent to treatment with troleandomycin. Similar benefits to patients with asthma have been observed with the newer macrolides.

Evaluating 23 asthmatic patients who were not receiving steroid therapy, Miyatake et al39

documented a decrease in bronchial hyperresponsiveness to a histamine challenge following 10 weeks of treatment with low-dose erythromycin. Similar results have been observed with clarithromycin and roxithromycin. In a double-blind, placebo-controlled, crossover study, Amayasu and coworkers40 measured bronchoconstriction caused by the inhalation of methacholine in 17 adults with bronchial asthma who received clarithromycin, 200 mg, or placebo twice daily for 8 weeks. The investigators reported a statistically significant decrease (vs placebo and the baseline values of clarithromycin) in symptoms, blood and sputum eosinophil counts, and sputum eosinophilic cationic protein, as well as in the suppression of bronchial hyperresponsiveness after 8 weeks of treatment.40 Shimizu and associates41 documented a significant decrease in airway hyperresponsiveness to a histamine challenge in 12 hospitalized asthmatic children after 4 weeks (p < 0.05) and 8 weeks (p < 0.01) of therapy with roxithromycin, 150 mg daily.

We conducted a double-blind, randomized, placebo-controlled, pilot study42 to evaluate the efficacy of therapy with clarithromycin, 500 mg twice daily for 6 weeks, in 21 patients with corticosteroid-dependent asthma (ie, patients had been receiving ≥ 5 mg prednisone for ≥ 6

months prior to study enrollment). Compared with baseline values, increases in FVC (p = 0.038) and FEV1 (p = 0.07), as well as decreases in nocturnal dyspnea (p = 0.05), social concerns (p = 0.048), and chest discomfort (p = 0.02) were found posttreatment (Table 3 ).42 The decrease in nighttime symptoms, a surrogate marker for inflammation, is suggestive of a clinical benefit based on the anti-inflammatory effects of macrolides. No increase in steroid dosage was required during the study. In fact, during the study, the majority of the patients were able to reduce their prednisone dosage, and two elderly patients discontinued prednisone therapy altogether.43

An anti-inflammatory bronchial effect also has been reported with roxithromycin. In a double-blind, placebo-controlled, crossover study44 of 14 patients with aspirin-intolerant asthma, patients’ symptoms, serum eosinophil counts, sputum eosinophil levels, and serum and sputum eosinophilic cationic protein levels were statistically significantly decreased after 8 weeks of therapy with roxithromycin, 150 mg twice daily. Kamoi and collaborators45 reported significantly reduced (p < 0.01) bronchial hyperreactivity and synthesis of free radicals (ie, superoxide anion) in 10 asthmatic patients who had been treated with roxithromycin, 150 mg daily for 3 months, compared to 10 healthy control subjects. Most patients required at least 2 months of macrolide therapy for demonstrable clinical improvement.

The efficacy of macrolide therapy in patients with asthma may not be based exclusively on their antiinflammatory effects. Atypical intracellular pathogens (Chlamydia pneumoniae and Mycoplasma pneumoniae) may play a role in the pathogenesis of reactive airway diseases,46474849

and macrolides possess antimicrobial activity against these pathogens.5051525354 In one study, 55 M pneumoniae or C pneumoniae was present in the airways (detected by polymerase chain reaction [PCR]) in more than half of stable patients with chronic asthma. Thus, it is difficult to distinguish between the anti-inflammatory and antimicrobial effects of macrolides compared with the beneficial responses in some patients with asthma.

Macrolide therapy improves lung function in patients with asthma associated with the presence of atypical pathogens. Hahn and Golubjatnikov56 treated 46 asthmatic patients with doxycycline (Vibramycin; Pfizer Pharmaceuticals; New York, NY), 100 mg twice daily, azithromycin, 1 g once weekly, or erythromycin, 1 g daily for a median of 4 weeks. The mean FEV1 (67.8% of predicted at baseline) increased by 12.5% after treatment (p = 0.003). Subsequently, Kraft and associates55

conducted a double-blind study in which 52 stable patients with chronic asthma were randomized to therapy with clarithromycin, 500 mg, or placebo twice daily for 6 weeks. Macrolide therapy resulted in significantly increased mean (± SD) FEV1 levels in asthmatic patients who were PCR-positive for Chlamydia or Mycoplasma (baseline, 2.50 ± 0.16 L; posttreatment, 2.69 ± 0.19 L; p = 0.05). In contrast, there was no improvement in FEV1 in patients who were PCR-negative (baseline, 2.59 ± 0.24 L; posttreatment, 2.54 ± 0.18 L; p = 0.85). A statistically significant reduction in inflammatory mediators (ie, IL-5, IL-12, and TNF-α),55

and in eosinophil and neutrophil levels in bronchoalveolar lavage fluid57 also was observed with clarithromycin, suggesting immunomodulatory activity.

Black et al58 randomized 232 asthmatic patients who were antibody-positive for C pneumoniae to roxithromycin, 150 mg, or placebo twice daily. After 6 weeks of therapy, patients treated with the macrolide had significantly increased nighttime peak expiratory flow (increase from baseline: roxithromycin, 15 L/min; placebo, 3 L/min; p = 0.02), but a nonsignificant change in the daytime peak expiratory flow (increase from baseline: roxithromycin, 14 L/min; placebo, 8 L/min). These benefits disappeared within 3 months of stopping the medication. The authors speculated that macrolide therapy might have temporarily mitigated the effects of chlamydial infection on the patient’s airways, with infection and its sequelae persisting after the discontinuation of treatment.

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COPDCOPD is a common and costly disease, with substantial morbidity and mortality. Approximately 16 million individuals in the United States have COPD.59 During 1999, COPD accounted for > 12 million physician visits and 713,000 hospitalizations.30 COPD ranks fourth among all causes of

death in the United States.30 Annual expenditures for health care and lost productivity due to COPD were estimated30 at $32 billion, including $18 billion in direct health-care expenditures, $6.8 billion in indirect morbidity costs, and $7.3 billion in indirect mortality costs.

COPD is characterized by progressive airflow limitation caused by an abnormal inflammatory response of the lungs to noxious particles or gases. An increasing appreciation for the role that inflammation plays in the pathophysiology of COPD has led to the use of inhaled corticosteroids in the treatment of this disease.606162 As summarized below, preliminary data document improvements in clinical end points as well as in pulmonary function test results with the administration of macrolides in patients with COPD, another line of evidence for the beneficial role of macrolides in treating respiratory tract diseases with an inflammatory component.

Banerjee and coworkers636465 randomized patients with moderate-to-severe COPD (ie, FEV1, < 60%) to 3 months of therapy, with either clarithromycin, 500 mg daily (24 patients), or matching placebo (33 patients). The study measured numerous parameters of airway inflammation, bacterial colonization, pulmonary function, exercise tolerance, and overall health status. At the conclusion of the treatment interval, clarithromycin had not altered the sputum total cell count, 63

inflammatory cytokine levels,63 or pathogen count64 in the sputum of stable COPD patients. While sputum total cell count and absolute neutrophil count did not correspond to measurements of pulmonary function or to the results from the shuttle walk test, findings did indicate a significant correlation between both total cell count and absolute neutrophil count with total health status impact, respiratory symptoms, and activity scores among clarithromycin-treated COPD patients (p < 0.03).65

In contrast, Nixon and coworkers66 documented improvements in spirometry findings as well as clinical benefits with macrolide therapy of COPD. In their study, 25 patients with COPD experiencing an exacerbation received clarithromycin, 500 mg twice daily for 2 weeks. The absolute FEV1 increased from 1.12 L at baseline to 1.34 L posttreatment (p = 0.003), and the mean total scores for signs and symptoms of COPD decreased from 11.12 (95% confidence interval, 10.46 to 11.78) to 5.40 (95% confidence interval, 4.08 to 6.73). The most profound improvement in symptoms occurred after the first week of treatment and was sustained during the second week. When treatment was prolonged to 4 weeks, improvement continued but did not show significant change after the second week of treatment.67

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DiscussionMacrolides possess immunomodulatory properties that may be of therapeutic benefit in patients with chronic airway inflammation. Prolonged treatment is likely to be beneficial in at least some patients with inflammatory disease, such as sinusitis and asthma. The role of macrolides for patients with COPD remains to be determined, although the preliminary data are encouraging.

There is debate with respect to the contribution of anti-inflammatory benefits vs antimicrobial action as they relate to the efficacy of macrolides in treating respiratory tract diseases. Evidence exists that suggests that the response to macrolides may be a consequence of anti-inflammatory effects. For example, pharmacokinetic studies show that the minimum inhibitory concentrations of clinically relevant pathogens in certain disease states are substantially higher than the maximum levels of erythromycin achieved in serum and sputum during long-term macrolide therapy. This suggests that a positive clinical outcome in a disease such as diffuse panbronchiolitis may be attributed to something other than an antibacterial effect.68 The relative ineffectiveness of 16-membered ring macrolides compared to that of 14-membered ring macrolides, despite the relatively comparable antimicrobial activity,69 also suggests a mechanism that is unrelated to antimicrobial activity.

In summary, as biological response modifiers, macrolides may improve both symptoms and function in patients with inflammatory respiratory diseases such as chronic sinusitis, asthma, or COPD. Large-scale, placebo-controlled studies are warranted to confirm the efficacy and safety of long-term treatment with macrolides for these diseases.

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CME QuestionsThe American College of Chest Physicians designates this continuing medical education activity for 1 credit hour in category 1 of the Physician’s Recognition Award of the American Medical Association. To obtain credit, please complete the question form at http://www.chestnet.org. Credit can be obtained ONLY through our online process.

1. Which of the following is not true of the effects of macrolides on neutrophils?

1. Decrease neutrophil oxidative burst

2. Inhibit phagocytosis

3. Inhibit neutrophil migration to inflammatory sites

4. Stimulate neutrophil adhesion

5. Increase neutrophil degranulation

2. All of the following are effects of macrolides relevant to airway inflammation except:

1. Inhibit synthesis and/or secretion of proinflammatory cytokines

2. Decrease eosinophilic inflammation

3. Increase mucociliary transport

4. Reduce goblet cell secretions

5. Increase bronchoconstriction

3. Clinical trials of the efficacy of macrolides for the treatment of asthma show all of the following except:

1. Increase in FVC and FEV1

2. Decrease in nocturnal dyspnea

3. Decrease in chest discomfort

4. Increase in dosage of prednisone

5. Decrease social concerns

4. Clinical experience with macrolide therapy for the treatment of chronic sinusitis shows all of the following except

1. Improvement in sinus symptoms such as sinus pain, headache, nasal congestion, nasal discharge, and mucopurulent discharge

2. Reduced mucociliary transport

3. Reduction in rhinorrhea, postnasal drip, nasal obstruction, and sense of dullness in the head

4. Reduced volume of secretions

5. Reduction of size of nasal polyps

5. Which of the following is not true of the efficacy of macrolides for the treatment of COPD?

1. Decreased sputum cell count

2. Increased FEV1

3. No correlation between neutrophil count or sputum total cell count and pulmonary function

4. Significant correlation between neutrophil count and respiratory symptoms

5. Significant correlation between total cell count and total health status

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Table 1.

Summary of Effects of Macrolides Relevant to Respiratory Tract Inflammation12345

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Table 2.

Clinical Experience with Macrolide Therapy for Chronic Sinusitis

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Figure 1.

Effect of clarithromycin in patients with chronic sinusitis.24

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Table 3.

Effect of Clarithromycin in Asthma*

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Footnotes Abbreviations: IL = interleukin; PCR = polymerase chain reaction; TNF = tumor necrosis

factor

Learning objectives:

1. To understand the clinical data on the efficacy of macrolides for the treatment of chronic sinusitis, asthma, and COPD.

2. To realize that large-scale, placebo-controlled studies determining the efficacy and safety of macrolides for the treatment of chronic sinusitis, asthma, or COPD are warranted.

3. To be aware of the prevalence and the significant economic burden that chronic sinusitis, asthma, and COPD have on society.

4. To understand the effects of macrolides on neutrophils.

5. To understand the effects of macrolides on airway inflammation.

Dr. Gotfried has received research grants from and is a member of the Speakers’ Bureau of Abbott Laboratories. He also received financial remuneration from Abbott Laboratories for his participation at the Roundtable Meeting.

This manuscript is derived from the proceedings of the Symposium on Macrolide Effects presented at the 2002 American College of Chest Physicians Annual Meeting.

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33. ↵ Wald, JA, Friedman, BF, Farr, RS An improved protocol for the use of troleandomycin (TAO) in the treatment of steroid-requiring asthma. J Allergy Clin Immunol 1986;78,36-43

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34. ↵ Ball, BD, Hill, MR, Brenner, M, et al Effect of low-dose troleandomycin on glucocorticoid pharmacokinetics and airway hyperresponsiveness in severely asthmatic children. Ann Allergy 1990;65,37-45

MedlineWeb of Science

35. ↵ Flotte, TR, Loughlin, GM Benefits and complications of troleandomycin (TAO) in young children with steroid-dependent asthma. Pediatr Pulmonol 1991;10,178-182

MedlineWeb of Science

36. ↵ Kamada, AK, Hill, MR, Ikle, DN, et al Efficacy and safety of low-dose troleandomycin therapy in children with severe, steroid-requiring asthma. J Allergy Clin Immunol 1993;91,873-882

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37. ↵ Eitches, RW, Rachelefsky, GS, Katz, RM, et al Methylprednisolone and troleandomycin in treatment of steroid-dependent asthmatic children. Am J Dis Child 1985;139,264-268

Abstract / FREE Full Text

38. ↵ Siracusa, A, Brugnami, G, Fiordi, T, et al Troleandomycin in the treatment of difficult asthma. J Allergy Clin Immunol 1993;92,677-682

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39. ↵ Miyatake, H, Taki, F, Taniguchi, H, et al Erythromycin reduces the severity of bronchial hyperresponsiveness in asthma. Chest 1991;99,670-673

Abstract / FREE Full Text

40. ↵ Amayasu, H, Yoshida, S, Ebana, S, et al Clarithromycin suppresses bronchial hyperresponsiveness associated with eosinophilic inflammation in patients with asthma. Ann Allergy Asthma Immunol 2000;84,594-598

MedlineWeb of Science

41. ↵ Shimizu, T, Kato, M, Mochizuki, H, et al Roxithromycin reduces the degree of bronchial hyperresponsiveness in children with asthma. Chest 1994;106,458-461

Abstract / FREE Full Text

42. ↵ Gotfried, MH, Jung, R, Messick, C, et al Placebo controlled trial evaluating the efficacy of clarithromycin in subjects with corticosteroid-dependent asthma [abstract]. J Antimicrob Chemother 1999;44(suppl),100

43. ↵ Garey, KW, Rubinstein, I, Gotfried, MH, et al Long-term clarithromycin decreases prednisone requirements in elderly patients with prednisone-dependent asthma. Chest 2000;118,1826-1827

Abstract / FREE Full Text

44. ↵

Shoji, T, Yoshida, S, Sakamoto, H, et al Anti-inflammatory effect of roxithromycin in patients with aspirin-intolerant asthma. Clin Exp Allergy 1999;29,950-956

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45. ↵ Kamoi, H, Kurihara, N, Fujiwara, H, et al The macrolide antibacterial roxithromycin reduces bronchial hyperresponsiveness and superoxide anion production by polymorphonuclear leukocytes in patients with asthma. J Asthma 1995;32,191-197

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46. ↵ Emre, U, Roblin, PM, Gelling, M, et al The association of Chlamydia pneumoniae infection and reactive airway disease in children. Arch Pediatr Adolesc Med 1994;148,727-732

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49. ↵ Black, PN, Scicchitano, R, Jenkins, CR, et al Serological evidence of infection with Chlamydia pneumoniae is related to the severity of asthma. Eur Respir J 2000;15,254-259

Abstract

50. ↵ Waites, KB, Cassell, GH, Canupp, KC, et al In vitro susceptibilities of mycoplasmas and ureaplasmas to new macrolides and aryl-fluoroquinolones. Antimicrob Agents Chemother 1988;32,1500-1502

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51. ↵ Fenelon, LE, Mumtaz, G, Ridgway, GL The in-vitro antibiotic susceptibility of Chlamydia pneumoniae. J Antimicrob Chemother 1990;26,763-767

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52. ↵ Critchley, IA, Jones, ME, Heinze, PD, et al In vitro activity of levofloxacin against contemporary clinical isolates of Legionella pneumophila, Mycoplasma pneumoniae, and Chlamydia pneumoniae from North America and Europe. Clin Microbiol Infect 2002;8,214-221

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53. ↵ Hammerschlag, MR, Qumei, KK, Roblin, PM In vitro activities of azithromycin, clarithromycin, L-ofloxacin, and other antibiotics against Chlamydia pneumoniae. Antimicrob Agents Chemother 1992;36,1573-1574

Abstract / FREE Full Text

54. ↵ Renaudin, H, Bebear, C Comparative. In vitro activity of azithromycin, clarithromycin, erythromycin and lomefloxacin against Mycoplasma pneumoniae, Mycoplasma hominis and Ureaplasma urealyticum. Eur J Clin Microbiol Infect Dis 1990;9,838-841

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55. ↵ Kraft, M, Cassell, GH, Pak, J, et al Mycoplasma pneumoniae and Chlamydia pneumoniae in asthma: effect of clarithromycin. Chest 2002;121,1782-1788

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56. ↵ Hahn, DL, Golubjatnikov, R Asthma and chlamydial infection: a case series. J Fam Pract 1994;38,589-595

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57. ↵ Kraft M, Cassell GH, Bettinger CM, et al. Mycoplasma pneumoniae as a cofactor in chronic asthma [abstract]. Available at:www.abstracts-on-line.com/abstracts/ATSALL. Accessed January 12, 2004

58. ↵ Black, PN, Blasi, F, Jenkins, CR, et al Trial of roxithromycin in subjects with asthma and serological evidence of infection with Chlamydia pneumoniae. Am J Respir Crit Care Med 2001;164,536-541

Abstract / FREE Full Text

59. ↵ National Heart, Lung, and Blood Institute. NHLBI data fact sheet: chronic obstructive pulmonary disease (COPD). Available at: http://www.nhlbi.nih.gov/health/public/lung/other/copd_fact.htm. Accessed January 12, 2004

60. ↵ Calverley, PM Modern treatment of chronic obstructive pulmonary disease. Eur Respir J 2001;34(suppl),60S-66S

61. ↵ Van der Valk, P, Monninkhof, E, van der Palen, J, et al Effect of discontinuation of inhaled corticosteroids in patients with chronic obstructive pulmonary disease: the COPE study. Am J Respir Crit Care Med 2002;166,1358-1363

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62. ↵ Sin, DD, Man, SF Inhaled corticosteroids and survival in chronic obstructive pulmonary disease: does the dose matter? Eur Respir J 2003;21,260-266

Abstract / FREE Full Text

63. ↵ Banerjee, D, Hussain, S, Khair, O, et al The effects of oral clarithromycin on airway inflammation in moderate to severe chronic obstructive pulmonary disease (COPD): a double blind randomised controlled study [abstract]. Eur Respir J 2001;18,338S

64. ↵ Banerjee, D, Clarke, B, Hill, SL, et al The effect of 3 months oral clarithromycin on sputum bacterial colonisation in stable moderate to severe chronic obstructive pulmonary disease (COPD) [abstract]. Eur Respir J 2001;18,153S

65. ↵ Banerjee, D, Khair, O, Honeybourne, D The relationship between pulmonary function, health status, shuttle walk distance with sputum airway inflammation in moderate to severe chronic obstructive pulmonary disease (COPD) [abstract]. Eur Respir J 2001;18,94S

66. ↵ Nixon LS, Boorman J, Papagiannis AJ, et al. Circulation and airways inflammatory markers in chronic obstructive pulmonary disease (COPD) during an exacerbation [abstract]. Available at: www.abstracts-on-line.com/abstracts/ATSALL. Accessed January 12, 2004

67. ↵ Nixon LS, Boorman J, Papagiannis AJ, et al. The effect of the length of antibiotic treatment on inflammatory markers in chronic obstructive pulmonary disease [abstract]. Available at: www.abstracts-on-line.com/abstracts/ATSALL. Accessed January 12, 2004

68. ↵ Nagai, H, Shishido, H, Yoneda, R, et al Long-term low-dose administration of erythromycin to patients with diffuse panbronchiolitis. Respiration 1991;58,145-149

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69. ↵ Shirai, T, Sato, A, Chida, K Effect of 14-membered ring macrolide therapy on chronic respiratory tract infections and polymorphonuclear leukocyte activity. Intern Med 1995;34,469-474

MedlineWeb of Science

Summary of Effects of Macrolides Relevant to Respiratory Tract Inflammation12345

Inhibit synthesis and/or secretion of proinflammatory cytokines

Effects on neutrophils

Decrease neutrophil oxidative  burst

Inhibit neutrophil migration (chemotaxis)  to inflammatory sites

Increase apoptosis of neutrophils  (?)

Neutrophil degranulation (?) 

Inhibit neutrophil adhesion 

Inhibit phagocytosis 

Decrease eosinophilic inflammation

Increase mucociliary transport

Reduce goblet cell secretion

Decrease bronchoconstriction (decrease endothelin-1 release, inhibit cholinergic responses of airway smooth muscle)

Table 3.

Effect of Clarithromycin in Asthma*

Pretreatment

Posttreatment

p Value

FEV1 1.6 ± 0.58 1.85 ± 0.76 0.07

FVC 2.7 ± 0.9L 3.0 ± 1L 0.0038

Chest discomfort 0.7 ± 0.8 0.5 ± 0.7 0.02

Nighttime SOB 3.20 ± 2.15 2.51 ± 2.16 0.051

Social concerns 3.6 ± 2.6 3.0 ± 2.6 0.048

* Values given as mean ± SD, unless otherwise indicated. SOB = shortness of breath. Table used with permission of Gotfried et al.42

Chronic Macrolide Therapy in Inflammatory Airways Diseases Chest November 2010 138:1202-1212;

Abstract Full Text Full Text (PDF)

doi: 10.1378/chest.10-0196 CHEST November 2010 vol. 138 no. 5 1202-1212

Chronic Macrolide Therapy in Inflammatory Airways Diseases

1. Adam L. Friedlander, MD and 2. Richard K. Albert, MD, FCCP

+ Author Affiliations

1. From the Division of Pulmonary Sciences and Critical Care Medicine (Drs Friedlander and Albert), and the Department of Medicine, Denver Health (Dr Albert), Department of Medicine, University of Colorado Denver Health Sciences Center; and the Department of Medicine (Dr Friedlander), National Jewish Health, Denver, CO.

1. Correspondence to:Adam L. Friedlander, MD, National Jewish Health, 1400 Jackson St, Denver, CO 80206; e-mail: Adam.Friedlander@UCDenver.edu

Abstract

Long-term therapy with the macrolide antibiotic erythromycin was shown to alter the clinical course of diffuse panbronchiolitis in the late 1980s. Since that time, macrolides have been found to have a large number of antiinflammatory properties in addition to being antimicrobials. These observations provided the rationale for many studies performed over the last decade to assess the usefulness of macrolides in other inflammatory airways diseases, such as cystic fibrosis, asthma, COPD, and bronchiolitis obliterans syndrome. This review summarizes the immunomodulatory properties of macrolides and the results of these recent studies demonstrating their potential for being disease-modifying agents.

Footnotes

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (http://www.chestpubs.org/site/misc/reprints.xhtml).

Abbreviations

AECOPD acute exacerbation of COPD

BALF

BAL fluid

BOOP

bronchiolitis obliterans organizing pneumonia

BOS

bronchiolitis obliterans syndrome

CF

cystic fibrosis

DPB

diffuse panbronchiolitis

TNF-α

tumor necrosis factor α

Received January 22, 2010. Accepted May 27, 2010.

© 2010 American College

Long-term Clarithromycin Decreases Prednisone Requirements in Elderly Patients With Prednisone-Dependent Asthma*

1. Kevin W. Garey, PharmD, 2. Israel Rubinstein, MD, FCCP, 3. Mark H. Gotfried, MD, FCCP, 4. Ishrat J. Khan, MBBS, 5. Suchitra Varma, MBBS and 6. Larry H. Danziger, PharmD

+ Author Affiliations

1. * From the University of Illinois at Chicago (Drs. Garey, Rubinstein, Gotfried, and Danziger; Mssrs. Varma and Khan), Chicago, IL; and The Good Samaritan Regional Medical Center (Dr. Gotfried), Phoenix, AZ.

1. Correspondence to: Israel Rubinstein, MD, FCCP, Section of Respiratory and Critical Care Medicine, Department of Medicine, University of Illinois at Chicago, 840 S. Wood St (M/C 787), Chicago, IL 60612-7323; e-mail: IRubinst@uic.edu

 Next Section

Abstract

Prolonged use of prednisone is associated with serious side effects, such as osteoporosis, particularly among elderly individuals. Macrolide antibiotics exhibit anti-inflammatory effects that are distinct from their antimicrobial properties. Thus, the purpose of this case report is to describe the effects of prolonged treatment with clarithromycin, 500 mg bid, in reducing prednisone requirements in three elderly patients with prednisone-dependent asthma. Three patients (one woman and two men) aged 63 to 69 years, who had been treated with 5 to 10 mg prednisone daily for at least the last 12 months, were given clarithromycin, 500 mg bid. They were followed regularly for changes in daily prednisone dose, spirometry, quality of life, and adverse events. The prednisone dose was tapered in a stepwise fashion at each clinic visit. Within 3 to 6 months of initiation of treatment with clarithromycin, and throughout the 12-month follow-up, two of three patients discontinued prednisone therapy, while the third patient displayed increased spirometry readings and noted an increasingly better quality of life. Pulmonary function tests were stable or improved over this time period, with no reported adverse events, including increased rate of infections. One patient relapsed upon discontinuation of clarithromycin therapy but has since responded to re-initiation of treatment. Long-term oral clarithromycin may have a role in reducing prednisone requirements in elderly patients with prednisone-dependent asthma.

anti -inflammatory

clarithromycin

macrolide s

prednisone-dependent asthma

Several studies have suggested that macrolide antibiotics have salutary effects in patients with asthma, including a corticosteroid-sparing effect.123 The mechanisms underlying this response are thought to be related, in part, to anti-inflammatory effects of the drugs, which are distinct from their antimicrobial effects.4 Elderly patients with prednisone-dependent asthma are at high risk for developing devastating side effects from prolonged use of the drug, particularly osteoporosis.5 Hence, the use of macrolides in these patients in an attempt to reduce prednisone dependency would be advantageous.

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Case Report This case report begins to address the issue by describing three elderly patients with prednisone-dependent asthma who reduced or discontinued oral prednisone therapy after long-term treatment with clarithromycin, a 14-membered ring macrolide.

Patient 1

A 63-year-old white man received a diagnosis of severe asthma in 1995 and had been prednisone-dependent since that time. He had received a diagnosis of asthma as a child, and that condition had resolved as he reached the age of 18 years. He had quit smoking approximately 20 years before this study (14 pack-year history). Skin allergy tests were positive for mold dust. Physical examination was significant for a cushingoid appearance. Baseline FVC and FEV1 were 1.72 L and 1.12 L/s, respectively (44% and 36% predicted, respectively). His current asthma treatment consisted of inhaled triamcinolone, 1,600 μg daily; inhaled albuterol, 810 μg daily; oral theophylline, 400 mg daily; and prednisone, 10 mg daily. His symptoms were aggravated by attempts to taper his prednisone dose. In August 1998, he was given clarithromycin, 500 mg bid. Five months later, he discontinued prednisone entirely with no significant change in spirometry. Due to unexplained ecchymoses while receiving clarithromycin alone for 2 months, the drug was discontinued. The patient experienced an acute exacerbation of

asthma 1 month later and was given oral prednisone and clarithromycin, 500 mg bid. Within 2 months, the patient discontinued prednisone. He has remained on clarithromycin through 12 months of follow-up. No other changes were made to his medications. Clarithromycin was well tolerated, and he has remained asymptomatic.

Patient 2

A 65-year-old white woman received a diagnosis of severe asthma in 1986. Her symptoms were frequently exacerbated by attempts to taper her prednisone dose. Her medical history was significant for a 22-year history of allergic rhinitis and infrequent symptoms of gastroesophageal reflux. The patient had quit smoking at the age of 27 years (5 pack-year history). Baseline FVC and FEV1 were 3.25 L and 2.26 L/s, respectively (115% and 100% predicted, respectively). Current asthma treatment regimen consisted of inhaled triamcinolone, 1,000 μg qd; inhaled metaproterenol, 7.8 mg qd; inhaled cromolyn sodium, 6,400 μg qd; and prednisone, 10 mg qd.

In February 1997, the patient was given clarithromycin, 500 mg bid. Within 3 months, she tapered her prednisone to 5 mg qd, with a concomitant increase in FVC and FEV1 to 3.54 L and 2.69 L/s, respectively (127% and 120% predicted, respectively). Three months later, she discontinued prednisone entirely. No changes in spirometry or adverse events were noted through 12 months of follow-up.

Patient 3

A 67-year-old white man had received a diagnosis of asthma in 1984 and had been dependent on prednisone for the past 1.5 years. He experienced four to five acute exacerbations of asthma per year. His medical history was significant for gastroesophageal reflux. He had no smoking history. Baseline FVC and FEV1 were 4.12 L and 2.57 L/s, respectively (97% and 76% predicted, respectively). He was treated with ipratropium, 144 μg qd; salmeterol, 84 μg qd; flunisolide, 2,000 μg qd; beclomethasone, 168 μg qd; theophylline, 600 mg qd; and prednisone, 5 mg qd. He was given clarithromycin, 500 mg bid, and within 3 months, FVC increased to 5.3 L (125% predicted) with no change in FEV1. Plasma theophylline concentrations were unchanged throughout the observation period. The patient noted a significant improvement in quality of life, manifested by increased energy levels and enthusiasm. Several attempts to taper oral prednisone to 5 mg qd failed. Nonetheless, the patient did not experience an acute exacerbation of asthma throughout the 12 months of clarithromycin therapy. No adverse events were noted.

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DiscussionThe new finding from these case reports is that long-term (12 months) treatment with oral clarithromycin, 500 mg bid, is associated with a significant reduction in prednisone dependency in elderly patients with prednisone-dependent asthma. Importantly, this phenomenon was associated with a significant improvement in asthma coupled with no reported adverse events, including an increased rate of infection. The salutary effects of clarithromycin were observed only after several weeks of continuous therapy while the prednisone dose was being tapered.

Previous studies from Japan have shown that relatively short-term (< 3 months) therapy with oral erythromycin and roxithromycin, two macrolide antibiotics, was associated with significant improvement in bronchial hyperreactivity in patients with asthma.678 However, the mechanisms underlying this response were not determined. Moreover, these patients were either children or adults. The results of our case studies support and extend these observations by showing that long-term treatment with clarithromycin may be beneficial in elderly patients with prednisone-dependent asthma. Whether the corticosteroid-sparing effects of this drug are related, in part, to downregulation of the inflammatory cascade in the airway of patients with asthma remains to be determined.491011

Prolonged use of prednisone in patients with asthma, particularly elderly patients, is associated with devastating side effects, including osteoporosis.5 Hence, therapeutic measures to reduce or

eliminate prednisone dependency in these patients are desirable. The results of this case report suggest that long-term administration of oral clarithromycin may be a useful approach to accomplish this goal. However, the mechanisms underlying the corticosteroid-sparing effect of clarithromycin were not elucidated in this study. Earlier studies had suggested possible interactions between macrolides and corticosteroids, causing increased concentrations of the steroid.12 This is unlikely in the cases reported here, as two patients were able to discontinue prednisone entirely for a sustained period while remaining in remission. Also, Fost et al13 recently demonstrated that clarithromycin did not affect the pharmacokinetics of prednisone. Clearly, additional prospective studies are indicated to investigate the role of long-term clarithromycin therapy in elderly patients with prednisone-dependent asthma.

In summary, long-term oral clarithromycin therapy may have a role in the treatment of elderly patients with prednisone-dependent asthma. Future research will be necessary to further elucidate their effects.

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Footnotes This study was supported in part by a grant from Abbott Laboratories.

o Received January 13, 2000. o Accepted April 13, 2000.

Previous Section  

References1. ↵

Itkin, IH, Menzel, ML (1970) The use of macrolide antibiotic substances in the treatment of asthma. J Allergy 45,146-162

CrossRefMedlineWeb of Science

2. ↵ Spector, SL Alternative treatments in the patient with intractable asthma. Curr Opin Pulm Med 1997;3,23-29

Medline

3. ↵ Rosenberg, SM, Gerhard, H, Grunstein, MM, et al Use of TAO without methylprednisolone in the treatment of severe asthma. Chest 1991;100,849-850

Abstract / FREE Full Text

4. ↵ Labro, MT Anti-inflammatory activity of macrolides: a new therapeutic potential? J Antimicrob Chemother 1998;41(suppl B),37-46

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5. ↵ Dunlap, NE, Bailey, WC Corticosteroids in asthma. South Med J 1990;83,428-432

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6. ↵

Miyatake, H, Taki, F, Taniguchi, H, et al Erythromycin reduces the severity of bronchial hyperresponsiveness in asthma [comments]. Chest 1991;99,670-673

Abstract / FREE Full Text

7. ↵ Shimizu, T, Kato, M, Mochizuki, H, et al Roxithromycin reduces the degree of bronchial hyperresponsiveness in children with asthma. Chest 1994;106,458-461

Abstract / FREE Full Text

8. ↵ Kamoi, H, Kurihara, N, Fujiwara, H, et al The macrolide antibacterial roxithromycin reduces bronchial hyperresponsiveness and superoxide anion production by polymorphonuclear leukocytes in patients with asthma. J Asthma 1995;32,191-197

MedlineWeb of Science

9. ↵ Feldman, C, Anderson, R, Theron, AJ, et al Roxithromycin, clarithromycin, and azithromycin attenuate the injurious effects of bioactive phospholipids on human respiratory epithelium in vitro. Inflammation 1997;21,655-665

CrossRefMedlineWeb of Science

10. ↵ Anderson, R, Theron, AJ, Feldman, C Membrane-stabilizing, anti-inflammatory interactions of macrolides with human neutrophils. Inflammation 1996;20,693-705

CrossRefMedlineWeb of Science

11. ↵ Konno, S, Asano, K, Kurokawa, M, et al Antiasthmatic activity of a macrolide antibiotic, roxithromycin: analysis of possible mechanisms in vitro and in vivo. Int Arch Allergy Immunol 1994;105,308-316

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12. ↵ Black, PN The use of macrolides in the treatment of asthma. Eur Respir Rev 1996;38,240-243

13. ↵ Fost, DA, Leung, DY, Martin, RJ, et al Inhibition of methylprednisolone elimination in the presence of clarithromycin therapy. J Allergy Clin Immunol

Immunomodulatory Activity and Effectiveness of Macrolides in Chronic Airway Disease*

1. Bruce K. Rubin, MEngr, MD, FCCP and 2. Markus O. Henke, MD

+ Author Affiliations

1. *From the Department of Pediatrics (Dr. Rubin), Wake Forest University School of Medicine, Winston-Salem, NC; and Department of Pulmonary Medicine (Dr. Henke), Philipps-University Marburg, Marburg, Germany.

 

Next Section

AbstractThe use of troleandomycin as adjunctive therapy for the treatment of patients with corticosteroid-dependent asthma first suggested an immunomodulatory effect of the macrolide antibiotics. This led to studies of the macrolides in other chronic airway diseases, such as diffuse panbronchiolitis (DPB), a disease occurring primarily in East Asia. The use of macrolides for the therapy of patients with DPB has led to dramatic improvements in pulmonary function and prolonged survival. Similar benefits have been documented in Japanese studies of bronchiectasis, chronic bronchitis, and sinobronchial syndrome. Clinical and pathologic similarities between DPB and cystic fibrosis (CF) led to the investigation of macrolides for the treatment of CF. Data now suggest that persons with CF will benefit from macrolide therapy. In vitro and in vivo studies suggest that macrolides may inhibit the pulmonary influx of neutrophils, inhibit the release of proinflammatory cytokines, protect the epithelium from bioactive phospholipids, and improve the transportability of airway secretions. The immunomodulatory effects of the macrolides also may be beneficial for the treatment of other chronic inflammatory conditions.

azithromycin

clarithromycin

cystic fibrosis

cytokines

diffuse panbronchiolitis

erythromycin

macrolide antibiotics

neutrophil

troleandomycin

Interest in the immunomodulatory effects of macrolide antibiotics began with the observation that patients with severe asthma required lower doses of steroids if they also had received troleandomycin (TAO).1 Subsequently, macrolides have been studied for other airway diseases including diffuse panbronchiolitis (DPB) and cystic fibrosis (CF). The most convincing demonstration of the immunomodulatory effects of macrolides has been in the treatment of

DPB, a pulmonary disease of unknown etiology that is found primarily in Japan. In 1984, the 5-year survival rate for DPB was only 26%, but treatment with macrolides has dramatically increased the 10-year survival rate of these patients to 94%.2 The effectiveness of these drugs appears to be limited to the 14-membered and 15-membered macrolides, such as erythromycin, clarithromycin, and azithromycin. These drugs improve pulmonary function, and decrease morbidity and mortality in patients with DPB.2345 These macrolides decrease proinflammatory cytokines in serum and BAL fluid (BALF), decrease mucus hypersecretion, and may protect the airway epithelium from damage.678

CF is similar to DPB in many ways including symptoms and pulmonary pathology. Both diseases are characterized by cough, persistent sinus disease, neutrophilic airway inflammation, susceptibility to persistent endobronchial infection with opportunistic pathogens, and progressive deterioration in pulmonary function, and both diseases are responsive to the immunomodulatory effects of macrolides. This article reviews the immunomodulatory effects of macrolides, and the evidence for their clinical efficacy for the treatment of DPB and CF.

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The Steroid-Sparing Effects of Macrolides A number of studies91011121314 have shown an improvement in the clinical symptoms of corticosteroid-dependent patients with asthma and a reduction in corticosteroid dosage with concomitant TAO therapy. Pharmacokinetic studies1516 have suggested that the beneficial effects of TAO therapy may be due, in part, to the inhibition of steroid metabolism. TAO was shown to significantly prolong the serum half-life of methylprednisolone. However, in reported studies, some steroid-dependent patients were able to completely discontinue concomitant oral steroid therapy without worsening asthma severity, suggesting that TAO had direct anti-inflammatory activities. Studies1417 also have shown that low-dose TAO directly attenuates bronchial hyperresponsiveness in children with severe asthma and that the effects were independent of its action on glucocorticoid metabolism. In another study, TAO appeared to inhibit T-cell proliferation in peripheral blood mononuclear cells from patients with steroid-resistant asthma.18 In this supplement to CHEST, Gotfried describes more recent studies designed to assess the direct effects of clarithromycin in adults with severe persistent asthma (see page 52S).

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The Effects of Macrolides on Mucus Secretion Macrolide antibiotics also appear to be mucoregulatory, that is, they are able to decrease mucus hypersecretion in persons with airway disease without suppressing baseline physiologic secretion. In a double-blind, placebo-controlled, 8-week trial of 31 patients with chronic bronchitis, bronchiectasis, or DPB, low-dose clarithromycin (100 mg twice daily) profoundly decreased the expectorated sputum volume from 51 to 24 g per day (p < 0.001).19 Treatment with clarithromycin also increased the percentage of solid composition and the elastic modulus of the sputum (p < 0.05) but did not alter its dynamic viscosity. Based on these data, the investigators suggested that clarithromycin reduces both mucus and water secretion. Clarithromycin also significantly reduced the volume of nasal mucus secretion, both at baseline and with methacholine stimulation, and improved the sneeze (airflow) transportability in 10 patients with purulent rhinitis.20 Roxithromycin therapy for 12 weeks significantly decreased sputum volume and “purulence” in 25 children with bronchiectasis.21 The mechanism by which macrolides inhibit mucus hypersecretion is thought to involve decreasing the inflammatory stimulus for hypersecretion.2223

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The Effects of Macrolides on DPB DPB is a chronic inflammatory pulmonary disease that is well-recognized in Japan and Korea, and is less commonly diagnosed in the West.242526 Although upper airway symptoms, including chronic sinusitis, usually begin in late childhood, DPB is usually diagnosed between the second and fifth decades of life, and is characterized by chronic, progressive, obstructive, and inflammatory

sinobronchial disease. The clinical diagnostic criteria of DPB are given in Table 1 .2 These criteria include airflow limitation, sinusitis, sputum expectoration, dyspnea, and chronic airway infection, often with mucoid Pseudomonas aeruginosa. The results of pulmonary function tests typically show a mixed obstructive/restrictive picture similar to that for CF. Radiographic findings include reticular or nodular shadows, and CT scans show the characteristic central nodules with a tree-in-bud appearance.2627

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Clinical StudiesKudoh and colleagues27 were the first to demonstrate that low-dose erythromycin ameliorated the signs and symptoms of DPB. Therapy often will improve the appearance of chest radiographs and normalize pulmonary function. A large number of studies352728 have confirmed the effectiveness of long-term macrolide therapy for the treatment of DPB. These are summarized here.

In a retrospective analysis of 498 Japanese patients with DPB,2 a significant improvement in survival was associated with treatment using 400 to 600 mg daily of erythromycin. Subjects were categorized into one of three groups based on the date of the initial diagnosis. Group A included 190 subjects who had received diagnoses between 1970 and 1979, group B included 221 subjects who had received diagnoses between 1980 and 1984, and group C included 87 subjects who had received diagnoses between 1985 and 1990. A comparison of Kaplan-Meier survival curves of subjects in each group (Fig 1 ) showed significantly improved survival for the 63 patients in group C who had been treated with erythromycin compared with those in group A (p < 0.0001), group B (p < 0.0001), and 24 patients from group C who had not been treated with erythromycin (p < 0.0056). The 5-year survival rates of subjects not treated with erythromycin in groups A and C did not differ significantly.

The long-term efficacy and safety of clarithromycin was evaluated in 10 subjects with DPB who were treated for 4 years with clarithromycin, 200 mg per day.3 Pulmonary function improved in most subjects within 6 months of initiating treatment with clarithromycin. The FEV1 increased from 1.74 L at baseline to 2.31 L at 6 months (p < 0.01), and the FVC increased from 2.67 L at baseline to 3.16 L at 6 months (p < 0.005) [Fig 2 ]. The resting PaO2 significantly increased within 3 months after beginning macrolide therapy (p < 0.05). Sputum cultures were positive for Haemophilus influenzae, Haemophilus parahaemolyticus, Streptococcus pneumoniae, and P aeruginosa at baseline but were negative within 6 months after beginning therapy. The treatment was well-tolerated, and clarithromycin provided a sustained clinical benefit.

Data from 28 subjects with DPB treated with erythromycin, 600 mg per day for 1 month, showed that the drug produced significant clinical improvement, and decreased the number of neutrophils and the concentration of interleukin (IL)-8 in BALF.29 These observations were independent of P aeruginosa infection in these subjects, suggesting a systemic, anti-inflammatory effect of erythromycin in patients with this disease.

The mechanism by which macrolides improve the symptoms of DPB probably includes inhibiting the pulmonary influx of neutrophils.630 In chronic inflammation of the airways, neutrophils accumulate in the airway secreting elastase, myeloperoxidase, and inflammatory mediators that can produce epithelial dysfunction. Many studies have evaluated the effects of macrolides on neutrophils. BALF from patients with DPB contains many neutrophils. Macrolides may inhibit the production or secretion of proinflammatory cytokines, which results in the reduced accumulation of neutrophils in the airway.31 In vitro studies32 have shown that macrolides inhibit the production of proinflammatory cytokines through the inhibition of transcription factors, nuclear factor κB, and activator protein-1. In vitro data also suggest that macrolides may protect the epithelium from bioactive phospholipids and may improve the transportability of airway secretions.619203334

Treatment with erythromycin, 600 mg daily for 6 to 12 months, was associated with a reduction in both neutrophil number (p < 0.01) and neutrophil- derived elastolytic activity (p < 0.001) in the BALF of 11 subjects with DPB.35 This was associated with improved pulmonary function. In 19 subjects with DPB, treatment with erythromycin, 600 mg per day, or roxithromycin, 150 mg per day for 1 to 24 months, improved the FVC and FEV1 (p < 0.01), and reduced the percentage of

neutrophils in BALF by 63.8% compared with baseline (p = 0.0001). A higher percentage of neutrophils and the concentration of IL-1β are associated with increasing levels of IL-8 in the BALF of patients with DPB.3637 IL-1β, tumor necrosis factor (TNF)-α, and IL-8 were measured in the BALF of 19 subjects with DPB, and were compared with 7 healthy subjects and 17 subjects with pulmonary sarcoidosis, who served as disease controls.31 The pretreatment concentrations of IL-1β and IL-8 in patients in the DPB group were higher than those of healthy subjects (p < 0.05) or of those with sarcoidosis (p < 0.01), and BALF concentrations of IL-1β (p < 0.015) and IL-8 (p < 0.05) were significantly reduced following macrolide therapy (Fig 3 , left). In subjects with DPB, there was a significant correlation between the percentage of neutrophils and the concentration of IL-8, and the concentrations of IL-1β and IL-8 (Fig 3, right).

In another study,39 macrolide therapy reduced neutrophil numbers, and the concentration of IL-8 in BALF in 14 subjects with DPB. It also improved the FVC percent predicted (p < 0.01), the FEV 1

percent predicted (p < 0.02), and the PaO2 (p < 0.01) over pretreatment values.38 Macrolide therapy also significantly decreased the concentration of β-defensin-2 but not β-defensin-1 in BALF, or concentrations of β-defensin-1 or β-defensin-2 in the plasma of these subjects.39 β-defensins are endogenous antimicrobial peptides, but they also may cause pulmonary injury.38

Similarly, 2 to 6 months treatment with clarithromycin, 200 mg per day, erythromycin, 600 mg per day, or roxithromycin, 150 mg per day, reduced the absolute number of lymphocytes and activated CD8+ cells in the BALF of subjects with DPB, with a corresponding increase in the CD4+/CD8+ ratio.40

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The Effects of Macrolides in CF Based on the similarities between DPB and CF, macrolide antibiotics have now been studied as immunomodulatory medications for the treatment of CF.4142 In a pilot study,43 daily azithromycin was given for > 3 months (and up to a year) to 7 children aged 6 to 17 years with CF and P aeruginosa infection. During the study, no concomitant therapy with steroids, dornase alfa, or IV Ig was administered to these subjects. Excluding the first 2 months of treatment from their analysis, the authors compared mean FVC and FEV1 percent predicted values in the 6 months before starting azithromycin with those after therapy in the final month of the trial. The FVC rose from 62.8 to 70.3% predicted, with a median improvement of 11.3% (p < 0.03), and FEV1 percent predicted increased by 11.0% (p < 0.03).

This group at the Royal Brompton Hospital then conducted a 15-month randomized, double-blind, placebo-controlled, crossover trial44 of orally administered azithromycin therapy in 41 children (age range, 8 to 18 years) with CF. Subjects received either azithromycin or placebo for 6 months followed by a 2-month washout period, and then were crossed over to the other treatment group. The primary outcome measure was a change in FEV1. They also measured FVC, concentrations of IL-8 and neutrophil elastase (NE) in sputum, exercise tolerance using a 3-min step test, change in antibiotic usage, frequency of respiratory exacerbations, Pseudomonas colony counts, and quality of life. Subjects who weighed ≤ 40 kg received either a single azithromycin tablet, 250 mg, daily or matching placebo, while subjects weighing > 40 kg received either two azithromycin tablets, 250 mg (total, 500 mg), or two matching placebo tablets daily. Fifteen of the 41 subjects (36.6%) continued the established treatment with dornase alfa.

The primary end point was FEV1, which improved by 5.4% (95% confidence interval [CI], 0.8 to 0.5%) with azithromycin compared with placebo in the fourth and sixth month treatment period visits (Fig 4 ). Fifty percent of the children had an improvement in the primary end point of at least 10%. There was a suggestion that children who were homozygous for the deltaF 508 mutation did better than the rest of the group. The mechanism of benefit could not be determined, in that there was no difference in sputum bacteriology results, sputum NE levels, or IL-8 levels. The authors did not assay NE activity, which could have been inhibited by azithromycin.

A post hoc comparison of the results in the groups of subjects either taking or not taking dornase alfa was conducted on the basis of an in vitro study,45 which suggested that azithromycin inhibits this enzyme. In this subgroup analysis, the children not inhaling dornase alfa (26 patients) had an increase in FEV1 of 11.5% (95% CI, 5.3 to 16.5), whereas those who also inhaled dornase alfa

had a decrease of 3.6% (95% CI, −22 to 3.9). However, before recommending that patients taking azithromycin discontinue therapy with dornase alfa, it should be remembered that this may be a chance finding in a study not adequately powered for subgroup analysis, and so needs confirmation by other studies.

Wolter et al46 conducted a 3-month, prospective, randomized, double-blind trial of azithromycin, 250 mg daily, in 60 adults with CF. Clinically stable subjects ranging in age from 18 to 44 years were randomized to receive either azithromycin or placebo. Statistical analysis was adjusted for differences between the two groups in gender, weight, and baseline pulmonary function, but subjects were not stratified by disease severity. Monthly assessments included spirometry, body weight, sputum cultures with quantitative bacterial counts, serum C-reactive protein (CRP), and erythrocyte sedimentation rate as markers of systemic inflammation, and quality of life domains measured by the chronic respiratory disease questionnaire. The mean FEV1 and FVC were 56.6% predicted and 72.4% predicted, respectively, at the start of the study. Significant differences were measured between the azithromycin-treated and placebo-treated groups in change in FEV1 percent predicted (p = 0.047) and change in FVC percent predicted (p = 0.001). Subjects randomized to azithromycin maintained pulmonary function over the 3 months of the study, whereas patients receiving placebo had a deterioration of FEV1 percent predicted and FVC percent predicted. The azithromycin group also required fewer days of therapy with IV antibiotics (p = 0.009), fewer days at home receiving IV antibiotics (p = 0.037), and fewer courses of IV antibiotics (p = 0.016). Subjects randomized to azithromycin scored higher on improvements in dyspnea (p = 0.042), fatigue (p = 0.003), emotional (p = 0.012) and mastery domains (p = 0.035), and total scores (p = 0.035) of the chronic respiratory disease questionnaire compared with those in the placebo arm.

In the azithromycin group, the median CRP declined steadily over time, while serum levels remained relatively constant in the placebo group. In subjects who received azithromycin, the reduction in CRP strongly correlated with baseline CRP, which negatively correlated with the FEV1

percent predicted (p < 0.001). No significant between-group differences were reported in erythrocyte sedimentation rate, body mass index, bacterial types, or density. The subjects in this study represented an older CF population with more severe respiratory disease who received a relatively short course of azithromycin compared with those reported by Equi et al.44 Despite the differences in demographics and study design, both young and older subjects with CF responded to therapy with azithromycin, as reflected in the improved pulmonary function and quality of life.

In contrast to these studies, Ordonez et al47 failed to show a therapeutic benefit of macrolide therapy in a small pilot study of 10 adults (age range, 19 to 26 years) with CF and P aeruginosa infection. Subjects were treated with placebo for 3 weeks followed by 6 weeks of therapy with clarithromycin, 500 mg twice daily. Clarithromycin had no significant effect on pulmonary function, the number of neutrophils, or the concentrations of IL-8, NE, TNF-α, and myeloperoxidase in induced sputum samples. The authors suggested that the lack of effect may have been due to there being too few subjects or too short of a treatment period, leading to a type 2 error.47

The Cystic Fibrosis Foundation sponsored a large trial that was presented at the North American Cystic Fibrosis Meeting in New Orleans in 2002. The design was parallel group, with a 2-week run-in period, a 168-day treatment period, and a 28-day washout period. The dose was 500 mg if the patient’s weight was ≥ 40 kg, 250 mg if the patient’s weight was < 40 kg, and was given on 3 days in the week, with provision for stepdown to a lower dose if that dose was not tolerated. One hundred eighty-five patients were randomized, of whom 87 received azithromycin and 98 received placebo. Only one subject (in the placebo limb) did not complete the follow-up. The groups were well-matched. The mean age was 20 years, just over half were men, and the starting FEV1 was approximately 70% predicted. The results showed a treatment benefit of 0.093 L or 6.21% predicted for FEV1, and 4.95% for FVC (highly statistically significant). There was marked variation in the individual response. Approximately 12% of patients increased FEV1 by ≥ 15% while receiving azithromycin (none receiving placebo), but the conditions of some patients actually deteriorated. Any benefit was lost within 28 days of discontinuing therapy. The investigators reported a 40% reduction in infective exacerbations, but only the percentage of subjects hospitalized (patients receiving azithromycin, 16%; patients receiving placebo, 30%)

reached statistical significance. The azithromycin group gained 800 g in weight compared with the placebo group at the end of the treatment period. This is important, because some macrolides are thought to be anorexigenic. Physical functioning on a quality-of-life score improved significantly while patients received azithromycin. There were no problems with the emergence of resistant microorganisms, with more new isolates of Staphylococcus aureus appearing in the placebo group. In terms of adverse events, nausea and diarrhea were common in the azithromycin group, which was not a surprise. What was surprising is that there was more wheezing reported in the azithromycin group despite improved lung function. One might speculate that this was due to secretions mobilizing in the major airways. There was no drug toxicity, and dose reduction or study drug discontinuation was rare and equally distributed between the two groups.

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ConclusionIn nearly all reports, patients with DPB or CF who have received macrolide antibiotics have responded with dramatic improvements in pulmonary function. The treatment of DPB is the most striking example of the benefits of macrolides. Before the introduction of macrolide therapy, the 10-year survival rate was reported to be 12 to 50%,2 but since the introduction of macrolide therapy the 10-year survival rate is now > 90%. It is probable that patients with CF may realize similar benefits with long-term macrolide therapy. This is the focus for ongoing research. There is also strong clinical evidence for the effectiveness of macrolides in the treatment of bronchiectasis, chronic bronchitis, and sinusitis, as described in the review by Gotfried in this supplement.

Both in vivo and in vitro studies strongly support the immunomodulatory effects of macrolides. Further studies will determine which of the macrolides are the most effective, the duration of the effect, the long-term consequences of the long-term use of these antibiotics, and their mechanisms of action. This information may lead to the development of more specific therapeutic agents. Based on the effectiveness of macrolides for the treatment of DPB and CF, these drugs may be beneficial for the treatment of other chronic inflammatory respiratory conditions, as well as other nonrespiratory diseases such as chronic arthritis, inflammatory bowel disease, and chronic inflammatory skin conditions.

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CME QuestionsThe American College of Chest Physicians designates this continuing medical education activity for 1 credit hour in category 1 of the Physician’s Recognition Award of the American Medical Association. To obtain credit, please complete the question form at http://www.chestnet.org. Credit can be obtained ONLY through our online process.

1. Diagnostic criteria for DPB include all of the following except:

1. FEV1 < 70% and PaO2 < 80 mm Hg

2. Elevated titers of cold hemagglutinin × ≥ 64

3. Bilateral fine nodular shadow

4. Decreased sputum secretion

5. History of parasinusitis

2. Macrolides may inhibit the production of proinflammatory cytokines, which results in which of the following?

1. Reduced accumulation of neutrophils in the airway

2. Increased accumulation of neutrophils in the airway

3. Inhibition of nuclear factor-κB and activator protein-1

4. Stimulation of nuclear factor-κB and activator protein-1 production

5. Stimulation of the CF transmembrane receptor function

3. Which of the following in not a potential mechanism by which macrolides exert their effect for the treatment of DPB and CF?

1. Supression of the CF transmembrane receptor function

2. Protection from bioactive phospholipids

3. Improvement in the mucociliary and cough transportability of airway secretions

4. Expression of the ▵508 CF transmembrane receptor mutation

5. Inhibition of proinflammatory cytokines

4. Which of the following is not affected by macrolides?

1. IL-8

2. IL-1β

3. TNF-α

4. β-defensins

5. IL-2

5. Which of the following has not been shown in clinical trials of macrolides for the treatment of DPB and CF?

1. Increased sputum production

2. Increased FEV1

3. FVC

4. Increased PaO2

5. Increased quality of life

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Table 1.

Diagnostic Criteria for DPB

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Figure 1.

The survival rate of patients treated with erythromycin (group c EM+) was significantly greater than that of untreated patients (group c EM-) [p < 0.0056]. Untreated patients were not different from historical control subjects (group a) [p < 0.2475]. This figure was adapted with permission from Kudoh et al.2

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Figure 2.

Top, A: Mean FEV1 increased within 3 months of beginning clarithromycin therapy in 10 subjects with DPB. A maximal value was reached at 6 months and was sustained for 4 years. Bottom, B: The FVC increased to a maximal level within 6 months of beginning clarithromycin and was sustained for 4 years. * = p < 0.01 compared to baseline; ** = p < 0.05 compared to baseline; ## = p < 0.005 compared to baseline. This figure was adapted with permission from Kadota et al.3

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Figure 3.

Left: The level of IL-8 (mean ± SE) in the BALF of subjects with DPB was compared before and after macrolide therapy, and was compared to subjects with sarcoidosis (SAR) or healthy volunteers. Right: Correlation between the percentage of neutrophils and the levels of IL-8 in the BALF of 19 subjects with DPB (r = 0.509; p < 0.05). This figure was adapted with permission from Sakito et al.31

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Figure 4.

Left, A: Mean (95% CI) change from baseline of FEV1 in 41 children with CF who were treated with azithromycin and placebo in a crossover trial. The mean FEV1 was greater during the azithromycin arm of the trial (p = 0.031). The median relative difference between azithromycin and placebo was 5.4% (95% CI, 0.8 to 10.5). Right, B: Mean (95% CI) change from baseline visit of FVC percent predicted for each treatment period. This figure was adapted with permission from Equi et al.44

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Footnotes Abbreviations: BALF = BAL fluid; CF = cystic fibrosis; CI = confidence interval; CRP = C-

reactive protein; DPB = diffuse panbronchiolitis; IL = interleukin; NE = neutrophil elastase; TAO = troleandomycin; TNF = tumor necrosis factor

Learning objectives:

1. To be aware of the diagnostic criteria for DPB.

2. To understand the clinical evidence for the efficacy of macrolides for the treatment of DPB and CF.

3. To understand the potential immunomodulatory effects of macrolides for the treatment of chronic diseases of the airways.

4. To understand the effects of macrolides on mucus secretion.

5. To realize the immunomodulatory effects of macrolides are independent of their antimicrobial effects.

6. To realize the clinical utility of these drugs for the treatment of chronic inflammatory conditions.

Neither Dr. Rubin, nor the department(s) with which he is affiliated, has received something of value (ie, any item, payment, or service valued in excess of $750.00) from a commercial or other party related directly or indirectly to the subject of this submission. He has received research grants and honoraria, and is a consultant for Abbott Laboratories. He has also received research grants from Zambon Pharmaceuticals. Neither Dr. Henke, nor the department(s) with which he is affiliated, has received something of value (ie, any item, payment, or service valued in excess of $750.00) from a commercial or other party related directly or indirectly to the subject of this submission. This article will be presenting information about immunomodulatory uses of macrolide antibiotics that is considered research and is not yet approved for any purpose.

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