Macrolide antibiotics as immunomodulatory medications: Proposed mechanisms of action

doi:10.1016/j.pharmthera.2007.11.001

Pharmacology & Therapeutics

Volume 117, Issue 3, March 2008, Pages 393-405

https://doi.org/10.1016/j.pharmthera.2007.11.001 Get rights and content

Abstract

Macrolide antibiotics administered in sub-antimicrobial doses improve pulmonary function and decrease exacerbation frequency for persons with diffuse panbronchiolitis or cystic fibrosis. Data also suggest a beneficial effect of macrolide antibiotics in the treatment of steroid dependent asthma. Many potential immunomodulatory effects of macrolide antibiotics have been reported including the ability to down-regulate prolonged inflammation, decreasing airway mucus secretion, inhibiting bacterial biofilm, decreasing the production of reactive oxygen species, inhibiting neutrophil activation and mobilization, accelerating neutrophil apoptosis, and blocking the activation of nuclear transcription factors. Macrolides initially decrease, then increase, and have finally a sustained suppression of cytokine secretions from normal human bronchial epithelial cells through inhibition and activation of extracellular signal-regulated kinases (ERK) and then reversibly retard cell proliferation probably through ERK. Consistent with this, macrolide antibiotics possibly reduce mucin production as well as neutrophil migration by interfering with ERK signal transduction.

Introduction

The term “macrolide” encompasses a diverse family of unrelated compounds with large macrolactam rings. The macrolide antibiotics consist of 14-, 15-, and 16- member macrolactam ring antimicrobials. Erythromycin A, the prototype macrolide antibiotic was isolated from a Philippine soil sample in the 1940s and was first marketed in 1952 as an alternative therapy to beta lactam agents for the treatment of infections with Gram positive cocci. During the 1990's clarithromycin, roxithromycin, and azithromycin were introduced. Macrolide antibiotics (henceforth referred to in this manuscript as “macrolides”) inhibit RNA-dependent protein synthesis by reversibly binding to the 50S ribosomal subunit of a susceptible microorganism.

Interest in the immunomodulatory effects of macrolides began in the 1960s with the observation that the 14-member antibiotic, troleandomycin, was an effective “steroid-sparing” agent when used to treat patients with severe asthma (Spector et al., 1974). It has been more than 20 years since the immunomodulatory effects of macrolides were accepted as a standard of care for the treatment of diffuse panbronchiolitis (DPB) in Japan (Kudoh et al., 1987). Erythromycin and clarithromycin are also widely used in Japan for the therapy of sinusitis and chronic obstructive pulmonary disease (COPD) (Tamaoki et al., 1995b). In more recent years, azithromycin has been widely adopted as immunomodulatory agents for the treatment of cystic fibrosis (CF) and bronchiectasis. In this paper, we review the clinical use and proposed mechanisms of action for macrolide immunomodulation (Labro & Abdelghaffar, 2001).

Section snippets

Asthma

A Cochrane review of macrolide treatment studies in patients with chronic stable asthma identified 7 studies (including 416 patients) that met the required criteria of randomized controlled studies of macrolide therapy versus placebo of greater than 4 weeks' duration (Gotfried, 2004, Richeldi et al., 2005). There was a significant effect on symptoms and eosinophilic inflammation with macrolide therapy. There was no significant difference in FEV1 in either parallel or crossover trials. However,

Rhinosinusitis

Macrolides have been used to treat chronic rhinosinusitis in persons with or without lower respiratory disease (Hatipoglu & Rubinstein, 2005) and it is thought that this is primarily due to an ability to modulate chronic inflammation (Cervin & Wallwork, 2005).

In a recent double-blind, randomized, placebo-controlled clinical trial low-dose of roxithromycin or placebo for 3 months in 64 subjects with chronic rhinosinusitis there were statistically significant improvements in the Sinonasal Outcome

Mechanisms of action for macrolide immunomodulatory effects

The proposed immunomodulatory effects of macrolides are summarized in Fig. 2. Low-dose macrolides are reported to have a broad array of effects on the immune system and on inflammation. Depending on the system studied these reported effects include the ability to suppress the production and secretion of proinflammatory cytokines, suppress iNOS-mediated NO production, decrease mucus synthesis and secretion, promote inflammatory cell apoptosis, decrease the production of nuclear transcription

Conclusion

Low-dose, long-term macrolide therapy, is the first line of therapy for DPB and is now recommended for treating CF lung disease. Data support a role for macrolide therapy in patients with chronic sinusitis with or without polyps and in patients with severe, steroid dependent asthma. Macrolides have a variety of immunomodulatory effects that differ from classic immunosuppression. Accumulating evidence supports the hypothesis that this immunomodulation is mediated, at least in part, by sequential

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Macrolides (MCs) are broad-spectrum antimicrobials with activity against many microorganisms. They are widely used, and the development of MC-resistant bacteria is a serious problem in Japan. It is therefore necessary to clarify the purpose and duration of administration, with the aim of promoting appropriate use.
Patients of all ages, for whom oral MCs were prescribed between 2016 and 2020 were included. They were divided into four groups based on the number of days per prescription. In the long-term treatment group, patients treated with MCs for ≥1000 days were specifically investigated for the purpose of treatment.
Macrolide prescriptions increased from 2019 to 2020. Most patients received ≥28 days of treatment based on one prescription. During the study period, 1212 patients (28.6%) received a total of ≥50 days and 152 patients (3.6%) received a total of ≥1000 days of treatment. Approximately a third of long-term administrations were for nontuberculous mycobacterial infections (NTMs), and 18.3% of patients with NTMs were treated with MCs alone. In addition, many MCs were administered for their anti-inflammatory effects on neutrophils.
Owing to their pleiotropic effects, MCs may also be administered for the treatment of noninfectious diseases. In general, the long-term administration of antimicrobials contradicts the strategy for the suppression of resistant bacteria. It is thus important to understand the actual clinical utility of MCs and the purpose and duration of administration. In addition, strategies for the appropriate use of MCs are required for each medical institution.
Azithromycin in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial
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Azithromycin has been proposed as a treatment for COVID-19 on the basis of its immunomodulatory actions. We aimed to evaluate the safety and efficacy of azithromycin in patients admitted to hospital with COVID-19.
In this randomised, controlled, open-label, adaptive platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]), several possible treatments were compared with usual care in patients admitted to hospital with COVID-19 in the UK. The trial is underway at 176 hospitals in the UK. Eligible and consenting patients were randomly allocated to either usual standard of care alone or usual standard of care plus azithromycin 500 mg once per day by mouth or intravenously for 10 days or until discharge (or allocation to one of the other RECOVERY treatment groups). Patients were assigned via web-based simple (unstratified) randomisation with allocation concealment and were twice as likely to be randomly assigned to usual care than to any of the active treatment groups. Participants and local study staff were not masked to the allocated treatment, but all others involved in the trial were masked to the outcome data during the trial. The primary outcome was 28-day all-cause mortality, assessed in the intention-to-treat population. The trial is registered with ISRCTN, 50189673, and ClinicalTrials.gov, NCT04381936.
Between April 7 and Nov 27, 2020, of 16 442 patients enrolled in the RECOVERY trial, 9433 (57%) were eligible and 7763 were included in the assessment of azithromycin. The mean age of these study participants was 65·3 years (SD 15·7) and approximately a third were women (2944 [38%] of 7763). 2582 patients were randomly allocated to receive azithromycin and 5181 patients were randomly allocated to usual care alone. Overall, 561 (22%) patients allocated to azithromycin and 1162 (22%) patients allocated to usual care died within 28 days (rate ratio 0·97, 95% CI 0·87–1·07; p=0·50). No significant difference was seen in duration of hospital stay (median 10 days [IQR 5 to >28] vs 11 days [5 to >28]) or the proportion of patients discharged from hospital alive within 28 days (rate ratio 1·04, 95% CI 0·98–1·10; p=0·19). Among those not on invasive mechanical ventilation at baseline, no significant difference was seen in the proportion meeting the composite endpoint of invasive mechanical ventilation or death (risk ratio 0·95, 95% CI 0·87–1·03; p=0·24).
In patients admitted to hospital with COVID-19, azithromycin did not improve survival or other prespecified clinical outcomes. Azithromycin use in patients admitted to hospital with COVID-19 should be restricted to patients in whom there is a clear antimicrobial indication.
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Citation Excerpt :
The paper reported that although DPB is not rare in China, it remains under-diagnosed and misinterpreted. Similarly, another review article summarizing the immunomodulatory effect of macrolide antibiotics was published by [35]. Only 83 articles were published after 2011 up to the time of this writing.
Given the well documented and undesired impact of diffuse panbronchiolitis (DPB), there is a need to create a statistical inventory of research output on DPB. The aim of this study was to identify and analyze different trends in publication over time, with technological additions.
Articles indexed in MEDLINE regarding DPB were retrieved using PubMed. Citation results were categorized by article type, year of publication, language, and country.
A total of 657 publications, published between 1969 and 2017 were retrieved from PubMed; the year with the highest number of articles published was 1992 (n = 32). Japan accounted for 68.34% (n = 449) publications, followed by the United States of America (USA; 6.70%, n = 44) and China (5.48%, n = 36). English (n = 401) was the most commonly used language in the publications, followed by Japanese (n = 223) and Chinese (n = 16). Articles were published in 218 different journals; The Japanese Journal of Thoracic Diseases published the maximum number of articles, accounting for 13.7% (n = 90) citations. Sugiyama Y was the most productive author and contributed to 12 publications.
This was the first bibliometric analysis of DPB. Between 1991 and 2000, the number of publications on DPB literature reached a peak, and although the frequency of publication has decreased recently, the quantity of DPB research during the past 48 years is adequate and satisfactory. Overall, the publications on DPB have undergone exponential growth over the last 30 years.
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Kaempferol is believed to exert these effects by moderating Janus activated kinase/signal transducers and activators of transcription (JAK/STAT) signaling, culminating in the disruption of NF-κB activation (Gong et al., 2012). Macrolide antibiotics including clarithromycin and rapamycin have been used on the basis of their immunosuppressive activity, to attenuate the symptoms of chronic airways disease (Essilfie et al., 2015; Gibson et al., 2017; Mushaben et al., 2011; Shinkai, Henke, & Rubin, 2008). In addition to reductions in airway hyperreactivity, cytokine secretion and airway inflammation, a decrease in goblet cell number is consistently observed following macrolide antibiotic treatment following allergen exposure (Mushaben et al., 2011; Nagashima et al., 2016).
Dysregulated induction of goblet cell differentiation results in excessive production and retention of mucus and is a common feature of several chronic airways diseases. To date, therapeutic strategies to reduce mucus accumulation have focused primarily on altering the properties of the mucus itself, or have aimed to limit the production of mucus-stimulating cytokines. Here we review the current knowledge of key molecular pathways that are dysregulated during persistent goblet cell differentiation and highlights both pre-existing and novel therapeutic strategies to combat this pathology.
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Macrolide antibiotics as immunomodulatory medications: Proposed mechanisms of action

Abstract

Introduction

Section snippets

Asthma

Rhinosinusitis

Mechanisms of action for macrolide immunomodulatory effects

Conclusion

Interleukin-8 gene repression by clarithromycin is mediated by the activator protein-1 binding site in human bronchial epithelial cells

Am J Respir Cell Mol Biol

Antibiotic cyclic AMP signaling by “primed” leukocytes confers anti-inflammatory cytoprotection

J Leukoc Biol

Early stimulation and late inhibition of extracellular signal-regulated kinase 1/2 phosphorylation by IGF-I: a potential mechanism mediating the switch in IGF-I action on skeletal muscle cell differentiation

Endocrinology

Effects of roxithromycin on adhesion molecules expressed on endothelial cells of the dermal microvasculature

J Int Med Res

Steroid-resistant asthma: immunologic and pharmacologic features

J Allergy Clin Immunol

Studies on the effects of ingestion of a single 500 mg oral dose of erythromycin stearate on leukocyte motility and transformation and on release in vitro of prostaglandin E2 by stimulated leucocytes

J Antimicrob Chemother

Erythromycin inhibits transcriptional activation of NF-kappa B, but not NFAT, through calcineurin-independent signaling in T cells

Antimicrob Agents Chemother

Erythromycin shortens neutrophil survival by accelerating apoptosis

Antimicrob Agents Chemother

Modulation of Th2 type cytokine production from human peripheral blood leukocytes by a macrolide antibiotic, roxithromycin, in vitro

Int Immunopharmacol

Elevated concentrations of defensins in bronchoalveolar lavage fluid in diffuse panbronchiolitis

Eur Respir J

The effect of azithromycin on reactive oxygen species in rosacea

Clin Exp Dermatol

Effect of low-dose troleandomycin on glucocorticoid pharmacokinetics and airway hyperresponsiveness in severely asthmatic children

Ann Allergy

Buccal adherence of Pseudomonas aeruginosa in patients with cystic fibrosis under long-term therapy with azithromycin

Infection

Lipopolysaccharide activation of the TPL-2/MEK/extracellular signal-regulated kinase mitogen-activated protein kinase cascade is regulated by Ikappa B kinase-induced proteolysis of NF-kappaB1 p105

Mol Cell Biol

Antibiotics in asthma

Curr Allergy Asthma Rep

Increased frequency of detection of Chlamydia pneumoniae in asthma

Eur Respir J

Trial of roxithromycin in subjects with asthma and serological evidence of infection with Chlamydia pneumoniae

Am J Respir Crit Care Med

Diffuse panbronchiolitis in an Asian immigrant

Thorax

Cytokines, chaos, and complexity

Immunity

A constitutive active MEK ® ERK pathway negatively regulates NF-kappa B-dependent gene expression by modulating TATA-binding protein phosphorylation

J Biol Chem

Anti-inflammatory effects of macrolide antibiotics in the treatment of chronic rhinosinusitis

Otolaryngol Clin North Am

Bradykinin B2 receptor mediates NF-kappa B activation and cyclooxygenase-2 expression via the Ras/Raf-1/ERK pathway in human airway epithelial cells

J Immunol

Azithromycin modulates neutrophil function and circulating inflammatory mediators in healthy human subjects

Eur J Pharmacol

Molecular mechanisms of anti-inflammatory action of erythromycinin human bronchial epithelial cells: possible role in the signaling pathway that regulates nuclear factor-kappaB activation

Antimicrob Agents Chemother

Erythromycinsuppresses nuclear factor-kappa B and activator protein-1 activation in human bronchial epithelial cells

Biochem Biophys Res Commun

Signaling by the JNK group of MAP kinases. c-jun N-terminal Kinase

J Clin Immunol

Long term azithromycin in children with cystic fibrosis: a randomised, placebo-controlled crossover trial

Lancet

Evaluation of the anti-inflammatory effect of erythromycin on aseptic inflammation of temporomandibular joint in rabbit: a scintigraphic and histopathologic study

Dent Traumatol

Roxithromycin, clarithromycin, and azithromycin attenuate the injurious effects of bioactive phospholipids on human respiratory epithelium in vitro

Inflammation

Diffuse panbronchiolitis in the United States

Am J Respir Crit Care Med

Benefits and complications of troleandomycin (TAO) in young children with steroid-dependent asthma

Pediatr Pulmonol

Erythromycin suppresses the expression of cyclooxygenase-2 in rheumatoid synovial cells

J Rheumatol

Long-term clarithromycin decreases prednisone requirements in elderly patients with prednisone-dependent asthma

Chest

The biology of nitrogen oxides in the airways

Am J Respir Crit Care Med

Erythromycin inhibits respiratory glycoconjugate secretion from human airways in vitro

Am Rev Respir Dis

Macrolides for the treatment of chronic sinusitis, asthma, and COPD

Chest