Tissue reparative effects of macrolide antibiotics in chronic inflammatory sinopulmonary diseases

It 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.     

Efficacy and Safety of Long-Term Antibiotics (Macrolides) for the Treatment of Chronic Rhinosinusitis

Long-term treatment of airway inflammation/infection with macrolide antibiotics has now been in use for almost 30 years. Whereas the beneficial clinical effect in cystic fibrosis and COPD have been backed up by randomized controlled trials, the evidence from the upper airways is not as strong. We have identified 22 open studies in chronic rhinosinusitis, with and without polyps, but only 2 randomized controlled trials. Of the controlled trials, the one including CRS patients just without polyps, showed a significant effect in sino-nasal outcome test, saccharine transit time, nasal endoscopy, and IL-8 levels in lavage fluid after 12 weeks of roxithromycin, whereas, in the other RCT with a mixed study group of CRS patients with and without polyps, 12 weeks of azithromycin showed no effect compared to placebo. Concerns regarding the risk of macrolides to induce arrhythmia have been raised. Recent FDA guidelines changes has recommended caution in patients with risk factors such as long QT syndrome, bradycardia, hypokalemia, or hypomagnesemia. Ototoxicity is another concern. Long-term macrolide antibiotics in the treatment of CRS patients is still a viable option in a select group of patients.     

Inhibitory effects of 14-membered ring macrolide antibiotics on bleomycin-induced acute lung injury

14-membered ring macrolides have been reported to have anti-inflammatory effects and to decrease neutrophil infiltration into the airways in chronic lower respiratory tract diseases. This study investigated the potential inhibitory effects of macrolide antibiotics on bleomycin-induced acute lung injury. Four drugs were studied: two 14-membered ring macrolides, clarithromycin (CAM) and roxithromycin (RXM); a 15-membered ring macrolide, azithromycin (AZM); and a 16-membered ring macrolide, josamycin (JM). Their effects were compared with macrolide untreated, pretreated, and post-treated groups. An acute lung injury was inhibited by pretreatment with CAM or RXM, which significantly ameliorated the bleomycin-induced increases in the total cell and neutrophil counts in bronchoalveolar lavage (BAL) fluids and the wet lung weight. The pretreatment with CAM or RXM also suppressed inflammatory cell infiltration and interstitial lung edema in the histopathological study. These inhibitory effects were associated with a decreased KC concentration in the BAL fluid and a decreased number of apoptotic cells in the lungs. Posttreatment with CAM or RXM had no marked inhibitory effects. Pretreatment with AZM was much less effective, and JM showed no inhibitory effects. These findings suggest that 14-membered ring macrolides have different effects on inflammatory lung disease than 15- and 16-membered ring macrolides and may be therapeutic agents for acute lung injury and pulmonary fibrosis.     

Anti-inflammatory treatment of chronic rhinosinusitis: A shifting paradigm

Treatment of chronic rhinosinusitis still represents an unmet medical need. Presently, the US Food and Drug Administration has not approved any drugs for the treatment of this common condition. Various inflammatory processes are involved in the pathogenesis of chronic rhinosinusitis. Treatment of infection and surgical intervention for correction of anatomical abnormalities often are inadequate in management when singly employed. Anti-inflammatory therapy such as topical cortico-steroids and more recently long-term, low-dose macrolide therapy have been integrated into the treatment algorithm for chronic rhinosinusitis. Better classification and point-of-care identification of inflammatory features may improve choice of anti-inflammatory therapy and thus outcome.     

Anti-inflammatory treatment of chronic rhinosinusitis: A shifting paradigm

Treatment of chronic rhinosinusitis still represents an unmet medical need. Presently, the US Food and Drug Administration has not approved any drugs for the treatment of this common condition. Various inflammatory processes are involved in the pathogenesis of chronic rhinosinusitis. Treatment of infection and surgical intervention to correct anatomic abnormalities often are inadequate in management when singly employed. Anti-inflammatory therapy such as topical corticosteroids and more recently long-term, low-dose macrolide therapy has been integrated into the treatment algorithm for chronic rhinosinusitis. Better classification and point-of-care identification of inflammatory features may improve choice of anti-inflammatory therapy and thus outcome.     

Antimicrobial therapy in chronic rhinosinusitis

Antimicrobial therapy has been a mainstay of treatment for chronic rhinosinusitis (CRS). The roles of bacterial and fungal infection in the primary pathogenesis of CRS recently have been called into question. Although many different bacteria and fungi can be isolated from CRS patients, antimicrobial treatment directed at their eradication has met with mixed clinical results. Overall, macrolide antibiotics hold the most promise before surgery. Topical antibiotics are safe, efficient, and effective for treating acute bacterial exacerbations of CRS after endoscopic sinus surgery and may prevent the development of subsequent bacterial resistance. Topical treatment of CRS with antifungal agents both before and after sinus surgery is of limited benefit and should not be considered as a primary treatment modality before surgery. Further research into the role of bacterial and fungal infection in the pathophysiology of CRS may offer better insights into appropriate antimicrobial choices, dosing, and treatment duration.     

Asthma and atypical bacterial infection

A growing body of basic and clinical science implicates the atypical bacterial pathogens Mycoplasma pneumoniae and Chlamydophila (formerly Chlamydia) pneumoniae as potentially important factors in asthma, although their exact contribution to asthma development and/or persistence remains to be determined. Evidence from human studies links both M pneumoniae and C pneumoniae to new-onset wheezing, exacerbations of prevalent asthma, and long-term decrements in lung function, suggesting that these organisms can play an important role in the natural history of asthma. Furthermore, animal models of acute and chronic infection with these organisms indicate that they have the ability to modulate allergic sensitization and pulmonary physiologic and immune response to allergen challenge. These findings raise the possibility that, in at least some individuals with asthma, antibiotic therapy might have a role in long-term treatment. While antibiotics do not currently have a defined role in the treatment of stable patients with chronic asthma, there is emerging evidence that asthma symptoms and biomarkers of airway inflammation can improve when patients who have atypical bacterial infection as a cofactor in their asthma are treated with macrolide antibiotics. Ongoing research into the importance of atypical pathogens in asthma will further elucidate whether these infections are important in disease development or whether their prevalence is increased in asthmatic subjects due to chronic airway inflammation or other, yet unidentified, predisposing factors. Current studies will further define the role of macrolide antibiotics in the treatment of stable patients with asthma, ultimately determining whether these therapeutic agents have a place in asthma management.     

Effect of a short course of clarithromycin therapy on sputum production in patients with chronic airway hypersecretion

STUDY OBJECTIVE: Long-term administration of macrolide antibiotics reduces sputum production in patients with chronic airway diseases, probably by inhibiting airway inflammation. The objective of the present study was to determine the acute effects of a macrolide on airway chloride secretion and sputum production. METHODS: We first investigated the effect of erythromycin treatment on chloride diffusion potential difference (CPD) across tracheal mucosa in vivo. Next, we conducted a double-blind, parallel-group study examining the effect of 7 days of treatment with clarithromycin (400 mg/d), amoxicillin (1,500 mg/d), or cefaclor (750 mg/d) in patients with chronic bronchitis or bronchiectasis without apparent respiratory infection. RESULTS: IV administration of erythromycin decreased the CPD of rabbit tracheal mucosa in a dose-dependent manner. Treatment of patients with clarithromycin decreased sputum production, whereas amoxicillin and cefaclor treatment had no effect. The percentage of patients whose sputum decreased > 30% from baseline (responders) was 38% in the clarithromycin group, 7% in the amoxicillin group, and 0% in the cefaclor group. During treatment with clarithromycin, the sputum solid composition increased and chloride concentration decreased in responders, but these changes were not observed in nonresponders. CONCLUSION: Short-term administration of 14-membered macrolide reduces chronic airway hypersecretion, presumably by inhibiting chloride secretion and the resultant water secretion across the airway mucosa.     

The clinical effectiveness of aspirin desensitization in chronic rhinosinusitis

Aspirin-exacerbated respiratory disease (AERD) is a chronic inflammatory disease characterized by chronic rhinosinusitis, nasal polyposis, asthma, and airway reactivity to aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs). For patients who have inadequately controlled rhinosinusitis and/or asthma despite treatment with topical corticosteroids and leukotriene-modifying drugs, aspirin desensitization is an important therapeutic option. This review examines the evidence supporting the effectiveness of aspirin desensitization for the treatment of chronic rhinosinusitis in patients with AERD. Practical aspects of conducting safe aspirin desensitization procedures and optimizing therapeutic benefits are also reviewed. When conducted in accordance with current guidelines, aspirin desensitization is a safe procedure that allows patients with AERD who have an indication for aspirin or other NSAIDs to safely ingest these medications. There is now strong evidence that aspirin desensitization and daily aspirin therapy is effective for treatment of the chronic inflammatory disease of the upper airway and lower airways in AERD.     

Effects of macrolide antibiotics against mucoid Pseudomonas aeruginosa

Macrolide antibiotics at concentrations by far lower than their MICs proved to inhibit the production of alginate, elastase, and protease by mucoid Pseudomonas aeruginosa. The morphological study of mucoid P. aeruginosa under the electron microscope revealed the slime-like structures common to the cell morphology of the organism in cultured colonies and foci in a model for respiratory tract infection in mice, and the strains of mucoid P. aeruginosa which had been allowed to get in contact with the drugs proved to produced obviously fewer slime-like structures than control strains. The effect of a 14-membered macrolide, erythromycin, against mucoid P. aeruginosa was also observed with a 16-membered macrolide, rokitamycin this effect appeared to be common to the macrolide.     

Diagnosis and Management of Rhinosinusitis: Highlights from the 2015 Practice Parameter

Rhinosinusitis is a commonly diagnosed disease in the USA. Rhinosinusitis is classified as acute, recurrent, or chronic (with or without nasal polyps). While acute rhinosinusitis is diagnosed by history and physical examination, chronic rhinosinusitis and recurrent acute rhinosinusitis are diagnosed based on symptoms and the presence of disease on either a sinus CT scan and/or endoscopy. Management of uncomplicated acute rhinosinusitis includes analgesics, saline irrigation, and/or intranasal steroids. Antibiotics and intranasal steroids are recommended for acute bacterial rhinosinusitis. Intranasal and oral steroids with antibiotics are recommended to treat chronic rhinosinusitis although the evidence for antibiotics is weak. Biologics such as omalizumab and mepolizumab are being investigated for the treatment of chronic rhinosinusitis with nasal polyps. Surgery may be indicated in management of refractory chronic rhinosinusitis and rarely for acute bacterial rhinosinusitis. This review discusses highlights of the updated 2014 practice parameter and up-to-date evidence from other literature sources.     

Diffuse panbronchiolitis

Diffuse panbronchiolitis (DPB) is characterized by chronic airway infection with diffuse bilateral micronodular pulmonary lesions. DPB is mainly distributed in east Asian people. Studies on causes of the disease point to a genetic predisposition unique to Asians. The advent of low-dose, long-term macrolide therapy has changed disease prognosis. The mechanism of action is attributed to anti-inflammatory actions of 14-membered and 15-membered ring macrolides. Recently, the success of macrolide therapy in DPB has extended its application to the treatment of other chronic airway inflammatory diseases.     

The benefits of long-term systemic antimicrobial therapy in chronic obstructive pulmonary disease

Acute exacerbations of chronic obstructive pulmonary disease (AECOPD) are major contributors to the morbidity and mortality associated with this disease. Current approaches that likely reduce chronic obstructive pulmonary disease (COPD) exacerbations include smoking cessation, influenza and pneumococcal vaccinations, long-acting bronchodilator and inhaled corticosteroid therapy, pulmonary rehabilitation, and mucolytic drugs. However, with optimal treatment using all of these modalities, we are only able to reduce exacerbations by about 40%. A significant proportion of COPD exacerbations are bacterial, therefore long-term antimicrobial therapy could have a role in preventing exacerbations. Long-term antibiotic treatment in COPD regimens that are being evaluated include low-dose macrolide therapy, pulsed fluoroquinolone administration and the use of inhaled antibiotics. Although initial results have been promising with significant reductions in exacerbations with these regimens, additional studies are required to identify the appropriate patient and regimen and elucidate the risk-benefit as well as cost effectiveness of long-term antibiotics in COPD.     

Macrolides in the treatment of asthma and cystic fibrosis

Asthma and cystic fibrosis are two respiratory diseases characterized by chronic inflammation, leading to remodelling of the airways. Macrolides are widely used antibiotics, with a peculiar anti-inflammatory effect. On the basis of the methodologies used by the Cochrane collaboration, this review discusses the evidence for their long-term use as anti-inflammatory agents in these two diseases. Three randomized-controlled trials (RCTs) were identified for both asthma and cystic fibrosis. A positive effect of macrolides on reducing eosinophil numbers and markers of eosinophilic inflammation was demonstrated in patients with asthma. Data on cystic fibrosis demonstrated an effect on lung function with an increase of 5.4% in forced vital capacity (FVC) in patients treated with macrolide vs. placebo, but without a significant effect on FEV1. Side-effects were rare, mild and reversible on withdrawal of treatment. Although preliminary data from small studies are promising, the role of macrolides in the treatment of these chronic disorders needs to be more firmly established with larger, well-designed trials, targeted to investigate major clinical outcomes.     

Ribosomal resistance: Emerging problems and potential solutions

Many systemic antibiotics use ribosomal inhibition to suppress the replication of bacteria. Current research suggests that resistance to macrolide, lincosamide, and streptogramin B (MLS_B) antibiotics is emerging among clinical isolates of Streptococcus pyogenes and Streptococcus pneumoniae. Erythromycin methylases, encoded by erm genes, modify an essential adenine residue in 23S rRNA and confer cross-resistance to MLS_B antibiotics. More recently, macrolide efflux (mef) genes were identified in isolates of S. pyogenes and S. pneumoniae that show resistance to 14- and 15-membered macrolides (M phenotype). Resistance to MLSB has been associated with the increased use of erythromycin, and the recent emergence of the M phenotype has coincided with the marketing of newer macrolides. However, despite increasing macrolide resistance among clinical isolates of S. pneumoniae, convincing data on treatment failures directly attributable to MLSB or M phenotypes are limited. Possible solutions to emerging MLS_B and M phenotype resistance include the introduction of alternative antibiotics, the more prudent use of antibiotics, combination therapy, molecular diagnostics, enhanced understanding of pharmacodynamic variables, and redefined resistance breakpoints.     

Macrolides in cystic fibrosis

Macrolide antibiotics have been licensed since the 1950s and have an important role in the treatment of a diverse range of infectious diseases. Macrolide antibiotics have antibacterial activity against gram-positive bacteria, some gram-negative bacteria and intracellular pathogens. The spectrum of antibacterial activity combined with excellent intracellular and tissue penetration has led to the extensive use of this class of drugs in respiratory disease. Macrolide antibiotics also have demonstrated anti-inflammatory properties in various in vitro and in vivo model systems. Novel antimicrobial and anti-inflammatory properties of macrolide may result in clinical benefits, particularly in conditions where the infectious agent is inherently resistant to macrolides. Three randomized control trials have demonstrated improved lung function in patients treated with the macrolide antibiotic, azithromycin. Azithromycin was generally well tolerated and resulted in reduction in the inflammatory response which may be due to an immunomodulatory role. Short term studies (three to six months) have not demonstrated the development of increased bacterial resistance or the emergence of new pathogens following azithromycin.     

Judicious antibiotic use and intranasal corticosteroids in acute rhinosinusitis

Most patients with symptoms of acute rhinosinusitis are treated with antibiotics. However, many cases of rhinosinusitis are secondary to viral infections and unlikely to benefit from antibiotic therapy. Inappropriate use of antibiotics in patients with acute nonbacterial rhinosinusitis contributes to the increase in bacterial antibiotic resistance. Consequently, safe and effective alternatives to antibiotics are needed in the treatment of acute rhinosinusitis caused by viral infections. Recent results from controlled trials have shown that intranasal corticosteroids, used in combination with antibiotics or as monotherapy in selected cases, provide significant symptom relief and resolution of acute rhinosinusitis. The use of intranasal corticosteroids in acute rhinosinusitis therefore might reduce the inappropriate use of antimicrobial therapy in acute rhinosinusitis.     

Management of Chronic Rhinosinusitis in Asthma Patients: Is There Still a Debate?

The united airway concept in which upper and lower respiratory conditions are present in one patient requires special consideration. There is some evidence linking chronic rhinosinusitis and asthma, but a good understanding of the pathophysiology and combined management is still lacking, a fact that leads to discussion. Bronchial asthma is more prevalent in patients who suffer chronic rhinosinusitis. On the other hand, patients with asthma have a greater prevalence of rhinosinusitis than patients without asthma. The effect of chronic rhinosinusitis in patients with or without nasal polyps on asthma treatment, whether medical or surgical, is controversial. Some studies show worsening, other trials improvement, and others no effect. Direct comparisons between surgical and medical treatments are few. Most of the current literature available about this intriguing combination does not provide a good level of evidence. Thus, randomized clinical trials should be performed to better understand the management when asthma and CRS occur together. This review aims to summarize the current state of this association regarding the effects of different types of treatment.     

大环内酯类抗生素治疗成人支气管哮喘临床疗效观察

目的探讨大环内酯类抗生素在治疗成人支气管哮喘中的临床疗效。方法将52例成人支气管哮喘患者进行随机分组，分别加用大环内酯类抗生素（治疗组）或青霉素类抗生素（对照组）治疗对比疗效。结果两组肺功能和临床症状均获得改善，其中治疗组控制优于对照组。结论大环内酯类抗生素在治疗成人支气管哮喘中疗效确切。     

Anti-inflammatory effects of macrolides in lung disease

During the past five decades there has been increasing interest in the potential anti-inflammatory effects of macrolide antibiotics. Low-dose macrolide therapy has dramatically increased survival in patients with diffuse panbronchiolitis, a disease with many similarities to cystic fibrosis (CF). This has led to further investigation into the potential use of macrolides in chronic lung diseases with an inflammatory component. This review summarizes the proposed anti-inflammatory mechanisms for this group of antibiotics, and examines the effect of macrolides on modulation of the inflammatory pathways, neutrophil function, bronchoconstriction, Pseudomonas biofilm, mucus rheology, bacterial adherence, and multidrug-resistant protein. It discusses the current status of clinical studies in children with CF, bronchiectasis, and asthma. While there are much in vitro data for different proposed anti-inflammatory effects, randomized controlled clinical trials in children with CF, bronchiectasis, and asthma are still just beginning. The benefits and potential side effects need to be determined before routine use can be advised.