Long-term macrolide treatment for chronic respiratory disease

Spagnolo, Paolo; Fabbri, Leonardo M.; Bush, Andrew

doi:10.1183/09031936.00136712

Cited by 126 publications

(88 citation statements)

References 127 publications

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“…acrolide antibiotics (for example, erythromycin, azithromycin, and clarithromycin) have caught interest for use in the treatment of chronic airway inflammation (1). Reduction of pulmonary exacerbations has been demonstrated in cystic fibrosis (CF) and chronic obstructive pulmonary disease (COPD) (2,3).…”

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confidence: 99%

The Nonantibiotic Macrolide EM703 Improves Survival in a Model of Quinolone-Treated Pseudomonas aeruginosa Airway Infection

Kasetty

Bhongir

Papareddy

et al. 2017

Antimicrob Agents Chemother

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Macrolide antibiotics are used as anti-inflammatory agents, e.g., for prevention of exacerbations in chronic obstructive pulmonary disease and cystic fibrosis. Several studies have shown improved outcomes after the addition of macrolides to ␤-lactam antibiotics for treatment of severe community-acquired pneumonia. However, a beneficial effect of macrolides in treating Gram-negative bacterial airway infections, e.g., those caused by Pseudomonas aeruginosa, remains to be shown. Macrolide antibiotics have significant side effects, in particular, motility-stimulating activity in the gastrointestinal tract and promotion of bacterial resistance. In this study, EM703, a modified macrolide lacking antibiotic and motility-stimulating activities but with retained anti-inflammatory properties, was used as an adjunct treatment for experimental P. aeruginosa lung infection, in combination with a conventional antibiotic. Airway infections in BALB/cJRj mice were induced by nasal instillation of P. aeruginosa; this was followed by treatment with the quinolone levofloxacin in the absence or presence of EM703. Survival, inflammatory responses, and cellular influx to the airways were monitored. Both pretreatment and simultaneous administration of EM703 dramatically improved survival in levofloxacin-treated mice with P. aeruginosa airway infections. In addition, EM703 reduced the levels of proinflammatory cytokines, increased the numbers of leukocytes in bronchoalveolar lavage fluid, and reduced the numbers of neutrophils present in lung tissue. In summary, the findings of this study show that the immunomodulatory properties of the modified macrolide EM703 can be important when treating Gram-negative pneumonia, as exemplified by P. aeruginosa infection in this study.KEYWORDS macrolide, EM703, host defense, anti-inflammatory, Pseudomonas aeruginosa M acrolide antibiotics (for example, erythromycin, azithromycin, and clarithromycin) have caught interest for use in the treatment of chronic airway inflammation (1). Reduction of pulmonary exacerbations has been demonstrated in cystic fibrosis (CF) and chronic obstructive pulmonary disease (COPD) (2, 3). Macrolides display broad biological responses, including bacteriostatic activity, stimulation of gastrointestinal motility, and anti-inflammatory properties (4-6). Each of these effects could be advantageous, depending on the clinical context; however, promotion of drug-resistant bacteria and diarrhea limit the clinical use of macrolides as anti-inflammatory agents.In severe community-acquired pneumonia, which is often caused by the Grampositive coccus Streptococcus pneumoniae, meta-analyses have shown that the addition of a macrolide antibiotic to a ␤-lactam has beneficial effects, reducing mortality rates (7-9). Pneumonia caused by Gram-negative bacteria, in particular, Pseudomonas aerugi-

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confidence: 99%

The Nonantibiotic Macrolide EM703 Improves Survival in a Model of Quinolone-Treated Pseudomonas aeruginosa Airway Infection

Kasetty

Bhongir

Papareddy

et al. 2017

Antimicrob Agents Chemother

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“…Many new treatments for COPD have been recently released or are about to be launched [11][12][13][14]. They include mostly new LABD, ICS and various combinations of these agents.…”

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Real-life use of long-acting antimuscarinic agents following their approval for COPD treatment

et al. 2014

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Chronic obstructive pulmonary disease (COPD) pharmacological treatment aims to reduce symptoms, represented mostly by dyspnoea and its impact on daily life, and future risk, i.e. lung function decline, mortality and exacerbations [1]. Inhaled therapies, including long-acting bronchodilators (LABD) and inhaled corticosteroids (ICS), are the main treatments recommended for COPD patients. LABD have been found not only to improve lung function, decrease dyspnoea, increase exercise tolerance and improve health status, but also to reduce the rate of exacerbations. In that respect, some studies suggested that long-acting antimuscarinic agents (LAMA) could be more effective than long-acting β 2 -agonists (LABA) [2]. In most countries, ICS are indicated only as part of fixed-dose combinations (FDC) with LABA and are used mostly to decrease the risk of exacerbations, which is associated with health status improvement [3]. Therefore, it appeared logical to restrict their use to patients at high risk of exacerbations. The long-term benefit of combining LAMA and FDC (triple therapy) is not strongly documented [4].

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“…Azithromycin significantly reduces airway neutrophilia and interleukin-8 mRNA expression [17]. The anti-inflammatory and immunomodulatory activity of macrolides purportedly contribute to their successful use as therapeutic agents for chronic lung diseases, including cystic fibrosis and diffuse panbronchiolitis [18].…”

Section: Discussionmentioning

confidence: 99%

Macrolides Are Associated with a Better Survival Rate in Patients Hospitalized with Community-Acquired But Not Healthcare-Associated Pneumonia

McEvoy

Micek²,

Reichley³

et al. 2014

Surgical Infections

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"Macrolides are associated with a better survival rate in patients hospitalized with community-acquired but not healthcareassociated pneumonia. " Surgical Infections.15,3. 283-289. (2014 Background: Macrolide-based treatment has been associated with survival benefit in patients hospitalized with community-acquired pneumonia (CAP). However, the influence of macrolide therapy in all patients hospitalized with pneumonia, including healthcare-associated pneumonia (HCAP), is unclear.Methods: Analysis of a retrospective single-center cohort.Results: Community-acquired pneumonia was present in 220 (22.5%) of all patients with pneumonia admitted through the emergency department of Barnes-Jewish Hospital, and HCAP was present in 757. Macrolide-based treatment was administered to 411 patients (42.1%). These patients were more likely to have CAP than were patients not receiving macrolide-based therapy (35.3% vs. 13.3%; p < 0.001) and had lower scores on the CURB-65 tool, a measure of the severity of illness (2.4 -1.5 vs. 3.1 -1.3; p < 0.001). Patients receiving macrolides also had a lower hospital mortality rate in univariable analysis (12.7% vs. 27.2%; p < 0.001). A propensity score analysis showed that macrolide-based treatment was associated with a lower in-hospital mortality rate (adjusted odds ratio [

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Long-term macrolide treatment for chronic respiratory disease

Cited by 126 publications

References 127 publications

The Nonantibiotic Macrolide EM703 Improves Survival in a Model of Quinolone-Treated Pseudomonas aeruginosa Airway Infection

The Nonantibiotic Macrolide EM703 Improves Survival in a Model of Quinolone-Treated Pseudomonas aeruginosa Airway Infection

Real-life use of long-acting antimuscarinic agents following their approval for COPD treatment

Macrolides Are Associated with a Better Survival Rate in Patients Hospitalized with Community-Acquired But Not Healthcare-Associated Pneumonia

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