Long-term Erythromycin Therapy Research Articles

Impact of Long-Term Erythromycin Therapy on the Oropharyngeal Microbiome and Resistance Gene Reservoir in Non-Cystic Fibrosis Bronchiectasis.

Long-term macrolide therapy reduces rates of pulmonary exacerbation in bronchiectasis. However, little is known about the potential for macrolide therapy to alter the composition and function of the oropharyngeal commensal microbiota or to increase the carriage of transmissible antimicrobial resistance. We assessed the effect of long-term erythromycin on oropharyngeal microbiota composition and the carriage of transmissible macrolide resistance genes in 84 adults with bronchiectasis, enrolled in the Bronchiectasis and Low-dose Erythromycin Study (BLESS) 48-week placebo-controlled trial of twice-daily erythromycin ethylsuccinate (400mg). Oropharyngeal microbiota composition and macrolide resistance gene carriage were determined by 16S rRNA gene amplicon sequencing and quantitative PCR, respectively. Long-term erythromycin treatment was associated with a significant increase in the relative abundance of oropharyngeal Haemophilus parainfluenzae (P = 0.041) and with significant decreases in the relative abundances of Streptococcus pseudopneumoniae (P = 0.024) and Actinomyces odontolyticus (P = 0.027). Validation of the sequencing results by quantitative PCR confirmed a significant decrease in the abundance of Actinomyces spp. (P = 0.046). Erythromycin treatment did not result in a significant increase in the number of subjects who carried erm(A), erm(B), erm(C), erm(F), mef(A/E), and msrA macrolide resistance genes. However, the abundance of erm(B) and mef(A/E) gene copies within carriers who had received erythromycin increased significantly (P < 0.05). Our findings indicate that changes in oropharyngeal microbiota composition resulting from long-term erythromycin treatment are modest and are limited to a discrete group of taxa. Associated increases in levels of transmissible antibiotic resistance genes within the oropharyngeal microbiota highlight the potential for this microbial system to act as a reservoir for resistance.IMPORTANCE Recent demonstrations that long-term macrolide therapy can prevent exacerbations in chronic airways diseases have led to a dramatic increase in their use. However, little is known about the wider, potentially adverse impacts of these treatments. Substantial disruption of the upper airway commensal microbiota might reduce its contribution to host defense and local immune regulation, while increases in macrolide resistance carriage would represent a serious public health concern. Using samples from a randomized controlled trial, we show that low-dose erythromycin given over 48weeks influences the composition of the oropharyngeal commensal microbiota. We report that macrolide therapy is associated with significant changes in the relative abundances of members of the Actinomyces genus and with significant increases in the carriage of transmissible macrolide resistance. Determining the clinical significance of these changes, relative to treatment benefit, now represents a research priority.

Effects of erythromycin on H2O2 generation by neutrophils

Low-dose long-term erythromycin therapy has been reported to be effective in diffuse panbronchiolitis, but the mode of action remains obscure. We therefore evaluated the effect of erythromycin the generation of H2O2 by neutrophils. In vitro, erythromycin (0.1, 1.0, and 20 micrograms/ml) suppressed both spontaneous and PMA-stimulated H2O2 generation. H2O2 generation by neutrophils obtained from peripheral blood and from bronchoalveolar lavage fluid from patients with diffuse panbronchiolitis was higher than that from healthy controls. After erythromycin therapy, H2O2 generation by neutrophils was lower. Compared with the control, H2O2 generation by peripheral neutrophils was low in the patients who responded clinically to erythromycin therapy, but was high in those who did not respond. These results suggest that at least some of the therapeutic effect of erythromycin in patients with diffuse panbronchiolitis is due to reduction in H2O2 generation by neutrophils.

Long-term Erythromycin Therapy Is Associated with Decreased Chronic Obstructive Pulmonary Disease Exacerbations

Frequent chronic obstructive pulmonary disease (COPD) exacerbations are a major cause of hospital admission and mortality and are associated with increased airway inflammation. Macrolides have airway antiinflammatory actions and may reduce the incidence of COPD exacerbations. To determine whether regular therapy with macrolides reduces exacerbation frequency. We performed a randomized, double-blind, placebo-controlled study of erythromycin administered at 250 mg twice daily to patients with COPD over 12 months, with primary outcome variable being the number of moderate and/or severe exacerbations (treated with systemic steroids, treated with antibiotics, or hospitalized). We randomized 109 outpatients: 69 (63%) males, 52 (48%) current smokers, mean (SD) age 67.2 (8.6) years, FEV1 1.32 (0.53) L, FEV1% predicted 50 (18)%. Thirty-eight (35%) of the patients had three or more exacerbations in the year before recruitment, with no differences between treatment groups. There were a total of 206 moderate to severe exacerbations: 125 occurred in the placebo arm. Ten in the placebo group and nine in the macrolide group withdrew. Generalized linear modeling showed that the rate ratio for exacerbations for the macrolide-treated patients compared with placebo-treated patients was 0.648 (95% confidence interval: 0.489, 0.859; P = 0.003) and that these patients had shorter duration exacerbations compared with placebo. There were no differences between the macrolide and placebo arms in terms of stable FEV1, sputum IL-6, IL-8, myeloperoxidase, bacterial flora, serum C-reactive protein, or serum IL-6 or in changes in these parameters from baseline to first exacerbation over the 1-year study period. Macrolide therapy was associated with a significant reduction in exacerbations compared with placebo and may be useful in decreasing the excessive disease burden in this important patient population. Clinical trial registered with www.clinicaltrials.gov (NCT 00147667).

Low-Dose and Long-Term Erythromycin Therapy in Children with a Mixed and Infectious Type Bronchial Asthma

Low-Dose and Long-Term Erythromycin Therapy in Children with a Mixed and Infectious Type Bronchial Asthma

Superoxide Dismutase in Alveolar Macrophages from Patients with Diffuse Panbronchiolitis

Background: Diffuse panbronchiolitis (DPB) is characterized by chronic neutrophil-mediated inflammation of the airway mediated by oxygen radical production. DPB can be controlled with low-dose and long-term erythromycin therapy based on its anti-inflammatory effect. Objective: In this study, the antioxidant levels were analyzed as an anti-inflammatory effect of erythromycin in the patients. Methods: We investigated the activity and protein level of an antioxidant enzyme, Cu, Zn-superoxide dismutase (SOD) in alveolar macrophages (AMs) of patients with DPB before and after erythromycin therapy. AMs were obtained from bronchoalveolar lavage fluid. Results: There was no significant difference in the activity of Cu, Zn-SOD between normal subjects and untreated patients. Erythromycin therapy (600 mg/day) significantly increased the activity of the enzyme relative to that before therapy and normal subjects [18.2 units/10⁶ cells (9.2–26.2) vs. 4.4 units/10⁶ cells (1.1–9.3), p < 0.01 and 10.4 units/10⁶ cells (2.4–20.6), p < 0.05, respectively]. Furthermore, the protein level of Cu, Zn-SOD in AMs in treated patients was significantly higher than in the other two groups [69.4 ng/10⁶ cells (34.2–147.1) vs. 20.1 ng/ 10⁶ cells (16.9–39.8) for untreated patients, p < 0.01 and 43.2 ng/10⁶ cells (32.6–68.2) for normal subjects, p < 0.01], but the levels in the latter groups were not different. Conclusion: Our results suggest that one of the anti-inflammatory effects of erythromycin in DPB may be, in part, mediated by enhancement of antioxidant activity in AMs.

Role of interleukin-8 (IL-8) and an inhibitory effect of erythromycin on IL-8 release in the airways of patients with chronic airway diseases

To evaluate of the role of interleukin-8 (IL-8), a chemotactic cytokine, in the continuous neutrophil accumulation in the airways of patients with chronic airway disease (CAD) and persistent Pseudomonas aeruginosa infection, we investigated the cell population, IL-8 levels, IL-1 beta levels, tumor necrosis factor (TNF) activities, and neutrophil elastase (NE) activities of bronchoalveolar lavage (BAL) fluids in 17 CAD patients (with P. aeruginosa infections [CAD+PA], n = 9; without any bacterial infections [CAD-PA], n = 8) and 8 normal volunteers. We found significant elevations of neutrophil numbers, IL-8/albumin ratios, and NE/albumin ratios in BAL fluids from CAD patients, in the following rank order: CAD+PA > CAD-PA > normal volunteers. IL-1 beta/albumin ratios were elevated only in CAD+PA, while no TNF bioactivity was detected in BAL fluids. The neutrophil numbers correlated significantly with the IL-8/albumin ratios and NE/albumin ratios in the BAL fluids of CAD patients. When anti-human IL-8 immunoglobulin G was used for neutralizing neutrophil chemotactic factor (NCF) activities in BAL fluids, the mean reduction rate of NCF activities in CAD+PA patients was significantly higher than that in CAD-PA patients. We also evaluated the effects of low-dose, long-term erythromycin therapy in BAL fluids from three CAD+PA and two CAD-PA patients. Treatment with erythromycin caused significant reductions of neutrophil numbers, IL-8/albumin ratios, and NE/albumin ratios in BAL fluids from these patients. To elucidate the mechanism of erythromycin therapy, we also examined whether erythromycin suppressed IL-8 production by human alveolar macrophages and neutrophils in vitro. We demonstrated a moderate inhibitory effect of erythromycin on IL-8 production in Pseudomonas-stimulated neutrophils but not in alveolar macrophages. Our data support the view that persistent P. aeruginosa infection enhances IL-8 production and IL-8-derived NCF activity, causing neutrophil accumulation in the airways and the progressive lung injuries observed in patients with CAD. The clinical efficacy of erythromycin therapy for CAD patients might be partly mediated through a reduced IL-8 production, diminishing neutrophil accumulation and NE release in the airways.

Erythromycin Therapy for Otitis Media With Effusion in Sinobronchial Syndrome

Chronic sinusitis is frequently associated with chronic lower respiratory tract diseases, and the association is referred to as sinobronchial syndrome (SBS). This study was carried out to determine the incidence of otitis media with effusion in the patients with sinobronchial syndrome and to investigate the efficacy of low-dose and long-term erythromycin therapy for otitis media with effusion associated with sinobronchial syndrome. We have found a high incidence of otitis media with effusion in patients with sinobronchial syndrome, the morbidity rate being 54% in 50 cases studied. This ear disease seems to be the major cause of hearing disturbance in patients with sinobronchial syndrome. Sixteen patients with both sinobronchial syndrome and otitis media with effusion were given low-dose and long-term erythromycin therapy (erythromycin base, 600 mg/d for more than 4 months); of these, 13 became effusion-free and most subjects showed improvement in the symptoms of sinobronchial syndrome. The erythromycin therapy thus seems to be exceedingly effective for the treatment of sinobronchial syndrome and associated otitis media with effusion.

慢性副鼻腔炎と少量エリスロマイシン療法

Fifty three patients with chronic sinusitis were treated with 600mg of erythromycin (EM) per day for an average of 5.5 month.Symptoms disappeared in 25 patients (52.1%), and some subjective improvement was noted in 21 cases (43.8%). Local signs of infection in the nasal cavity were significantly improved in 25 patients (52.1%). Improvement was observed during the second month in most cases. No positive correlation was noted between the efficacy of EM and the sensitivity to EM of microorganisms in the discharge from the middle nasal meatus. The clinical effects were less in patients with higher serum IgA before EM chemotherapy. The EM effect on chronic sinusitis was not considered to be associated with bactericidal control.Low-dose, long-term EM therapy is useful in the treatment of chronic sinusitis.