Background Patients with severe asthma are at increased risk of exacerbations and lower respiratory tract infections (LRTI). Severe asthma is heterogeneous, encompassing eosinophilic and non-eosinophilic (mainly neutrophilic) phenotypes. Patients with neutropilic airway diseases may benefit from macrolides. Methods We performed a randomised double-blind placebo-controlled trial in subjects with exacerbationprone severe asthma. Subjects received low-dose azithromycin (n=55) or placebo (n=54) as add-on treatment to combination therapy of inhaled corticosteroids and long-acting β 2 agonists for 6 months. The primary outcome was the rate of severe exacerbations and LRTI requiring treatment with antibiotics during the 26-week treatment phase. Secondary efficacy outcomes included lung function and scores on the Asthma Control Questionnaire (ACQ) and Asthma Quality of Life Questionnaire (AQLQ). Results The rate of primary endpoints (PEPs) during 6 months was not significantly different between the two treatment groups: 0.75 PEPs (95% CI 0.55 to 1.01) per subject in the azithromycin group versus 0.81 PEPs (95% CI 0.61 to 1.09) in the placebo group (p=0.682). In a predefined subgroup analysis according to the inflammatory phenotype, azithromycin was associated with a significantly lower PEP rate than placebo in subjects with noneosinophilic severe asthma (blood eosinophilia ≤200/ml): 0.44 PEPs (95% CI 0.25 to 0.78) versus 1.03 PEPs (95% CI 0.72 to 1.48) (p=0.013). Azithromycin significantly improved the AQLQ score but there were no significant between-group differences in the ACQ score or lung function. Azithromycin was well tolerated, but was associated with increased oropharyngeal carriage of macrolide-resistant streptococci. Conclusions Azithromycin did not reduce the rate of severe exacerbations and LRTI in patients with severe asthma. However, the significant reduction in the PEP rate in azithromycin-treated patients with non-eosinophilic severe asthma warrants further study. ClinicalTrials.gov number NCT00760838.

Augustinus-A Debrock (PI), P Ardies (Coordinator). Imelda ziekenhuis-T Lauwerier (PI), A Delbaere (Coordinator). UZ Brussel-W Vincken (PI), S Hanon (Co-I), D Schuermans, K Van Eeckhoudt (Coordinators). CHU St.-Pierre-V Ninane (PI), M Gabrovska (Co-I), F De Cock, S Carlier (Coordinators).

Objectives.To compare the type of pathogens isolated from patients with early-onset intensive care unit (ICU)-acquired pneumonia with those isolated from patients with late-onset ICU-acquired pneumonia and to study risk factors for the isolation of pathogens that are potentially resistant to multiple drugs.Design.Prospective cohort study.Setting.Patients admitted to the ICU of a 677-bed, university-affiliated teaching hospital in Belgium during 1997-2002.Methods.ICU-acquired pneumonia was defined as a case of pneumonia that occurred 2 days or more after admission to the ICU in combination with a positive results of radiologic analysis, clinical signs and symptoms, and a positive culture result. All cases of pneumonia were categorized as either early onset (within 7 days after admission) and late onset (7 days or more after admission), with or without previous antibiotic treatment, and the corresponding pathogens were analyzed. Risk factors for the isolation of pathogens potentially resistant to multiple drugs (ie, Pseudomonas aeruginosa, Serratia marcescens, Enterobacter species, Morganella morganii, methicillin-resistant Stapylococcus aureus, Citrobacter species, Acinetobacter species, Burkholderia species, extended-spectrum β-lactamase–producing pathogens, and Stenotrophomonas maltophilia) were analyzed using logistic regression analysis.Results.A total of 4,200 patients stayed at the ICU for 2 or more days, 298 of whom developed ICU-acquired pneumonia, for an overall incidence of 13 cases (95% confidence interval [CI], 11-14 cases) per 1,000 ICU-days. Pathogens potentially resistant to multiple drugs were isolated from 52% of patients with early-onset pneumonia. Risk factors for the isolation of these pathogens were greater age and previous receipt of antibiotic prophylaxis (adjusted odds ratio [aOR], 4.6 [95% CI, 1.6-13.0]) or antibiotic therapy (aOR, 8.2 [95% CI, 2.8-23.8]). The length of ICU admission and hospital stay were weaker risk factors for the isolation of these pathogens.Conclusions.Pathogens potentially resistant to multiple drugs were isolated in 52% of cases of early-onset ICU-acquired pneumonia. Previous antibiotic use (both prophylactic and therapeutic) is the main risk factor for the isolation of these pathogens.

BackgroundThis study of the oropharyngeal microbiome complements the previously published AZIthromycin in Severe ASThma (AZISAST) clinical trial, where the use of azithromycin was assessed in subjects with exacerbation-prone severe asthma. Here, we determined the composition of the oropharyngeal microbial community by means of deep sequencing of the amplified 16S rRNA gene in oropharyngeal swabs from patients with exacerbation-prone severe asthma, at baseline and during and after 6 months treatment with azithromycin or placebo.ResultsA total of 1429 OTUs were observed, of which only 59 were represented by more than 0.02% of the reads. Firmicutes, Bacteroidetes, Fusobacteria, Proteobacteria and Actinobacteria were the most abundant phyla and Streptococcus and Prevotella were the most abundant genera in all the samples. Thirteen species only accounted for two thirds of the reads and two species only, i.e. Prevotella melaninogenica and Streptococcus mitis/pneumoniae, accounted for one fourth of the reads.We found that the overall composition of the oropharyngeal microbiome in patients with severe asthma is comparable to that of the healthy population, confirming the results of previous studies. Long term treatment (6 months) with azithromycin increased the species Streptococcus salivarius approximately 5-fold and decreased the species Leptotrichia wadei approximately 5-fold. This was confirmed by Boruta feature selection, which also indicated a significant decrease of L. buccalis/L. hofstadtii and of Fusobacterium nucleatum. Four of the 8 treated patients regained their initial microbial composition within one month after cessation of treatment.ConclusionsDespite large diversity of the oropharyngeal microbiome, only a few species predominate. We confirm the absence of significant differences between the oropharyngeal microbiomes of people with and without severe asthma. Possibly, long term azithromycin treatment may have long term effects on the composition of the oropharygeal microbiome in half of the patients.Electronic supplementary materialThe online version of this article (doi:10.1186/s12866-017-1022-6) contains supplementary material, which is available to authorized users.

No abstract