Azithromycin in Pediatric Bronchiectasis: What Factors Influence Efficacy? 

Long-term azithromycin therapy for non-cystic fibrosis (CF) pediatric bronchiectasis is most effective in reducing acute respiratory exacerbations between 17 and 62 weeks of treatment, according to study findings published in Chest.

Researchers conducted a secondary analysis of the Bronchiectasis Intervention Study — a multicenter, double-blind, randomized, 1:1 parallel-group, placebo, randomized controlled trial (RCT) of 89 indigenous children in Australia and New Zealand, aged 1 to 8 years, with non-CF bronchiectasis. Notably, children of indigenous ethnicity in Australia and New Zealand are known to have more severe bronchiectasis and higher body weight. While the initial RCT analysis showed that long-term azithromycin therapy effectively reduced acute respiratory exacerbations in those studied, the secondary analysis aimed to determine: (1) the time period when the treatment was most effective; and (2) factors affecting azithromycin’s effectiveness.

The primary study outcome was acute respiratory exacerbation rate. In the primary RCT, exacerbations were defined when antibiotics were prescribed for any of the following: increased cough, sputum volume or color intensity, increased dyspnea, new chest examination or radiographic findings, deterioration in predicted forced expiratory volume in 1 second percentage by more than 10%, or hemoptysis.

Among the 89 study participants, 45 were treated with azithromycin and 44 received placebo. Overall, 37% of the children were under 3 years of age, 53% were boys, and 53% were recruited from Australia. The study period ranged from 13 to 120 weeks, with a median of 102 weeks (range, 74 to 105 weeks), and was similar across both groups. Overall, 69% of the children received azithromycin for between 79 and 105 weeks. During the study period, the participants experienced a total of 299 exacerbations.

Results of the study showed that the crude incidence rate ratio (IRR) of the placebo arm — 1.93 — was almost 2 times that of the azithromycin arm (95% CI, 1.52-2.45; P <.0001). Researchers calculated the treatment difference as the mean difference between the study cohorts (ie, placebo minus azithromycin) in per child-week counts of respiratory exacerbations. In further analyses, the IRR of weeks 17 to 62 was 2.0 when compared with weeks 1 to 16 (95% CI, 1.1 to 3.8; P =.034) and 1.8 when compared with weeks 63 to 105, (95% CI, 1.04 to 3.1; P =.037).

A total of 11 factors were associated with varied effects of azithromycin, with 4 of them deemed statistically significant. A higher reduction in exacerbations was reported in the following groups relative to their counterparts: (1) children with nasopharyngeal carriage of bacterial pathogens (IRR, 0.81; 95% CI, 0.57-1.14 vs IRR, 0.29; 95% CI, 0.20 to 0.44; P <.001); (2) New Zealand children (IRR, 0.73; 95% CI, 0.51-1.03 vs IRR, 0.39; 95% CI, 0.28-0.55; P =.012); (3) those with higher weight-for-height z-scores (IRR, 0.82; 95% CI, 0.67-0.99; P =.044). In contrast, a lower reduction in exacerbations was reported in those born preterm vs those who were not (IRR, 0.41; 95% CI, 0.30-0.55 vs IRR, 0.74; 95% CI, 0.49-1.10; P =.012).

Study limitations include the inability to control for confounders at the individual level, given that treatment effect over time was evaluated using data obtained by combining the time-series of all incident respiratory exacerbations from each participant. Further, it was not possible to control for seasonality, a potentially important confounder among participants from New Zealand.

The investigators concluded that although “these azithromycin-related phenotype data are insufficient to change current clinical practice, they deserve further evaluation in future studies.”

Disclosure: Some of the study authors have declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures. 

Reference

Vicendese D, Yerkovich S, Grimwood K, et al. Long-term azithromycin in children with bronchiectasis unrelated to cystic fibrosis: treatment effects over time. Chest. Published online August 25, 2022. doi:10.1016/j.chest.2022.08.2216