To estimate prescribing rates for azithromycin as immunomodulation among critically ill children hospitalized for acute bronchiolitis and identify institutional and chronological prescribing variation.

Multicenter, observational, retrospective cohort study using the Pediatric Health Information Systems registry from 2013 to 2022.

Forty-seven PICUs in the United States.

Critically ill children 0-3 years old hospitalized for acute viral bronchiolitis excluding those prescribed azithromycin with alternative indication (i.e., concurrent Bordetella pertussis infection, urethritis, atypical pneumonia, acute upper respiratory infections, and asthma-related diagnoses).

Azithromycin prescription during hospitalization.

A total of 82,677 children met study criteria of which 3,161 (3.8%) were prescribed azithromycin. Mean (± sd ) center-specific azithromycin prescribing rates exhibited a multilinear decreasing trend (joinpoint breakpoint noted in 2017) going from 4.0% ± 4.6% in 2013 to 2.2% ± 0.8% in 2022 (-0.7%/yr). The median institutional azithromycin prescribing rate was 2.8% (interquartile range [IQR], 1.8-3.9%; total range, 1.2-24.3%). Compared with those not prescribed azithromycin, receipt of azithromycin was associated with the following: older age (median, 10 mo [IQR, 3.2-20.3 mo] vs. 7.8 mo [IQR, 2.9-15.2 mo]; p < 0.001); receiving corticosteroids (57.1% vs. 38.1%; p < 0.001) or continuous albuterol (35.9% vs. 22.4%; p < 0.001); use of noninvasive respiratory support (13.4% vs. 9.7%; p < 0.001) or invasive ventilation (35.9% vs. 22.4%; p < 0.001); and extracorporeal life support (0.5% vs. 0.1%; p < 0.001).

In this 2013-2022, U.S. multicenter registry-based cohort study, the azithromycin prescribing rate for critically ill children with bronchiolitis was 3.8%. Exposure varied by institution, patient age, and revealed a decreasing trend over the last decade.

Early life respiratory syncytial virus (RSV) bronchiolitis is a significant risk factor for childhood asthma. In vitro and in vivo studies suggested that decreasing levels of airway matrix metalloproteinase (MMP)-9 during RSV bronchiolitis may be associated with clinical benefits.

To investigate whether azithromycin therapy during severe RSV bronchiolitis reduces upper airway MMP-9 levels, whether upper airway MMP-9 levels correlate with upper airway interleukin IL-8 levels, and whether MMP-9 level reduction is associated with reduced post-RSV recurrent wheeze (RW).

A total of 200 otherwise healthy 1- to 18-month-old infants hospitalized with RSV bronchiolitis were randomized into a double-blind, placebo-controlled trial of oral azithromycin (10 mg/kg daily for 7 days followed by 5 mg/kg daily for 7 days) or placebo. Infants were followed for 2 to 4 years for the outcome of RW (3 or more wheezing episodes). Nasal lavage samples for MMP-9 levels were obtained at baseline, day 14 (end of the study treatment), and after 6 months.

Upper airway MMP-9 levels were highly correlated with IL-8 levels at all 3 time points: randomization, day 14, and 6 months (r = 0.80; P < .0001 for all time points). MMP-9 levels were similar between treatment groups at randomization, were lower on day 14 among children treated with azithromycin (P = .0085), but no longer different after 6 months. MMP-9 levels at baseline and change from baseline to day 14 were not associated with the development of RW (P = .49, .39, respectively).

Azithromycin therapy in children hospitalized with RSV bronchiolitis had a short-term anti-inflammatory effect in reducing upper airway MMP-9 levels. However, the reduction in MMP-9 levels did not relate to subsequent RW post-RSV.

This study is a secondary analysis of the Azithromycin to Prevent Wheezing following severe RSV bronchiolitis-II clinical trial registered at Clinicaltrials.gov (NCT02911935).

Drug carriers to deliver macrolide antibiotics, such as azithromycin, show promise as antibacterial agents. Macrolide drug carriers have largely focused on improving the drug stability and pharmacokinetics, while reducing adverse reactions and improving antibacterial activity. Recently, macrolides have shown promise in treating inflammatory conditions by promoting a reparative effect and limiting detrimental pro-inflammatory responses, which shifts the immunologic setpoint from suppression to balance. While macrolide drug carriers have only recently been investigated for their ability to modulate immune responses, the previous strategies that deliver macrolides for antibacterial therapy provide a roadmap for repurposing the macrolide drug carriers for therapeutic interventions targeting inflammatory conditions. This review describes the antibacterial and immunomodulatory activity of macrolides, while assessing the past in vivo evaluation of drug carriers used to deliver macrolides with the intention of presenting a case for increased effort to translate macrolide drug carriers into the clinic.

Early-life severe respiratory syncytial virus (RSV) bronchiolitis is a risk factor for childhood asthma. Because azithromycin may attenuate airway inflammation during RSV bronchiolitis, we evaluated whether it would reduce the occurrence of post-RSV recurrent wheeze.

We prospectively enrolled 200 otherwise healthy 1- to 18-month-old children hospitalized with RSV bronchiolitis in this single-center, double-blind, placebo-controlled study and randomly assigned them to receive oral azithromycin (10 mg/kg daily for 7 days, followed by 5 mg/kg daily for 7 days) or placebo. Randomization was stratified by recent open-label antibiotic use. The primary outcome was the occurrence of recurrent wheeze, defined as a third episode of post-RSV wheeze over the following 2 to 4 years.

As an indication of the biologic activity of azithromycin, nasal wash interleukin-8 levels, at day 14 after randomization, were lower among azithromycin-treated participants (P<0.01). Despite evidence of biologic activity, azithromycin did not reduce the risk of post-RSV recurrent wheeze (47% in the azithromycin group vs. 36% in the placebo group; adjusted hazard ratio, 1.45; 95% confidence interval [CI], 0.92 to 2.29; P=0.11). Azithromycin also did not modify the risk of recurrent wheeze among participants already receiving other antibiotic treatment at the time of enrollment (hazard ratio, 0.94; 95% CI, 0.43 to 2.07). There was a potential signal among antibiotic-naïve participants who received azithromycin to have an increased risk of recurrent wheeze (hazard ratio, 1.79; 95% CI, 1.03 to 3.1).

Azithromycin therapy for 14 days during acute severe RSV bronchiolitis did not reduce recurrent wheeze occurrence over the following 2 to 4 years. Our data suggest no benefit of azithromycin administration with the goal of preventing recurrent wheeze in later life. (Funded by the National Heart, Lung, and Blood Institute; ClinicalTrials.gov number, NCT02911935.).