Azithromycin was not distinguished from placebo for episodes of wheezing in preschool children in emergency medicine departments regardless of presence or absence of pathogenic bacteria in the upper airway, in a randomized trial conducted at 8 pediatric emergency departments in the US.1 The trial was discontinued early, at a planned interim analysis, with no evident difference between the azithromycin and placebo groups in reducing severity of symptoms, nor in secondary study measures of length of stay in the emergency department or hospital, or in return visits within 72 hours.
"Although the decision to stop the trial early was justified, given the results of the interim analysis, stopping early limited the sample size, decreased the precision of estimated differences, and greatly reduced the power of the trial.However, the results show that a moderate or large true effect is implausible," remarked co-lead authors Kurt Denninghoff, MD, Department of Emergency Medicine and the Arizona Emergency Medicine Research Center, University of Arizona, Tucson, and Charles Casper, PhD, Department of Pediatrics, University of Utah, Salt Lake City, and colleagues of the PECARN AZ-SWED Trial Study Group.
Even with an early halt, the investigators had randomized 840 patients between 18 to 59 months of age who had presented to the ER with a moderate-to-severe episode of expiratory wheezing.Eligibility to participate in the trial was subject to a Pediatric Respiratory Assessment Measure (PRAM) score of 4 or higher.A key excluding factor was having received antibiotics for any reason within 2 weeks of assessment in the ER.
Nasopharyngeal samples were taken following randomization and prior to initiating drug or placebo. Respiratory viruses were isolated from most, but 521 of the 840 patients (61%) were positive for one or more of three pathogenic bacteria tracked in the study: Steptococcus pneumoniae, Moraxella catarrhalis, and Haemophilus influenzae. A sub-analysis of the measured outcomes from azithromycin vs placebo was performed between those with pathogenic bacteria (group "positive") and those without (group "negative").These patients were drawn from both the azithromycin and placebo cohorts, as culture results were received subsequent to randomization.
What You Need to Know
In a randomized trial of 840 preschoolers with moderate-to-severe wheezing across 8 US pediatric ERs, azithromycin showed no benefit over placebo for symptom severity, ER/hospital length of stay, or 72-hour return visits.
The lack of benefit held true regardless of whether children tested positive for pathogenic bacteria (S pneumoniae, M catarrhalis, H influenzae) in nasopharyngeal samples, even though azithromycin cleared bacteria far more effectively than placebo (58.7% vs. 11.4%).
Though the trial was stopped early for futility—limiting its statistical power—the authors concluded a moderate-to-large treatment effect is implausible and advised against using azithromycin for children with established respiratory distress in the ER setting.
The primary study outcome was the sum of scores on the Asthma Flare-up Diary for Young Children (ADYC) over 5 days, as reported by caregivers.The three secondary outcomes were length of stay in the ER, in the hospital, and number of return visits to either within 72 hours after randomization.
The investigators reported no statistically significant difference in any outcome measure between those receiving azithromycin or placebo.This was also the case between those with or without isolates of pathogenic bacteria in nasopharyngeal samples—despite reasoning that outcomes would improve with the bacterial clearance linked to azithromycin (58.7% vs 11.4% with placebo). In all participants, the investigators found that the severity of illness decreased substantially after the first day of treatment with antibiotic or placebo, becoming relatively mild by the fifth day.
Denninghoff, Casper and colleagues acknowledge other studies with different results, however, and that azithromycin has been found to exert some anti-inflammatory as well as antibacterial effect, which may enhance its effectiveness for less severe presentations.
"...we speculate that azithromycin may have been more effective in the out-patient setting than in our emergency department cohort with more severe illness owing to the preventive anti-inflammatory effects of the drug, and we suggest that azithromycin should not be used to treat children with established respiratory distress," the investigators advised.
Reference
1. Denninghoff KR, Casper TC, Zorc JJ, et al. Azithromycin for preschoolers with wheezing in the emergency department. N Engl J Med. 2026; 395:753-764.
