In a multi-center study, 607 preschool-age children (mean 41 months old, range 12-71) with a history of recurrent severe wheezing that had seemingly been triggered by upper respiratory infections were randomized to receive either azithromycin (12 mg/kg daily for 5 days) or placebo at the onset of their next viral upper respiratory tract illness. All children were given scheduled and as-needed doses of a bronchodilator with onset of the upper respiratory symptoms. During the 52-78 week follow-up period, 443 children had another upper respiratory illness and were included in the analysis (223 with azithromycin, 220 with placebo).

Children who received azithromycin were less likely to progress to a severe lower respiratory tract illness than were children who received placebo (hazard ratio 0.64; 95% confidence interval, 0.41-0.98= P = 0.04). It was necessary to treat 33 children with azithromycin to prevent one child from progressing to wheezing with the next upper respiratory infection. The rates of development of subsequent respiratory illnesses were not different between the azithromycin and placebo groups.

COMMENTARY

Macrolides have both favorable and unfavorable effects. They cure infections in individuals, but they also alter microbiomes and promote infection by resistant organisms in both individuals and populations. They improve gastrointestinal function in patients with dysmotility, but they also stimulate adherence-altering abdominal cramping in some treated subjects. In addition, macrolides impact inflammatory responses, even separate from their effects on infection.

It is not clear just how macrolides alter inflammation. Interleukin 8 is the primary chemoattractant for neutrophils, and asthma patients treated with clarithromycin have decreased neutrophilic inflammation. Thus, Bacharier and colleagues evaluated the interleukin 8 gene in their subjects but found no link to outcomes, whether treated by azithromycin or placebo. In a recent laboratory-based study of epithelial cells from patients with cystic fibrosis, azithromycin markedly reduced rhinovirus replication, possibly due to effects on the interferon pathway.1 Bacharier had previously been involved in a study showing that other inflammation-altering agents (inhaled steroid and oral montelukast) given during upper respiratory infections did not change long-term asthma outcomes.2 In a recent clinical study, weekly azithromycin (30 mg/kg, three total doses) did not improve outcomes in children already sick with bronchiolitis.3

Unfortunately, antibacterial agents are already over-prescribed for patients with apparent viral upper respiratory infections. A recent review of prescription medication use during the month following a diagnosis of presumed viral acute respiratory infection showed that 49% of patients filled an antibiotic prescription.4 Antibiotics were most likely used following evaluation in an urgent care center and least likely used when care was provided by a pediatrician. The recent study of anti-inflammatory effects of azithromycin in children with recurrent wheezing should not be construed as a reason to indiscriminately prescribe azithromycin for children with viral infections.

Further research is needed prior to generalization of the findings in this study. As Cohen and Pelton stated well in an editorial accompanying Bacharier’s paper, “the consequences of widespread use of azithromycin, both known and hypothesized, outweigh the benefit for most children.”5 None-theless, these new data do offer optimism that some subpopulation groups with inflammatory conditions might indeed benefit from the use of azithromycin in some settings.

REFERENCES

  1. Schögler A, et al. Novel antiviral properties of azithromycin in cystic fibrosis airway epithelial cells. Eur Respir J 2015;45:428-439.
  2. Bacharier LB, et al. Episodic use of an inhaled corticosteroid or leukotriene receptor antagonist in preschool children with moderate-to-severe intermittent wheezing. J Allergy Clin Immunol 2008;122:1127-1135.
  3. McCallum GB, et al. Three-weekly doses of azithromycin for indigenous infants hospitalized with bronchiolitis: A multicentre, randomized, placebo-controlled trial. Front Pediatr 2015;3:32.
  4. Ebell MH, Radke T. Antibiotic use for viral acute respiratory tract infections remains common. Am J Manag Care 2015;21:e567-575.
  5. Cohen RT, Pelton SI. Individual benefit vs societal effect of antibiotic prescribing for preschool children with recurrent wheeze. JAMA 2015;314:2027-2029.