Azithromycin Fails to Ease Burden of Bronchopulmonary Dysplasia in Preemies

Azithromycin for premature newborns requiring breathing support failed to improve rates of survival without moderate or severe bronchopulmonary dysplasia at 36 weeks' postmenstrual age, though it proved safe in a large randomized trial from the U.K.

Of nearly 800 infants in the so-called AZTEC study, that primary endpoint occurred in 42% of those prophylactically treated with intravenous azithromycin versus 45% of those assigned to placebo (P=0.43), reported Sailesh Kotecha, PhD, of Cardiff University School of Medicine in Wales, and colleagues.

Important secondary endpoints, including rates of death, postnatal steroid use, and respiratory support were no different between groups, nor were the rates of treated nosocomial infections, necrotizing enterocolitis, patent ductus arteriosus, or intraventricular haemorrhage, according to the findings in Lancet Respiratory Medicine.

Bronchopulmonary dysplasia, also called chronic lung disease of prematurity (CLD), is common among infants born premature and is associated with a number of adverse outcomes, including the risk of premature development of chronic obstructive lung disease and life-long morbidity, the researchers explained.

"Since increased use of antibiotics in preterm infants is associated with increased morbidity (e.g., due to necrotizing enterocolitis), increased mortality, and increased antibiotic microbial resistance, caution is required to prophylactically use azithromycin in this vulnerable population to prevent the development of CLD," wrote Kotecha and coauthors in conclusion.

The researchers had hypothesized that targeting Ureaplasma spp colonization -- common in the respiratory tracts of preterm infants -- along with early lung inflammation could help prevent bronchopulmonary dysplasia, given their known associations with the serious lung condition.

Azithromycin has shown activity against Ureaplasma spp and also has anti-inflammatory properties. A 2014 meta-analysis had suggested the antibiotic may help prevent bronchopulmonary dysplasia or death in preterm infants, though a more recent meta-analysis concluded with low-certainty evidence that the benefit was restricted to patients with Ureaplasma colonization, calling for an adequately powered trial to settle the matter.

In the current study, however, an analysis of the newborns with Ureaplasma in their respiratory tracts at baseline -- shown in 22% of the pretreatment samples -- still demonstrated no treatment effect with azithromycin. Colonization of the bacteria between the second and third postnatal weeks increased to 45% in the azithromycin group and 55% in the placebo group.

"Whether this indicates persistent colonization or infection in the same infants, possibly underestimated when tested initially due to early assessment, or new colonization or infection in untreated infants, remains unclear," noted Abdul Razak, MD, of Monash University in Melbourne, Australia, writing in an accompanying editorial.

"This distinction is crucial, especially since many infants in the azithromycin group still showed Ureaplasma colonization despite therapy, raising questions about the drug's effectiveness in eliminating the bacteria without reinfection or recolonization," he added.

Razak also questioned whether the azithromycin dose was sufficient to produce an anti-inflammatory response (this was not evaluated in the current analysis) or a response as potent as corticosteroids, which are typically reserved for infants on ventilators due to neurodevelopmental risks.

Ultimately, the macrolide cannot be recommended based on the current findings, he concluded.

"CLD is a multifaceted condition that is influenced not only by perinatal infections such as Ureaplasma spp, but also by various other factors, and simply administering azithromycin might not adequately address the intricate interplay of factors associated with CLD," said Razak.

Other recent trials targeting alternate risk factors for bronchopulmonary dysplasia with different interventions -- the less-potent glucocorticoid hydrocortisone, omega-3 fatty acid docosahexaenoic acid, and enteral vitamin A supplementation, among others -- have also failed to improve rates of survival without moderate to severe disease in similar patient populations.

"There will almost certainly never be a single solution -- neither golden nor silver -- to reduce or prevent CLD," according to the editorialist. "Efforts must be collective, ongoing, and initiated from the outset."

The primary analysis for AZTEC (Azithromycin Therapy for Prevention of CLD) included 796 preterm infants (<30 weeks' gestation) who within 72 hours of birth needed non-invasive or invasive respiratory support.

Participants were enrolled from 28 tertiary neonatal intensive care units in the U.K. and randomized 1:1 to either azithromycin (20 mg/kg per day for 3 days, then 10 mg/kg for 7 days) or matching placebo. Endotracheal and nasopharyngeal aspirates were used to capture respiratory samples to analyze Ureaplasma spp.

Infants had a median gestational age of 27 weeks at the time of birth and a median birthweight of 895 g. A majority (56%) were boys and 59% were born via caesarean section. Over 80% required invasive ventilation before randomization.

The trial's primary endpoint was survival without moderate or severe bronchopulmonary dysplasia at 36 weeks' postmenstrual age. At this point, 91% of infants in the azithromycin group were alive versus 92% of those in the placebo group (P=0.69); rates of moderate or severe bronchopulmonary dysplasia were 54% and 51%, respectively (P=0.48).

Nearly all secondary endpoints showed no significant differences between the azithromycin and placebo groups: invasive ventilation (median 49 vs 48 days, respectively), non-invasive ventilation (median 23 days for each group), postnatal corticosteroid use (43% in each group), treated patent ductus arteriosus (37% vs 40%), treated nosocomial infection (65% vs 62%), severe intraventricular hemorrhage (14% vs 13%), or severe necrotizing enterocolitis (14% vs 15%).

A significant reduction in rates of treated retinopathy of prematurity was observed in survivors assigned to azithromycin (4% vs 7%), but not when death was included in the outcome.

The researchers called the safety profile of azithromycin "reassuring," with seven serious adverse events (five severe) in the intervention group versus six in the placebo group (two severe). A similar proportion of adverse cardiac events occurred in the two groups, and the single case of pyloric stenosis in the azithromycin remained in line with expected rates.

"Important limitations include the missed oxygen reduction tests, inadequate collection of respiratory support data, and lower than anticipated baseline sampling," noted Kotecha and colleagues, though they added that none would have affected the primary outcome.

Comment