Assessment of macrolide resistance in the respiratory tract of preterm-born infants during treatment with azithromycin in the AZTEC clinical trial

BACKGROUND: Our multicentre, double-blind, randomised, placebo-controlled Azithromycin therapy for prevention of chronic lung disease of prematurity trial assessed if early 10-day azithromycin treatment improved survival without development of chronic lung disease of prematurity when compared with placebo in 796 preterm-born infants. Since antibiotic resistance remains a significant global health priority, we had preplanned macrolide-resistance assessment in recruited infants. We, therefore, identified baseline macrolide-resistant genes in respiratory samples and determined if this was altered by azithromycin treatment. Furthermore, we assessed if macrolide-resistant bacteria isolated from respiratory samples were also resistant to other common antibiotic classes. METHODS: (A) were identified by quantitative PCR (qPCR) from serial nasopharyngeal and endotracheal aspirates from recruited infants at baseline (pretreatment), day-5, day-10 and day-14 (post treatment). Azithromycin-resistant bacteria were assessed by culture in presence/absence of azithromycin and underlying resistance mechanisms were confirmed by qPCR. Resistance to other common antibiotics was also evaluated and molecular determinants were identified by whole genome sequencing. RESULTS: (C) gene increased by azithromycin. Azithromycin-resistant bacteria were resistant to multiple clinically used antibiotics, being associated with several different underlying resistance mechanisms. Coagulase-negative staphylococci (CoNS) were the most recovered macrolide-resistant bacteria. CONCLUSIONS: Macrolide-resistant genes were noticeably prevalent in the placebo group, with minimal increase with azithromycin treatment, suggesting that, regardless of the additional use of azithromycin, judicious use of antibiotics is required in preterm-born infants.