Centre For Trials Research, Cardiff University, Cardiff, UK.
Department of Child Health, Cardiff University School of Medicine, Cardiff, UK.
Lancet Respir Med. 2024 Aug;12(8):608-618. doi: 10.1016/S2213-2600(24)00079-1. Epub 2024 Apr 25.
Systematic reviews have reported conflicting evidence on whether macrolide antibiotics reduce rates of chronic lung disease of prematurity (CLD) in at-risk preterm infants born at less than 30 weeks' gestation, including in those colonised with pulmonary Ureaplasma spp. Since an adequately powered trial has been lacking, we aimed to assess if the macrolide azithromycin improved survival without the development of physiologically defined moderate or severe CLD in preterm infants.
AZTEC was a multicentre, double-blind, randomised, placebo-controlled trial conducted in 28 tertiary neonatal intensive care units in the UK. Infants were eligible if they were born at less than 30 weeks' gestation and had received at least 2 h of either non-invasive (continuous positive airway pressure or humidified high flow nasal cannula therapy) or invasive respiratory support (via endotracheal tube) within 72 h of birth. Eligible infants were randomly allocated in a 1:1 ratio using random permuted blocks of four to receive either intravenous azithromycin at 20 mg/kg per day for 3 days followed by 10 mg/kg for 7 days, or to placebo. Allocation was stratified by centre and gestational age at birth (<28 weeks vs ≥28 weeks). Azithromycin and placebo vials were encased in tamper-evident custom cardboard cartons to ensure masking for clinicians, parents, and the research team. The primary outcome was survival without development of physiologically defined moderate or severe CLD at 36 weeks' postmenstrual age. Outcomes and safety were analysed on an intention-to-treat basis (all randomly allocated infants, regardless of any post-randomisation events). The study was registered with ISRCRN (11650227) and is closed.
Infants were recruited between Oct 9, 2019, and March 22, 2022. 799 (53·1%) of 1505 eligible infants underwent random allocation; three infants were withdrawn, including consent to use their data, leaving 796 infants for analysis. Survival without moderate or severe CLD occurred in 166 (42%) of 394 infants in the intervention group and 179 (45%) of 402 in the placebo group (three-level adjusted OR [aOR] 0·84, 95% CI 0·55-1·29, p=0·43). Pulmonary Ureaplasma spp colonisation did not influence treatment effect. Overall, seven serious adverse events were reported for the azithromycin group (five graded as severe, two as moderate), and six serious adverse events were reported in the placebo group (two severe, two moderate, and two mild), as assessed by the local principal investigators.
Since prophylactic use of azithromycin did not improve survival without development of physiologically-defined CLD, regardless of Ureaplasma spp colonisation, it cannot be recommended in clinical practice.
UK National Institute for Health and Care Research.
系统评价报告称，在孕 28 周以下出生的有风险的早产儿中，大环内酯类抗生素是否能降低慢性肺病早产儿（CLD）的发生率存在矛盾的证据，包括肺部脲原体属定植的早产儿。由于缺乏足够大的试验，我们旨在评估大环内酯类药物阿奇霉素是否能改善早产儿的存活率，而不会发展为生理性定义的中重度 CLD。
AZTEC 是一项在英国 28 个三级新生儿重症监护病房进行的多中心、双盲、随机、安慰剂对照试验。如果婴儿在孕 30 周以下出生，且在出生后 72 小时内接受了至少 2 小时的非侵入性（持续气道正压通气或湿化高流量鼻导管治疗）或侵入性呼吸支持（通过气管内管），则符合入组条件。符合条件的婴儿按照 1:1 的比例随机分配，使用随机排列的 4 个区组的随机分配，接受 20mg/kg/天的静脉注射阿奇霉素治疗 3 天，然后 10mg/kg/天治疗 7 天，或安慰剂。所有分配均按中心和出生时的胎龄（<28 周 vs ≥28 周）分层。阿奇霉素和安慰剂小瓶装在防篡改的定制纸板盒中，以确保对临床医生、家长和研究团队进行掩蔽。主要结局是在出生后 36 周的校正孕龄时无生理性定义的中重度 CLD 且存活。根据意向治疗原则（所有随机分配的婴儿，无论是否发生任何随机后事件）对结局和安全性进行分析。该研究在 ISRCRN 注册（11650227），现已关闭。
婴儿于 2019 年 10 月 9 日至 2022 年 3 月 22 日入组。795（53.1%）名符合条件的 1505 名婴儿接受了随机分配；3 名婴儿退出，包括同意使用其数据，共有 796 名婴儿进行了分析。干预组中 394 名婴儿中有 166 名（42%）和安慰剂组中 402 名婴儿中有 179 名（45%）无中重度 CLD 存活（三水平调整 OR [aOR] 0.84，95%CI 0.55-1.29，p=0.43）。脲原体属定植不影响治疗效果。总体而言，阿奇霉素组报告了 7 例严重不良事件（5 例为严重，2 例为中度），安慰剂组报告了 6 例严重不良事件（2 例为严重，2 例为中度，2 例为轻度），由当地主要研究者评估。
由于预防性使用阿奇霉素并不能改善生理性 CLD 无发展的存活率，因此无论脲原体属是否定植，都不能在临床实践中推荐使用。
英国国家卫生与保健优化研究所。
