Department of Respiratory and Sleep Medicine, Queensland Children's Hospital, Brisbane, QLD, Australia; Australian Centre for Health Services Innovation, Queensland University of Technology, Brisbane, QLD, Australia; Academic Department of Paediatrics, The Royal Alexandra Children's Hospital, Brighton and Sussex Medical School, Brighton, UK.
Department of Respiratory and Sleep Medicine, Queensland Children's Hospital, Brisbane, QLD, Australia; Australian Centre for Health Services Innovation, Queensland University of Technology, Brisbane, QLD, Australia; Department of Pediatrics, Gold Coast Health, Gold Coast, QLD, Australia.
Lancet Respir Med. 2021 Oct;9(10):1121-1129. doi: 10.1016/S2213-2600(21)00104-1. Epub 2021 May 25.
Protracted bacterial bronchitis (PBB) is a leading cause of chronic wet cough in children. The current standard treatment in European and American guidelines is 2 weeks of antibiotics, but the optimal duration of therapy is unknown. We describe the first randomised controlled trial to assess the duration of antibiotic treatment in children with chronic wet cough and suspected PBB. We hypothesise that 4 weeks of amoxicillin-clavulanate is superior to 2 weeks for improving clinical outcomes.
Our parallel, double-blind, placebo-controlled, randomised controlled trial was completed in four Australian hospitals. Children aged 2 months to 19 years with chronic (>4 weeks duration) wet cough, and suspected PBB were randomly assigned (1:1) using permuted block randomisation (stratified by age and site) to 4 weeks of amoxicillin-clavulanate (25-35 mg/kg twice daily oral suspension; 4-week group) or 2 weeks of amoxicillin-clavulanate followed by 2 weeks of placebo (2-week group). The children, caregivers, all the study coordinators, and investigators were masked to treatment assignment until data analysis was completed. The primary outcome was clinical cure (cough resolution) by day 28. Secondary outcomes were recurrence of PBB at 6 months, time to next exacerbation, change in Parent-proxy Cough-Specific Quality-of-Life (PC-QoL) score from baseline to day 28 and from day 28 to 7 months, adverse events, nasal swab bacteriology, and antimicrobial resistance. Analyses followed the intention-to-treat principle. This trial is complete and registered with Australian/New Zealand Registry, ACTRN12616001725459.
Between March 8, 2017, and Sept 30, 2019, 106 children were randomly assigned (52 in the 4-week group, median age 2·2 years [IQR 1·3-4·1]; 54 in the 2-week group, median age 1·7 years [1·2-3·8]) with 90 children completing the 4-week treatment. By day 28, the primary endpoint of clinical cure in the 4-week group (32 [62%] of 52 patients) was not significantly different to the 2-week group (38 [70%] of 54 patients; adjusted relative risk 0·87 [95% CI 0·60 to 1·28]; p=0·49). Time to next wet cough exacerbation was significantly longer in the 4-week group than the 2-week group (median 150 days [IQR 38-181] vs 36 days [15-181]; adjusted hazard ratio 0·47 [0·25 to 0·90]; p=0·02). The rate of recurrence of PBB at 6 months was 17 (53%) of 32 patients in the 4-week group vs 28 (74%) of 38 patients in the 2-week group, but the difference between the groups was not significant (adjusted odds ratio 0·39 [0·14 to 1·04]; p=0·07). PC-QoL significantly improved from baseline to day 28 in both groups, but there was no significant difference between them (mean difference in change -0·2 [95% CI -1·0 to 0·6]; p=0·64). From day 28 to 7 months, median PC-QoL remained stable in both groups with no difference in change between them. Data on respiratory pathogens and antimicrobial resistance (paired swabs available for 48 children) were similar between groups. Adverse events occurred in 13 (25%) children in the 2-week group and ten (19%) in the 4-week group (p=0·57).
A 4-week course of amoxicillin-clavulanate for treating children with chronic wet cough and suspected PBB confers little advantage compared with a 2-week course in achieving clinical cure by 28 days. However, as a 4-week duration led to a longer cough-free period, identifying children who would benefit from a longer antibiotic course is a priority.
Queensland Children's Hospital Foundation.
迁延性细菌性支气管炎（PBB）是儿童慢性湿性咳嗽的主要原因。目前，欧美指南中的标准治疗方法是使用抗生素治疗 2 周，但最佳治疗持续时间尚不清楚。我们描述了第一项随机对照试验，以评估慢性湿性咳嗽和疑似 PBB 患儿的抗生素治疗持续时间。我们假设，阿莫西林克拉维酸钾治疗 4 周优于 2 周，可改善临床结局。
我们的平行、双盲、安慰剂对照、随机对照试验在澳大利亚的四家医院完成。入组年龄在 2 个月至 19 岁之间、慢性（持续时间超过 4 周）湿性咳嗽且疑似 PBB 的儿童，按年龄和地点分层，采用区组随机化（区组大小为 4）分为 4 周阿莫西林克拉维酸钾组（25-35 mg/kg 每日两次口服混悬剂；4 周组）或 2 周阿莫西林克拉维酸钾组加 2 周安慰剂组（2 周组）。在数据分析完成之前，儿童、照料者、所有研究协调员和研究人员对治疗分配均不知情。主要结局是第 28 天的临床治愈率（咳嗽缓解）。次要结局是 6 个月时 PBB 的复发率、下一次加重的时间、从基线到第 28 天以及从第 28 天到 7 个月的父母代理咳嗽特异性生活质量（PC-QoL）评分变化、不良事件、鼻拭子细菌学和抗菌药物耐药性。分析遵循意向治疗原则。该试验已完成，并在澳大利亚/新西兰注册中心（ACTRN12616001725459）注册。
2017 年 3 月 8 日至 2019 年 9 月 30 日期间，共纳入 106 名儿童（4 周组 52 例，中位年龄 2.2 岁[IQR 1.3-4.1]；2 周组 54 例，中位年龄 1.7 岁[1.2-3.8]），其中 90 例完成了 4 周治疗。第 28 天，4 周组的主要结局（52 例患者中有 32 例[62%]）与 2 周组（54 例患者中有 38 例[70%]）的临床治愈率无显著差异（调整后的相对风险 0.87[95%CI 0.60-1.28]；p=0.49）。4 周组的咳嗽再次加重时间明显长于 2 周组（中位时间 150 天[IQR 38-181]vs 36 天[15-181]；调整后的风险比 0.47[0.25-0.90]；p=0.02）。6 个月时 PBB 的复发率在 4 周组为 32 例患者中的 17 例（53%），在 2 周组为 38 例患者中的 28 例（74%），但两组之间的差异无统计学意义（调整后的优势比 0.39[0.14-0.94]；p=0.04）。PC-QoL 从基线到第 28 天均有显著改善，但两组之间无显著差异（平均差值-0.2[95%CI-1.0 至 0.6]；p=0.64）。从第 28 天到 7 个月，两组的 PC-QoL 中位数均保持稳定，两组之间无差异。两组的呼吸道病原体和抗菌药物耐药性（48 例患儿可提供配对拭子）数据相似。2 周组和 4 周组各有 13 例（25%）和 10 例（19%）患儿发生不良事件（p=0.57）。
与 2 周疗程相比，治疗慢性湿性咳嗽和疑似 PBB 儿童的阿莫西林克拉维酸钾 4 周疗程在第 28 天达到临床治愈率方面优势不大。然而，由于 4 周疗程导致咳嗽无发作期延长，确定哪些儿童将从更长的抗生素疗程中受益是当务之急。
昆士兰儿童医院基金会。
