Azithromycin for the prevention of rehospitalisation and death among Kenyan children being discharged from hospital: a double-blind, placebo-controlled, randomised controlled trial,The Lancet Global Health

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Azithromycin for the prevention of rehospitalisation and death among Kenyan children being discharged from hospital: a double-blind, placebo-controlled, randomised controlled trial
The Lancet Global Health ( IF 19.9 ) Pub Date : 2021-09-21 , DOI: 10.1016/s2214-109x(21)00347-8
Patricia B Pavlinac ₁ , Benson O Singa ₂ , Kirkby D Tickell ₃ , Rebecca L Brander ₄ , Christine J McGrath ₃ , Mary Amondi ₅ , Joyce Otieno ₆ , Elizabeth Akinyi ₆ , Doreen Rwigi ₆ , Joseph D Carreon ₇ , Stephanie N Tornberg-Belanger ₈ , Ruth Nduati ₉ , Joseph B Babigumira ₁ , Liru Meshak ₁₀ , George Bogonko ₁₁ , Samuel Kariuki ₁₂ , Barbra A Richardson ₁₃ , Grace C John-Stewart ₁₄ , Judd L Walson ₁₅

Affiliation

Department of Global Health, University of Washington, Seattle, WA, USA.
Department of Global Health, University of Washington, Seattle, WA, USA; Centre for Clinical Research, Kenya Medical Research Institute, Nairobi, Kenya; Childhood Acute Illness and Nutrition Network, Nairobi, Kenya.
Department of Global Health, University of Washington, Seattle, WA, USA; Childhood Acute Illness and Nutrition Network, Nairobi, Kenya.
Bill & Melinda Gates Foundation, Seattle, WA, USA.
International AIDS Vaccine Initiative, Nairobi, Kenya.
Centre for Clinical Research, Kenya Medical Research Institute, Nairobi, Kenya.
The Clovers' Leaves Limited Company, Tempe, AZ, USA.
Department of Epidemiology, University of Washington, Seattle, WA, USA.
Department of Pediatrics and Child Health, University of Nairobi, Kenyatta National Hospital, Nairobi, Kenya.
Homa Bay Teaching and Referral Hospital, Homa Bay, Kenya.
Kisii Teaching and Referral Hospital, Kisii, Kenya.
Centre for Microbiology Research, Kenya Medical Research Institute, Nairobi, Kenya.
Department of Global Health, University of Washington, Seattle, WA, USA; Department of Biostatistics, University of Washington, Seattle, WA, USA.
Department of Global Health, University of Washington, Seattle, WA, USA; Department of Epidemiology, University of Washington, Seattle, WA, USA; Departments of Pediatrics and Medicine-Allergy and Infectious Diseases, University of Washington, Seattle, WA, USA.
Department of Global Health, University of Washington, Seattle, WA, USA; Department of Epidemiology, University of Washington, Seattle, WA, USA; Departments of Pediatrics and Medicine-Allergy and Infectious Diseases, University of Washington, Seattle, WA, USA; Childhood Acute Illness and Nutrition Network, Nairobi, Kenya.

Background

Mass drug administration of azithromycin to children in sub-Saharan Africa has been shown to improve survival in high-mortality settings. The period after hospital discharge is a time of elevated risk unaddressed by current interventions and might provide an opportunity for targeting empirical azithromycin administration. We aimed to assess the efficacy of azithromycin administered at hospital discharge on risk of death and rehospitalisation in Kenyan children younger than 5 years.

Methods

In this double-blind, placebo-controlled randomised trial, children were randomly assigned (1:1) to receive a 5-day course of azithromycin (oral suspension 10 mg/kg on day 1, followed by 5mg/kg per day on days 2–5) or identically appearing and tasting placebo at discharge from four hospitals in western Kenya. Children were eligible if they were aged 1–59 months at hospital discharge, weighed at least 2 kg, and had been admitted to hospital for any medical reason other than trauma, poisoning, or congenital anomaly. The primary outcome was death or rehospitalisation in the subsequent 6-month period in a modified intention-to-treat population, compared by randomisation group with Cox proportional hazards regression and Kaplan-Meier. Azithromycin resistance in Escherichia coli isolates from a random subset of children was compared by randomisation group with generalised estimating equations. This trial is registered with ClinicalTrials.gov, NCT02414399.

Findings

Between June 28, 2016, and Nov 4, 2019, 1400 children were enrolled in the trial at discharge from hospital, with 703 (50·2%) randomly assigned to azithromycin and 697 (49·8%) to placebo. Among the 1398 children included in the modified intention-to-treat analysis (702 in the azithromycin group and 696 in the placebo group), the incidence of death or rehospitalisation was 20·4 per 100 child-years in the azithromycin group and 22·5 per 100 child-years in the placebo group (adjusted hazard ratio 0·91, 95·5% CI 0·64–1·29, p=0·58). Azithromycin resistance was common in commensal E coli isolates from enrolled children before randomisation (37·7% of 406 isolates) despite only 3·7% of children having received a macrolide antibiotic during the hospitalisation. Azithromycin resistance was slightly higher at 3 months after randomisation in the azithromycin group (26·9%) than in the placebo group (19·1%; adjusted prevalence ratio 1·41, 95% CI 0·95–2·09, p=0·088), with no difference observed at 6 months (1·17, 0·78–1·76, p=0·44).

Interpretation

We did not observe a significant benefit of a 5-day course of azithromycin delivered to children younger than 5 years at hospital discharge despite the overall high risk of mortality and rehospitalisation. These findings highlight the need for more research into mechanisms and interventions for prevention of morbidity and mortality in the post-discharge period.

Funding

Eunice Kennedy Shriver National Institute of Child Health & Human Development.

中文翻译：

阿奇霉素预防肯尼亚出院儿童再住院和死亡：一项双盲、安慰剂对照、随机对照试验

背景

对撒哈拉以南非洲地区儿童的大规模给药阿奇霉素已被证明可以提高高死亡率环境中的生存率。出院后的时期是当前干预措施未解决的高风险时期，可能为针对经验性阿奇霉素给药提供机会。我们旨在评估出院时给予阿奇霉素对 5 岁以下肯尼亚儿童死亡和再住院风险的疗效。

方法

在这项双盲、安慰剂对照的随机试验中，儿童被随机分配（1:1）接受为期 5 天的阿奇霉素疗程（第 1 天口服混悬液 10 mg/kg，随后每天 5mg/kg 2-5）或在肯尼亚西部的四家医院出院时出现和品尝相同的安慰剂。如果儿童出院时年龄在 1-59 个月，体重至少 2 公斤，并且因创伤、中毒或先天性异常以外的任何医疗原因入院，则儿童符合条件。与 Cox 比例风险回归和 Kaplan-Meier 随机分组相比，主要结局是改良意向治疗人群在随后 6 个月期间的死亡或再次住院。大肠杆菌中的阿奇霉素耐药性随机分组与广义估计方程对来自儿童随机子集的分离株进行了比较。该试验已在 ClinicalTrials.gov 注册，NCT02414399。

发现

2016 年 6 月 28 日至 2019 年 11 月 4 日期间，1400 名儿童出院时参加了试验，其中 703 名（50·2%）随机分配到阿奇霉素组，697 名（49·8%）分配到安慰剂组。在改良意向治疗分析中纳入的 1398 名儿童中（阿奇霉素组 702 人，安慰剂组 696 人），阿奇霉素组的死亡或再住院发生率为 20·4/100 儿童年，22·安慰剂组每 100 个儿童年 5 例（调整后的风险比 0·91, 95·5% CI 0·64–1·29, p=0·58）。阿奇霉素耐药在共生大肠杆菌中很常见尽管只有 3·7% 的儿童在住院期间接受了大环内酯类抗生素治疗，但随机分组前已从登记儿童中分离出分离株（406 株中的 37·7%）。随机分组后 3 个月，阿奇霉素组的阿奇霉素耐药性 (26·9%) 略高于安慰剂组 (19·1%；调整后的患病率 1·41, 95% CI 0·95–2·09, p =0·088)，在 6 个月时没有观察到差异 (1·17, 0·78–1·76, p=0·44)。