Mogeni Polycarp, Ochieng John Benjamin, Atlas Hannah E, Tickell Kirkby D, Rwigi Doreen, Kariuki Kevin, Aluoch Laura Riziki, Sonye Catherine, Apondi Evans, Ambila Lilian, Diakhate Mame M, Singa Benson O, Liu Jie, Platts-Mills James A, Fang Ferric C, Walson Judd L, Houpt Eric R, Pavlinac Patricia B
Center for Microbiology Research, Kenya Medical Research Institute, Nairobi, Kenya.
Department of Global Health, University of Washington, Seattle, Washington, USA.
J Infect Dis. 2025 Aug 14;232(2):e301-e308. doi: 10.1093/infdis/jiaf208.
The Toto Bora trial tested whether a 5-day course of azithromycin reduced the risk of rehospitalization or death in the 6 months following hospitalization among Kenyan children and found no overall benefit. We hypothesized that macrolide resistance in gut microbes could modify azithromycin's effect.
From June 2016 to November 2019, Kenyan children aged 1-59 months were enrolled at hospital discharge and randomized to azithromycin or placebo. DNA from fecal samples and Escherichia coli isolates was analyzed for common macrolide resistance genes. Cox proportional hazards regression models, including interaction terms between randomization arm and individual macrolide resistance genes, were used to analyze time to rehospitalization or death, with Bonferroni correction applied to account for multiple comparisons.
Among 1393 children tested, 94.7% had at least 1 macrolide resistance gene in their fecal DNA at hospital discharge, most commonly mph(A) (68.6% [955/1393]), followed by msr(D) (67.3% [937/1393]) and erm(B) (60.7% [846/1393]). Mef(A) (23.7% [330/1393]) was the only macrolide resistance gene that modified azithromycin's effect on rehospitalization or death (interaction P = .008). In children without the mef(A) gene, azithromycin reduced the hazard of rehospitalization or death by a third (hazard ratio [HR], 0.66 [95% confidence interval {CI}, .45-.99]) whereas among children with the mef(A) gene, there was a higher risk in those randomized to azithromycin (HR, 2.72 [95% CI, 1.21-6.09]). The effect size of azithromycin's impact on mortality and rehospitalization as separate outcomes in children with and without mef(A) were consistent but underpowered.
Macrolide resistance in the gut microbiome may influence the efficacy of azithromycin in children discharged from the hospital. Clinical Trials Registration. NCT02414399.
托托博拉试验旨在测试阿奇霉素5天疗程能否降低肯尼亚儿童住院后6个月内再次住院或死亡的风险，结果发现总体并无益处。我们推测肠道微生物中的大环内酯类耐药性可能会改变阿奇霉素的疗效。
2016年6月至2019年11月，1至59个月大的肯尼亚儿童在出院时入组，并随机分为阿奇霉素组或安慰剂组。对粪便样本和大肠杆菌分离株的DNA进行常见大环内酯类耐药基因分析。采用Cox比例风险回归模型，包括随机分组臂与个体大环内酯类耐药基因之间的交互项，来分析再次住院或死亡的时间，并应用Bonferroni校正以考虑多重比较。
在1393名接受检测的儿童中，94.7%在出院时其粪便DNA中至少有1个大环内酯类耐药基因，最常见的是mph(A)（68.6%[955/1393]），其次是msr(D)（67.3%[937/1393]）和erm(B)（60.7%[846/1393]）。Mef(A)（23.7%[330/1393]）是唯一能改变阿奇霉素对再次住院或死亡影响的大环内酯类耐药基因（交互P = 0.008）。在没有mef(A)基因的儿童中，阿奇霉素将再次住院或死亡的风险降低了三分之一（风险比[HR]，0.66[95%置信区间{CI}，0.45 - 0.99]），而在有mef(A)基因的儿童中，随机分配到阿奇霉素组的儿童风险更高（HR，2.72[95%CI，1.21 - 6.09]）。阿奇霉素对有和没有mef(A)基因的儿童作为单独结局的死亡率和再次住院率的影响大小是一致的，但效能不足。
肠道微生物群中的大环内酯类耐药性可能会影响阿奇霉素对出院儿童的疗效。临床试验注册编号：NCT02414399。
Zotero 插件
