ImportanceThe effects of probiotic interventions on colonization with resistant bacteria and early microbiome development in preterm infants remain to be clarified.ObjectiveTo examine the efficacy of Bifidobacterium longum subsp infantis, Bifidobacterium animalis subsp lactis (BB-12), and Lactobacillus acidophilus (La-5) probiotics to prevent colonization with multidrug-resistant organisms or highly epidemic bacteria (MDRO+) and to shape the microbiome of preterm infants toward the eubiotic state of healthy full-term infants.Design, Setting, and ParticipantsThe multicenter, double-blinded, placebo-controlled, group sequential, phase 3 Priming Immunity at the Beginning of Life (PRIMAL) randomized clinical trial, conducted from April 2018 to June 2020, included infants with gestational age of 28 to 32 weeks at 18 German neonatal units. Data analyses were conducted from March 2020 to August 2023.InterventionA total of 28 days of multistrain probiotics diluted in human milk/formula starting within the first 72 hours of life.Main Outcomes and MeasuresColonization with MDRO+ at day 30 of life (primary end point), late-onset sepsis and severe gastrointestinal complication (safety end points), and gut dysbiosis, ie, deviations from the microbiome of healthy, term infants (eubiosis score) based on 16-subunit ribosomal RNA and metagenomic sequencing.ResultsAmong the 643 infants randomized until the stop of recruitment based on interim results, 618 (median [IQR] gestational age, 31.0 [29.7-32.1] weeks; 333 male [53.9%]; mean [SD] birth weight, 1502 [369] g) had follow-up at day 30. The interim analysis with all available data from 219 infants revealed MDRO+ colonization in 43 of 115 infants (37.4%) in the probiotics group and in 39 of 104 infants (37.5%) in the control group (adjusted risk ratio, 0.99; 95% CI, 0.54-1.81; P = .97). Safety outcomes were similar in both groups, ie, late-onset sepsis (probiotics group: 8 of 316 infants [2.5%]; control group: 12 of 322 infants [3.7%]) and severe gastrointestinal complications (probiotics group: 6 of 316 infants [1.9%]; control group: 7 of 322 infants [2.2%]). The probiotics group had higher eubiosis scores than the control group at the genus level (254 vs 258 infants; median scores, 0.47 vs 0.41; odds ratio [OR], 1.07; 95% CI, 1.02-1.13) and species level (96 vs 83 infants; median scores, 0.87 vs 0.59; OR, 1.28; 95% CI, 1.19-1.38). Environmental uptake of the B infantis probiotic strain in the control group was common (41 of 84 [49%]), which was highly variable across sites and particularly occurred in infants with a sibling who was treated with probiotics.Conclusions and RelevanceMultistrain probiotics did not reduce the incidence of MDRO+ colonization at day 30 of life in preterm infants but modulated their microbiome toward eubiosis.Trial RegistrationGerman Clinical Trials Register: DRKS00013197

中文翻译：

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双歧杆菌和乳酸菌益生菌与早产儿肠道菌群失调


益生菌干预对早产儿耐药菌定植和早期微生物组发育的影响仍有待阐明。目的检查长双歧杆菌婴儿亚种、动物双歧杆菌乳酸亚种 (BB-12) 和嗜酸乳杆菌 (La-5) 的功效益生菌可防止多重耐药微生物或高流行性细菌 (MDRO+) 的​​定植，并塑造早产儿的微生物群，使其接近健康足月婴儿的优生状态。 设计、环境和参与者多中心、双盲、安慰剂对照2018 年 4 月至 2020 年 6 月进行的分组序贯、生命之初启动免疫 (PRIMAL) 3 期随机临床试验，纳入了 18 个德国新生儿单位的胎龄 28 至 32 周的婴儿。数据分析于 2020 年 3 月至 2023 年 8 月进行。干预从出生后 72 小时内开始，在母乳/配方奶粉中稀释多菌株益生菌，为期 28 天。主要结果和措施在出生后第 30 天进行 MDRO+ 定植（主要终点） 、迟发性脓毒症和严重胃肠道并发症（安全终点），以及肠道菌群失调，即基于 16 亚基核糖体 RNA 和宏基因组测序的健康足月婴儿微生物组的偏差（优生评分）。 结果 在 643 名婴儿中随机分组直到根据中期结果停止招募为止，618 名（中位 [IQR] 胎龄，31.0 [29.7-32.1] 周；333 名男性 [53.9%]；平均 [SD] 出生体重，1502 [369] g）进行了随访-第 30 天时，对 219 名婴儿的所有可用数据进行的中期分析显示，益生菌组 115 名婴儿中有 43 名 (37.4%) 存在 MDRO+ 定植，104 名婴儿中有 39 名 (37.4%) 存在 MDRO+ 定植。5%）在对照组（调整后的风险比，0.99；95% CI，0.54-1.81；P = .97）。两组的安全性结果相似，即迟发性败血症（益生菌组：316 名婴儿中的 8 名[2.5%]；对照组：322 名婴儿中的 12 名[3.7%]）和严重胃肠道并发症（益生菌组：316 名婴儿中的 6 名）婴儿[1.9%]；对照组：322 名婴儿中的 7 名[2.2%]）。益生菌组在属水平（254 vs 258 名婴儿；中位数分数，0.47 vs 0.41；比值比 [OR]，1.07；95% CI，1.02-1.13）和物种水平（96 vs 258 名婴儿）的优生分数高于对照组。 83 名婴儿；中位分数，0.87 vs 0.59；OR，1.28；95% CI，1.19-1.38）。对照组中婴儿双歧杆菌益生菌菌株的环境摄取很常见（84 例中的 41 例 [49%]），这种情况在不同地点之间差异很大，特别是在有兄弟姐妹接受益生菌治疗的婴儿中。结论和相关性多菌株益生菌没有降低早产儿出生后 30 天时 MDRO+ 定植的发生率，但调节其微生物组以实现优生。试验注册德国临床试验注册号：DRKS00013197