European Molecular Biology Laboratory, Heidelberg, Germany.
Department of Pediatrics, University Hospital Schleswig-Holstein, Campus Lübeck, Lübeck, Germany.
JAMA Pediatr. 2024 Oct 1;178(10):985-995. doi: 10.1001/jamapediatrics.2024.2626.
The effects of probiotic interventions on colonization with resistant bacteria and early microbiome development in preterm infants remain to be clarified.
To 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 PARTICIPANTS: The 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.
A total of 28 days of multistrain probiotics diluted in human milk/formula starting within the first 72 hours of life.
Colonization 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.
Among 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.
Multistrain probiotics did not reduce the incidence of MDRO+ colonization at day 30 of life in preterm infants but modulated their microbiome toward eubiosis.
German Clinical Trials Register: DRKS00013197.
重要性：益生菌干预对早产儿定植耐药菌和早期微生物组发育的影响仍需阐明。
目的：研究长双歧杆菌亚种婴儿、动物双歧杆菌亚种乳双歧杆菌（BB-12）和嗜酸乳杆菌（La-5）益生菌预防多重耐药菌或高度流行菌（MDRO+）定植的效果，并使早产儿的微生物组向健康足月婴儿的生态状态发展。
设计、地点和参与者：多中心、双盲、安慰剂对照、分组序贯、III 期 Priming Immunity at the Beginning of Life（PRIMAL）随机临床试验，于 2018 年 4 月至 2020 年 6 月在德国 18 个新生儿单位进行。数据分析于 2020 年 3 月至 2023 年 8 月进行。
干预措施：在生命最初 72 小时内，每天 28 天用母乳/配方奶稀释的多菌株益生菌。
主要结局和测量指标：生命第 30 天的 MDRO+定植（主要终点）、晚发性败血症和严重胃肠道并发症（安全性终点）以及肠道菌群失调，即根据 16S 核糖体 RNA 和宏基因组测序，偏离健康足月婴儿的微生物组（生态评分）。
结果：在基于中期结果停止招募的 643 名随机婴儿中，618 名（中位数[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）在第 30 天进行了随访。219 名婴儿的所有可用数据的中期分析显示，益生菌组 115 名婴儿中有 43 名（37.4%）定植 MDRO+，对照组 104 名婴儿中有 39 名（37.5%）定植 MDRO+（调整风险比，0.99；95%CI，0.54-1.81；P=0.97）。两组的安全性结局相似，即晚发性败血症（益生菌组：316 名婴儿中有 8 名[2.5%]；对照组：322 名婴儿中有 12 名[3.7%]）和严重胃肠道并发症（益生菌组：316 名婴儿中有 6 名[1.9%]；对照组：322 名婴儿中有 7 名[2.2%]）。与对照组相比，益生菌组在属水平（254 名 vs 258 名婴儿；中位数评分，0.47 vs 0.41；优势比[OR]，1.07；95%CI，1.02-1.13）和种水平（96 名 vs 83 名婴儿；中位数评分，0.87 vs 0.59；OR，1.28；95%CI，1.19-1.38）的生态评分更高。对照组中 B infantis 益生菌株的环境摄取很常见（84 名婴儿中有 41 名[49%]），这种情况在不同地点差异很大，特别是在有接受益生菌治疗的兄弟姐妹的婴儿中更为常见。
结论和相关性：多菌株益生菌不能降低早产儿生命第 30 天 MDRO+定植的发生率，但可使微生物组向生态状态发展。
试验注册：德国临床试验注册处：DRKS00013197。
