Thea Van Rossum, Annette Haiß, Rebecca L Knoll, Janina Marißen, Daniel Podlesny, Julia Pagel, Marina Bleskina, Maren Vens, Ingmar Fortmann, Bastian Siller, Isabell Ricklefs, Jonas Klopp, Katja Hilbert, Claudius Meyer, Roman Thielemann, Sybelle Goedicke-Fritz, Martin Kuntz, Christian Wieg, Norbert Teig, Thorsten Körner, Angela Kribs, Hannes Hudalla, Markus Knuf, Anja Stein, Christian Gille, Soyhan Bagci, Frank Dohle, Hans Proquitté, Dirk M Olbertz, Esther Schmidt, Lutz Koch, Sabine Pirr, Jan Rupp, Juliane Spiegler, Matthias V Kopp, Wolfgang Göpel, Egbert Herting, Sofia K Forslund, Dorothee Viemann, Michael Zemlin, Peer Bork, Stephan Gehring, Inke R König, Philipp Henneke, Christoph Härtel
{"title":"双歧杆菌和乳酸杆菌益生菌与早产儿肠道菌群失调：PRIMAL 随机临床试验》。","authors":"Thea Van Rossum, Annette Haiß, Rebecca L Knoll, Janina Marißen, Daniel Podlesny, Julia Pagel, Marina Bleskina, Maren Vens, Ingmar Fortmann, Bastian Siller, Isabell Ricklefs, Jonas Klopp, Katja Hilbert, Claudius Meyer, Roman Thielemann, Sybelle Goedicke-Fritz, Martin Kuntz, Christian Wieg, Norbert Teig, Thorsten Körner, Angela Kribs, Hannes Hudalla, Markus Knuf, Anja Stein, Christian Gille, Soyhan Bagci, Frank Dohle, Hans Proquitté, Dirk M Olbertz, Esther Schmidt, Lutz Koch, Sabine Pirr, Jan Rupp, Juliane Spiegler, Matthias V Kopp, Wolfgang Göpel, Egbert Herting, Sofia K Forslund, Dorothee Viemann, Michael Zemlin, Peer Bork, Stephan Gehring, Inke R König, Philipp Henneke, Christoph Härtel","doi":"10.1001/jamapediatrics.2024.2626","DOIUrl":null,"url":null,"abstract":"<p><strong>Importance: </strong>The effects of probiotic interventions on colonization with resistant bacteria and early microbiome development in preterm infants remain to be clarified.</p><p><strong>Objective: </strong>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.</p><p><strong>Design, setting, and participants: </strong>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.</p><p><strong>Intervention: </strong>A total of 28 days of multistrain probiotics diluted in human milk/formula starting within the first 72 hours of life.</p><p><strong>Main outcomes and measures: </strong>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.</p><p><strong>Results: </strong>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.</p><p><strong>Conclusions and relevance: </strong>Multistrain probiotics did not reduce the incidence of MDRO+ colonization at day 30 of life in preterm infants but modulated their microbiome toward eubiosis.</p><p><strong>Trial registration: </strong>German Clinical Trials Register: DRKS00013197.</p>","PeriodicalId":14683,"journal":{"name":"JAMA Pediatrics","volume":null,"pages":null},"PeriodicalIF":24.7000,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Bifidobacterium and Lactobacillus Probiotics and Gut Dysbiosis in Preterm Infants: The PRIMAL Randomized Clinical Trial.\",\"authors\":\"Thea Van Rossum, Annette Haiß, Rebecca L Knoll, Janina Marißen, Daniel Podlesny, Julia Pagel, Marina Bleskina, Maren Vens, Ingmar Fortmann, Bastian Siller, Isabell Ricklefs, Jonas Klopp, Katja Hilbert, Claudius Meyer, Roman Thielemann, Sybelle Goedicke-Fritz, Martin Kuntz, Christian Wieg, Norbert Teig, Thorsten Körner, Angela Kribs, Hannes Hudalla, Markus Knuf, Anja Stein, Christian Gille, Soyhan Bagci, Frank Dohle, Hans Proquitté, Dirk M Olbertz, Esther Schmidt, Lutz Koch, Sabine Pirr, Jan Rupp, Juliane Spiegler, Matthias V Kopp, Wolfgang Göpel, Egbert Herting, Sofia K Forslund, Dorothee Viemann, Michael Zemlin, Peer Bork, Stephan Gehring, Inke R König, Philipp Henneke, Christoph Härtel\",\"doi\":\"10.1001/jamapediatrics.2024.2626\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Importance: </strong>The effects of probiotic interventions on colonization with resistant bacteria and early microbiome development in preterm infants remain to be clarified.</p><p><strong>Objective: </strong>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.</p><p><strong>Design, setting, and participants: </strong>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.</p><p><strong>Intervention: </strong>A total of 28 days of multistrain probiotics diluted in human milk/formula starting within the first 72 hours of life.</p><p><strong>Main outcomes and measures: </strong>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.</p><p><strong>Results: </strong>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). 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Bifidobacterium and Lactobacillus Probiotics and Gut Dysbiosis in Preterm Infants: The PRIMAL Randomized Clinical Trial.
Importance: The effects of probiotic interventions on colonization with resistant bacteria and early microbiome development in preterm infants remain to be clarified.
Objective: 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.
Intervention: A total of 28 days of multistrain probiotics diluted in human milk/formula starting within the first 72 hours of life.
Main outcomes and measures: 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.
Results: 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.
Conclusions and relevance: Multistrain probiotics did not reduce the incidence of MDRO+ colonization at day 30 of life in preterm infants but modulated their microbiome toward eubiosis.
Trial registration: German Clinical Trials Register: DRKS00013197.
期刊介绍：
JAMA Pediatrics, the oldest continuously published pediatric journal in the US since 1911, is an international peer-reviewed publication and a part of the JAMA Network. Published weekly online and in 12 issues annually, it garners over 8.4 million article views and downloads yearly. All research articles become freely accessible online after 12 months without any author fees, and through the WHO's HINARI program, the online version is accessible to institutions in developing countries.
With a focus on advancing the health of infants, children, and adolescents, JAMA Pediatrics serves as a platform for discussing crucial issues and policies in child and adolescent health care. Leveraging the latest technology, it ensures timely access to information for its readers worldwide.
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