Bifidobacterium and Lactobacillus Probiotics and Gut Dysbiosis in Preterm Infants: The PRIMAL Randomized Clinical Trial

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

Bifidobacterium and Lactobacillus Probiotics and Gut Dysbiosis in Preterm Infants: The PRIMAL Randomized Clinical Trial

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 KörnerAngela 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

27 Zitate (Scopus)

Abstract

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.

Originalsprache	Englisch
Zeitschrift	JAMA Pediatrics
Jahrgang	178
Ausgabenummer	10
Seiten (von - bis)	985-995
Seitenumfang	11
ISSN	2168-6203
Publikationsstatus	Veröffentlicht - 07.10.2024

Fördermittel

Conflict of Interest Disclosures: Dr Klopp reported receiving grants from German Ministry of Education and Research during the conduct of the study. Dr Kuntz reported receiving grants from the German Ministry of Education and Research during the conduct of the study. Dr Kribs reported receiving lecture fees from Chiesi outside the submitted work. Dr Stein reported receiving grants from Universit\u00E4tsklinikum Schleswig Holstein to support data acquisition and lecture fees from Chiesi outside the submitted work. Dr Gille reported receiving grants from the Federal Ministry of Education and Research and the German Center for Infection Research outside the submitted work; in addition, Dr Gille reported having a patent for US 11,591,568 B2 licensed. Dr Pirr reported receiving grants from the German Ministry of Education and Research and the Deutsche Forschungsgemeinschaft outside the submitted work. Dr Kopp reported receiving grants from the University of Bern and personal fees from Infectopharm GmbH, Allergopharma GmbH, and Sanofi GmbH outside the submitted work. Dr G\u00F6pel reported receiving grants from German Ministry of Education and Research for the PRIMAL study during the conduct of the study. Dr Herting reported receiving grants from Klinik f\u00FCr Kinder und Jugendmedizin, the University of L\u00FCbeck, and the German Government. Dr Zemlin reported receiving grants from BMBF during the conduct of the study. Dr K\u00F6nig reported receiving grants from German Ministry of Education and Research during the conduct of the study. Dr Henneke reported receiving grants from BMBF, German Research Council, and the Else-Kr\u00F6ner Foundation and personal fees from BioNTech and GSK outside the submitted work. Dr H\u00E4rtel reported receiving lecture fees from Chiesi and being involved in national and international guidelines related to neonatal infection. No other disclosures were reported. This work was supported by grant 01GL1746B from the German Ministry of Education and Research.

Träger	Trägernummer
Klinik für Kinder und Jugendmedizin
Bundesministerium für Bildung und Forschung
Allergopharma GmbH
Deutsche Forschungsgemeinschaft
University of Bern
Universität zu Lübeck
Else-Kröner Foundation

UN SDGs

Dieser Output leistet einen Beitrag zu folgendem(n) Ziel(en) für nachhaltige Entwicklung

SDG 3 – Gesundheit und Wohlergehen
SDG 6 – Sauberes Wasser und sanitäre Einrichtungen

Strategische Forschungsbereiche und Zentren

Forschungsschwerpunkt: Infektion und Entzündung - Zentrum für Infektions- und Entzündungsforschung Lübeck (ZIEL)

DFG-Fachsystematik

2.21-03 Medizinische Mikrobiologie und Mykologie, Hygiene, Molekulare Infektionsbiologie

Weitere Links

Zitieren

Van Rossum, T., Haiß, A., Knoll, R. L., Marißen, J., Podlesny, D., Pagel, J., Bleskina, M., Vens, M., Fortmann, I., Siller, B., Ricklefs, I., Klopp, J., Hilbert, K., Meyer, C., Thielemann, R., Goedicke-Fritz, S., Kuntz, M., Wieg, C., Teig, N., ... Härtel, C. (2024). Bifidobacterium and Lactobacillus Probiotics and Gut Dysbiosis in Preterm Infants: The PRIMAL Randomized Clinical Trial. JAMA Pediatrics, 178(10), 985-995.

@article{4dd45893f94b4e10af30b93fbcb0b8e8,

title = "Bifidobacterium and Lactobacillus Probiotics and Gut Dysbiosis in Preterm Infants: The PRIMAL Randomized Clinical Trial",

abstract = "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.",

author = "\{Van Rossum\}, Thea and Annette Hai{\ss} and Knoll, \{Rebecca L\} and Janina Mari{\ss}en and Daniel Podlesny and Julia Pagel and Marina Bleskina and Maren Vens and Ingmar Fortmann and Bastian Siller and Isabell Ricklefs and Jonas Klopp and Katja Hilbert and Claudius Meyer and Roman Thielemann and Sybelle Goedicke-Fritz and Martin Kuntz and Christian Wieg and Norbert Teig and Thorsten K{\"o}rner and Angela Kribs and Hannes Hudalla and Markus Knuf and Anja Stein and Christian Gille and Soyhan Bagci and Frank Dohle and Hans Proquitt{\'e} and Olbertz, \{Dirk M\} and Esther Schmidt and Lutz Koch and Sabine Pirr and Jan Rupp and Juliane Spiegler and Kopp, \{Matthias V\} and Wolfgang G{\"o}pel and Egbert Herting and Forslund, \{Sofia K\} and Dorothee Viemann and Michael Zemlin and Peer Bork and Stephan Gehring and K{\"o}nig, \{Inke R\} and Philipp Henneke and Christoph H{\"a}rtel",

note = "Publisher Copyright: Copyright {\textcopyright} 2024 Van Rossum T et al.",

year = "2024",

month = oct,

day = "7",

language = "English",

volume = "178",

pages = "985--995",

journal = "JAMA Pediatrics",

issn = "2168-6203",

publisher = "American Medical Association",

number = "10",

}

Van Rossum, T, Haiß, A, Knoll, RL, Marißen, J, Podlesny, D, Pagel, J, Bleskina, M, Vens, M, Fortmann, I, Siller, B, Ricklefs, I, Klopp, J, Hilbert, K, Meyer, C, Thielemann, R, Goedicke-Fritz, S, Kuntz, M, Wieg, C, Teig, N, Körner, T, Kribs, A, Hudalla, H, Knuf, M, Stein, A, Gille, C, Bagci, S, Dohle, F, Proquitté, H, Olbertz, DM, Schmidt, E, Koch, L, Pirr, S, Rupp, J, Spiegler, J, Kopp, MV, Göpel, W, Herting, E, Forslund, SK, Viemann, D, Zemlin, M, Bork, P, Gehring, S, König, IR, Henneke, P & Härtel, C 2024, 'Bifidobacterium and Lactobacillus Probiotics and Gut Dysbiosis in Preterm Infants: The PRIMAL Randomized Clinical Trial', JAMA Pediatrics, Jg. 178, Nr. 10, S. 985-995.

TY - JOUR

T1 - Bifidobacterium and Lactobacillus Probiotics and Gut Dysbiosis in Preterm Infants

T2 - The PRIMAL Randomized Clinical Trial

AU - Van Rossum, Thea

AU - Haiß, Annette

AU - Knoll, Rebecca L

AU - Marißen, Janina

AU - Podlesny, Daniel

AU - Pagel, Julia

AU - Bleskina, Marina

AU - Vens, Maren

AU - Fortmann, Ingmar

AU - Siller, Bastian

AU - Ricklefs, Isabell

AU - Klopp, Jonas

AU - Hilbert, Katja

AU - Meyer, Claudius

AU - Thielemann, Roman

AU - Goedicke-Fritz, Sybelle

AU - Kuntz, Martin

AU - Wieg, Christian

AU - Teig, Norbert

AU - Körner, Thorsten

AU - Kribs, Angela

AU - Hudalla, Hannes

AU - Knuf, Markus

AU - Stein, Anja

AU - Gille, Christian

AU - Bagci, Soyhan

AU - Dohle, Frank

AU - Proquitté, Hans

AU - Olbertz, Dirk M

AU - Schmidt, Esther

AU - Koch, Lutz

AU - Pirr, Sabine

AU - Rupp, Jan

AU - Spiegler, Juliane

AU - Kopp, Matthias V

AU - Göpel, Wolfgang

AU - Herting, Egbert

AU - Forslund, Sofia K

AU - Viemann, Dorothee

AU - Zemlin, Michael

AU - Bork, Peer

AU - Gehring, Stephan

AU - König, Inke R

AU - Henneke, Philipp

AU - Härtel, Christoph

PY - 2024/10/7

Y1 - 2024/10/7

N2 - 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.

AB - 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.

UR - https://www.scopus.com/pages/publications/85200645428

UR - https://www.mendeley.com/catalogue/329d5666-5e72-3e6f-a309-9c8d1df62ddd/

M3 - Journal articles

C2 - 39102225

SN - 2168-6203

VL - 178

SP - 985

EP - 995

JO - JAMA Pediatrics

JF - JAMA Pediatrics

IS - 10

ER -

Bifidobacterium and Lactobacillus Probiotics and Gut Dysbiosis in Preterm Infants: The PRIMAL Randomized Clinical Trial

Abstract

Fördermittel

UN SDGs

Strategische Forschungsbereiche und Zentren

DFG-Fachsystematik

Weitere Links

Fingerprint

Zitieren