SUMMER CONFERENCE ON NEONATOLOGY AVIGNON 2017 · S. thermophilus and B. lactis reduced severe NEC in very preterm infants, but not definite LOS or mortality. Probiotics may have greatest

Controversies on the use of

probiotics in neonatology

Teresa del Moral MD, MPH

University of Miami

SUMMER CONFERENCE ON NEONATOLOGY

AVIGNON 2017

Disclosure

Probiotics Research supported by IBT.

Outline

• Newborn microbiota

• Premature infant dysbacteriosis

• Manipulation of the microbiota: probiotics

– Evidence

– Controversies

Monks

(Refine Fermentation)

PasteurizationSumerians

(Cheese)

Abraham

(Milk & curds)

Celts & Huns

(Khefir)

Ingestion of Bacteria

Antibiotics

In the last 100 years, we drastically

changed our ingestion of microbes and our

microbial environment.

20002000 BC AD3500 BC

Intestine + Microbioma = Ecosystem

-

SIMBIOSISThe interaction between these bacteria and the intestine is an

ecosystem in which the microbiota does many jobs in exchange

for the raw material / nutritional substrates and the shelter its host

provides

DC

DC

TLRIFNγ

NF-kb

MAPK

BC PC IgADevelopment of tolerance

Modulation immune system

ROLE OF MICROBIOTIA IN THE IMMATURE INTESTINE

Tolerance

Undigested

carbohydrates

Vit K

Lactic, formic acetic acid

Short Chain Fatty Acids Acid Barrier function

Digestion

Digestion

Newborn microbioma

-Intrauterine : partial colonization

-Delivery : vaginal ?

-Post natal: breast feeding

Sharon Unger(2015) 77, 205-213. doi:10.1038/pr.2014.162

Gut microbiota of the very low birth weight infant

Alteration of the Intestinal Colonization in

Premature Infants

•Type of delivery

•Environment

•Diet

•Use of antibiotics

GUT MICROBIOTA

DYSBIOSIS

2

Development of the Intestinal Bacterial Composition in

Hospitalized Preterm Infants in Comparison with

Breast-Fed, Full-Term Infants. (SCHWIERTZ 2009)

Ped Pediatric Research. 54(3):393-399, September 2003

Premature infants is a population

that can benefit the most from

restauration of intestinal microflora

Manipulation: Probiotics

Oral Probiotics Reduce the Incidence and

Severity of Necrotizing Enterocolitis in Very

Low Birth Weight Infants (Lin 2005)

• Probiotic Control p

• N 180 187

• BW 1104 (242) 1071 (243)

• Mortality 3.9% 10.7% 0.009

• Sepsis 12.2% 19.3% 0.03

• NEC II-III 1.1% 5.3% 0.04

Prospective, RCT, 1999-2003, Level III NICU of Taiwan

Infants <1500g who started feeds enterally and survived beyond the 7th

day

L. acidophilus and B. infantis 125 mg/kg per dose BID ???

Probiotics for prevention ofnecrotizing enterocolitis in preterm infantsSawh et al. (2016), PeerJ, DOI 10.7717/peerj.2429

•Randomized controlled trials of any enteral probiotic supplementation in preterm infants < 37 weeks gestation or infants < 2500g

•Treatment continued for 7 days

A total of 38 trials enrolling 10,520 infants were

eligible for inclusion in the meta-analysis.

Prevention of NEC with probiotics: a systematic review and meta-analysis.

Sawh et al. (2016), PeerJ, DOI 10.7717/peerj.2429

38 trials n = 10,520 subjects

Severe NEC in all infants. RR 0.53 95% CI (0.42-0.66)



8 trials n= 1618 Subjects < 1000 g

NEC no significant differences



31 trials n= 8.707 subjects

Sepsis RR 0.88 95% CI (0.77-1.00)



29 trials n= 9.507 subjects

All causes mortality RR 0.79 95% CI (0.68- 0.93)]

-A multicenter, double-blinded, placebo-controlled, randomized trial

-Bifidobacterium infantis, Streptococcus thermophilus and Bifidobacterium lactis (ABC Dophilus Probiotic Powder for Infants, Solgar USA) containing 1 x 109 total organisms] (maltodextrin)

-very preterm infants, born before 32 completed weeks' gestation and weighing under 1500g.

-Primary outcome was the incidence of at least one episode of definite culture positive LOS.

The ProPrems Randomized Trial Investigating the Effects of Probiotics on Late Onset Sepsis in Very Preterm Infants

Costeloe, The Probiotics in Preterm Infants Study Collaborative Group*

Lancet 2016; 387: 649–60

Trial profile.

Jacobs et al. Pediatrics 2013;132:1055-1062

Probiotic Effects on Late-onset Sepsis in Very Preterm

Infants: A Randomized Controlled Trial. Jacobs et all

Pediatrics 2013

The ProPrems Randomized Trial Investigating the Effects of Probiotics on Late Onset Sepsis in Very Preterm Infants

4.4%

2.0%

Jacobs et al .Pediatrics 2013

Supplementation with the probiotic combination B. infantis, S. thermophilus and B. lactis reduced severe NEC in very preterm infants, but not definite LOS or mortality.

Probiotics may have greatest impact globally in settings with higher rates of NEC, mortality and LOS than in Australia and New Zealand.

The ProPrems Randomized Trial Investigating the Effects of Probiotics on Late Onset Sepsis in Very Preterm Infants (Jacobs 2013)

Bifidobacterium breve BBG-001 in very preterm infants: a randomized

controlled phase 3 trial

Kate Costeloe, Lancet 2016; 387: 649–60

Bifidobacterium breve BBG-001 in very preterm infants:

a randomized controlled phase 3 trial

Costeloe, The Probiotics in Preterm Infants Study Collaborative Group*

Lancet 2016; 387: 649–60

Bifidobacterium breve BBG-001 in very preterm infants:

a randomised controlled phase 3 trial Kate Costeloe, and The Probiotics in Preterm Infants Study Collaborative Group*

Lancet 2016; 387: 649–60

Should the use of

probiotics in the preterm

be routine?

Millar M, Wilks M, Fleming P, et al. Arch Dis Child Fetal Neonatal Ed (Sep 2010).

Should the use of probiotics in

the preterm be routine?

• Do all probiotics have the same effect ?

• What are the mechanism of action ?

• What are the long term consequences ?

• Will routine administration produce cross

colonization ?

Millar M, Wilks M, Fleming P, et al. Arch Dis Child Fetal Neonatal Ed (Sep 2010).

- MORTALITY (4) 0.61 (0.38-0.97)

- NECROTIZING ENTEROCOLITIS (4) 0.37 (0.19-0.73)

LACTOBACILLUS

- MORTALITY (5) 0.47 (0.26-0.87)


LACTOBACILLUS + BIFIDOBACTERIA

- MORTALITY (3) 0.74 (0.18-2.97)


Relative Risk and 95% CI

Outcome Relative Risk( 95% CI ) 0.5 1.0 2.0 4.00.2

Decreased IncreasedRisk

0.5 1.0 2.0 4.00.2

Probiotic supplement reduces risk of necrotizing enterocolitis and

mortality in preterm very low-birth-weight infants: an updated

meta-analysis of 20 randomized, controlled trial

Wang 2012

BIFIDOBACTERIA

Effects of probiotics can not be generalized

Do different probiotics have the same

mechanisms ?

Effect of a probiotic formula on intestinal Ig A

production in healthy children

Total Ig A

0

0.5

1

1.5

2

2.5

3

3.5

4

4.5

Days of B. Bb 12 intake

mg

/g

feces

Before 3 8 20 After

Fukushima 1997

Anti-poliovirus IgA

0

0.05

0.1

0.15

0.2

0.25

Days of B. Bb 12 intake

Ab

so

ran

ce 4

50/6

50 n

m

Before 3 8 20 After

* *

Alive and Dead Lactobacillus rhamnosus GG

decrease TNFα –Induced Interleukine-8

Production in Caco-2 Cells

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

Control TNF LGG TNF+LGG

IL-

8/ G

AP

DH

(re

lati

ve

in

tes

ity

Zhang 2005

Table 1. Inhibitory activities of various L. reuteri strains

toward pathogenic bacteria

Organism Inhibitory Activity*

Strain Origin S. aureus S. enteritidis

11284

T1

4020

2010

1063

M164

SD2112

Chicken

Turkey

Mouse

Rat

Pig

Rhesus monkey

Human

++

++

-

+

++

++

+++

++

++

-

+

++

+++

+++

*- = no inhibition, + = increasing degree of inhibition

Sinkievicz 2001


- Evaluate probiotic strain specific

mechanisms of action


Evaluate strain specific mechanisms

Source of probiotic

Probiotics in very preterm infants:

the PiPS trial

Deshpande, et al: www.thelancet.com Vol 388, 2016

Effects of probiotics can not be

generalized

Evaluate strain specific mechanisms

Source of probiotic

How to assess colonization

They are live microorganisms/ infections

Occasional cases of bacteriemia associated with probiotics

No serious adverse effects have been reported in any of the RTC in newborn infants

REGULATIONS

Safety

EfficacyOnly products containing well defined strains and

quantity

Strains-specific effects and mechanisms of action have

been characterized

A new risk factor for neonatal vancomycin-

resistant Enterococcus colonisation: bacterial

probiotics (Topcuoglu 2014)

Validating bifidobacterial species and subspecies identity in

commercial probiotic products

Lewis et al: Ped Res 79, 445-451. 2016

Validating bifidobacterial species and subspecies identity in

commercial probiotic products

Lewis et al: Ped Res 79, 445-451. 2016

FDA REGULATIONS

• Dietary supplement – Center for Food Safety and Applied Nutrition

– GRAS (Generally Recognized As Save)

• Live Biotherapeutic – A probiotic used to diagnosis, cure treat or prevent

diseases is a drug and a biological product

– The Center for Biologics Evaluation and Research

regulates biological products when used for clinical

indications

– IND (US, 21CFR 312)

Research to fully understand the potential benefits

of biotherapeutics

• Each potential biotherapeutic should be assessed independently

– Identification of strains that can withstand the intestinal tract

– Extrapolation of data from closely related strains is not acceptable

• Only well defined strains products and study populations should be used in trials

• Range of minimal effective doses

• Long term effects on immune and gastrointestinal systems

Probiotic suitable for premature infant

• Evaluation of mechanisms of action

• Source of bacteria

• Assess colonization

• Safety and regulatory issues

A randomized, double blind, parallel-

group, dose escalation placebo-

controlled multicenter study to

investigate the safety and tolerability

of IBP-9414 administered to preterm

infants

Lactobacillus Reuteri

• Indigeneus bacteria (Peruviam mother 1991)

• Proven colonization of the human gastrointestinal tract (Valeur 20030)

• Survival capacities during passage of the gastrointestinal tract (Nollet 1999)

• Produces a potent, broad spectrum antimicrobial substance termed reuterin

Human-derived probiotic Lactobacillus reuteri

strains differentially reduce intestinal inflammation .

Liu Y et al. Am J Physiol Gastrointest Liver Physiol

2010;299:G1087-G1096©2010 by American Physiological Society

• Primary objetive

• To assess safety and tolerability in premature infants of given IBP 9414-

– at two doses 1x10 8 and 1x 10 9 cfu vs placebo in

– two birth weight categories 1001 – 2000 g and 500-1000 g.

• Exploratory Objectives

• Validity and utility of outcome measures including NEC, feeding patterns and NICU discharge will be examined.

Drug Product IBP-9414

IBP-9414•Freeze-dried powder for oral suspension•Oral-enteral feeding

Development of IBP-9414 as a live bacterial therapy for the prevention of NEC.

Under drug manufacture and regulations . Manufacturing process developed to allow opening of IND

IBP-9414 has been approved by the FDA for orphan drug designation for the prevention of NEC.

Study design

Phase II clinical trial ongoing at 15 sites in the US

Placenta

Breast milk

Induce maturation

Clinical benefits

Probiotics to the mother

Probiotics to the newborn

PROBIOTICOS IN PERINATOLOGY

Prebiotics

Picasso

Thank you

Documents

SUMMER CONFERENCE ON NEONATOLOGY AVIGNON 2017 · S. thermophilus and B. lactis reduced severe NEC in very preterm infants, but not definite LOS or mortality. Probiotics may have greatest