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Controversies on the use of
probiotics in neonatology
Teresa del Moral MD, MPH
University of Miami
SUMMER CONFERENCE ON NEONATOLOGY
AVIGNON 2017
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)
Prevention of NEC with probiotics: a systematic review and meta-analysis.
Sawh et al. (2016), PeerJ, DOI 10.7717/peerj.2429
8 trials n= 1618 Subjects < 1000 g
NEC no significant differences
Prevention of NEC with probiotics: a systematic review and meta-analysis.
Sawh et al. (2016), PeerJ, DOI 10.7717/peerj.2429
31 trials n= 8.707 subjects
Sepsis RR 0.88 95% CI (0.77-1.00)
Prevention of NEC with probiotics: a systematic review and meta-analysis.
Sawh et al. (2016), PeerJ, DOI 10.7717/peerj.2429
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
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)
- NECROTIZING ENTEROCOLITIS (6) 0.33 (0.19-0.58)
LACTOBACILLUS + BIFIDOBACTERIA
- MORTALITY (3) 0.74 (0.18-2.97)
- NECROTIZING ENTEROCOLITIS (8) 0.30 (0.16-0.58)
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
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
Effects of probiotics can not be generalized
- Evaluate probiotic strain specific
mechanisms of action
Effects of probiotics can not be generalized
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.
Placenta
Breast milk
Induce maturation
Clinical benefits
Probiotics to the mother
Probiotics to the newborn
PROBIOTICOS IN PERINATOLOGY
Prebiotics