Probiotics and prevention of NEC

Transcription

1 Probiotics and prevention of NEC

2 Indirect evidence

3 Innate recognition of of bacteria in in human milk is is mediated by by a milk-derived highly expressed pattern recognition receptor, soluble CD14C MO MO Labeta.. J Exp Exp Med Med 2000;191: breast milk of healthy women is a source of commensal bacteria to the infant gut. Cultivation-independent independent assessment of the bacterial diversity of breast milk among healthy women. Martín R. Res Microbiol. 2007;158:31-7 Diversity of the Lactobacillus group in breast milk and vagina of healthy women and potential role in the colonization of the infant gut. Martín R. J Appl Microbiol. 2007;103:

4 manipulation of of flora during pregnancy.. Broad-spectrum antibiotics for for preterm, prelabour rupture of of fetal membranes (p-prom): the the ORACLE I I randomised trial. Kenyon Kenyon SL SL et et al. al. Lancet Lancet 2001;357: women spontaneous preterm labour n women neonatal death Erythromycin (12.7 %) %) Co-amoxiclav 1212 NS to to placebo Erythro + Co-amoxi 1192 NS to to placebo Placebo (15.2%) p : : 0.08 Erythro: : prolongation duration pregnancy, reduction in in surfactant, decrease in in O² OO² at at day 28, 28, reduction cerebral abrmalities, reduction pos blood cultures Co-amoxiclav : : prolongation pregnancy NEC in in co-amoxiclav >> >> erythromycin or or placebo

5 NEC and bifidobacteria Caplan CaplanMS. JPGN JPGN 2000;30 (Suppl( (Suppl 2):S18-S22 S22 Rats; supplemented : 10 9 Bifidobacteria infantis NEC Endotoxin Permeability control 19/ supplemented 7/ <0.01 <0.001 NS

6 Clinical studies

7 Probiotics feeding in in prevention of of urinary tract infection, bacterial sepsis and necrotizing enterocolitis in in preterm infants. A prospective double-blind blind study. Dani Dani C. CC. Biol BiolNeonate. 2002;82:103-8 DBPCR in 12 Italian NICUs in 585 newborn infants standard preterm formula supplemented with Lactobacillus GG (Dicoflor dose of 6 x 10 9 cfu / day until discharge GA <33 weeks BW <1,500 g Dicoflor, Dicofarm,, Rome, Italy) Placebo L GG N Duration supplementation hrs UTI % NS NEC % NS Bacterial sepsis % NS

8 Oral probiotics reduce the incidence and severity of of necrotizing enterocolitis in in very low birth weight infants. Lin Lin HC. HC. Pediatrics 2005;115:1-4 DBPCR in VLBW (<1500 g) infants (enteral( feeding > 7 th day) Breast milk +/- Infloran (Lactobacillus acidophilus and Bifidobacterium primary outcome was death or NEC (>or= stage 2). intervention placebo N Death / NEC (>( stage 2) 9 24 NEC (>( stage 2) 2 10 Nec Bell stage Pos blood culture 0 0 Lactobacillus Bifidobacterium Bifidobacterium infantis)

9 Oral probiotics prevent necrotizing enterocolitis in in VLBW neonates. Bin-Nun A. AA. J Pediatr. 2005;147:192-6 Neonates < 1500 g BW +/- probiotic mixture (Bifido Bifido infantis, Strepto thermo, Bifido bifidus; Solgar,, Israel) 10 9 CFU/day Intervention Placebo N BW g GA weeks Full feeds after days NS NEC 4% 16.4% P=.03 Bell's criteria P=.005 Death 0 15

10 Enteral feeding of of premature infants with Saccharomyces boulardii. Costalos C. C. Early Hum Hum Dev Dev2003;74: Randomized, controlled study in 87 infants, gestational age: weeks Ability of SB to modify gut microbial ecology and its function Preterm formula +/- S. boulardii (50 mg/kg every 12 hours for 30 days) (680 nmol polyamines/kg/day) Log viable bacterial counts per gram <0.001 <0.001 <0.001 <0.05 With Sb Without Sb E. coli Bifidobacteria Staphylococci Enterococci Bacterial counts

11 Necrotizing enterocolitis & sepsis NEC NS Sepsis NS Without Sb With Sb Polyamines Weight gain: NS D-Xylose / lipid absorption: NS

12 Enteral feeding of of premature infants with Saccharomyces boulardii. Costalos C. C. Early Hum Hum Dev Dev2003;74: SAFETY S. boulardii supplemented formula is well tolerated IN NONE of the babies with NEC or sepsis was S. boulardii isolated from blood or stools

13 Oral supplementation with Lactobacillus casei subspecies rhamsus prevents enteric colonization by bycandida species in in preterm neonates: : a randomized study. Manzoni P. P. Clin ClinInfect Dis Dis 2006;42: DBPCR trial; CFU/day L GG 6 weeks or discharge Intervention placebo N Any NEC 1 2 NEC > NEC Mortality (overall) 5 6 Groups to small to detect difference t powered

14 Probiotics for necrotizing enterocolitis: a systematic review. Barclay AR. AR. J Pediatr Gastroenterol Nutr. Nutr. 2007;45: previous studies: Dani / Lin / Bin Nun / Manzoni / Costalos Cumulative: significant benefit probiotics Intervention placebo N Any NEC NEC > NEC NEC mortality 0 5 Overall mortality

15 Early administration of of Bifidobacterium breve to to preterm infants: randomised controlled trial. Kitajima H, H, Arch Arch Dis DisChild Fetal Neonatal Ed. Ed. 1997;76:F101-7

16 Early administration of of Bifidobacterium breve to to preterm infants: randomised controlled trial. Kitajima H, H, Arch Arch Dis DisChild Fetal Neonatal Ed. Ed. 1997;76:F101-7

17 Enteral feeding of of premature infants with Lactobacillus GG. Millar MR MRArch Dis DisChild. 1993;69(5 Spec Spec No):483-7 Twenty preterm infants GA < 33 weeks Control group milk feeds Intervention group milk feeds + Lactob GG 10 8 CFU 2x/day 2 weeks

18 Lack of of effect of of Lactobacillus on on gastrointestinal bacterial colonization in in premature infants. Reuman PD. PD. Pediatr Infect Dis. Dis. 1986;5: premature infants, within 72 hours lactobacilli-containing containing formula (n CFU?) n-lactobacilli lactobacilli-containing containing formula. intervention control Lactobacilli + 13 / 15 3 / 15 (< 0.001) Gram-neg 47 % 49 % N resistant organisms ns

19 Effects of of bifidobacterium breve supplementation on on intestinal flora of of low birth weight infants. Li Li Y. YY. Pediatr Int. Int. 2004;46: Oral administration of Bifidobacterium breve in group BW < 1489 g Group A from birth 1.6 x 108 cells of B. breve 2x/day B 24 hrs after birth 1.6 x 10 8 cells of B. breve 2x/day C control group ( supplement) Group A B C N Bifidobacterium-predominant flora 2 weeks 4 weeks t Enterobacteriaceae at 2 weeks <<< Early administration : bifido-dominant dominant flora

20 Probiotics for prevention of of necrotizing enterocolitis in in preterm infants Alfaleh K. K. Cochrane Database Syst SystRev. 2008;(1):CD eligible trials randomizing 1425 infants In In a meta-analysis analysis of of trial data, enteral probiotics supplementation significantly reduced --incidence of of severe NEC (stage II II or ormore) [typical RR 0.32 (95% CI CI 0.17, 0.60)] --mortality [typical RR 0.43 (95% CI CI 0.25, 0.75] evidence of of significant reduction of of socomial sepsis [typical RR 0.93 (95% CI CI 0.73, 1.19)] or ordays on ontotal parenteral nutrition (TPN) [WMD -1.9 (95% CI CI -4.6, 0.77)] Enteral supplementation of of probiotics reduced the the risk of of severe NEC and mortality in in preterm infants.???? change in in practice in in premature infants > 1000 g at at birth.

21 Probiotics for prevention of of necrotizing enterocolitis in in preterm infants Alfaleh K. K. Cochrane Database Syst SystRev. 2008;(1):CD005496

22 Probiotics for prevention of of necrotizing enterocolitis in in preterm infants Alfaleh K. K. Cochrane Database Syst SystRev. 2008;(1):CD005496

23 Oral probiotics prevent NEC in in VLBW preterm infants: a multicenter, randomized, controlled trial. Lin HC. HC. Pediatrics. 2008;122: NICUs in Taiwan VLBW <1500 g Breast milk + formula + Bifidob bifidum and Lactob acidophilus (2x/day 6 weeks) control group

24 Early administration of of probiotics alters bacterial colonization and limits diet-induced induced gut dysfunction and severity of of necrotizing enterocolitis in in preterm pigs. Siggers RH. RH. J Nutr. Nutr. 2008;138: Caesarean-delivered preterm pigs total parenteral nutrition (1.5 d) + enteral feeding (2 d) Clinical NEC scores were reduced (P < 0.05) formula + probiotic porcine colostrum formula (FORM-P; Bifidobacterium animalis,, L. acidophilus, L. casei, L. pentosus,, L. plantarum)

25 Supplementation with Saccharomyces boulardii ameliorates hypoxia/reoxygenation-induced induced necrotizing enterocolitis in in young mice. Akisu M. M. Eur EurJ Pediatr Surg. 2003;13: Mice were subjected to hypoxia-reoxygenation (H/R) Group 1 untreated Group 2 lyophilized S. boulardii for 10 days Group 3 controls ( hypoxia-reoxygenation reoxygenation) hypoxia/reoxygenation important role in the pathogenesis of NEC dietary supplementation with S. boulardii ameliorates the histologic evidence of H/R-induced intestinal injury.

26 The probiotic Lactobacillus GG may augment intestinal host defense by by regulating apoptosis and promoting cytoprotective responses in in the developing murine gut. Lin Lin PW. PW. Pediatr Res Res2008;64:511-6 LGG up-regulates a battery of genes with kwn and likely cytoprotective effects. stimulating antiapoptotic and cytoprotective responses (apoptosis: ~ precursor to NEC)

27 1. 1. Increase in in lactic acid bacteria (given as as probiotic) (1) (1) human mice Peyer s patches B cell number yes response to to T-T T- and B mitogens yes Peyer pacthes yes antibacterial activity of of PP PP (via IgA) yes IgA production yes total Ig Igproduction yes GALT IgA in in faeces/intestinal content yes yes IgA in in small bowel wall extracts yes total IgG in in intestinal contents yes Mesenteric lymph de response to to mitogens yes Blood

28 1. 1. Increase in in lactic acid bacteria (given as as probiotic) (2) (2) human mice Peyer s patches GALT Mesenteric lymph de Blood phagocytosis by byblood Lc Lc yes yes phagocytic function of of RES yes NK-cell tumour killing activity yes B-cell number yes IFN-γ production by bylc yes IgA // IgA secreting cells yes IgE production yes total Ig Igproduction yes Spleen

29 1. 1. Increase in in lactic acid bacteria (given as as probiotic) (3) (3) human mice Peyer s patches GALT Mesenteric lymph des Blood Spleen response to to T-T T-and B-mitogens yes IgM cells yes IgE from stimulated spleen cells yes IL-4, IL-5, IL-6, IL-10 yes IFN- γ, γ, IL-2 yes Peritoneal cells macrophagephagocytic/enzymatic enzymatic activity yes IL-6, IL-12, IFN- γ and nitric oxide yes Lung macrophages phagocytic function yes

30 Conclusion Probiotics are are likely to to decrease NEC No No studies in in developing countries Insufficient data in in VLBW infants Limited n n trials (more reviews that original data) different preparations / / different dosages differences in in time of of initiation (1st hrs hrs first feed during 1st 1st week oral feed) differences in in duration ( days discharge) Strain specificity Side-effects effects short term sepsis long term immune system?