Probiotics and prevention of NEC Probiotics and prevention of NEC by mikeholy

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									    Probiotics
    Probiotics
       and
       and
prevention of NEC
prevention of NEC
Indirect evidence
Indirect evidence
Innate recognition of bacteria in human milk is mediated by aa
 Innate recognition of bacteria in human milk is mediated by
milk-derived highly expressed pattern recognition receptor, soluble CD14
 milk-derived highly expressed pattern recognition receptor, soluble CD14
MO Labeta. JJExp Med 2000;191:1807-12
MO Labeta. Exp Med 2000;191:1807-12


             breast milk of healthy women
  is a source of commensal bacteria to the infant gut.


           Cultivation-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;103:2638-44
…manipulation of flora during pregnancy …..
…manipulation of flora during pregnancy …..
 Broad-spectrum antibiotics for preterm, prelabour rupture of fetal membranes
  Broad-spectrum antibiotics for preterm, prelabour rupture of fetal membranes
 (p-PROM): the ORACLE IIrandomised trial.
  (p-PROM): the ORACLE randomised trial.
 Kenyon SL et al. Lancet 2001;357:979-88
 Kenyon SL et al. Lancet 2001;357:979-88

     4826 women spontaneous preterm labour
     4826 women spontaneous preterm labour
                        n women
                         n women       neonatal death
                                        neonatal death
     Erythromycin
      Erythromycin      1197
                         1197          151 (12.7 %)
                                        151 (12.7 %)
     Co-amoxiclav
     Co-amoxiclav       1212
                         1212          NS to placebo
                                       NS to placebo
     Erythro + Co-amoxi 1192
     Erythro + Co-amoxi 1192           NS to placebo
                                       NS to placebo
     Placebo
     Placebo            1225
                         1225          186 (15.2%)
                                       186 (15.2%)                   p ::0.08
                                                                     p 0.08
     Erythro: prolongation duration pregnancy, reduction in surfactant,
     Erythro: prolongation duration pregnancy, reduction in surfactant,
            decrease in O² at day 28, reduction cerebral abnormalities,
             decrease in O² at day 28, reduction cerebral abnormalities,
            reduction pos blood cultures
             reduction pos blood cultures
     Co-amoxiclav ::prolongation pregnancy
     Co-amoxiclav prolongation pregnancy
     NEC in “co-amoxiclav” >> “erythromycin” or “placebo”
     NEC in “co-amoxiclav” >> “erythromycin” or “placebo”
NEC and bifidobacteria
NEC and bifidobacteria
 Caplan MS. JPGN 2000;30 Suppl 2):S18-S22
Caplan MS. JPGN 2000;30 ((Suppl2):S18-S22


       Rats; supplemented : 109 Bifidobacteria infantis


                        NEC Endotoxin
                        NEC Endotoxin        Permeability
                                             Permeability

       control
        control     19/27
                     19/27       191 + 31
                                  191 + 31   0.55 + 0.23
                                              0.55 + 0.23
       supplemented 7/24
        supplemented 7/24         21 + 3
                                   21 + 3    0.46 + 0.13
                                             0.46 + 0.13
                    <0.01
                     <0.01       <0.001
                                  <0.001        NS
                                                 NS
Clinical studies
Clinical studies
Probiotics feeding in prevention of urinary tract infection,
Probiotics feeding in prevention of urinary tract infection,
bacterial sepsis and necrotizing enterocolitis in preterm infants.
bacterial sepsis and necrotizing enterocolitis in preterm infants.
A prospective double-blind study.
A prospective double-blind study.
Dani C. Biol Neonate. 2002;82:103-8
Dani C. Biol Neonate. 2002;82:103-8

 DBPCR in 12 Italian NICUs in 585 newborn infants                 GA <33 weeks
                                                                  BW <1,500 g
          standard preterm formula
          supplemented with Lactobacillus GG (Dicoflor, Dicofarm, Rome, Italy)
                 dose of 6 x 109 cfu / day until discharge

                                  Placebo                 L GG
 N                                290                     295
 Duration supplementation         48.2 + 24.3             47.3 + 26.0     hrs
        UTI                       3.4                     5.8 %           NS
        NEC                       1.4                     2.7 %           NS
        Bacterial sepsis          3.8                     4.4%            NS
Oral probiotics reduce the incidence and severity of necrotizing enterocolitis
 Oral probiotics reduce the incidence and severity of necrotizing enterocolitis
in very low birth weight infants.
 in very low birth weight infants.
Lin HC. Pediatrics 2005;115:1-4
 Lin HC. Pediatrics 2005;115:1-4


       DBPCR in VLBW (<1500 g) infants (enteral feeding > 7th day)
       Breast milk +/- Infloran (Lactobacillus acidophilus and Bifidobacterium infantis)
       primary outcome was death or NEC (>or= stage 2).

                                           intervention      placebo
       N                                   180               187
       Death / NEC (> stage 2)             9                 24
       NEC (> stage 2)                     2                 10
       Nec Bell stage 3                    0                 6
       Pos blood culture                   0                 0
              Lactobacillus
              Bifidobacterium
Oral probiotics prevent necrotizing enterocolitis in VLBW neonates.
Oral probiotics prevent necrotizing enterocolitis in VLBW neonates.
Bin-Nun A. JJPediatr. 2005;147:192-6
Bin-Nun A. Pediatr. 2005;147:192-6


Neonates < 1500 g BW
+/- probiotic mixture (Bifido infantis, Strepto thermo, Bifido bifidus; Solgar, Israel) 109 CFU/day

                        Intervention           Placebo
        N               72                     73
        BW              1152 + 262             1111 + 278         g
        GA              30 + 3                 29 + 4             weeks
Full feeds after        14.6 + 8.7             17.5 + 13.6        days               NS
        NEC             4%                     16.4%                                 P=.03
        Bell's criteria 1.3 + 0.5              2.3 + 0.5                             P=.005
        Death           0                      15
Enteral feeding of premature infants with Saccharomyces boulardii.
Enteral feeding of premature infants with Saccharomyces boulardii.
Costalos C. Early Hum Dev 2003;74:89-96
Costalos C. Early Hum Dev 2003;74:89-96

•   Randomized, controlled study in 87 infants, gestational age: 28 – 32 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                                                 With Sb
                                                                  <0.001                                  Without Sb

                                                                                               <0.05


                                                                               <0.001




                                                   E. coli   Bifidobacteria Staphylococci   Enterococci
                                                             Bacterial counts
Necrotizing enterocolitis & sepsis
Necrotizing enterocolitis & sepsis
               NS
                                        Without Sb
                                        With Sb



                               NS




         NEC          Sepsis

                                     Polyamines
                                    • Weight gain: NS
                                    • D-Xylose / lipid absorption: NS
Enteral feeding of premature infants with Saccharomyces boulardii.
Enteral feeding of premature infants with Saccharomyces boulardii.
Costalos C. Early Hum Dev 2003;74:89-96
Costalos C. Early Hum Dev 2003;74:89-96



  SAFETY
  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
Oral supplementation with Lactobacillus casei subspecies rhamnosus prevents
 Oral supplementation with Lactobacillus casei subspecies rhamnosus prevents
enteric colonization by candida species in preterm neonates: aarandomized study.
 enteric colonization by candida species in preterm neonates: randomized study.
Manzoni P. Clin Infect Dis 2006;42:1735-42
Manzoni P. Clin Infect Dis 2006;42:1735-42



         DBPCR trial; 6 109 CFU/day L GG – 6 weeks or discharge

                           Intervention      placebo
         N                      39             41
         Any NEC                1              2
         NEC > 2                1              2
         NEC 3                  0              1
         Mortality (overall)    5              6


         Groups to small to detect difference – not powered
Probiotics for necrotizing enterocolitis: a systematic review.
Probiotics for necrotizing enterocolitis: a systematic review.
Barclay AR. JJPediatr Gastroenterol Nutr. 2007;45:569-76
Barclay AR. Pediatr Gastroenterol Nutr. 2007;45:569-76

 • 5 previous studies: Dani / Lin / Bin Nun / Manzoni / Costalos


                  Cumulative: significant benefit probiotics
                  Cumulative: significant benefit probiotics

                                    Intervention
                                     Intervention          placebo
                                                           placebo
                  N
                  N                       640
                                           640               627
                                                              627
                  Any NEC
                  Any NEC                 15
                                           15                45
                                                              45
                  NEC > 2
                  NEC > 2                 88                 30
                                                              30
                  NEC 3
                  NEC 3                   0
                                          0                  10
                                                             10
                  NEC mortality
                  NEC mortality           0
                                          0                  55
                  Overall mortality
                  Overall mortality       15
                                          15                 34
                                                              34
Early administration of Bifidobacterium breve to preterm infants:
 Early administration of Bifidobacterium breve to preterm infants:
randomised controlled trial.
 randomised controlled trial.
Kitajima H, Arch Dis Child Fetal Neonatal Ed. 1997;76:F101-7
Kitajima H, Arch Dis Child Fetal Neonatal Ed. 1997;76:F101-7
Early administration of Bifidobacterium breve to preterm infants:
 Early administration of Bifidobacterium breve to preterm infants:
randomised controlled trial.
 randomised controlled trial.
Kitajima H, Arch Dis Child Fetal Neonatal Ed. 1997;76:F101-7
Kitajima H, Arch Dis Child Fetal Neonatal Ed. 1997;76:F101-7
Enteral feeding of premature infants with Lactobacillus GG.
Enteral feeding of premature infants with Lactobacillus GG.
Millar MR Arch Dis Child. 1993;69(5 Spec No):483-7
Millar MR Arch Dis Child. 1993;69(5 Spec No):483-7

Twenty preterm infants GA < 33 weeks
• Control group      milk feeds
• Intervention group milk feeds + Lactob GG 108 CFU 2x/day 2 weeks
Lack of effect of Lactobacillus on gastrointestinal bacterial colonization
 Lack of effect of Lactobacillus on gastrointestinal bacterial colonization
in premature infants.
 in premature infants.
Reuman PD. Pediatr Infect Dis. 1986;5:663-8
 Reuman PD. Pediatr Infect Dis. 1986;5:663-8



    30 premature infants, within 72 hours
           lactobacilli-containing formula (n° CFU?)
           non-lactobacilli-containing formula .
                           intervention          control
    Lactobacilli +         13 / 15               3 / 15       (< 0.001)
    Gram-neg               47 %                  49 %
    N° resistant organisms               ns
Effects of bifidobacterium breve supplementation
Effects of bifidobacterium breve supplementation
on intestinal flora of low birth weight infants.
on intestinal flora of low birth weight infants.
Li Y. Pediatr Int. 2004;46:509-15
 Li Y. Pediatr Int. 2004;46:509-15


        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 108 cells of B. breve 2x/day
              C control group (no supplement)

                 Group                    A                 B           C
        N                                 10                10          10
        Bifidobacterium-predominant flora 2 weeks           4 weeks     not
        Enterobacteriaceae at 2 weeks           <<<

        Early administration : bifido-dominant flora
Probiotics for prevention of necrotizing enterocolitis in preterm infants
Probiotics for prevention of necrotizing enterocolitis in preterm infants
Alfaleh K. Cochrane Database Syst Rev. 2008;(1):CD005496
Alfaleh K. Cochrane Database Syst Rev. 2008;(1):CD005496
     9 eligible trials randomizing 1425 infants
     9 eligible trials randomizing 1425 infants

     In aameta-analysis of trial data,
      In meta-analysis of trial data,
     enteral probiotics supplementation significantly reduced
      enteral probiotics supplementation significantly reduced
             --incidence of severe NEC (stage II or more)
                incidence of severe NEC (stage II or more)
                      typical RR 0.32 (95% CI 0.17, 0.60)]
                     [[typicalRR 0.32 (95% CI 0.17, 0.60)]
                mortality typical RR 0.43 (95% CI 0.25, 0.75]
             --mortality [[typicalRR 0.43 (95% CI 0.25, 0.75]
     no evidence of significant reduction of nosocomial sepsis
      no evidence of significant reduction of nosocomial sepsis
                      typical RR 0.93 (95% CI 0.73, 1.19)]
                     [[typicalRR 0.93 (95% CI 0.73, 1.19)]
              or days on total parenteral nutrition TPN)
             or days on total parenteral nutrition ((TPN)
                      [WMD 1.9 (95% CI 4.6, 0.77)]
                     [WMD --1.9(95% CI --4.6,0.77)]

     Enteral supplementation of probiotics reduced the risk of severe NEC
      Enteral supplementation of probiotics reduced the risk of severe NEC
     and mortality in preterm infants.
      and mortality in preterm infants.
        ?? change in practice in premature infants > 1000 g at birth.
         ?? change in practice in premature infants > 1000 g at birth.
Probiotics for prevention of necrotizing enterocolitis in preterm infants
Probiotics for prevention of necrotizing enterocolitis in preterm infants
Alfaleh K. Cochrane Database Syst Rev. 2008;(1):CD005496
Alfaleh K. Cochrane Database Syst Rev. 2008;(1):CD005496
Probiotics for prevention of necrotizing enterocolitis in preterm infants
Probiotics for prevention of necrotizing enterocolitis in preterm infants
Alfaleh K. Cochrane Database Syst Rev. 2008;(1):CD005496
Alfaleh K. Cochrane Database Syst Rev. 2008;(1):CD005496
Oral probiotics prevent NEC in VLBW preterm infants:
Oral probiotics prevent NEC in VLBW preterm infants:
a multicenter, randomized, controlled trial.
a multicenter, randomized, controlled trial.
Lin HC. Pediatrics. 2008;122:693-700
 Lin HC. Pediatrics. 2008;122:693-700

  7 NICUs in Taiwan – VLBW <1500 g
  Breast milk + formula
     • + Bifidob bifidum and Lactob acidophilus (2x/day – 6 weeks)
     • control group
Early administration of probiotics alters bacterial colonization and
 Early administration of probiotics alters bacterial colonization and
limits diet-induced gut dysfunction and severity of necrotizing enterocolitis
 limits diet-induced gut dysfunction and severity of necrotizing enterocolitis
in preterm pigs.
 in preterm pigs.
Siggers RH. JJNutr. 2008;138:1437-44
 Siggers RH. Nutr. 2008;138:1437-44


       Caesarean-delivered preterm pigs
              total parenteral nutrition (1.5 d) + enteral feeding (2 d)

       Clinical NEC scores were reduced (P < 0.05)
              formula + probiotic 2.0 + 0.2
              porcine colostrum    1.7 + 0.5
              formula              3.4 + 0.6

       (FORM-P; Bifidobacterium animalis, L. acidophilus, L. casei, L. pentosus, L. plantarum)
Supplementation with Saccharomyces boulardii ameliorates
Supplementation with Saccharomyces boulardii ameliorates
hypoxia/reoxygenation-induced necrotizing enterocolitis in young mice.
hypoxia/reoxygenation-induced necrotizing enterocolitis in young mice.
Akisu M. Eur JJPediatr Surg. 2003;13:319-23
Akisu M. Eur Pediatr Surg. 2003;13:319-23



          Mice were subjected to hypoxia-reoxygenation (H/R)
                Group 1        untreated
                Group 2        lyophilized S. boulardii for 10 days
                Group 3        controls (no hypoxia-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.
The probiotic Lactobacillus GG may augment intestinal host defense
 The probiotic Lactobacillus GG may augment intestinal host defense
by regulating apoptosis and promoting cytoprotective responses
 by regulating apoptosis and promoting cytoprotective responses
in the developing murine gut.
 in the developing murine gut.
Lin PW. Pediatr Res 2008;64:511-6
 Lin PW. Pediatr Res 2008;64:511-6




                         LGG up-regulates a battery of genes
                    with known and likely cytoprotective effects.
                stimulating antiapoptotic and cytoprotective responses
                           (apoptosis: ~ precursor to NEC)
1. Increase in lactic acid bacteria given as probiotic) (1)
1. Increase in lactic acid bacteria ((givenas probiotic) (1)

                                                               human mice
                                                               human mice
     Peyer’s patches
     Peyer’s patches
              B cell number
               B cell number                                   no
                                                                no    yes
                                                                       yes
              response to T- and B –mitogens
               response to T- and B –mitogens                  no
                                                                no    yes
                                                                       yes
              Peyer pacthes
               Peyer pacthes                                   no
                                                                no    yes
                                                                       yes
              antibacterial activity of PP (via IgA)
               antibacterial activity of PP (via IgA)          no
                                                                no    yes
                                                                       yes
              IgA production
               IgA production                                  no
                                                                no    yes
                                                                       yes
              total Ig production
               total Ig production                             no
                                                               no     yes
                                                                      yes
     GALT
     GALT
              IgA in faeces/intestinal content
               IgA in faeces/intestinal content                yes
                                                                yes   yes
                                                                       yes
              IgA in small bowel wall extracts
               IgA in small bowel wall extracts                no
                                                                no    yes
                                                                       yes
              total IgG in intestinal contents
               total IgG in intestinal contents                no
                                                                no    yes
                                                                       yes
     Mesenteric lymph node
     Mesenteric lymph node
              response to mitogens
               response to mitogens                            no
                                                                no    yes
                                                                       yes
     Blood
     Blood
1. Increase in lactic acid bacteria given as probiotic) (2)
1. Increase in lactic acid bacteria ((givenas probiotic) (2)

                                                               human mice
                                                               human mice
     Peyer’s patches
     Peyer’s patches
     GALT
     GALT
     Mesenteric lymph node
     Mesenteric lymph node
     Blood
     Blood
              phagocytosis by blood Lc
               phagocytosis by blood Lc                        yes
                                                                yes   yes
                                                                       yes
              phagocytic function of RES
               phagocytic function of RES                      no
                                                                no    yes
                                                                       yes
              NK-cell tumour killing activity
               NK-cell tumour killing activity                 yes
                                                                yes   no
                                                                       no
              B-cell number
               B-cell number                                   yes
                                                               yes    no
                                                                      no
              IFN-γ production by Lc
               IFN-γ production by Lc                          yes
                                                                yes   no
                                                                       no
              IgA //IgA secreting cells
               IgA IgA secreting cells                         yes
                                                                yes   no
                                                                       no
              IgE production
               IgE production                                  no
                                                                no    yes
                                                                       yes
              total Ig production
               total Ig production                             no
                                                               no     yes
                                                                      yes
     Spleen
     Spleen
1. Increase in lactic acid bacteria given as probiotic) (3)
1. Increase in lactic acid bacteria ((givenas probiotic) (3)

                                                               human mice
                                                               human mice
     Peyer’s patches
     Peyer’s patches
     GALT
     GALT
     Mesenteric lymph nodes
     Mesenteric lymph nodes
     Blood
     Blood
     Spleen
     Spleen             response to T- and B-mitogens
                         response to T- and B-mitogens    no
                                                           no       yes
                                                                     yes
                        IgM cells
                         IgM cells                        no
                                                          no        yes
                                                                    yes
                        IgE from stimulated spleen cells no
                         IgE from stimulated spleen cells no        yes
                                                                     yes
                        IL-4, IL-5, IL-6, IL-10
                         IL-4, IL-5, IL-6, IL-10          no
                                                           no       yes
                                                                     yes
                       IFN- γγ,IL-2
                        IFN- , IL-2                       no
                                                           no       yes
                                                                     yes
     Peritoneal cells
     Peritoneal cells
               macrophagephagocytic/enzymatic activity no
                macrophagephagocytic/enzymatic activity no          yes
                                                                     yes
               IL-6, IL-12, IFN- γγand nitric oxide
                IL-6, IL-12, IFN- and nitric oxide        no
                                                           no       yes
                                                                     yes
     Lung macrophages
     Lung macrophages
               phagocytic function
                phagocytic function                       no
                                                           no       yes
                                                                     yes
Conclusion
Conclusion
      ••Probiotics are likely to decrease NEC
        Probiotics are likely to decrease NEC

      ••No studies in developing countries
         No studies in developing countries
      ••Insufficient data in VLBW infants
         Insufficient data in VLBW infants
      ••Limited n° trials (more reviews that original data)
         Limited n° trials (more reviews that original data)
      ••different preparations //different dosages
         different preparations different dosages
      ••differences in time of initiation
         differences in time of initiation
               (1st 24 hrs – first feed – during 1st week oral feed)
                (1st 24 hrs – first feed – during 1st week oral feed)
      ••differences in duration (14 – 28 – 30 days – discharge)
         differences in duration (14 – 28 – 30 days – discharge)

      ••Strain specificity
        Strain specificity
      ••Side-effects
        Side-effects
              short term
               short term             sepsis
                                       sepsis
              long term
               long term              immune system ??
                                       immune system

								
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