Tag Archives: probiotics

Pushback on Probiotics

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I had not paid much attention to a study last year (Lancet 2013; 382: 1249-57) titled, “Lactobacilli and bifidobacteria in the prevention of antibiotic-associated diarrhea and Clostridium difficile diarrhea in older patients (PLACIDE): a randomized, double-blind, placebo-controlled, multcentre trial.”

A useful review (Gastroenterol 2014; 146: 1822-23) of this study provides some useful insight into the use of probiotics.  The authors state that “in the last decade, medical and non medical professionals have endorsed the use of probiotics as a means of preventing AAD through a dogma that adding ‘good bacteria’ will prevent dysbiosis caused by ‘bad bacteria.'”  They note that several meta-analysis have supported a positive benefit for probiotics in this setting; yet, the “results merit cautious interpretation owing to a high risk of bias and notable heterogeneity of included studies.”

The PLACIDE study overcomes many of the previous limitations in this well-designed study design which enrolled a large cohort of 2,981 patients (≥65 years old).  The probiotics used in this trial were lactobacillus acidophilus along with bidodbacterium bifidum and lactis.  Ultimately, “patients receiving probiotics were as likely to develop AAD as patients in the placebo arm (relative risk 1.04).”  The rate of C difficile infection was ~1% and lower than expected.

While this study did not demonstrate any benefit from probiotics, there was no significant harm identified from probiotics; though, patients receiving probiotics were more likely to develop flatus and bloating in comparison to placebo.

Take-home message: “This study now also points away from probiotics being of benefit…probiotics use will not diminish as a result of this trial.  Parties will, argue rightly or wrongly, that the wrong strains were chosen…However, what the PLACIDE trial does point is that there is no clear evidence for use of probiotics in this setting until high-quality RCTs are conducted.”

Another probiotic reference:

JAMA Pediatr 2014; 168: 228-33.  This randomized double-blind, controlled trial conducted in 9 neonatal units in Italy compared L reuteri DSM 17938 to placebo for prevention of colic.  Mean duration of daily crying was 38 min in probiotic group compared with 71 min in placebo-treated patients, though these measures were with a nonvalidated diary.  Conclusions of authors: “prophylactic use of L reuteri DSM 17938 during the first 3 months of life reduced the magnitude of crying and functional gastrointestinal disorders.”

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Probiotics for Hepatic Encephalopathy

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A recent open-label, randomized prospective study (Clin Gastroenterol Hepatol 2014; 12: 1003-08) indicates that probiotics (VSL#3) can be effective as primary prophylaxis of hepatic encephalopathy (HE) in at risk patients with cirrhosis.

While cirrhosis-related HE is an uncommon problem in pediatric gastroenterology/hepatology, there are few effective therapeutic options.  This study randomly assigned the 160 patients to groups given probiotics three times daily or to controls (no test article).  These patients were studied extensively including psychometric analysis, glucose hydrogen breath tests, critical flicker fusion, and lactulose hydrogen breath tests to assess orocecal transit time.

Key result: Three months of probiotics reduced HE scores.  Seven probiotic subjects developed overt HE which was significantly lower than the 14 patients in the control group (P<.05).

Bottomline: Probiotics may reduce the development of overt HE in patients with cirrhosis.

Therapeutic Inertia in U.S Neonatal Units (vis-a-vis Probiotics)

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“More than 90% of very low birth weight (VLBW) infants receive substandard care” could be the headline of a recent article/editorial (J Pediatr 2014; 164: 980-5 & 959-60).  Instead they are titled: “Cohort Study of Probiotics in a North American Neonatal Intensive Care Unit” and “Probiotic Supplementation in Preterm Infants: It is Time to Change Practice.”

In the article introduction, the authors state: “In 2011, faced with overwhelming evidence that probiotics could decrease NEC in preterm infants, and because there were no significant risks described in the extensive literature, we decided to introduce probiotics as routine care for the prevention of NEC.”

Methods: Prospective cohort study of infants at a single center NICU.  Examined rates of necrotizing enterocolitis (NEC) and death for 17 months before and after introduction of a probiotic (FloraBABY).  This probiotic (0.5 g) was mixed with water and administered just before milk once a day.  It was started at the first feeding and continued until the infant reached 34 weeks postmenstrual age.

Key findings:

  • Probiotics reduced NEC from 9.8% to 5.4% (OR for NEC 0.51)
  • Probiotics reduced combined outcome for NEC or death from 17% to 10.5% (OR 0.56).  Reduction in death by itself did not meet statistical significance.

Why, in 2012, were probiotics only used in 8-9% of VLBW?

Potential profits for probiotics are small which has limited studies of specific strains.  The probiotic, FloraBABY, in this study cost 11 cents per day in amount used; however, since the probiotic came in a tub, the actual cost was $12.79 for a 60-g tub for each patient.  Thus, manufacturers are unlikely to support studies to garner FDA approval.

Yet, there have been 22 randomized controlled trials published which “showed substantial benefits of probiotics and no adverse events.” A recently completed ProPrems trial (Jacob S et al, presented at 2013 PAS Annual Meeting) used a probiotic called ABC Dophilus Probiotic Powder for Infants.  This trial showed “a significant, >50%, reduction in NEC despite an incidence in their control patients of only 4.4%” and despite the fact that >95% of infants received breast milk.

“Good quality control and confirmation of the contents of the preparation are essential…There seems to be no further reason to delay the introduction of this evidence-based therapy in the NICU.”  The adoption of probiotics could avoid 2500 cases of NEC every year in North America.

The editorial notes that the evidence for probiotics is much better than many other therapies used in NICUs.  They note that some have argued that “the evidence that probiotics reduce mortality rates is as conclusive as that for surfactant for respiratory distress syndrome.”  A recent Cochrane review of 17 trials and >4900 VLBW infants showed that the RR of severe NEC for probiotics versus control was 0.41.

If people really understood this issue, there would be outrage over this issue.  In the U.S., there was recently extensive coverage over inaction about a faulty ignition switch which has been linked to at least 13 deaths.  The potential reduction in NEC and deaths with probiotics is likely much greater.

While the editorial recommends involving parent representative groups, I recommend discussing this issue with your neonatology colleagues along with your “quality care” team to find out what they are going to do about it.  Given the enormous costs in most NICUs, it is likely that each unit could self-fund a quality project (with consented patients) to provide probiotics to this vulnerable population.

Bottomline: Probiotics have excellent evidence as prophylaxis for NEC in VLBW infants.  Physicians need to advocate for their usage to “avoid years of therapeutic inertia.”

Related blog post: One More Day Syndrome & Necrotizing Enterocolitis …

Disclaimer: These blog posts are for educational purposes only. Specific dosing of medications/diets (along with potential adverse effects) should be confirmed by prescribing physician/nutritionist.  This content is not a substitute for medical advice, diagnosis or treatment provided by a qualified healthcare provider. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a condition.

“Low quality of evidence; strong recommendation” for Probiotics in Gastroenteritis

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Recently a position paper on “Use of probiotics for management of acute gastroenteritis: a position paper by the ESPGHAN working group for probiotics and prebiotics” was published (JPGN 2014; 58: 531-39).

Two specific probiotics were recommended “strongly” but the working group describes the evidence for both as “low quality.”  This strikes me as odd.  The authors extensively reviewed previous studies and used the “GRADE” system to classify the quality of evidence and the category of recommendation.  There were 4 categories of quality of evidence: high, moderate, low and very low.  There were 2 possible recommendation categories: strong or weak.

The summary recommendations included the following:

  • Rehydration is the key treatment for AGE
  • Probiotics, overall, reduce diarrhea by approximately 1 day
  • However, probiotic effects are strain specific; findings from one probiotic cannot be extrapolated to another
  • The group recommends choosing probiotics with efficacy confirmed in well-conducted RCTs from a reputable manufacturer
  • Two specific recommended probiotics: Lactobacillus GG and Saccromyces boulardii

Take-home message: This article summarizes the available evidence for the use of probiotics in acute gastroenteritis.  Despite their classification as  “low quality of evidence,” the authors provide a strong recommendation for two probiotics (Lactobacillus GG and Saccromyces boulardii) as adjunctive therapy.

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Briefly Noted…Scoliosis, Cystic Fibrosis, Specific Carbohydrate Diet, GGT, Surgeon General

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“Net effect of scoliosis surgery on gastric emptying, upper gastrointestinal symptoms, and clinical nutritional status was minimal”  according to this prospective study of 31 children: JPGN 2014; 58: 38-45.

Lactobacillus reuteri ATCC55730 was associated with reduced pulmonary exacerbations (but not improved FEV1) in 61 patients with cystic fibrosis who were enrolled in a prospective randomized, double-blind, placebo-controlled study over 6 months between 2007-2009 (JPGN 2014; 58: 81-86).

A retrospective chart review of seven children with Crohn disease who were treated with the specific carbohydrate diet with an average diet duration of 14.6 months showed that all symptoms resolved and laboratory studies improved or normalized.  (JPGN 2014; 58: 87-91). More studies on this diet are expected to be published soon.

Data from 200 preterm infants and 383 term infants help provide updated GGT (gamma-glutamyl transferase) reference values.  In preterm infants during 1st 7 days: 141 ± 89 U/L, then between days 8-28: 131 ± 85 U/L.  In term infants the values were similar 140 ±86 U/L and 145 ± 87 U/L respectively. (JPGN 2014; 58: 99-101).

And from NEJM twitter feed, Congress may allow the NRA veto power in the selection the next surgeon general: http://nej.md/1nECFlM.

Do Probiotics Really Help Crying Infants?

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This is the question from a recent meta-analysis (JAMA Pediatr 2013; 167: 1150-57 -thanks to Ben Gold for this reference).

Table 1 details the study designs, probiotic intervention, and outcomes.

Results: “Of the 12 eligible studies (1825 infants), 6 suggested that probiotics reduced crying and 6 did not…Meta-analysis of 3 small trials of breastfed infants with colic found that Lactobacillus reuteri markedly reduced crying time at 21 days…However, all trials had potential biases.”

In the three breastfed trials alluded to above, there were concerns regarding inadequate blinding of the intervention, unequal baseline characteristics, and use of non validated crying “diaries” which could be prone to recall bias.

More data are needed; fortunately there are several ongoing trials.

Bottomline (from the authors’ conclusion): “Although L reuteri may be effective as treatment for crying in exclusively breastfed infants with colic, there is still insufficient evidence to support probiotic use to manage colic, especially in formula-fed infants.”

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Probiotics for Colic

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Another study has shown the potential for probiotics to help colicy infants.  In an editorial, Carlos Lifschitz sums up the paper (The Journal of Pediatrics Volume 163, Issue 5 , Pages 1250-1252, November 2013); here is an excerpt (link from Kipp Ellsworth twitter feed —goo.gl/b3iMFu):

For reasons that are not clear, human infants are born with a well-developed capacity to cry.1 …Unexplained and severe crying affects 3%-28% of breastfed or formula-fed (otherwise-healthy) young infants.2 Although excessive, inconsolable crying and colic are considered to be a benign, self-resolving problem, they can be very distressing and lead to marital conflict and parental exhaustion.3 Infantile colic is defined as paroxysmal, excessive, inconsolable crying without an identifiable cause in an otherwise-healthy infant occurring in the first 3 months of life and lasting a minimum of 3 hours per day, 3 days per week, for 3 weeks…

Enter probiotics. Lactobacillus reuteri DSM 17 938 at a dose of 108 colony-forming units per day in breastfed infants improved symptoms of infantile colic,19 a finding that was further corroborated.20 Despite evidence that altering the microbiota may result in reduced crying, the physiopathology still remains unclear…

In this issue of The Journal, Pärtty et al22 attempt to prevent excessive crying in former premature infants….To determine whether excessive crying is preventable by manipulation of intestinal microbiota, 94 preterm infants, some breast- and formula-fed, with gestational ages ranging from 32 to 36 weeks and birth weights >1500 g, were randomized in the first 3 days of life in a double-blind study to receive for the following 2 months either a mixture of galacto-oligosaccharide and polydextrose (prebiotic group), Lactobacillus rhamnosus GG (probiotic group), or placebo…Follow-up consultations were conducted by the same study nurse at the age of 1, 2, 4, 6, and 12 months…

Significantly less frequent crying was observed in both the pre- and probiotic groups compared with the placebo group (19% vs 19% vs 47%, respectively; P = .02). At 1 month of age, the infants’ fecal microbiota were investigated. The proportion ofLactobacillus-Lactococcus-Enterococcus group to total bacterial count and the proportion of Clostridium histolyticum group to total bacterial count was greater in excessive criers than in contented infants in all 3 study groups (pre-, probiotics, and placebo). The authors concluded that early pre- and probiotic supplementation may alleviate symptoms associated with crying and fussing in preterm infants.

Although in the study the following associations did not reach statistical significance, they are of interest for future investigation: contented infants were more often exclusively breast-fed during the first 2 months (42% vs 22%, respectively, P= .09) and their mothers had received perinatal antibiotics less often (22% vs 41%, respectively, P = .07) than criers… Contrary to this hypothesis, however, is the finding that persistent criers were more often born by vaginal delivery as opposed to cesarean delivery (81% vs 63%, P = .07) than contented babies. This finding is surprising because birth by cesarean delivery and, therefore, lack of exposure to the microbiota of the vaginal canal and perineum, has been associated with abnormal development of intestinal microbiota and several diseases.

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In a video, Dr. Sanjay Gupta and Dr. John Bachman say ‘we don’t know why babies have colic, but it will end and is not the parent’s fault:’ ow.ly/q4IsW 

Disclaimer: These blog posts are for educational purposes only. Specific dosing of medications (along with potential adverse effects) and specific medical interventions should be confirmed by prescribing physician.  Application of the information in a particular situation remains the professional responsibility of the practitioner.

Additional references:

  • -Pediatrics 2010; 126: e526.  Double-blind randomized placebo-controlled trial of Lactobacillus reuteri.
  • -J Pediatr 2009; 155:823. Increased calprotectin in colicy infants. n=36. editorial pg 772.
  • -J Pediatr 2009; 154: 514-20. Colic and reflux. (Orenstein et al), & 475 (editorial -Putnam). PPIs (lansoprazole) do not help colicy Sx in infants c GERD. n=162. Increased resp infections in pts on PPIs. 44% response in Rx & control group.
  • -J Pediatr 2008; 152: 801. Probiotic helped reduce colic sx in 30 preterm infants, Lactobacillus reuteri
  • -Pediatrics 2007; 119; e124. Probiotics reduced colic in breastfed babies more than simethicone. n=83, lactobacillus reuteri, 10-8th power per day. Decreased crying 18 minutes per day at 1 week compared to simethicone & by 94 minutes/day at 4 weeks (95% response vs 7% of simethicone)
  • -Pediatrics 2005; 116: e709. Low-allergen maternal diet was helpful.
  • -Hochman JA, Simms C: “The role of small bowel bacterial overgrowth in infantile colic“J Pediatr 2005; 147: 410-411 (Letter to Editor).
  • -Arch Pediatr Adol Med 2002; 1183 &1172. lack of sequelae on maternal mental health.
  • -Arch Pediatr Adol Med 2002; 156: 1123-1128. colic 24% of infants, breastfeeding did not help.
  • -Pediatrics 2002; 109: 797-805. carbohydrate malabsorption with breath testing in colicy infants, n=30. 2 hour fasting period.

One More Day Syndrome & Necrotizing Enterocolitis

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In many situations, the advice is to wait one more day and then decide/act; however, sometimes one more day winds up being a week, a month, or longer.  A recent editorial indicates that there is enough evidence now for probiotic usage in neonates to prevent necrotizing enterocolitis (NEC).  The authors state that to continue “with the standard of care, in which no new products are provided…is ethically unacceptable” (JAMA Pediatrics 2013; 167: 885-6).  Thanks to Ben Gold for this reference.

Key arguments:

  • A 2011 Cochrane review identified 16 eligible trials with 2842 premature infants (<2500 g, <37 weeks).  Probiotics reduced the incidence of NEC with a relative risk of 0.35 and mortality with a relative risk of 0.40.  Despite the typically cautious recommendations from Cochrane reviews, the authors state “updated review of available evidence supports a change in practice.”
  • While the American Academy of Pediatrics in 2010 noted there is some evidence to support probiotic usage and called for more studies, there are no studies currently being conducted in the U.S.
  • The authors note that the “FDA Center for Biologic Evaluation and Research is committed to policies that effectively prohibit probiotic efficacy trials.” Under current policies, the authors state these “studies will not be conducted in a US setting for the next 20 to 30 years.”
  • Other countries , like Australia, allow use of probiotic with parental consent.
  • The authors propose that probiotic efficacy be studied in a comparative effectiveness design.

Bottomline: Current regulations have stymied the use of probiotic trials for NEC.  What will it take for regulatory agencies to relent and allow this promising research?

Related blog posts:

Disclaimer: These blog posts are for educational purposes only. Specific dosing of medications (along with potential adverse effects) and specific medical management interventions should be confirmed by prescribing physician.  Application of the information in a particular situation remains the professional responsibility of the practitioner.

Probiotics, Atopy, and Asthma

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Moving from theory to practice with probiotics has been problematic in many areas.  That is, theoretically probiotics by altering the microbiome should have numerous beneficial effects; however, demonstrating these positive effects in practice has been difficult for many conditions.  A recent study (thanks to Mike Hart for this reference) highlights this issue with regard to asthma:  Pediatrics 2013; 132: e666-76. Full article:

http://pediatrics.aappublications.org/content/132/3/e666.full.html

Background: Due to the immune modulating effects of probiotics and mindful of the hygiene hypothesis regarding the rise of atopic diseases, some have proposed the use of probiotics to reduce the risk of atopy and asthma in children.

Methods: In this study, the authors performed a meta-analysis of numerous randomized studies.  Out of a total of 1081 articles, 25 studies met predefined criteria, with a total of 4031 participants (see Table 1 in publication).  Numerous probiotics were administered.  The most common probiotic in these trials, Lactobacillus GG,  was used in 8 of the studies.

Results:

  • For serum immunoglobulin E (IgE) levels, 9 of the trials (n=1103) provided data.  Probiotics were associated with a -7.59 U/mL reduction in total IgE (P= .044).  The effect of probiotics was more pronounced with longer, follow-up periods.
  • Probiotics, in comparison to placebo, were associated with a reduced risk of atopic sensitization based on positive skin prick and/or elevated specific IgE to common allergens.  This was true whether the probiotic was administered prenatally (relative risk 0.88, P=.035) or postnatally (relative risk 0.86, P=.027)
  • Probiotics did not reduce the risk of asthma/wheeze (relative risk 0.96 [95% CI 0.85-1.07]

Study limitations: heterogeneity of clinical trials in meta-analysis, various probiotic strains, variable duration and timing of probiotic use.

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Probiotics for Crohn’s Disease –No Beneficial Effects Noted

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With all the buzz regarding how a patient’s microbiome seems to affect everything from metabolic syndrome and colic to autoimmune diseases and inflammatory bowel disease, more attention has been paid in attempts to alter the microbiome for therapeutic benefits.  In Crohn’s disease (CD), the fact that antibiotics have shown beneficial effects have led to a number of studies of probiotics.  A recent study, like previous ones, did not demostrate any benefit with Saccharomyces boulardii (Clin Gastroenterol Hepatol 2013; 11: 982-87).

In this prospective double-blind, placebo-controlled study of 165 patients who achieved remission after steroids or salicylates, subjects were randomly assigned to groups given S boulardii (1 gram per day) or placebo for 52 weeks.

Results:

  • CD relapse occurred in 80 patients: 38 (47.5%) in the probiotic group  and 42 (53.2%) in the placebo group
  • Time to relapse did not differ significantly: 40.7 weeks in probiotic group vs 39 weeks in placebo group
  • No differences were seen in disease activity scores or serum inflammatory markers
  • In post hoc analysis, nonsmokers given S boulardii were less likely to experience a relapse compared with nonsmoker control patients (34.5 % vs. 72%)

One important limitation of this study was not examining the effects of the probiotic on the microbiome of these patients.  Perhaps, other probiotics would be more effective in restoring a “healthy” flora.

Based on these results, and others, the accompanying editorial (pg 988-89), advocates use of probiotics only for prevention of antibiotic-associated diarrhea, prevention of recurrent Clostridium difficile, and treatment/prevention of pouchitis.

Bottom-line: Probiotics have not been demonstrated to be helpful for Crohn’s disease.

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