Probiotics for treatment of acute
diarrhea in children: randomized
clinical trial of five different
preparations
Jessica Hersman M.D.
January 15, 2009
Is this study applicable to my
practice and my patients?…
“This one time, while covering the parent
pager…”
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Mom: “Dr.! My baby won’t stop pooping, and its really runny!”
“What do I do?”
Resident: “That’s too bad, unfortunately your baby probably has
a viral gastro and it will just take time for the illness to run its
course.”
Mom: “But Dr. its everywhere!” “Do you have kids, do you know
what I’m going through right now?”
Resident: “No, but I have a dog :)”
Mom: “Well that’s great…has you’re dog ever had diarrhea?”
Resident: “No.”
Mom: “Well, this is awful and I can’t take it anymore…I can’t keep
him in diapers! You have to help me!”
Resident: “I wish I could offer you more but just make sure that
your baby stays well hydrated and come see me in clinic if if
doesn’t get any better…Well, gotta run, ABP is about to close and
I hear they came out with a new sandwich!… have a good day!”
Acute Diarrhea
 Diarrhea - WHO
QuickTime™ and a
TIFF (U ncompressed) decompressor
are needed to see t his picture.
defines as passage of
loose or watery stools;
3 or more per day.
 Among children in the
U.S., diarrhea
accounts for more
than 1.5 million
outpatient visits,
200,000
hospitalizations, and
~300 deaths per year.
Probiotics?
 There are three
general methods by
which the intestinal
microflora can be
altered:
1. Administration of
antibiotics.
2. Administration of
prebiotics - dietary
compounds that promote
the growth and
metabolic activity of
beneficial bacteria.
3. Administration of
probiotics or beneficial
bacteria.
Probiotics? - “Help me, help
you!”
 Probiotics are
microorganisims that have
beneficial properties for
the host.
 Most have been derived
from food sources,
especially cultured milk
products.
 Many studies have
suggested potential
efficacy in several GI
illnesses including IBD,
Antibioitic related
diarrhea, C diff colitis, and
most applicable to this
talk, infectious diarrhea.
What’s the mechanism?
 The mechanism for the benefits of
probiotics are incompletely
understood.
Mechanism of Action
 Suppression of growth
or epithelial
binding/invasion by
pathogenic bacteria
 1. Decrease luminal
pH
 2. Secrete
antimicrobial peptides
 3. Inhibit bacterial
invasion
 4. Block bacterial
adhesion to epithelial
cells
Mechanism of Action
 Enhancement of
intestinal barrier
function.
 1. Increase mucus
production
 2. Decrease chloride
and water secretion
 3. Bind epithelial cells
at their apical junctions
through tight junction
proteins
Mechanism of Action
 Modulation of the
immune system.
 1. Induce
protective
cytokines (IL-10
and TFG-beta)
 2. Suppress
proinflammatory
cytokines (TNF)
And now, the nitty gritty…
The Objective
 To compare the efficacy of five
probiotic preparations
recommended to parents in the
treatment of acute diarrhea in
children.
The Methods
 This study was a prospective single blind
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randomized controlled trial.
The study design was discussed with six family
pediatricians in three meetings.
Diarrhea was defined as three or more outputs
of loose or liquid stool per day.
Eligible children were ages 3 to 36 months who
were seen in pediatricians offices from October
1999 to September 2000 because of diarrhea.
Included in the study were all children with
diarrhea lasting less than 48 hours for whom
parents gave informed consent.
“You’re either in or you’re
out…and you’re out!”
 Exclusion criteria
 Malnutrition
 Clinical symptoms of
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QuickTime™ and a
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are needed to see this picture.
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severe dehydration
Coexisting acute systemic
illness
Immunodeficiency
Chronic disease
CF
Food allergy
Use of probiotics in
previous 3 wks
Use of Abx or any
antidiarrheal medications
in previous 3 wks
Poor compliance (<4
doses)
Flow of participants through trial of probiotic preparations for treatment of childhood
acute diarrhoea
Canani, R. B. et al. BMJ 2007;335:340
Copyright ©2007 BMJ Publishing Group Ltd.
Methods cont…
All children
given ORT for
3-6 hrs.
Kids then fed with either full
strength formula containing lactose
or cowsÕmil k depending on age.
Children randomized to oral rehydration alone,
or Lactobacillus GG, S boulardii, Bacillus clasii,
mix of L delbrueckii bulgaricus, Steptococcus
thermophilus, L acidophilus, and
Bifidobacterium bifidum, or E faecium strain
Sf68.
Parents received a coded reporting form on
which to record clinical data. Parents were
instructed to record daily the number of fecal
ouputs and their consistency, the type and
doses of probiotic preps taken by the child,
the presence of vomiting and fever, any
necessity for hospital amission, and all
adverse events.
Probiotic preparations were
prescribed for five days and
administered orally in 20ml of
water according to the
manufacturersÕinstructions.
Randomization
 Patients were allocated to each group
according to a computer generated
randomization list.
 Random allocation was made in blocks of six to
obtain groups of similar size and the sequence
was concealed until treatments were assigned.
 The researchers responsible for enrolling the
patients allocated the next available number on
entry into the trial, and the parent of each child
received written instructions to purchase the
assigned probiotic product.
 The baseline features of the patients enrolled
were similar with respect to age, sex, weight,
and feeding regimen.
Outcome Measures
 Primary outcome
measures:
 Total duration of
diarrhea (time in hrs
from first to last
abnormal stool).
 Number of stools/day
and consistency
(based on grading
scale from 1-4 with 1
being normal and 4
being liquid).
 Secondary outcome
measures:
 The incidence and
median duration of
vomiting, fever, and
the number of hospital
admissions in each
group.
 Safety and tolerability
were also investigated.
The blind leading the blind?
In order to address the problems
of performing a double blind
study of commercially available
products the study designers
used the third party blind
observer method to assess
efficacy.
 To ensure unbiased assessment,
the pediatricians, who were in
charge of treatment allocation,
gave written instructions to
parents to purchase a brand of
probiotic and verified
compliance on the reporting
form, whereas the investigators
collecting the reporting forms
were blinded to the assigned
treatment.

QuickTime™ and a
TIFF (Uncompressed) decompressor
are needed to see this picture.
The Results
 The total duration of
diarrhea was
significantly lower in
children receiving
Lactobacillus GG and
in those receiving the
bacterial mix than in
those receiving ORT
alone.
 78.5 hrs and 70.0 hrs vs.
115.5 hrs respectively,
both with P values of
<0.001.
 The three other
preparations had no
effect on diarrhea,
and the duration of
diarrhea in the other
groups was similar to
that in the group
receiving ORT alone.
The Results
 Daily stool output was
significantly lower in
groups 2 and 5
(Lactobacillus GG
and the probiotic mix)
with P value of <0.001
starting the day after
the first day of
therapy.
 Stool consistency,
judged by the scoring
system 1-4, differed
significantly starting
the day after
therapy,(P<0.001) in
groups 2 and 5 versus
the other groups.
There was a quicker
transition to more
normal stool
consistency in groups
2 and 5.
The Results
 There were no significant
findings in terms of
secondary outcomes in
any of the probiotic
groups vs. those receiving
ORT alone.
 All parents purchased the
product indicated by the
pediatrician and all of the
preparations included in
the study were well
received and no adverse
events were observed.
The Good
 Is this study applicable to
my patients?….Yes!
 Is the treatment feasible to
use in my practice?…Yes!
 Were both statistical and
clinical significance
considered?…Both strains
deemed efficacious in the
treatment of acute
diarrhea were statistically
significant with P values of
<0.001. I think it would have
been interesting in terms of
clinical significance to
survey parents after
completion of therapy to
assess their attitudes about
efficacy and satisfaction.
 Was there at least 80%
follow up…Yes! Of the
600 patients assessed for
eligibility, 29 were
excluded initially for
either refusal to
participate or for not
meeting inclusion
criteria. Of the 571
patients enrolled, only 21
pts did not complete the
study usually due to
faster resolution of
symptoms or noncompliance. (97 %
follow-up)
The Good…part deux
 Definitions - the study did a great job
defining key concepts i.e. diarrhea,
compliance, exclusion criteria, and
expounded upon sample size in terms of
what n would be necessary to obtain a
certain power.
 Methods - the study design was clearly
described and would be reproducible by
a third party.
The Good…Continued
 Randomization - Patients were allocated to
each group according to a computer
generated randomization list which resulted in six
groups of similar size and of similar baseline
characteristics. This is essential to the study
design as the study enrolled 3 to 36 month old
children, a patient population in which feeding
regimen can very substantially among
participants. For example, would the
immunological effects of breast milk in
exclusively breast-fed infants have had a
confounding effect on the primary outcomes
measured had the patients not been
randomized?
The Bad…
 Single blinded - By failing to implement a study design
in which the parents, and coincidentally the data
collectors/reporters are also blind to their prescribed
strain of probiotic, the study designers leave their
results open and subject to parental bias.
 In the paper the authors describe this problem as
“possible confounding,” as opposed to bias, and
rationalize that since these products are were not
advertised in the media and because they were all
available in pharmacies, parental preconceptions
were unlikely.
The Bad…part deux
 Lack of “hard facts” -
Primary end points
measured were not
objective facts but
relied upon subjective
parental opinion.
Grading scale of stool
consistency from 1 to
4 is very open to
interpretation.
 Data/results relied
upon parental recall.
The bad…continued
 “In
conclusion…we
believe that
probiotic
preparations
should be
classified as
drugs…”
 This notion went
completely
unaddressed
throughout the
article. Safety was
not mentioned in
depth and though
this study did speak to
efficacy, whether
probiotics should be
regarded as food
supplements or drugs
in another question
entirely.
The bottom line
 Overall, I think this was a good,
randomized controlled study with well
thought out methods that offers an
extremely relevant assessment of a
potentially beneficial therapy for a
ubiquitous pediatric problem.
 While the most glaring negative has to be
the lack of a double blinded design and
the reliance upon parental recall, one
could argue that this deficiency allowed
for a more real world setting in which to
more authentically assess efficacy.
Sources
 Canani, Roberto et al. Probiotics for treatment of acute
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diarrhea in children: randomized clinical trial of five different
preparation. BMJ 2007; 335.
Guandalini, Stefano. Acute Diarrhea in Children in Europe:
Do We Know How to Treat It? Journal of Pediatric
Gastroenterology and Nutrition 2008; 46: 77-80.
Guandalini, Stefano. Probiotics for Children With Diarrhea: An
Update. Journal of Clinical Gastroenterology 2008; 00; 000000.
Guarino et al. Probiotics as prevention and treatment for
diarrhea. Current Opinion in Gastroenterology 2008; 25: 1823.
Sartour, R Balfour. Probiotics for gastrointestinal disease. Up to
date 2008.
S.C. Ng et al. Mechanisms of Action of Probiotics: Recent
Advances. Inflammatory Bowel Disease 2009; 15:300-310.