US Pharm. 2014;39(5):22-26.
ABSTRACT: Probiotics are living microorganisms that are taken for
their preventive or therapeutic effects on a wide variety of disease
states, many of which are common in the pediatric population. A wide
variety of probiotic species are available, but Lactobacillus species
are the most investigated. The majority of probiotic use revolves around
gastrointestinal diseases. Pharmacists play a key role in educating
patients and caregivers on the effectiveness of probiotics for certain
disease states, as well as in choosing the appropriate probiotic strain
and recommended dosage for pediatric patients.
Probiotics are active living microorganisms that have a defined
health benefit—either therapeutic or preventive—when ingested in
sufficient quantity.1 These microorganisms are usually
consumed with the intent to replace or increase an individual’s
microflora. Probiotics must be resistant to stomach acid and bile to
survive passage through the digestive tract, must be able to proliferate
and colonize the gut, and must be able to attach and adhere to the
lining of the gastrointestinal (GI) tract.1,2
Early Exposure to Bacteria
The human gut is a sterile environment until birth. Following birth,
infants are exposed to a wide variety of bacteria. This early exposure
to bacteria establishes the normal bacterial flora that will be present
for the rest of an individual’s life. During early infancy, the
intestinal immune system begins to recognize that some bacteria are good
and some bacteria are bad, and that bad bacteria require an immune
response to be mounted. For the rest of the individual’s life, any
ingestion of bacteria that alter the normal gut flora could trigger an
immune response targeting the bad bacteria.1 It has been
asserted that probiotics play a beneficial role in the digestive and
immunologic function of the human body by maintaining or enhancing gut
microflora and the intestines’ natural function. These actions may
significantly alleviate numerous diseases in children.1,2
Effects of Probiotics
Several mechanisms have been proposed to explain the actions of
probiotics, but in most cases the exact mechanism of action is not fully
understood, and it is likely that a number of mechanisms are working
Probiotics induce an increase in the number of intestinal bacteria.
Beneficial effects are likely due to a multitude of actions, including
modulation of immune function leading to stimulated host defense
mechanisms; downregulation of inflammatory cytokines resulting in
decreased chronic gut inflammation; enhanced immunoglobulin (Ig)G/IgA
antibody responses to bad bacteria; and reduced production of
allergen-specific IgE production. The benefits of probiotics in
preventing and treating GI disease are likely due to a combination of
direct competition between the probiotic and pathogenic bacteria in the
gut and GI-tract immunomodulation.3-5
Probiotic use has been advocated for a wide range of disease states,
with varying degrees of supporting evidence. Most of the benefit is
observed with GI diseases. Disease states with clinical studies
validating the use of probiotics include viral diarrhea,
antibiotic-associated diarrhea (AAD), Clostridium difficile–associated diarrhea (CDAD), traveler’s diarrhea, atopic dermatitis, pouchitis, and irritable bowel syndrome.1
However, probiotics’ beneficial effects may extend to additional
disease states, including rheumatoid arthritis, Crohn’s disease, dental
caries, asthma, and colon cancer.1
There are a multitude of disease states obtaining varying degrees of
benefit from probiotics, but this article will focus on the use of
probiotics for GI diseases in children.
Types of Probiotics
A wide variety of probiotic species are available, but the most investigated are species of Lactobacillus (L acidophilus, L rhamnosus, L bulgaricus, L reuteri, L casei) and Bifidobacterium. Additional probiotic species include Saccharomyces boulardii, Streptococcus and Enterococcus species, Propionibacterium species, and Escherichia coli strain Nissle 1917.6,7
In the United States, probiotics are available primarily as dietary
supplements in capsule, tablet, or powder formulations. In addition,
probiotics occur in yogurt, sauerkraut, and other fermented foods.7 Some of the more common probiotic products in the U.S. are listed in TABLE 1.
Overview of Diarrhea
There are many different types of diarrhea, including infectious diarrhea, CDAD, and AAD. The World Health Organization defines diarrhea as three or more loose or watery bowel movements per day, or more frequent bowel movements than normal for that individual.8 Infectious diarrhea can be caused by any type of bacteria, whereas only C difficile
causes CDAD. AAD is defined as three or more loose bowel movements for 2
or more days within 14 days of starting antibiotic therapy.6 Diarrhea may be considered either acute or persistent, with persistent diarrhea lasting for at least 14 days.9
Diarrheal disorders in pediatric patients place a significant burden
on the patient, caregivers, and the healthcare system. Because of their
role in modifying the gut microflora, probiotics have been studied in
the management of many diarrheal disorders, including acute infectious
diarrhea and AAD.
Acute Infectious Diarrhea: Infectious diarrhea
is a common disease worldwide and is most common in developing
countries. Most of the time, diagnostic and confirmatory tests are not
performed to discover the specific bacterium that caused the diarrhea.10 Several randomized, controlled trials have evaluated the use of probiotics for acute infectious diarrhea in children.
The use of Lactobacillus in children with acute infectious
diarrhea was assessed in two meta-analyses. In the first analysis, there
was a reduction in diarrhea duration of 0.7 days (95% CI 0.3-1.2 days)
and a reduction in diarrhea frequency of 1.6 stools on treatment day 2
(95% CI 0.7-2.6).11 Similarly, in the second analysis, Lactobacillus GG reduced diarrhea duration by approximately 1 day (–1.05 days, 95% CI –1.7 to –0.4).12 Both meta-analyses suggested that Lactobacillus doses ≥10 billion colony-forming units (CFU) per day are associated with the greatest benefit in diarrhea reduction.11,12
A different meta-analysis found that administration of probiotics to
otherwise healthy children aged <5 years with acute diarrhea reduced
the diarrhea duration by 0.8 days (95% CI –1.1 to –0.6 days, P <.001). The trials in this analysis used various probiotics, including lactobacilli, Streptococcus thermophilus, S boulardii, bifidobacteria, enterococci, or combinations of these.13
A Cochrane review concluded that probiotics administered to patients
with acute infectious diarrhea reduced the mean duration of diarrhea by
24.76 hours (95% CI 15.9 to 33.6 hours), reduced the incidence of
diarrhea lasting ≥4 days (risk ratio [RR] 0.41, 95% CI 0.32-0.53), and
decreased stool frequency by 0.8 stool on day 2 (95% CI 0.45-1.14). Both
adults and children were studied, but 80% of participants were aged
<18 years. A wide variety of probiotics were used, with Lactobacillus GG, S boulardii, and enterococci being the most common.10
Overall, these analyses provide evidence supporting the use of probiotics, especially Lactobacillus in doses ≥10 billion CFU per day, to achieve a reduction in diarrhea duration of approximately 1 day.14
The studies used several different strains and doses of probiotics.
Further study is needed to better delineate the populations receiving
the greatest clinical benefit from probiotics, as well as the most
effective dose, frequency, and type of probiotic.
AAD: Diarrhea commonly occurs secondary to
antibiotic use. About 30% of patients taking antibiotics experience
diarrhea, through a variety of mechanisms.6 Antibiotics may
kill the good bacteria in the patient’s gut, creating opportunities for
pathogenic organisms to overtake the gut. Diarrhea is a common adverse
effect (AE) in children receiving antibiotics, especially antibiotics
with activity against anaerobic organisms. The use of probiotics as
preventive therapy (initiated concurrently with antibiotic therapy) for
AAD has been studied in several randomized, controlled trials.
A trial in children aged 6 to 36 months compared the incidence of AAD
when a probiotic versus placebo was added to infant formula in patients
also receiving antibiotics. Probiotics decreased the incidence of AAD
by 47.7% (31.2% vs. 16.3%; P = .044).15 Similarly, a trial in children aged 3 months to 14 years found that the addition of L rhamnosus versus placebo in subjects receiving antibiotics reduced the incidence of AAD from 16.7% to 7.5% (RR 0.45, 95% CI 0.2-0.9).16
A meta-analysis reviewed trials of probiotics compared with placebo
on the risk of AAD in children. Probiotics reduced the risk of AAD from
28.5% to 11.9% (RR 0.44, 95% CI 0.25-0.77). This analysis suggests that
for every seven patients who would develop AAD, one fewer would develop
it if probiotics were administered along with antibiotics.17 The studies employed a number of different probiotics and varying dosing.
A Cochrane review suggests an overall benefit of probiotics in
preventing AAD despite differences in probiotic strain, dose, and
duration, as well as issues with study quality that affected the
validity of the data. In a subgroup analysis, the use of high-dose
probiotics (≥5 billion CFU/day) provided a number needed to treat (NNT)
of seven patients to prevent one case of diarrhea in children receiving
antibiotics (NNT 7; 95% CI 6-10).18
This evidence suggests that probiotics may be beneficial in reducing
the incidence of AAD in children. However, there is a lack of large,
well-designed, randomized trials assessing the true impact.
CDAD: Although infectious diarrhea and AAD are
fairly common, CDAD occurs in about four of every 1,000 hospital
admissions in children.19 Whenever the normal gut flora are
upset, there is a possibility that harmful bacteria can grow out of
control. One of the worst bacteria that can then overwhelm the gut flora
is C difficile. C difficile infection can present with a wide range of symptom severity. Antibiotics are used to kill the overgrowth of C difficile bacteria.
A Cochrane review evaluated the use of probiotics for preventing CDAD
in adults and children receiving antibiotics. There was a 64% relative
risk reduction in CDAD incidence from 5.5% in the placebo or
no-treatment group to 2% in the probiotic group, but this was considered
only a moderate reduction overall.20
Although probiotics have been studied for CDAD prevention in
children, their role in the treatment of CDAD remains unclear. A
Cochrane review found insufficient evidence to support the use of
probiotics for CDAD treatment in adults.21 Probiotic use for CDAD treatment in children is currently not recommended, as this has not been adequately studied.14
Safety of Probiotics
Given the growing use of probiotics to treat a variety of disease
states, a review of safety concerns is warranted. Probiotics are live
microorganisms and therefore carry the risk of producing an active
infection, although this risk is quite low.
A recent meta-analysis was conducted to assess the safety profile of probiotics.7
This analysis of randomized, controlled trials, case series, and case
reports investigated all probiotic agents, but the large majority of
trials involved Lactobacillus and Bifidobacterium. The
most commonly observed AEs included bacterial sepsis, fungemia, and GI
ischemia. The true incidence of AEs is hard to quantify, since much
information regarding their negative impact comes from small case series
or case reports. However, patient populations that may be at higher
risk for AEs could include critically ill ICU patients, patients with
any kind of immunodeficiency, and patients with indwelling central
venous catheters.7,10 Overall, evidence suggests that
probiotics are safe, but that their use in higher-risk patient
populations should be carefully considered.
Challenges Surrounding Probiotic Use
There are several challenges with adopting probiotics as a definitive
treatment option. In the majority of foods produced in the U.S., all
living organisms have been eradicated in order to enhance shelf life, so
few probiotic-containing products are available. Many patients are
afraid to use probiotics because they are living microorganisms that
confer the risk of active infection.
There is also a great degree of confusion over probiotic agents. Many
products make numerous health claims, not all of them based on
scientific literature. This can confuse the consumer in terms of
unwarranted anticipated benefits. When there is proven benefit in
clinical trials, information on the exact dose and type of probiotic can
be hard to find, making it difficult for pharmacists to recommend
It also has been found that many probiotic products do not contain
the stated individual probiotic, contain less than the stated amount of
probiotic, contain nonviable living organisms, or provide probiotic
strains with no proven clinical benefit.
All of these challenges contribute to a lack of knowledge about
differences in available microorganisms and recommended doses or
As the field of probiotics continues to expand in the U.S., so does
the need for pharmacist awareness of probiotic use. Probiotics,
specifically Lactobacillus 10 billion CFU per day, may decrease
the duration of infectious diarrhea and may also reduce the incidence of
AAD. The benefits of probiotics for CDAD remain unclear. Pharmacists
must be able to identify specific product formulations, doses, and
strain availability while also communicating the effects of probiotics
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