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ABSTRACT
the use of probiotics for preventing AAD is considered because of the
This article provides recommendations, developed by the Working
existence of risk factors such as class of antibiotic(s), duration of antibiotic
Group (WG) on Probiotics of the European Society for Pediatric Gastro-
treatment, age, need for hospitalization, comorbidities, or previous episodes
enterology, Hepatology, and Nutrition, for the use of probiotics for the
of AAD diarrhea, the WG recommends using Lactobacillus rhamnosus GG
prevention of antibiotic-associated diarrhea (AAD) in children based on a
(moderate QoE, strong recommendation) or Saccharomyces boulardii (mod-
systematic review of previously completed systematic reviews and of
erate QoE, strong recommendation). If the use of probiotics for preventing
randomized controlled trials published subsequently to these reviews.
Clostridium difficile-associated diarrhea is considered, the WG suggests
The use of probiotics for the treatment of AAD is not covered.
using S boulardii (low QoE, conditional recommendation). Other strains or
The recommendations were formulated only if at least 2 randomized
combinations of strains have been tested, but sufficient evidence is still
controlled trials that used a given probiotic (with strain specification) were
lacking.
available. The quality of evidence (QoE) was assessed using the Grading of
Recommendations Assessment, Development, and Evaluation guidelines. If
Key Words: Clostridium difficile, dysbiosis, guideline, infants, microbiota, influence properties of probiotic bacteria (9). At present, whether
probiotics, RCT, systematic review or not these manufacturing differences translate into differences in
vivo, as well as clinical outcomes, however, remains unclear.
(JPGN 2016;62: 495506) Consequently, the taxonomically equivalent probiotics are pre-
sented jointly, regardless of the manufacturer. The WG also
realizes that the same brand may have a different composition
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JPGN Volume 62, Number 3, March 2016 Probiotics for the Prevention of AAD
TABLE 1. The grades of the quality of evidence and strength of recommendation set by the GRADE Working Group
Quality of evidence High quality We are very confident that the true effect lies close to that of the estimate of the effect.
Moderate quality We are moderately confident in the effect estimate: the true effect is likely to be close to the
estimate of the effect, but there is a possibility that it is substantially different.
Low quality Confidence in the effect estimate is limited: the true effect may be substantially different from
the estimate of the effect.
Very low quality Very little confidence in the effect estimate: the true effect is likely to be substantially different
from the estimate of the effect.
Strength of recommendation Strong When the evidence showed that the benefit of the intervention clearly outweighs the
undesirable effects.
Conditional (weak) When the trade-offs were less certain (either because of the low quality of evidence or because
the evidence suggests that desirable and undesirable effects are closely balanced).
A draft of the position paper was sent to the WG members for trials, 59 lacked adequate information to assess the overall risk of
review and further comments. All of the critical feedback was bias. There was no placebo group in some trials. Included trials
discussed through e-mail or during personal contacts, and changes used different definitions of diarrhea/AAD, and in some, no
were incorporated as necessary. Recommendations were formulated definition of these outcomes was provided. Moreover, significant
and graded. The WG members voted anonymously on each recom- heterogeneity between trials for both primary and secondary out-
mendation using an online electronic survey tool (SurveyMonkey comes was detected. The authors concluded that the evidence is
Inc, Palo Alto, CA, www.surveymonkey.com). Any disagreement insufficient to determine whether this association varies system-
following voting was resolved by discussion, and for all recom- atically by population, antibiotic characteristic, or probiotic
mendations, a full consensus was reached. A finalized document preparation.
was submitted to the ESPGHAN Council for final acceptance A 2013 systematic review with a meta-analysis assessed
before publication. the efficacy and safety of probiotics for preventing C difficile-
The WG recommendations may need to be modified by associated diarrhea or C difficile infection in adults and children
different countries considering differences in health care systems, (17). A complete case analysis (ie, participants who completed
local values and preferences, including availability, quality, and the study) showed that compared with placebo or no treatment,
costs of probiotics, and should help local policy makers to decide administration of probiotics reduced the risk of C difficile-
whether to use routinely probiotics with documented efficacy for associated diarrhea by 64% (23 RCTs, n 4213, RR 0.36, 95%
preventing AAD in children receiving antibiotics based on local CI 0.26 0.51) in adults and children. In children, probiotic
cost-effectiveness analysis. This is particularly important in low- administration reduced the risk of C difficile-associated diarrhea
and middle-income countries. from 5.9% to 2.3% (3 RCTs, n 605, RR 0.40, 95% CI 0.170.96)
Clearly, an individual patients risk of developing AAD or C (17).
difficile-associated diarrhea depends on a number of factors such as For this report, 21 RCTs involving 3255 children were
class of antibiotic(s), duration of antibiotic treatment, age, need for included (1838). Among them, 11 RCTs were included in 2
hospitalization, comorbidities, and previous episodes of AAD or C strain-specific systematic reviews initiated as part of the develop-
difficile-associated diarrhea (13). These risk factors should be ment of these guidelines (39,40). One unpublished study (29) was
considered when making decisions on the use of probiotics in identified in the systematic review by Johnston et al (7). For
children for preventing AAD or C difficile-associated diarrhea. characteristics of the included RCTs, see Table 2, and for a
The WG acknowledges that the judicious use of antibiotics remains methodological quality summary, see Figure 1. The pooled results
the best method of preventing AAD. of 21 RCTs showed that compared with placebo or no intervention,
The conclusions of this document may require revision in the probiotics as a class reduced the risk of AAD by 52% (21.2% vs
future as new information becomes available. It is the intention of 9.1%, respectively; RR 0.48, 95% CI 0.370.61) (Fig. 2). Only 2
the WG to revise the recommendations not later than 5 years from probiotics were evaluated in >1 RCT. These were Lactobacillus
now and produce an updated document. rhamnosus GG (LGG) and Saccharomyces boulardii. Compared
with placebo, the administration of probiotics also reduced the risk
PROBIOTICS OVERALL of C difficile-associated diarrhea (4 RCTs, n 938, RR 0.34, 95%
A number of systematic reviews and meta-analyses have CI 0.150.76) (Fig. 3).
shown that probiotics as a group are effective in preventing AAD
(7,16,17).
A 2012 meta-analysis by Hempel et al (16) collected
PROBIOTICS WITH RECOMMENDATIONS
data from 82 RCTs that evaluated the efficacy of probiotics for L rhamnosus GG (LGG)
preventing AAD in subjects of all ages. Probiotics, as a group,
reduced the risk of AAD (63 RCTs, n 11,811 participants, RR
0.58, 95% CI 0.500.68). Sixteen RCTs were carried out in infants RECOMMENDATION. If the use of probiotics for
and young children and reported a reduced risk of AAD with preventing AAD in children is considered, the WG
probiotic administration (RR 0.55, 95% CI 0.380.80). In the recommends using L rhamnosus GG.
majority of trials, Lactobacillus-based interventions, alone or in QUALITY OF EVIDENCE: Moderate.
combination with other genera, were used. Strains were poorly STRENGTH OF RECOMMENDATION: Strong
documented. The quality of evidence was low. Of 63 included
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TABLE 2. Characteristics of the included trials
498
Probiotic dose Duration of Antibiotic/s Definition of diarrhea
Reference Participants (age) (CFU/day) intervention Follow-up (administration) or AAD Manufacturer Sponsor
Lactobacillus rhamnosus GG
Szajewska et al
Arvola et al (19) N 119, inpatients, 2 1010 For the duration of 3 mo Penicillin, 3 watery stools/day Not reported Finnish
(2 wk13 y) antibiotic therapy Amoxicillin, for minimum of 2 Foundation for
Cephalosporins, consecutive days Gastroentero-
Erythromycin, logical
Trimetoprim-sulfa Research
King et al (20) N 15, inpatients 30 109 For the duration of Not mentioned Various 3 loose stools in Not reported Not reported
(21 days11 y) antibiotic therapy 24 h
Szajewska et al (22) N 66, inpatients, 1 109 For the duration of 6 wk Amoxicillin, 3 loose or watery Dicofarm, Rome, Medical
(mean age 12 y; antibiotic therapy Clarithromycin stools per day for Italy University of
age range not (7 days) (oral) at least 48 h Warsaw
reported)
Vaisanen et al (21) N 59, outpatients 4 108 For the duration of Not mentioned Amoxicillin (oral) Defined by parents Not reported Not reported
(5 mo11 y) antibiotic therapy
(7 days)
Vanderhoof et al (18) N 188, outpatients 12 1010 For the duration of 10 days Amoxicillin, 2 liquid stools/day CAG Functional Grant from CAG
(6 mo10 y) antibiotic therapy amoxicillin/ Food Nutrition, a
(10 days) clavulanate, division of
cefprozil, ConAgra
clarithromycin,
other (oral).
Saccharomyces boulardii
Bin et al (27) N 205, exact data 250 mg (0.5 1010) For the duration No data Amoxicillin, Diarrhea: increase in No information Biocodex, Paris,
not given of antibiotic clarithromycin, the frequency of given France, Chinese
(22 mo16 y) treatment metronidazole bowel movements brand name:
(14 days) (>3/day) or a YiHuo. S
decrease in stool boulardii
consistency (Bristol CNCM I-745
stool scale 5 or 6)
JPGN
Casem et al (24) N 140, hospitalized 500 mg (1 1010) For the duration of No data Various (oral or Diarrhea: 3 loose Not reported Not reported
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JPGN
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Reference Participants (age) (CFU/day) intervention Follow-up (administration) or AAD Manufacturer Sponsor
Kotowska et al (23) N 269, inpatients 500 mg (1 1010) For the duration of 2 wk Various (oral or Diarrhea: 3 loose or No information No information
and outpatients antibiotic intravenous) watery stools per given (Enterol given (Medical
(6 mo14 y) treatment (SB day for a minimum Biocodex University of
group 7.8 1 of 48 h during and/ information Warsaw
days; control or up to 2 wk after from the information
group 8.1 1 the end of antibiotic authors) from the
days) treatment. AAD: As authors)
above, caused by C
difficile or for
otherwise
Volume 62, Number 3, March 2016
unexplained
diarrhea
Shan et al (26) N 333, inpatients 500 mg (1 1010) For the duration of 2 wk Various (intravenous) Diarrhea: 3 loose or One of the Bioflor, China
(6 mo14 y) antibiotic watery stools per investigators
treatment (exact day or during 48 serves as a
data not given) h, occurring during consultant in
and/or up to 2 wk Biocodex
after the end of
antibiotic treatment
Zhao et al (28) N 240 (79 y 2 y) 500 mg (1 1010) For the duration of 8 wk Amoxicillin, No definition given Not reported Not reported
antibiotic clarithromycin
treatment (14
days)
Bacillus clausii
Destura et al (29) N 323, inpatients 4 109 Until end of Until end of Penicillins, Change in bowel Study funded by Study funded by
and outpatients antibiotic therapy antibiotic cephalosporin, habits with the industry industry
(mean age 4 y) (721 days) therapy coamoxyclav/ passage of 3 or
(721 days) ampicillin- more liquid stools
sulbactam, and per day for at least 2
others consecutive days 48
h after initiation of
antibiotic therapy
Bifidobacterium lactis and Str thermophilus
Correa et al (30) N 157, inpatients B lactis 107 CFU/g 15 days 30 days Various Change in bowel Nestle Nestle
(636 mo) and Str habits with the
thermophilus 106 passage of 3 or
CFU/g more liquid stools
per day for at least 2
consecutive days
Probiotics for the Prevention of AAD
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Probiotic dose Duration of Antibiotic/s Definition of diarrhea
500
Reference Participants (age) (CFU/day) intervention Follow-up (administration) or AAD Manufacturer Sponsor
(1 y12 y) Bb-12 (5.9 109) their antibiotic treatment macrolides, different levels of (Brisbane, (Brisbane,
and La-5 treatment plus 1week tetracyclines severity: for Queensland, Queensland,
(8.3 109) example, less Australia) Australia)
severe (stool
frequency 2/day
for 2 or more days
with stool
consistency 5 on
the BSS); more
severe (stool
frequency 3/day
for 2 or more days
with stool
consistency 6 on
the BSS)
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Probiotic dose Duration of Antibiotic/s Definition of diarrhea
Reference Participants (age) (CFU/day) intervention Follow-up (administration) or AAD Manufacturer Sponsor
JPGN
Lactobacillus acidophilus and Lactobacillus rhamnosus and Lactobacillus bulgaricus and Lactobacillus casei and Str thermophilus and Bifidobacterium infantis and Bifidobacterium breve
Khodadad et al (38) N 66, inpatients 1 109 CFU/day For the duration of Not stated Amoxicillin, Not stated Protexin Co, UK Not reported
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(314 y) Helicobacter furazolidone
pylori eradication
therapy (4 wk?;
not clearly stated)
Kefir
Merenstein et al (36) N 125, outpatients At least half of a For the duration 14 days Antibiotics for upper Not reported Probugs (Lifeway Lifeway Foods,
(15 y) 150 mL drink of antibiotic respiratory tract Foods, Inc, Inc
containing 7 to treatment infections (not Chicago, IL)
109 CFU bacteria (10 days) specified otherwise)
and yeast
AAD antibiotic-associated diarrhea; BSS Bristol Stool Scale; CFU colony-forming units; SB S boulardii.
As calculated by the authors.
Volume 62, Number 3, March 2016
Zhao 2014
Vanderhoof 1999
Vaisanen 1998
Tankanow 1990
Szymanski 2008
Szajewska 2009
Shan 2013
Ruszczynski 2008
Merenstein 2009
Kotowska 2005
King 2010
Khodadad 2013
Jirapinyo 2002
Fox 2015
Erdeve 2004
Destura (unpublished)
Correa 2005
Contardi 1991
Casem 2013
Bin 2015
Arvola 1999
501
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Szajewska et al JPGN Volume 62, Number 3, March 2016
1.1.3 B clausii
Destura (unpublished) 3 162 7 161 2.8% 0.43 (0.11, 1.62)
Subtotal (95% CI) 162 161 2.8% 0.43 (0.11, 1.62)
Total events 3 7
Heterogeneity : Not applicable
Test for overall effect: Z = 1.25 (P = 0.21)
FIGURE 2. Effect of individual probiotic strains and probiotics as a group for preventing antibiotic-associated diarrhea.
(Continued on next page )
the overall quality of evidence was rated as moderate (Table S1, effect of LGG on the risk of C difficile-associated diarrhea in children
http://links.lww.com/MPG/A587). and found no effect (RR 0.95, 95% CI 0.0614.85) (Fig. 3).
Compared with placebo or no treatment, LGG administration The optimal daily dose of LGG for preventing AAD remains
in children reduced the risk of AAD, regardless of the reason for unclear (40). In children, the best effect (reduction in the risk of
which probiotics were used (ie, as part of Helicobacter pylori AAD by 71%) was achieved with the highest dose (12 1010
eradication or for other reasons), from 23% to 9.6% (5 RCTs, CFU) (18). A similar effect size was, however, not achieved in
n 445, RR 0.48, 95% CI 0.260.89; number needed to treat, another trial using the same dose (19), perhaps because of a lower
NNT, 8, 95% CI 640) (Fig. 2). No significant heterogeneity was baseline risk of AAD. In adults, there was no clear link between the
found (x2 6.61, P 0.16, I2 40%). Only 1 trial (19) evaluated the effect size and the LGG dose.
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JPGN Volume 62, Number 3, March 2016 Probiotics for the Prevention of AAD
1.1.9 L acidophilus & L rhamnosus & L bulgaricus & L casei & Str therophilus & B infantis & B breve
Khodadad 2013 2 33 8 33 2.4% 0.25 (0.06, 1.09)
Subtotal (95% CI) 33 33 2.4% 0.25 (0.06, 1.09)
Total events 2 8
Heterogeneity : Not applicable
Test for overall effect: Z = 1.85 (P = 0.06)
1.1.12 Kefir
Merenstein 2009 11 57 14 60 6.4% 0.83 (0.41, 1.67)
Subtotal (95% CI) 57 60 6.4% 0.83 (0.41, 1.67)
Total events 11 14
Heterogeneity : Not applicable
Test for overall effect: Z = 0.53 (P = 0.60)
FIGURE 2. (Continued )
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Szajewska et al JPGN Volume 62, Number 3, March 2016
1.2.2 Lactobacillus GG
Arvola 1999 1 61 1 58 8.5% 0.95 (0.06, 14.85)
Subtotal (95% CI) 61 58 8.5% 0.95 (0.06, 14.85)
Total events 1 1
Heterogeneity: Not applicable
Test for overall effect: Z = 0.04 (P = 0.97)
FIGURE 3. Effect of individual probiotic strains and probiotics as a group for preventing Clostridium difficile-associated diarrhea.
the risk of AAD (31.2% vs 16.3%, respectively; RR 0.52, 95% CI L rhamnosus GG, Bb-12 and L acidophilus La-5 or a pasteurized
0.290.95, NNT 7, 95% CI 462) (30). placebo yogurt (containing Streptococcus thermophilus plus L
bulgaricus) for the same duration as their antibiotic treatment.
L acidophilus/L bulgaricus Compared with the placebo group, children in the probiotic group
experienced a significant reduction in the risk of diarrhea (RR 0.05,
One small RCT (n 38) showed that compared with placebo 95% CI 0.010.35) (33).
(lactose), administration of L acidophilus/L bulgaricus (strain
specification not given) had no effect on the risk of AAD (RR B longum PL03/L rhamnosus KL53A/L
0.96, 95% CI 0.611.5) (31). plantarum PL02
L acidophilus/Bifidobacterium infantis One RCT (n 78) showed that compared with placebo, the
administration of B longum, L rhamnosus, and L plantarum had no
One small RCT (n 18) showed that compared with placebo effect on the risk of AAD (RR 0.47, 95% CI 0.045.03) (34).
(sugar), administration of L acidophilus/B infantis (strain specifica-
tion not given) had no effect on the risk of AAD (8/10 vs 3/8, L rhamnosus E/N, Oxy, Pen
respectively; RR 0.47, 95% 0.181.21) (32).
One RCT involving 240 children showed that compared with
L acidophilus/Bifidobacterium breve placebo, the administration of L rhamnosus (strains E/N, Oxy and
Pen) reduced the risk of any diarrhea (RR 0.45, 95% CI 0.210.95),
One small RCT (n 40) showed no cases of AAD in either but it did not have an effect on the risk of C difficile-associated
the L acidophilus/B infantis (strain specification not given) group diarrhea (RR 0.43, 95% CI 0.111.62) (35).
or the placebo (sugar) group (0/20 vs 0/20, respectively). Thus,
the efficacy of this probiotic combination could not be evaluated L acidophilus/L rhamnosus/L bulgaricus/L
(37).
casei/Str thermophilus/B infantis/B breve
L rhamnosus GG/Bb-12/L acidophilus La-5 One RCT involving 66 children showed that compared
with placebo, the administration of L acidophilus/L rhamnosus/L
In a multisite, double-blind, placebo-controlled RCT, chil- bulgaricus/L casei/Str thermophilus/B infantis/B breve (strain
dren (n 70), age 1 to 12 years, who were prescribed antibiotics specification not given) reduced the risk of diarrhea (RR 0.25,
were randomized to receive 200 g/day of either a yogurt containing 95% CI 0.061.09) (38).
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Szajewska et al JPGN Volume 62, Number 3, March 2016
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