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Probiotics for treating infectious diarrhoea

  1. Stephen J Allen1,*,
  2. B Okoko2,
  3. Elizabeth G Martinez3,
  4. Germana V Gregorio3,
  5. Leonila F Dans4

Editorial Group: Cochrane Infectious Diseases Group

Published Online: 21 JAN 2009

Assessed as up-to-date: 19 JUN 2003

DOI: 10.1002/14651858.CD003048.pub2

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Allen SJ, Okoko B, Martinez EG, Gregorio GV, Dans LF. Probiotics for treating infectious diarrhoea. Cochrane Database of Systematic Reviews 2003, Issue 4. Art. No.: CD003048. DOI: 10.1002/14651858.CD003048.pub2.

Author Information

  1. 1

    Swansea University, School of Medicine, Swansea, West Glamorgan, UK

  2. 2

    Medical Research Council Laboratories, Banjul, Gambia

  3. 3

    College of Medicine-Philippine General Hospital, University of the Philippines, Department of Pediatrics, Manila, National Capital Region, Philippines

  4. 4

    Philippine General Hospital, University of the Philippines, Department of Pediatrics and Clinical Epidemiology, Manila, National Capital Region, Philippines

*Stephen J Allen, School of Medicine, Swansea University, Room 314, The Grove Building, Singleton Park, Swansea, West Glamorgan, SA2 8PP, UK. S.J.Allen@swansea.ac.uk.

Publication History

  1. Publication Status: Edited (no change to conclusions)
  2. Published Online: 21 JAN 2009

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Characteristics of included studies [ordered by study ID]
Bhatnagar 1998
MethodsStudy design: RCT; 2 centres.
ParticipantsInclusion criteria: inpatients; malnourished boys (weight for height < 80% NCHS median) with diarrhoea (≥ 5 liquid stools in preceding 24 h) for ≤ 96 h.

Exclusion criteria: females; severe non-gastrointestinal illness; gross blood in the stools; exclusive breast feeding.

Number completing study: 47/49 (95.9%) in probiotic group (2 withdrawn because cholera in stool cultures); 49/53 (92.5%) in control group (2 withdrawn because cholera in stool cultures and 2 left against medical advice).
Interventions(1) Yogurt formula (Lactogen-2, Nestle India Ltd; after fermentation with 90 g Streptococcus thermophilus and Lactobacillus bulgaricus standard starter (International Yoghurt Manufacturers Club, Paris) 120 ml/kg/day for at least 72 h) added to milk formula.

(2) Non-fermented Lactogen-2.

Given after 8 h initial observation. All participants received rehydration fluids (IV if stool > 4 g/kg/h), IV cephalosporin and gentamicin, and fed with rice lentil oil gruel.
Outcomes(1) Proportion recovered at 48 h and 72 h (defined as 2 consecutive formed stools, ≤ 3 stools in 24 h of which at least 2 were formed, or no stool for 12 h).
(2) Median duration of diarrhoea.
(3) Treatment failures (episode of diarrhoea after 72 h or stool weight > 150 g/kg on any day).

No comment regarding adverse events.
NotesStudy location: India (high child and adult mortality).




Boulloche 1994
MethodsStudy design: RCT; 1 centre.
ParticipantsInclusion criteria: inpatients; young children with acute diarrhoea (definition not stated; 3/4 had diarrhoea < 3 days); weight loss of at least 5%.

Exclusion criteria: any treatment that could have affected diarrhoea during hospitalization.

Number completing study: 38/38 (100%) in probiotic group and 33/33 (100%) in control group.
Interventions(1) Killed Lactobacillus acidophilus (LB strain, Lacteol Forte, France; 1 sachet tds for first 24 h, then 1 sachet bd for next 3 days).
(2) Placebo (no details provided; same regimen).
(3) Loperamide.

Timing of start of administration not stated. All young infants were given Pregestimil, and older children were given an anti-diarrhoeal diet.
Outcomes(1) Time to first normal stool.
(2) Failure defined as no improvement by the end of day 2 (clinical criteria). No adverse events observed.
NotesStudy location: France (very low child and adult mortality).

18% all participants had positive stool cultures and 49% positive virology tests (no further details given).

Results presented for oral rehydration group only and all children. Resolution of diarrhoea in killed L. acidophilus group similar for rotavirus positive and negative participants.




Bruno 1981
MethodsStudy design: RCT; 1 centre.
ParticipantsInclusion criteria: inpatients; adults with "acute enteritis" (diarrhoea, fever, vomiting, nausea, abdominal pain with or without toxicity; duration not stated).

Exclusion criteria: typhoid cases.

Number completing study: stool cultures available after randomization; participants with Salmonella typhi withdrawn (number not stated); for non-typhoid participants, results presented for 25/25 (100%) in probiotic group and 24/24 (100%) in control group.
Interventions(1) Enterococcus LAB SF68 (Bioflorin; ≥ 75 million lyophilized bacteria tds for 10 days).
(2) Placebo.

Timing of start of administration not stated.
Outcomes(1) Proportion of participants with diarrhoea by day of treatment.

Resolution of diarrhoea defined as 2 or less formed stools/day and no abdominal pain or fever.
No adverse events observed.
NotesStudy location: Italy (very low child and adult mortality).

Bacterial stool culture (probiotic group/placebo group): Salmonella 4/3; enteropathogenic E. coli 18/20; other enteropathogen 1/3.




Bruno 1983
MethodsStudy design: RCT; 1 centre.
ParticipantsInclusion criteria: inpatients; adults with "acute febrile enteritis" (duration of diarrhoea not stated).

Exclusion criteria: typhoid cases.

Number completing study: 10/10 (100%) in the probiotic group and 11/11 (100%) in the control group.
Interventions(1) Enterococcus LAB SF68 (Bioflorin; ≥ 75 million lyophilized bacteria tds for at least 10 days).
(2) Placebo.

Intervention started after initial treatment with chloramphenicol (all participants) and after stool culture results available.
Outcomes(1) Proportion of participants with diarrhoea by day of treatment (definition for recovery from diarrhoea not stated).
No adverse events observed.
NotesStudy location: Italy (very low child and adult mortality).




Buydens 1996
MethodsStudy design: RCT; 2 centres.
ParticipantsInclusion criteria: inpatients and outpatients; adults with acute diarrhoea (≥ 3 watery or loose stools in last 24 h).

Exclusion criteria: diarrhoea > 3 days; blood in faeces; faecal leukocytes; temperature > 39 °C; friable and haemorrhagic mucosa in rectosigmoid; history of chronic diarrhoea; polyps; colon cancer; Crohn's disease; ulcerative colitis; malabsorption; use of antidiarrheals or antibiotics in past 7 days; severe diarrhoea (dehydration with weight loss > 10%); associated major diseases.

Number completing study: 93/105 (88.6%) in probiotic group (4 violated protocol, 5 did not comply with study medications, 3 lost to follow up) and 92/106 (86.8%) in control group (5 violated protocol, 7 did not comply with study medications, 2 lost to follow up).
Interventions(1) Enterococcus strain SF68, lyophilized (Bioflorin; 75 million CFU tds for ≥ 5 days).
(2) Placebo.

Started on day of presentation.
Outcomes(1) Number of participants with diarrhoea by day of treatment.
(2) Mean stool frequency by day of treatment.

Diarrhoea resolved when stool frequency < 3/day and semisolid or solid and no associated symptoms.

No adverse events observed.
NotesStudy location: Belgium (very low child and adult mortality).

Highly significant reduction in duration of diarrhoea in the probiotic group confirmed by an intention to treat analysis, which included the excluded participants as non-recovered on day 7 (but no data shown).




Carague-Orendain
MethodsStudy design: RCT; 1 centre.
ParticipantsInclusion criteria: inpatients and outpatients; children with non-bloody diarrhoea (not defined) of less than 5 days duration.

Exclusion criteria: antimicrobials in the last 72 h; concomittent illness; severe malnutrition; antidiarrhoeal drugs; immunocompromise.

Participants completing study: 35/35 (100%) in probiotic group and 35/35 (100%) in control group.
Interventions(1) Lactobacillus acidophilus and Lactobacillus bifidus (Infloran Berna).
(2) Placebo (no details given; unclear whether or not placebo was identical to probiotic).

No details of dose, when treatment started, or duration of treatment.
Outcomes(1) Resolution of diarrhoea (defined as no passage of stool for 12 h or 2 consecutive formed stools). Assessed in outpatients by phoning the parents.

No adverse events observed.
NotesUnpublished data.

Study location: Philippines (low child and adult mortality).

42 children had some dehydration (none severe) and 28 had no dehydration.




Cetina-Sauri 1994
MethodsStudy design: RCT; 1 centre.
ParticipantsInclusion criteria: unclear whether inpatients and/or outpatients; children aged 3 months to 3 years with acute (duration not stated) non-bloody diarrhoea; no dehydration; no concomitant illness; no antibiotics or drugs affecting gut motility.

Number completing study: unclear how many participants randomized; participants who deteriorated, developed concomitant illness, and needed other drugs, or who wished to withdraw were excluded from the analysis (details not given).
Interventions(1) Saccharomyces boulardii (live Saccharomyces cerevisiae Hansen CBS 5926) 200 mg tds.
(2) Glucose placebo (diluted in 5 ml cold water).

Start and duration of treatment not stated.
Outcomes(1) Number of stools per day.
(2) First day stools formed.
(3) Side effects.

Cure defined as < 4 stools in 24 h and absence of liquid stools.

No adverse events observed.
NotesStudy location: Mexico (low child and adult mortality).




D'Apuzzo 1982
MethodsStudy design: RCT; unclear whether single or multicentre.
ParticipantsInclusion criteria: unclear whether inpatients and/or outpatients; children with acute enteritis (duration and definition not given).

Exclusion criteria: none stated.

Number completing study: 21/21 (100%) in probiotic group and 18/18 (100%) in control group.
Interventions(1) Streptococcus faecium (Streptococcus faecium 68; 75 million live bacteria tds for 7 days).
(2) Placebo (details not given).

When interventions started not stated.
Outcomes(1) Number of participants with < 2 stools/day. (2) Formed, yellow/brown stools without mucus.
(3) No abdominal pains vomiting or fever for the whole day.

No adverse events observed.
NotesStudy location: Switzerland (very low child and adult mortality).

7 participants in each group had positive stool cultures for bacteria.

Streptococcus faecium 68 also appeared to promote recovery from abdominal pains, fever, and vomiting.




Guandalini 2000
MethodsStudy design: RCT; multicentre.
ParticipantsInclusion criteria: inpatients and outpatients; infants and children with > 4 liquid or semi-liquid stools/day for 1 to 5 days.

Exclusion criteria: previous probiotic usage; underlying chronic untreated small bowel disease; inflammatory bowel disease; any underlying chronic disease or immunosuppressive disease or treatment.

Number completing study: 287 forms (269 participants) of total of 323 forms (88.9%) received at the co-ordinating center were analysed (36 incomplete data or not compliant with protocol); unclear whether withdrawals occurred at participating centres.
Interventions(1) Lactobacillus GG (ATC 53103, ≥ 10,000 million CFU/250 ml) with ORF.
(2) ORF with placebo.

Interventions added to ORF and started at recruitment.
Outcomes(1) Number of treatment failures (need for IV fluids).
(2) Mean duration of diarrhoea (time to last recorded fluid stool).
(3) Weight gain.
(4) Proportion of children with diarrhoea longer than 7 days.
(5) Mean stool frequency by day of treatment (standard deviations not given).
(6) Mean hospital stay.

Some outcomes also reported for rotavirus, bacterial, and no organisms isolated subgroups.

No comment regarding adverse events.
NotesStudy locations: Poland (low child and low adult mortality), Egypt (high child and high adult mortality), Croatia, Italy, Slovenia, The Netherlands, Greece, Israel, United Kingdom, Portugal (all very low child and very low adult mortality).

Stool analyses: rotavirus (56 probiotic/45 placebo); bacteria (35/34); parasites (7/6); no pathogen (45/54).




Guarino 1997
MethodsStudy design: RCT; 1 centre.
ParticipantsInclusion criteria: consecutive outpatients attending 3 family physicians; infants and children with ≥ 3 watery stools/day of < 48 h duration.

Exclusion criteria: antibiotic treatment in preceding 3 weeks, breastfeeding, and weight:height ratio < 5th percentile.

Number completing study: 52/52 (100%) in probiotic group and 48/48 (100%) in control group.
Interventions(1) Lyophilized Lactobacillus casei strain GG (Dicloflor 30; 3,000 million CFU bd for maximum 5 days) resuspended in milk or formula feed.
(2) ORF only.

Interventions started after 6 h of ORF.
Outcomes(1) Mean duration of diarrhoea.

Recovery from diarrhoea defined as time to last loose or liquid stools and assessed by mothers.

Results for rotavirus subgroup also presented.
No comment regarding adverse events.
NotesStudy location: Italy (very low child and adult mortality).

The study author clarified that Figure 1 in the published article reports the mean and standard error for the duration of diarrhoea; standard deviations derived from graph. We also extracted data from Canani 1997 (abstract), which also reports standard errors.

Duration of diarrhoea derived from graph.

Probiotic also reduced prevalence of rotavirus in stools on day 6.




Hochter 1990
MethodsStudy design: RCT; multicentre.
ParticipantsInclusion criteria: outpatients attending general practitioners, gastroenterologists, and internal physicians; adults with "acute diarrhoea" (> 3 liquid stools in last 24 h; in great majority duration 2 days or less; 1 participant in the placebo group had diarrhoea for > 10 days).

Exclusion criteria: chronic diarrhoea; blood in stools; drug-induced diarrhoea; antimicrobial treatment; inflammatory bowel disease.

Number completing study: 92/107 (86.0%) randomized participants completed study (1 took additional drugs, 14 < 3 liquid stools at presentation). 3 participants dropped out (2 probiotic, 1 placebo) because intervention not effective; results included in analysis.
Interventions(1) Saccharomyces boulardii (Perenterol) 200 mg tds for 2 days then 100 mg tds on days 3 to 7.
(2) Placebo.

Interventions started at presentation.
Outcomes(1) Mean stool frequency on days 1, 3, and 8; score derived from stool frequency and consistency.

No adverse events observed.
NotesStudy location: Germany (very low child and adult mortality).




Isolauri 1994
MethodsStudy design: RCT; 1 centre.
ParticipantsInclusion criteria: inpatients; infants and children with > 3 watery stools/day for < 7 days and stools positive for rotavirus.

Exclusion criteria: not stated.

Definition of recovery from diarrhoea not stated. Number completing study: 21/21 (100%) in probiotic group and 21/21 (100%) in control group.
Interventions(1) Freeze-dried Lactobacillus casei strain GG (10,000 million CFU bd for 5 days).
(2) No probiotic.

Interventions started after 6 h ORF.
Outcomes(1) Mean weight gain.
(2) Mean duration of diarrhoea.
(3) Proportion of participants with diarrhoea by day of treatment.

No comment regarding adverse events.
NotesStudy location: Finland (very low child and adult mortality).

Stools positive for rotavirus antigen (Rotazyme, Abbott) in all cases.




Oandasan 1999
MethodsStudy design: RCT; 1 centre.
ParticipantsInclusion criteria: inpatients; infants and children with non-bloody diarrhoea (characteristics not stated) for < 5 days.

Exclusion criteria: antibiotics in last 72 h; antidiarrhoeal drugs; other illness; severe malnutrition; immunocompromise.

Number completing study: 47/47 (100%) in probiotic group and 47/47 (100%) in placebo group.
Interventions(1) Lyophilized Lactobacillus acidophilius and Lactobacillus bifidus (Infloran berna; 1,000 million organisms tds).
(2) Placebo.

When interventions started not stated.
Outcomes(1) Mean duration of diarrhoea.
(2) Proportion of participants with diarrhoea by day of treatment.
(3) Mean hospital stay.

Diarrhoea improved when no stool for 12 h or 2 consecutive formed stools.
No adverse events observed.
NotesUnpublished data.
Study location: Philippines (low child and adult mortality).

Unpublished data.




Pant 1996
MethodsStudy design: RCT; 1 centre.
ParticipantsInclusion criteria: inpatients; infants and children with > 3 watery stools in last 24 h and diarrhoea for < 14 days.

Exclusion criteria: exclusive breastfeeding; septicaemia.

Number completing study: 20/20 (100%) in probiotic group and 19/19 (100%) in placebo group. However, data extractable for subset with watery diarrhoea only: 14/20 (70%) in probiotic group and 12/19 (63.2%) in placebo group. No data for children with bloody stools presented.
Interventions(1) Freeze dried Lactobacillus GG (10,000 million to 100,000 thousand million CFU bd for 2 days).
(2) Placebo.

Interventions started after 6 h ORF.
Outcomes(1) Mean duration of diarrhoea (time to last watery stool).
(2) Mean stool frequency on days 1 and 2.
Vomiting occurred in one child in the placebo group but did nt occur in the probiotic group. No other comment regarding adverse effects.
NotesStudy location: Thailand (low child and adult mortality).

Mean (standard deviation) weight for age z score -1.15 (0.95) in the probiotic group and -1.8 (1.4) in the placebo group.

Bloody stools in 6 children in probiotic and 7 in placebo group.

All stools negative for parasites and cryptosporidium; electron microscopy showed 2 rotavirus and 1 astrovirus cases in the probiotic group and 5 rotavirus cases in the placebo group.




Raza 1995
MethodsStudy design: RCT; 1 centre.
ParticipantsInclusion criteria: inpatients; undernourished infants and children with > 3 watery stools in last 24 h for < 14 days duration and at least moderate dehydration.

Exclusion criteria: severe malnutrition; septicaemia.

Number completing study: 36/40 participants; 4 withdrawals (2 diagnosed with cholera, 1 developed pneumonia, 1 refused anything by mouth). Results presented for 19/21 (90.5%) in probiotic group and 17/19 (89.5%) in placebo group.
Interventions(1) Freeze dried Lactobacillus GG (100,000 million to one billion CFU bd for 2 days).
(2) Placebo.

Interventions started after 4 to 6 h ORF.
Outcomes(1) Stool frequency on days 1 and 2.
(2) Frequency of vomiting on days 1 and 2.
(3) Weight gain.
(4) Outcomes for watery (non-bloody) diarrhoea also presented: mean (standard deviation) stool frequency day 2 for probiotic (n = 16) versus placebo (n = 16) was 4.4 (2.0) versus 6.6 (4.2), P ≤ 0.05, and persistent diarrhoea at 48 h was 5 (31%) versus 12 (75%), P ≤ 0.01. Definition of persistent diarrhoea not stated.

Less vomiting in the probiotic group; myoclonic jerks occurred in one child in each group; no other comment regarding adverse events.
NotesStudy location: Pakistan (high child and adult mortality).

Children with bloody stools included. Duration of diarrhoea not measured (many children discharged before stool character had changed).




Rosenfeldt 2002a
MethodsStudy design: RCT; 2 centres.
ParticipantsInclusion: inpatients; children aged 6 to 36 months with 2 or more consecutive loose stools in 24 h and duration no more than 7 days.

Exclusion criteria: underlying chronic disease or antibiotics prescribed during study period.

Number completing study: 86 children enrolled of which 69 (80.2%) completed the study; exclusions after randomization were because antibiotics prescribed (3 control group/2 probiotic group), rapid recovery before intervention started (3 control group/1 probiotic group), non-compliant to protocol (4 control group/4 probiotic group).
Interventions(1) Lyophilized Lactobacillus rhamnosus 19070-2 and Lactobacillus reuteri DSM 12246 (10,000 million CFU of each given twice daily for 5 days).
(2) Identical placebo (skim milk powder and dextrose anhydrate).

Interventions started as soon as possible after randomization and did not await rehydration.
Outcomes(1) Duration of diarrhoea (time from treatment start to appearance of first normal stool as recorded by parents).
(2) Persistence of diarrhoea at end of intervention (day 5).

No comment regarding adverse events.
NotesStudy location: Denmark (very low child and adult mortality).

Stool analysis showed rotavirus as the only pathogen in 40 (58%) children; 6 children had rotavirus and a bacterial pathogen identified; in addition, Campylobacter jejuni was isolated in 3 children and Salmonella typhimurium in 1 child.

32 children (15 probiotic group, 17 control group) had mild/moderate dehydration on admission; none were severely dehydrated.

The probiotics appeared to reduce significantly the duration of diarrhoea in children treated within 60 hours of the onset of diarrhoea.

Hospital stay was shorter in the probiotic group than the controls (mean 1.6 (standard deviation 1.0) versus 2.7 (standard deviation 2.0) respectively; P = 0.02).

The probiotics also appeared to reduce significantly the number of children excreting rotavirus in the stools on day 5.




Rosenfeldt 2002b
MethodsStudy design: RCT; 19 day-care centres.
ParticipantsInclusion criteria: outpatients; children aged 6 to 36 months with 2 or more consecutive loose stools in 24 h as assessed by parents and with a duration no more than 7 days.

Exclusion criteria: underlying chronic disease; antibiotics prescribed during study period.

Number completing study: 50 children enrolled of which 43 (86%) participants completed the study. Exclusions were because of hospitalization with excessive vomiting and moderate dehydration (2 placebo group/3 probiotic group), 1 antibiotics prescribed (placebo group), 1 non-compliant with protocol (placebo group).
Interventions(1) Lyophilized Lactobacillus rhamnosus 19070-2 and Lactobacillus reuteri DSM 12246 (10,000 million CFU of each given twice daily for 5 days).
(2) Identical placebo.

Interventions started as soon as possible after randomization.
Outcomes(1) Duration of diarrhoea (time from treatment start to appearance of first normal stool as recorded by parents).
(2) Persistence of diarrhoea at end of intervention (day 5).

No serious adverse events observed.
NotesStudy location: Denmark (very low child and adult mortality).

Stool analysis showed rotavirus as the only pathogen in 25 children, 2 had rotavirus and a bacterial pathogen identified, 2 had infection with Campylobacter jejuni and Salmonella typhimurium.

7 children (3 probiotic group, 4 placebo group) had mild/moderate dehydration on presentation; none were severely dehydrated.

The probiotics appeared to reduce significantly the duration of diarrhoea in children treated within 60 h of the onset of diarrhoea.

One participant in the probiotic group complained of constipation (no stools passed from day 3 for 10 days).




Shornikova 1997a
MethodsStudy design: RCT; 1 centre.
ParticipantsInclusion criteria: inpatients; infants and children with ≥ 1 watery stool in last 24 h and diarrhoea for < 5 days.

Exclusion criteria: not stated.

Number completing study: 123/214 (57%) eligible children admitted during the study period enrolled; no reasons given for those not enrolled. 59/59 children allocated to probiotic group and 64/64 (100%) in placebo group completed the trial.
Interventions(1) Lactobacillus strain GG (American type culture collection 53 103; 5000 million CFU bd as a dried powder for 5 days).
(2) Placebo.

Interventions started with oral rehydration solution. All participants with positive stool cultures received antibiotics.

Effect of isotonic versus hypotonic oral rehydration solution also assessed.
Outcomes(1) Duration of diarrhoea (defined as last appearance of watery stools).
(2) Weight gain.
(3) Duration of hospital stay.

No comment regarding adverse events.
NotesStudy location: Russia (low child and high adult mortality).

Amongst children with rotavirus diarrhoea, the probiotic (n = 13) reduced the number of watery stools compared with placebo (n = 21; P = 0.02, but no data given). A beneficial effect of the probiotic was not seen in those with bacterial diarrhoea (probiotic (n = 11) and placebo (n = 115), P = 0.42).

Stool samples tested for rotavirus (Rotazyme, Dakopotts AS, Denmark) and cultured for Salmonella and Shigella.




Shornikova 1997b
MethodsStudy design: RCT; 2 centres.
ParticipantsInclusion criteria: inpatients; infants and children with ≥ 3 watery stools in last 24 h, diarrhoea for < 7 days; stools positive for rotavirus antigen (IDEIA Rotavirus, UK).

Exclusion criteria: not stated.

Number completing study: 86/97 (89%) enrolled participants were positive for rotavirus. 20 participants who received exclusively or mainly IV fluids were excluded. Results presented for 66/86 (77%) participants who received oral rehydration (20 in small dose group, 21 in large dose group, 25 in placebo group).
Interventions(1) Freeze-dried Lactobacillus reuteri (low dose: 10 million CFU o.d. for maximum 5 days; high dose: 10,000 million to 100,000 million CFU o.d. for maximum 5 days).
(2) Placebo.

Interventions started with ORF.
Outcomes(1) Duration of diarrhoea (time to last watery stool in a 24-h period with no watery stools).
(2) Stool frequency on day 2 of treatment.
(3) Weight gain.

No comment regarding adverse events.
NotesStudy location: Finland (very low child and adult mortality).

Data from high dose probiotic group used for continous outcomes. Data from low and high dose groups combined for non-continous outcomes.

Duration of diarrhoea before admission greater in probiotic group (4.2 (standard deviation 1.4) days) than placebo group (2.9 (standard deviation 1.2) days). Number with persistent diarrhoea on day 3 derived from graph.




Shornikova 1997c
MethodsStudy design: RCT; 1 centre.
ParticipantsInclusion criteria: inpatients; infants and children with ≥ 3 watery stools in last 24 h; diarrhoea for < 7 days; ingested bovine dairy products.

Exclusion criteria: immunosuppressive therapy or immune deficiency; allergy to bovine milk; serious underlying disorder; taken an investigational product during the preceding month.

Number completing study: 41 participants initially enrolled; 19/19 (100%) in the probiotic group and 21/22 (95.5%) in the placebo group (1 participant in the placebo group removed because probiotic agent (Lactobacillus reuteri) was detected in stool; probiotic was administered to his sibling).
Interventions(1) Freeze-dried Lactobacillus reuteri SD 2112 (10,000 million to 100,000 million CFU o.d.) for a maximum of 5 days.
(2) Placebo for a maximum of 5 days.

Interventions started at recruitment.
Outcomes(1) Weight gain.
(2) Duration of diarrhoea (last appearance of watery stools).
(3) Number of participants with watery diarrhoea according to day of treatment.
(4) Stool frequency on days 2 and 3.
(5) Number of participants with vomiting according to day of treatment.

Less vomiting in the probiotic group; no other comment regarding adverse events.
NotesStudy location: Finland (very low child and adult mortality).

12 (63%) of placebo group and 18 (86%) of probiotic group had stools positive for rotavirus antigen by enzyme immunoassay.

Mean (standard deviation) percentage dehydration was greater in probiotic group (n = 19; 3.9 (1.3)) versus placebo group (n = 21; 3.0 (1.2); P = 0.02).




Simakachorn 2000
MethodsStudy design: RCT; 1 centre.
ParticipantsInclusion criteria: inpatients; infants and children with acute, watery diarrhoea (stool frequency not stated) for ≤ 5 days.

Exclusion criteria: mucous bloody stools or major systemic illness.

Number completing study: 37/37 (100%) in probiotic group and 36/36 (100%) in placebo group.
Interventions(1) Lyophilized, heat-killed Lactobacillus acidophilus LB (MA65/4E; Lacteol Fort sachets, Laboratoire du Lacteol du Docteur Boucard, Houdan, France; 20,000 million organisms and fermented culture medium 5 doses over 48 h).
(2) Placebo.

Interventions mixed with 5 ml water and started with ORF.
Outcomes(1) Duration of diarrhoea (2 consecutive well formed stools or no stool passed for 12 h).
(2) Recovery from diarrhoea by day of treatment.
(3) Recovery from diarrhoea at 24 h in rotavirus-positive cases.

No comment regarding adverse events.
NotesStudy location: Thailand (low child and adult mortality).

40 children (17 probiotic and 23 placebo) had received antibiotics before admission. Effect of probiotic in shortening duration of diarrhoea more marked in children who had not received antibiotics before admission.




Sugita 1994
MethodsStudy design: quasi-RCT; 1 centre.
ParticipantsInclusion criteria: inpatients; infants and children < 2 years with acute rotavirus diarrhoea (stool characteristics described for each participant; stool frequency x 1-10/day; duration not stated); none had bloody stools.

Exclusion criteria: none stated.

Number completing study: 16/17 (94.1%) in probiotic group and 11/15 (73.3%) in control group.
Interventions(1) Live Lactobacillus casei (1.5 g/day in 3 doses) for up to 3 weeks.
(2) No additional treatment.

Not stated when interventions started. All participants received lactase (1.5 g/day in 3 doses) and albumin tannate (0.1/kg/day in 3 doses).
Outcomes(1) Efficacy, as judged by a clinician.
(2) Time to first formed stool.
(3) Average stool frequency before and after treatment.
(4) Persistence of stool rotavirus antigen 1 week after intervention.

No adverse events observed.
NotesStudy location: Japan (very low child and adult mortality).

Results for time to first formed stool given for 16/17 (94.1%) participants in the probiotic group and 11/15 (73.3%) in the control group. Reasons for missing data not stated.

Rotavirus antigen persisted in the stools of 1/9 (11.1%) children in the probiotic group and 2/8 (25%) in the control group.




Wunderlich 1989
MethodsStudy location: RCT; 10 centres.
ParticipantsInclusion criteria: adults with "acute diarrhoea" (characteristics and duration not stated).

Exclusion criteria: not stated.

Number completing study (for persisting diarrhoea outcomes): 40/40 (100%) in probiotic group and 38/38 (100%) in placebo group; 3 participants from each group withdrawn on day 4 or later (causes for drop outs stated to be unrelated to medication); 4 participants assigned to probiotic group and 5 assigned to placebo group did not complete the study (reasons not stated).
Interventions(1) Lyophilized Enterococcus SF 68 (Bioflorin; 75 million bacteria tds for 7 days).
(2) Placebo.

Not stated when interventions started.
Outcomes(1) Number of cases cured by day of treatment (definition of cure not stated).

No adverse events observed.
NotesStudy location: Switzerland and Lichtenstein (very low child and adult mortality).
 bd: twice daily; CFU: colony-forming units; IV: intravenous; NCHS: National Centre for Health Statistics; o.d.: once daily ORF: oral rehydration fluid; RCT: randomized controlled trial; tds: three times daily.


 
Characteristics of excluded studies [ordered by study ID]
StudyReason for exclusion
Alexander 1971Not a randomized controlled trial; no non-probiotic group.
Alvisi 1982Intervention groups not treated equally; antibiotics given to the non-probiotic group.
Barone 2000No non-probiotic group.
Beck 1961Not a randomized controlled trial.
Bellomo 1979Cause of diarrhoea unclear. Additional treatment given to children with persisting diarrhoea.
Bellomo 1980No extractable outcome data for meta-analysis: no non-probiotic group. Study included children with diarrhoea secondary to antibiotic treatment or associated with respiratory infection.
Bellomo 1982Cause of diarrhoea unclear.
Bin Li Xie 1995Intervention groups not treated equally; antibacterials given to the non-probiotic group.
Camarri 1981Intervention groups not treated equally; antibiotics given to the non-probiotic group.
Chapoy 1985No extractable outcome data for meta-analysis.
Chicoine 1973No extractable outcome data for meta-analysis.
Costa-Ribeiro 2000aUnclear whether a randomized controlled trial.
Costa-Ribeiro 2000bAssessment of Lactobacillus GG in the prevention of diarrhoea.
de dios Pozo-O 1978Assessment of probiotic in the prevention of traveller's diarrhoea.
Frigerio 1986No extractable data for meta-analysis.
Girola 1995Children with gastroenteritis and antibiotic-associated diarrhoea studied together.
Gracheva 1996No non-probiotic group; details of randomization and allocation concealment not given.
Isolauri 1991No non-probiotic group.
Kaila 1992No non-probiotic group.
Kaila 1995No non-probiotic group.
Korviakova 2000Not a randomized controlled trial; probiotic versus antibiotic.
Majamaa 1995No non-probiotic group.
Michielutti 1995Not a randomized controlled trial.
Mitra 1990No non-probiotic group.
Niv 1963Not a randomized controlled trial; some children with diarrhoea thought to be caused by antibiotic treatment also included.
Ortlieb 1974No extractable outcome data for meta-analysis; participants with acute diarrhoea and antibiotic-associated diarrhoea combined.
Pearce 1974Intervention groups not treated equally; calcium carbonate given as the placebo and may have reduced diarrhoea in the non-probiotic group.
Pedone 1999Assessment of milk fermented by Lactobacillus casei (strain DN-114 001) in the prevention of diarrhoea.
Pedone 2000Assessment of milk fermented by Lactobacillus casei (strain DN-114 001) in the prevention of diarrhoea.
Pene 1966No non-probiotic group; participants with diarrhoea of various causes (infectious, post-antibiotics) grouped together.
Rautanen 1998No extractable outcome data for meta-analysis; no data presented for placebo group.
Saint-Marc 1991Not a randomized controlled trial; no non-probiotic group.
Satoh 1984Not a randomized controlled trial; no non-probiotic group.
Sepp 1995No extractable outcome data for meta-analysis; duration of diarrhoea given as median value only; proportion of participants cured stated for days 5 and 10 only.
Singh 1987No probiotic specified.
Tojo 1987Unclear whether diarrhoea acute and whether a randomized controlled trial.


 
Characteristics of studies awaiting assessment [ordered by study ID]
Cetina-Sauri 1990
Methods—
Participants
Interventions—
Outcomes
Notes—




Contreras 1983
Methods—
Participants—
Interventions—
Outcomes—
Notes—




Fourrier 1968
Methods—
Participants—
Interventions—
Outcomes—
Notes—




Salazar-Lindo
Methods—
Participants—
Interventions—
Outcomes—
Notes—




Salgado
Methods—
Participants—
Interventions—
Outcomes—
Notes—




Taborska 1997
Methods—
Participants—
Interventions—
Outcomes—
Notes—


 
Comparison 1. Probiotic versus control
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
 1 Diarrhoea lasting 3 or more days151341Risk Ratio (M-H, Random, 95% CI)0.66 [0.55, 0.77]
    1.1 Live Lactobacillus casei strain GG
2329Risk Ratio (M-H, Random, 95% CI)0.51 [0.14, 1.83]
    1.2 Live Lactobacillus reuteri
2106Risk Ratio (M-H, Random, 95% CI)0.49 [0.26, 0.94]
    1.3 Live Enterococcus LAB strain SF68
5372Risk Ratio (M-H, Random, 95% CI)0.59 [0.47, 0.74]
    1.4 Live Lactobacillus acidophilus and Lactobacillus bifidus
2164Risk Ratio (M-H, Random, 95% CI)0.52 [0.21, 1.28]
    1.5 Live Streptococcus thermophilus and Lactobacillus bulgaricus
196Risk Ratio (M-H, Random, 95% CI)1.08 [0.76, 1.55]
    1.6 Killed Lactobacillus acidophilus LB strain
2144Risk Ratio (M-H, Random, 95% CI)0.77 [0.40, 1.46]
    1.7 Saccharomyces boulardii
1130Risk Ratio (M-H, Random, 95% CI)0.71 [0.58, 0.87]
 2 Diarrhoea lasting 4 or more days131228Risk Ratio (M-H, Random, 95% CI)0.31 [0.19, 0.50]
    2.1 Live Lactobacillus casei strain GG
1287Risk Ratio (M-H, Random, 95% CI)0.61 [0.43, 0.85]
    2.2 Live Lactobacillus reuteri
2106Risk Ratio (M-H, Random, 95% CI)0.29 [0.06, 1.51]
    2.3 Live Enterococcus LAB strain SF68
5372Risk Ratio (M-H, Random, 95% CI)0.23 [0.11, 0.49]
    2.4 Live Lactobacillus acidophilus and Lactobacillus bifidus
2164Risk Ratio (M-H, Random, 95% CI)0.06 [0.01, 0.31]
    2.5 Live Streptococcus thermophilus and Lactobacillus bulgaricus
196Risk Ratio (M-H, Random, 95% CI)1.04 [0.61, 1.79]
    2.6 Killed Lactobacillus acidophilus LB strain
173Risk Ratio (M-H, Random, 95% CI)0.11 [0.01, 0.81]
    2.7 Saccharomyces boulardii
1130Risk Ratio (M-H, Random, 95% CI)0.41 [0.26, 0.66]
 3 Mean duration of diarrhoea (hours)12970Mean Difference (IV, Random, 95% CI)-30.48 [-42.46, -18.51]
    3.1 Live Lactobacillus casei strain GG
5578Mean Difference (IV, Random, 95% CI)-31.18 [-51.62, -10.75]
    3.2 Live Lactobacillus reuteri
286Mean Difference (IV, Random, 95% CI)-25.33 [-40.70, -9.95]
    3.3 Live Lactobacillus casei
127Mean Difference (IV, Random, 95% CI)-36.0 [-65.87, -6.13]
    3.4 Live Lactobacillus rhamnosus and Lactobacillus reuteri
2112Mean Difference (IV, Random, 95% CI)-23.43 [-41.47, -5.40]
    3.5 Live Lactobacillus acidophilus and Lactobacillus bifidus
194Mean Difference (IV, Random, 95% CI)-51.07 [-60.09, -42.05]
    3.6 Killed Lactobacillus acidophilus LB strain
173Mean Difference (IV, Random, 95% CI)-13.60 [-28.10, 0.90]
 4 Mean stool frequency on day 25417Mean Difference (IV, Fixed, 95% CI)-1.51 [-1.85, -1.17]
    4.1 Live Lactobacillus casei strain GG
262Mean Difference (IV, Fixed, 95% CI)-1.50 [-2.83, -0.17]
    4.2 Live Lactobacillus reuteri
140Mean Difference (IV, Fixed, 95% CI)-1.5 [-2.93, -0.07]
    4.3 Live Enterococcus LAB strain SF68
1185Mean Difference (IV, Fixed, 95% CI)-1.70 [-2.10, -1.30]
    4.4 Saccharomyces boulardii
1130Mean Difference (IV, Fixed, 95% CI)-0.62 [-1.49, 0.25]
 5 Mean stool frequency on day 34447Mean Difference (IV, Fixed, 95% CI)-1.31 [-1.56, -1.07]
    5.1 LIve Lactobacillus reuteri
140Mean Difference (IV, Fixed, 95% CI)-1.2 [-2.60, 0.20]
    5.2 Live Enterococcus LAB strain SF68
1185Mean Difference (IV, Fixed, 95% CI)-1.4 [-1.67, -1.13]
    5.3 Saccharomyces boulardii
2222Mean Difference (IV, Fixed, 95% CI)-0.92 [-1.52, -0.32]
 
Comparison 2. Sensitivity analysis; diarrhoea lasting 3 or more days
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
 1 Generation of allocation sequence15Risk Ratio (M-H, Random, 95% CI)Subtotals only
    1.1 Adequate
8710Risk Ratio (M-H, Random, 95% CI)0.67 [0.53, 0.84]
    1.2 Inadequate or unclear
7631Risk Ratio (M-H, Random, 95% CI)0.60 [0.44, 0.82]
 2 Allocation concealment15Risk Ratio (M-H, Random, 95% CI)Subtotals only
    2.1 Adequate
4392Risk Ratio (M-H, Random, 95% CI)0.53 [0.35, 0.81]
    2.2 Inadequate or unclear
11949Risk Ratio (M-H, Random, 95% CI)0.70 [0.58, 0.85]
 3 Blinding15Risk Ratio (M-H, Random, 95% CI)Subtotals only
    3.1 Adequate
8872Risk Ratio (M-H, Random, 95% CI)0.62 [0.50, 0.77]
    3.2 Inadequate or unclear
7469Risk Ratio (M-H, Random, 95% CI)0.70 [0.50, 0.97]
 4 Follow up15Risk Ratio (M-H, Random, 95% CI)Subtotals only
    4.1 Adequate
10624Risk Ratio (M-H, Random, 95% CI)0.58 [0.41, 0.82]
    4.2 Inadequate or unclear
5717Risk Ratio (M-H, Random, 95% CI)0.69 [0.58, 0.81]
 
Comparison 3. Sensitivity analysis: diarrhoea lasting 4 or more days
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
 1 Generation of allocation sequence13Risk Ratio (M-H, Random, 95% CI)Subtotals only
    1.1 Adequate
7639Risk Ratio (M-H, Random, 95% CI)0.26 [0.11, 0.62]
    1.2 Indequate or unclear
6589Risk Ratio (M-H, Random, 95% CI)0.42 [0.27, 0.66]
 2 Allocation concealment13Risk Ratio (M-H, Random, 95% CI)Subtotals only
    2.1 Adequate
4392Risk Ratio (M-H, Random, 95% CI)0.15 [0.05, 0.41]
    2.2 Inadequate or unclear
9836Risk Ratio (M-H, Random, 95% CI)0.46 [0.31, 0.68]
 3 Blinding13Risk Ratio (M-H, Random, 95% CI)Subtotals only
    3.1 Adequate
8872Risk Ratio (M-H, Random, 95% CI)0.24 [0.12, 0.48]
    3.2 Inadequate or unclear
5356Risk Ratio (M-H, Random, 95% CI)0.46 [0.23, 0.93]
 4 Follow up13Risk Ratio (M-H, Random, 95% CI)Subtotals only
    4.1 Adequate
8511Risk Ratio (M-H, Random, 95% CI)0.33 [0.16, 0.69]
    4.2 Inadequate or unclear
5717Risk Ratio (M-H, Random, 95% CI)0.27 [0.13, 0.56]
 
Comparison 4. Sensitivity analysis; mean duration of diarrhoea (hours)
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
 1 Generation of allocation sequence12Mean Difference (IV, Random, 95% CI)Subtotals only
    1.1 Adequate
5430Mean Difference (IV, Random, 95% CI)-38.00 [-57.48, -18.53]
    1.2 Inadequate or unclear
7540Mean Difference (IV, Random, 95% CI)-18.02 [-23.38, -12.65]
 2 Allocation concealment12Mean Difference (IV, Random, 95% CI)Subtotals only
    2.1 Adequate
4330Mean Difference (IV, Random, 95% CI)-30.64 [-52.20, -9.08]
    2.2 Inadequate or unclear
8640Mean Difference (IV, Random, 95% CI)-30.36 [-45.36, -15.37]
 3 Blinding12Mean Difference (IV, Random, 95% CI)Subtotals only
    3.1 Adequate
9801Mean Difference (IV, Random, 95% CI)-26.94 [-39.87, -14.00]
    3.2 Inadequate or unclear
3169Mean Difference (IV, Random, 95% CI)-40.12 [-73.60, -6.65]
 4 Follow up12Mean Difference (IV, Random, 95% CI)Subtotals only
    4.1 Adequate
6375Mean Difference (IV, Random, 95% CI)-35.72 [-54.04, -17.40]
    4.2 Inadequate or unclear
6595Mean Difference (IV, Random, 95% CI)-17.78 [-23.80, -11.76]
 
Comparison 5. Children with rotavirus diarrhoea
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
 1 Mean duration of diarrhoea (hours)4231Mean Difference (IV, Random, 95% CI)-38.10 [-68.10, -8.10]
 
Comparison 6. Mortality stratum for children and adults in the countries where trials were undertaken (children/adults)
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
 1 Diarrhoea lasting 3 or more days14Risk Ratio (M-H, Random, 95% CI)Subtotals only
    1.1 Very low/very low
9591Risk Ratio (M-H, Random, 95% CI)0.57 [0.46, 0.70]
    1.2 Low/low
4367Risk Ratio (M-H, Random, 95% CI)0.64 [0.44, 0.92]
    1.3 High/high
196Risk Ratio (M-H, Random, 95% CI)1.08 [0.76, 1.55]
 2 Diarrhoea lasting 4 or more days12Risk Ratio (M-H, Random, 95% CI)Subtotals only
    2.1 Very low/very low
7478Risk Ratio (M-H, Random, 95% CI)0.25 [0.13, 0.46]
    2.2 Low/low
4367Risk Ratio (M-H, Random, 95% CI)0.15 [0.04, 0.61]
    2.3 High/high
196Risk Ratio (M-H, Random, 95% CI)1.04 [0.61, 1.79]
 3 Mean duration of diarrhoea (hours)11Mean Difference (IV, Random, 95% CI)Subtotals only
    3.1 Very low/very low
7367Mean Difference (IV, Random, 95% CI)-33.02 [-49.89, -16.14]
    3.2 Low/low
3193Mean Difference (IV, Random, 95% CI)-33.08 [-61.24, -4.92]
    3.3 Low/high
1123Mean Difference (IV, Random, 95% CI)-26.40 [-47.67, -5.13]
 4 Mean stool frequency on day 25Mean Difference (IV, Fixed, 95% CI)Subtotals only
    4.1 Very low/very low
2225Mean Difference (IV, Fixed, 95% CI)-1.69 [-2.07, -1.30]
    4.2 Low/low
2156Mean Difference (IV, Fixed, 95% CI)-0.84 [-1.62, -0.06]
    4.3 High/high
136Mean Difference (IV, Fixed, 95% CI)-1.20 [-3.30, 0.90]
 5 Mean stool frequency on day 34Mean Difference (IV, Fixed, 95% CI)Subtotals only
    5.1 Very low/very low
3317Mean Difference (IV, Fixed, 95% CI)-1.34 [-1.60, -1.08]
    5.2 Low/low
1130Mean Difference (IV, Fixed, 95% CI)-1.1 [-1.85, -0.35]
 
Comparison 7. Age of participants
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
 1 Diarrhoea lasting 3 or more days15Risk Ratio (M-H, Random, 95% CI)Subtotals only
    1.1 Infants and children
111008Risk Ratio (M-H, Random, 95% CI)0.68 [0.54, 0.85]
    1.2 Adults
4333Risk Ratio (M-H, Random, 95% CI)0.62 [0.51, 0.74]
 2 Diarrhoea lasting 4 or more days13Risk Ratio (M-H, Random, 95% CI)Subtotals only
    2.1 Infants and children
9895Risk Ratio (M-H, Random, 95% CI)0.41 [0.24, 0.68]
    2.2 Adults
4333Risk Ratio (M-H, Random, 95% CI)0.21 [0.08, 0.52]
 3 Mean stool frequency on day 25Mean Difference (IV, Fixed, 95% CI)Subtotals only
    3.1 Infants and children
4232Mean Difference (IV, Fixed, 95% CI)-1.01 [-1.66, -0.36]
    3.2 Adults
1185Mean Difference (IV, Fixed, 95% CI)-1.70 [-2.10, -1.30]
 4 Mean stool frequency on day 34Mean Difference (IV, Fixed, 95% CI)Subtotals only
    4.1 Infants and children
2170Mean Difference (IV, Fixed, 95% CI)-1.12 [-1.79, -0.46]
    4.2 Adults
2277Mean Difference (IV, Fixed, 95% CI)-1.35 [-1.61, -1.08]
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