Probiotics

Probiotics 

Updated 2013 May 27 05:01:00 AM: probiotic Lactobacillus reuteri supplement may reduce crying in infants with colic (J Pediatr 2013 Feb) view updateShow more updates

Related Summaries:   

Probiotics to prevent antibiotic-associated diarrhea Probiotics for irritable bowel syndrome Lactobacillus acidophilus

Overview: 

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prevention of disease o probiotics shown to reduce rate of antibiotic-associated diarrhea (level 1 [likely reliable] evidence) o some probiotics appear effective in prevention of traveler's diarrhea but nonviable Lactobacillus acidophilus does not appear effective (level 2 [midlevel] evidence) o some oral probiotics reduce incidence of diarrhea and fever in infants attending child care (level 1 [likely reliable] evidence) o probiotics may reduce rate of nosocomial diarrhea in infants and children (level 2 [mid-level] evidence) o probiotics may reduce episodes of acute upper respiratory infections (level 2 [mid-level] evidence); Lactobacillus reuteri may reduce reported sick-leave and sick day frequency (level 2 [mid-level] evidence) o Lactobacillus GG may decrease risk of nosocomial respiratory infections in children (level 2 [mid-level] evidence) o probiotics may prevent infections in critically ill patients  probiotics appear to reduce infectious complications but not mortality or length of hospital stay in critically ill patients (level 2 [mid-level] evidence)  probiotics may reduce ICU-acquired pneumonia and ICU length of stay in critically ill adults (level 2 [mid-level] evidence) o enteral probiotic supplementation reduces incidence of severe necrotizing enterocolitis and mortality in preterm infants (level 1 [likely reliable] evidence) o some oral probiotics given prenatally through infancy appear to reduce incidence of atopic dermatitis or eczema in infants at risk for allergic disease (level 2 [mid-level] evidence) o probiotic-supplemented formula or milk may reduce risk of infectious illness in infants and young children (level 2 [mid-level] evidence) treatment of diarrhea

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probiotics may reduce duration of acute infectious diarrhea (level 2 [midlevel] evidence); probiotics with efficacy data include Lactobacillus casei strain GG, Enterococcus LAB SF68, Saccharomyces boulardii and Escherichia coli strain Nissle 1917 o insufficient evidence to evaluate addition of probiotics to antibiotic therapy for treatment of Clostridium difficile colitis treatment of other gastrointestinal disease o some probiotics or probiotic mixtures may reduce irritable bowel syndrome (IBS) symptoms (level 2 [mid-level] evidence) o some probiotics may be effective for treatment of constipation in adults (level 2 [mid-level] evidence), but evidence for probiotic supplementation for constipation in children is limited and inconsistent o ulcerative colitis  VSL#3 may increase remission rates in ulcerative colitis (level 2 [mid-level] evidence), other probiotics have limited evidence  some probiotics may maintain remission in ulcerative colitis and may be as effective as mesalazine (level 2 [mid-level] evidence)  VSL#3 is effective for maintenance of remission in chronic pouchitis and prevention of chronic pouchitis after ileal pouch-anal anastomosis for ulcerative colitis (level 1 [likely reliable] evidence) o no evidence to support probiotics for inducing remission, maintaining remission or preventing postoperative recurrence of Crohn's disease o probiotics may reduce side effects during Helicobacter pylori eradication therapy (level 2 [mid-level] evidence) but effect on eradication rates uncertain (level 3 [lacking direct] evidence) o probiotic yogurt associated with improved symptoms in patients with chronic liver disease (level 2 [mid-level] evidence) o probiotics have limited and inconclusive evidence for effect on recovery rates in patients with hepatic encephalopathy for bacterial vaginosis some probiotics (with Lactobacillus) orally or intravaginally might increase eradication rates or reduce recurrence rates (level 2 [mid-level] evidence) inconsistent evidence for efficacy of probiotics in treatment of atopic dermatitis probiotic Lactobacillus reuteri supplement may reduce crying in infants with colic (level 2 [mid-level] evidence)

General Information Mechanism of action:   

exact mechanisms unknown(1) acetic, lactic, and propionic acids produced by Lactobacillus can lower pH and inhibit growth of pathogenic bacteria such as E. coli and Clostridium species(1) presence of probiotics in intestinal tract may physically or chemically may prevent adhesion or colonization of pathogenic bacteria (1)

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probiotics may induce or enhance immune responses(1)

Preparations: 

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available as fermented dairy products and fermented drinks, and as dietary supplement formulations including powders, liquids, and capsules; quality and purity of these preparations is uncertain(1) one of the most common preparations is Lactobacillus acidophilus brand name for Lactobacillus GG 10 billion bacteria/capsule is Culturelle (Prescriber's Letter 2006 Jul;13(7):40) brand name for Lactobacillus casei is DanActive, provided in bottles by Dannon (Prescriber's Letter 2006 Jul;13(7):40) brand name for Saccharomyces boulardii 5 billion bacteria (250 mg) per capsule or packet is Florastor (Prescriber's Letter 2006 Jul;13(7):40) partial listing of probiotic brands in United States o Align contains Bifidobacterium infantis 35624 o Culturelle contains Lactobacillus GG plus inulin o Flora Q contains L. acidophilus, Bifidobacterium, L. paracasei, and Streptococcus hemophilus o Floranex contains L. acidophilus and L. bulgaricus o Florastor contains Saccharomyces boulardii o Lactinex contains L. acidophilus and L. bulgaricus o Phillips Colon Health contains L. acidophilus, B. bifidum, and B. longum o Systenex contains Bacillus coagulans o Reference - Ann Pharmacother 2011 Jul;45(7-8):960

Adverse effects:  

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mild gastrointestinal effects (gas, bloating) usually transient (1) infectious complications reported o sepsis with Lactobacillus casei and liver abscess with Lactobacillus GG have been reported in highly immunosuppressed and/or critically ill patients, especially those with indwelling vascular catheters (1) o Lactobacillus infections rare, and association with probiotics limited to case reports (BMJ 2006 Nov 11;333(7576):1006), commentary can be found in BMJ 2006 Dec 16;333(7581):1272 o Saccharomyces boulardii fungemia and septicemia reported in 3 cases in immunocompromised and immunocompetent individuals (J Clin Microbiol 1998 Sep;36(9):2613 ) insufficient evidence to determine safety of probiotics based on systematic review of 622 studies, no increased risk of infection (RR 1, 95% CI 0.87-1.16) in 65 trials (AHRQ Evidence Report on Safety of Probiotics Used to Reduce Risk and Prevent or Treat Disease 2011 Apr PDF) probiotics may increase risk of noninfectious complications in patients receiving enteral nutrition (level 2 [mid-level] evidence) o based on systematic review with heterogeneity

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systematic review of 20 case reports and 53 trials (41 randomized controlled trials, 12 nonrandomized trials) evaluating probiotic use in 4,163 patients receiving enteral or parenteral nutrition meta-analysis not done due to heterogeneity of patient groups, probiotic strains and doses, study designs, and outcomes reported 2 trials showed increase in noninfectious complications in patients receiving probiotics  66 patients receiving enteral nutrition via nasogastric tube after liver transplant were randomized to probiotics (Pediococcus pentosaceus, Leuconostoc mesenteroides, Lactobacillus paracasei, and L. plantarum) vs. control for 14 days  addition of probiotic to enteral nutrition associated with  significantly increased rate of noninfectious complications (p = 0.022, NNH 4), including biliary tract stenosis, fistula, lienalis-steal syndrome, abdominal hemorrhage, acute renal failure  no significant differences in hospital stay  significantly reduced infections and antibiotic duration  296 patients with severe acute pancreatitis receiving enteral nutrition via nasogastric tube were randomized to probiotics (L. acidophilus, L. casei, L. salivarius, L. lactis, Bifidobacterium bifidum, B. lactis) vs. control for up to 28 days  probiotic associated with  mortality (p = 0.01, NNH 10)  bowel ischemia (detected during surgery or autopsy) (p = 0.004, NNH 16)  no significant differences in infections Reference - Am J Clin Nutr 2010 Mar;91(3):687

Drug interactions:  

Florastor (which contains Saccharomyces boulardii) should not be taken with oral systemic antifungals such as fluconazole, according to manufacturer(1) potential drug interactions with Lactobacillus acidophilus o L. acidophilus may be negatively affected by antibiotics and alcohol o L. acidophilus may affect metabolism of sulfasalazine, chloramphenicol and palmitate o Reference - Alternative Medicine Alert 1999 May;2(5):53

Prevention of Diarrhea Prevention of antibiotic-associated diarrhea: 

probiotics shown to reduce rate of antibiotic-associated diarrhea (level 1 [likely reliable] evidence) in 7 systematic reviews and meta-analyses

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effective probiotics include Saccharomyces boulardii, Lactobacillus rhamnosus GG, and probiotic mixtures

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see Probiotics to prevent antibiotic-associated diarrhea for details

Prevention of traveler's diarrhea: 

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some probiotics appear effective in prevention of traveler's diarrhea o based on systematic review o meta-analysis included 12 randomized trials o probiotics with significant efficacy included Saccharomyces boulardii, and mixture of Lactobacillus acidophilus and Bifidobacterium bifidum o Reference - Travel Med Infect Dis 2007 Mar;5(2):97 Saccharomyces boulardii appeared to reduce traveler's diarrhea in dosedependent fashion in randomized placebo-controlled trial of 3,000 Austrian travelers (Fortschr Med 1993 Mar 30;111(9):152) Lactobacillus acidophilus to prevent traveler's diarrhea has inconsistent evidence o 2 trials suggest mild to modest benefit  820 tourists traveling to Turkey randomized to Lactobacillus GG powder containing 2 billion Lactobacilli vs. placebo starting 2 days prior to departure, only 756 completed study and intention to treat analysis not performed, results based on questionnaire completed on return flight, 41% vs. 46.5% experienced traveler's diarrhea (NNT 18) with only certain travel destinations showing significant differences (Ann Med 1990 Feb;22(1):53)  245 Americans traveling to developing countries for 1-3 weeks randomized to Lactobacillus GG vs. placebo, risk of having diarrhea on any given travel day was 3.9% vs. 7.4% (p = 0.05, NNT 29), risk of diarrhea 16.7% vs. 29% among patients with prior history of traveler's diarrhea (NNT 8) (J Travel Med 1997 Mar 1;4(1):41) o 2 trials suggest no benefit  282 British soldiers deployed to Belize randomized to L. acidophilus vs. placebo for 3 weeks, no difference in incidence of diarrhea (N Engl J Med 1995 Nov 16;333(20):1360 )  50 American tourists traveling to Mexico randomized to Lactobacillus vs. placebo preparations for 1 week, no difference in diarrhea incidence for 4 weeks (Gastroenterology 1978 May;74(5 Pt 1):829) o Reference - Alternative Medicine Alert 1999 May;2(5):53 nonviable Lactobacillus acidophilus does not appear effective in prevention of traveler's diarrhea (level 2 [mid-level] evidence) o based on randomized trial with only 70% randomized patients in intentionto-treat analysis o 348 travelers to high-risk areas were randomized to nonviable Lactobacillus acidophilus vs. placebo from 1 day before departure until 3 days after their return

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travelers self-reported number and consistency of stools and adherence to treatment diarrhea defined as ≥ 3 unformed stools in 24-hour period incidence of diarrhea 61.4 cases per 100 person-months with Lactobacillus acidophilus vs. 43.4 cases per 100 person-months with placebo (p = 0.14) only 245 patients included in intention-to-treat analysis no significant differences in intention-to-treat analysis after adjusting for travel duration and other variables Reference - Clin Infect Dis 2006 Nov 1;43(9):1170 , summary in Am Fam Physician 2007 Mar 15;75(6):916, commentary can be found in Clin Infect Dis 2007 Mar 15;44(6):886

Prevention of acute diarrhea: 

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probiotics may reduce risk of antibiotic-associated diarrhea and of acute diarrhea of diverse causes o based on systematic review and meta-analysis of 34 randomized placebocontrolled trials o Reference - Lancet Infect Dis 2006 Jun;6(6):374, commentary can be found in Am Fam Physician 2006 Oct 15;74(8):1410 some oral probiotics reduce incidence of diarrhea and fever in infants attending child care (level 1 [likely reliable] evidence) o based on randomized trial o 201 healthy term infants aged 4-10 months who were exclusively formulafed and were attending child care were randomized to formula supplemented with Bifidobacterium lactis vs. formula supplemented with Lactobacillus reuteri vs. no probiotics for 12 weeks o comparing B. lactis vs. L. reuteri vs. no treatment  mean number of febrile episodes 0.27 vs. 0.11 vs. 0.41  mean number of days with fever 0.86 vs. 0.17 vs. 0.83 (only significant for L. reuteri)  mean number of diarrhea episodes 0.13 vs. 0.02 vs. 0.31  mean number of days with diarrhea 0.37 vs. 0.15 vs. 0.59 o L. reuteri also significantly reduced clinic visits, child care absences, and antibiotic prescriptions o no significant differences in rate and duration of respiratory illnesses o Reference - Pediatrics 2005 Jan;115(1):5 , editorial can be found in Pediatrics 2005 Jan;115(1):174, commentary can be found in Am Fam Physician 2005 Oct 15;72(8):1601

Prevention of nosocomial diarrhea: 

Lactobacillus GG supplement may reduce risk of nosocomial diarrhea in children (level 2 [mid-level] evidence) o based on systematic review of trials with allocation concealment not stated o systematic review of 3 randomized trials comparing Lactobacillus GG vs. placebo in 1,092 hospitalized children aged 1 month to 18 years

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Lactobacillus rhamnosus GG (1 x 109 colony-forming unit [CFU] to 1.2 x 1010 CFU) supplement given daily in capsule, sachet, or with fermented milk supplement for duration of hospital stay follow-up ranged from 3-7 days after hospital discharge Lactobacillus GG associated with reduced risk of  diarrhea in analysis of 2 trials with 823 children  relative risk 0.37 (95% CI 0.23-0.59)  NNT 10-18 with diarrhea in 13.9% of placebo group  symptomatic rotavirus gastroenteritis in analysis of 3 trials with 1,043 children  relative risk 0.49 (95% CI 0.28-0.86)  NNT 24-121 with symptomatic rotavirus gastroenteritis in 5.9% of placebo group no significant differences in duration of diarrhea, duration of hospital stay, or incidence of asymptomatic rotavirus infection Reference - Aliment Pharmacol Ther 2011 Nov;34(9):1079

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Lactobacillus reuteri DSM 17938 does not reduce incidence of diarrhea or rotavirus in hospitalized children (level 1 [likely reliable] evidence) o based on randomized trial o 106 children aged 1-48 months without diarrhea at time of hospital admission randomized to L. reuteri DSM 17938 (1 x 108 CFU/day) orally vs. placebo during hospital stay o comparing L. reuteri DSM 17938 vs. placebo  nosocomial diarrhea in 33% vs. 31% (not significant)  rotavirus infection in 18% vs. 17% (not significant)  mean hospital stay 7.7 days vs. 7.3 days (not significant) o Reference - J Pediatr 2012 Jul;161(1):40

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probiotics may reduce rate of diarrhea in infants admitted to long-term care hospital (level 2 [mid-level] evidence) o based on small randomized trial o 60 infants aged 5-24 months admitted to long-term care hospital were randomized to standard infant formula vs. same formula supplemented with Bifidobacterium bifidum and Streptococcus thermophilus o 5 infants who had formula < 24 hours were excluded from analysis o infants followed for 4,447 patient-days over 17 months o comparing standard formula vs. supplemented formula  mean duration of formula supplementation 82.8 vs. 79.1 days (not significant)  diarrhea developed in 31% vs. 7% (p = 0.035, NNT 5)  rotavirus shedding (at some time during the study) in 39% vs. 10% (p = 0.025, NNT 4) o Reference - Lancet 1994 Oct 15;344(8929):1046

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see also Probiotics to prevent antibiotic-associated diarrhea

Prevention of Other Illness Prevention of respiratory illness and sick leave: 

probiotics may reduce episodes of acute upper respiratory infections (URIs) (level 2 [mid-level] evidence) o based on Cochrane review with heterogeneity o systematic review of 14 randomized trials comparing probiotics vs. placebo for prevention of URI o only 10 trials with 3,451 participants suitable for meta-analysis o trials conducted in infants, children, and adults about 40 years old o all but 1 trial had ≥ 1 of the following methodologic limitations  unclear randomization  unclear allocation concealment  unclear blinding of patients and caregivers  unclear blinding of outcome assessors o probiotics associated with fewer participants  experiencing ≥ 1 acute URI episode in analysis of 6 trials with 1,836 participants  odds ratio (OR) 0.58 (95% CI 0.36-0.92)  NNT 6-58 with 30% experiencing ≥ 1 acute URI episode in placebo group  analysis limited by significant heterogeneity  experiencing ≥ 3 acute URI episodes in analysis of 3 trials with 650 participants  OR 0.53 (95% CI 0.36-0.8)  NNT 7-23 with 29% experiencing ≥ 3 acute URI episodes in placebo group  using antibiotics in analysis of 3 trials with 1,104 participants  OR 0.67 (95% CI 0.45-0.98)  NNT 20-575 with 10% in placebo group using antibiotics o inconsistent results for mean duration of acute URI episodes in 2 trials (1 trial reported decrease with probiotics and 1 trial reported increase with probiotics) o no trials reported on time off from school or work o side effects of probiotics minor with gastrointestinal symptoms most common o probiotics used in trials showing benefit included  Actimel with Lactobacillus paracasei (L. casei), Streptococcus thermophilus, and L. bulgaricus  L. plantarum HEAL 9 plus L. paracasei 8700:2  L. rhamnosus strain GG  L. rhamnosus plus Bifidobacterium lactis Bb-12  L. acidophilus plus L. casei  L. gasseri PA 16/8, B. longum SP 07/3, and B. bifidum MF 20/5 o Reference - Cochrane Database Syst Rev 2011 Sep 7;(9):CD006895

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Lactobacillus GG may decrease risk of nosocomial respiratory infections in children (level 2 [mid-level] evidence) o based on randomized trial with allocation concealment not stated o 742 hospitalized children > 12 months old (mean age 10 years) without gastrointestinal or respiratory tract infection randomized to fermented milk product 100 mL plus Lactobacillus GG (1 × 109 colony-forming units) vs. placebo (fermented milk alone) once daily during hospital stay o upper respiratory tract infection diagnosed during hospitalization in 2.1% with Lactobacillus GG vs. 5.5% with placebo (relative risk 0.38, 95% CI 0.18-0.85, NNT 30) o Reference - Pediatrics 2010 May;125(5):e1171 Lactobacillus reuteri may reduce reported sick leave and sick day frequency (level 2 [mid-level] evidence) o based on randomized trial with high dropout rate o 262 healthy adult day workers and third shift workers were randomized to drinking straw containing Lactobacillus reuteri 108 colony-forming units. vs. placebo straw to be used with ≥ 100 mL liquid daily for 80 days o 181 (69%) completed the trial o comparing probiotic vs. placebo  sick leave reported in 10.6% vs. 26.4% (p < 0.01, NNT 7)  sick day frequency 0.4% vs. 0.9% (p < 0.01, NNT 200 person-days) o Reference - Environ Health 2005 Nov 7;4:25

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Lactobacillus casei Shirota may not reduce days with respiratory symptoms in elderly people (level 2 [mid-level] evidence) o based on randomized trial with high dropout rate o 737 people ≥ 65 years old in nursing home randomized to fermented milk with L. casei Shirota 109 colony-forming units vs. fermented milk without probiotic for 176 days o 25% of participants dropped out before trial end o all patients received influenza vaccine after 21 days o no significant difference in number of days with respiratory symptoms or influenza immune response o Reference - Am J Clin Nutr 2012 May;95(5):1165

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Lactobacillus fermentum associated with reduction in number of days and severity of respiratory illness in long distance runners (level 2 [mid-level] evidence) o based on randomized placebo-controlled crossover trial in 20 highly trained long distance runners o Reference - Br J Sports Med 2010 Mar;44(4):222

Prevention of illness in children: 

efficacy of probiotic-supplemented formula in infants o addition of Lactobacillus fermentum to standard formula with galactooligosaccharides for 6 months may reduce gastrointestinal and

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upper respiratory tract infections in infants aged 6-12 months (level 2 [mid-level] evidence)  based on randomized trial without intention-to-treat analysis  215 infants aged 6-12 months randomized to standard formula plus galactooligosaccharides plus L. fermentum CECT5716 vs. standard formula plus galactooligosaccharides without L. fermentum for 6 months 8  L. fermentum dose was 2 x 10 CFU daily  87.4% of infants were included in analysis  comparing incidence rates (mean number of episodes per infant) for formula with L. fermentum vs. formula without L. fermentum  gastrointestinal infection 0.196 vs. 0.363 (p = 0.032)  upper respiratory tract infection 0.969 vs. 1.33 (p = 0.026)  any infection 1.464 vs. 2.08 (p = 0.003)  no significant differences in incidence rates of otitis, urinary tract infections, febrile episodes, or antibiotic treatment  Reference - J Pediatr Gastroenterol Nutr 2012 Jan;54(1):55 probiotic-supplemented formula may reduce acute otitis media and recurrent respiratory infections in infants (level 2 [mid-level] evidence)  based on randomized trial with inadequate statistical power to detect differences  81 infants in Finland requiring formula before age 2 months were randomized to formula supplemented with probiotics vs. placebo until age 12 months  probiotics-supplemented formula contained Lactobacillus rhamnosus and Bifidobacterium lactis (1 x 1010 colony-forming units of each)  comparing supplementation with probiotics vs. placebo at age 7 months  recurrent (≥ 3) respiratory infections in 28% vs. 55% (p = 0.022, NNT 4)  acute otitis media in 22% vs. 50% (p = 0.014, NNT 4)  antibiotic use in 31% vs. 60% (p = 0.015, NNT 4)  probiotics associated with trend toward decreased risk of tympanostomy (0 vs. 10% with placebo, p = 0.066)  no significant differences in  respiratory infection  gastrointestinal infection  recurrent (≥ 3) acute otitis media  Reference - Br J Nutr 2009 Jun;101(11):1722 Bifidobacterium breve and a galacto/fructooligosaccharide mixture associated with reduced wheezing in infants with atopic dermatitis (level 2 [mid-level] evidence)  based on randomized trial without intention-to-treat analysis  90 infants aged < 7 months with atopic dermatitis randomized to hydrolyzed formula with B. breve M-16V plus galacto/fructooligosaccharide mixture vs. same formula without synbiotic for 12 weeks and followed for 1 year

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83% completed 1 year follow-up analysis comparing synbiotic mixture vs. formula alone  frequent wheezing in 13.9% vs. 34.2% (p < 0.05, NNT 5)  wheezing and/or noisy breathing apart from colds in 2.8% vs.

30.8% (p < 0.05, NNT 4)  asthma medication started by 5.6% vs. 25.6% (p < 0.05, NNT 5)  Reference - Allergy 2011 Feb;66(2):170 efficacy of probiotic-supplemented milk in children o probiotic milk may prevent some infectious illnesses in children attending day care (level 2 [mid-level] evidence)  571 healthy children aged 1-6 years in 18 day care centers in Finland randomized to drink milk with vs. without Lactobacillus GG 3 times daily 5 days/week for 7 months  4.9 vs. 5.8 days of absence from day care because of illness (p = 0.03)  39% vs. 47% had respiratory infections with "complications" (acute otitis media or sinusitis) or lower respiratory tract infections (acute bronchitis or pneumonia) (p = 0.05, NNT 12.5)  none of these results were statistically significant after adjusting for age  Reference - BMJ 2001 Jun 2;322(7298):1327, editorial be found in BMJ 2001 Jun 2;322(7298):1318 o probiotics appear to reduce incidence of fever, upper respiratory symptoms and absence from group childcare in preschoolers (level 2 [mid-level] evidence)  based on randomized trial with high loss to follow-up  326 children aged 3-5 years randomized to twice daily oral supplementation (added to 1% milk) with Lactobacillus acidophilus vs. combination of L. acidophilus and Bifidobacterium animalis subspecies lactis Bi-07 vs. placebo for 6 months  follow-up in 76% Comparison of Outcomes with Probiotic Supplementation vs.

Placebo: Lactobacillus Lactobacillus acidophilus and Placebo acidophilus Bifidobacterium animalis 28.2% (p = Fever 63.5% 16.1% (p = 0.0009) 0.0085) Cough 83.7% 46.4% (p = 0.027) 29.5% (p = 0.005) 55.5% (not Rhinorrhea 81.7% 31.3% (p = 0.03) significant) Mean 6.5 days 4.5 days (32% 3.4 days (48% reduction,

Comparison of Outcomes with Probiotic Supplementation vs.

Placebo: Lactobacillus Lactobacillus acidophilus and Placebo acidophilus Bifidobacterium animalis symptom reduction, p = p < 0.001) duration 0.0023) 16.4% (p = Antibiotic use 54.8% 8% (p < 0.0001) 0.0002) Reduction in 31.8% (p = 0.002) 27.7% (p < 0.001) days absent 

Reference - Pediatrics 2009 Aug;124(2):e172

Prevention of necrotizing enterocolitis in preterm infants: 

enteral probiotic supplementation reduces incidence of severe necrotizing enterocolitis and mortality in preterm infants (level 1 [likely reliable] evidence) o based on Cochrane review o systematic review of 16 randomized trials evaluating enteral probiotics for ≥ 7 days for prevention of severe necrotizing enterocolitis or sepsis in 2,842 preterm infants born at < 37 weeks gestational age or with birth weight < 2,500 g  patients and interventions varied with regard to birth weight, gestational age, baseline risk of necrotizing enterocolitis in control groups, timing, dose, and formulation of probiotics, and feeding regimens  4 trials were high quality (in terms of allocation concealment, blinding and completeness of follow-up) and included in primary analysis o probiotics associated with  decreased incidence of severe necrotizing enterocolitis (stage II-III) in analysis of 4 high-quality trials with 1,705 patients  risk ratio (RR) 0.25 (95% CI 0.13-0.49)  NNT 23-40 assuming 5% incidence of severe necrotizing enterocolitis in controls  reduced all-cause mortality in analysis of 10 trials with 2,331 patients  RR 0.4 (95% CI 0.27-0.6)  NNT 20-36 assuming 7% mortality in controls  reduced necrotizing enterocolitis-related mortality in analysis of 5 trials with 1,476 patients  RR 0.31 (95% CI 0.1-0.94)

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NNT 112-1,667 assuming 1% necrotizing enterocolitisrelated mortality in controls no significant differences in nosocomial sepsis or days on total parenteral nutrition no trials reported systemic infection with probiotics organism Reference - Cochrane Database Syst Rev 2011 Mar 16;(3):CD005496 DynaMed commentary -- although no statistical heterogeneity was found, it is unclear if different probiotics are appropriate to combine in single metaanalysis similar findings (reduction in necrotizing enterocolitis and mortality) in systematic review of 11 randomized trials with 2,176 patients (Pediatrics 2010 May;125(5):921 ), editorial can be found in Pediatrics 2010 May;125(5):1068, commentary can be found in Pediatrics 2010 Sep;126(3):e741, Pediatrics 2010 Sep;126(3):e740, Pediatrics 2010 Sep;126(3):e742

enteral probiotic supplementation associated with reduced risk of necrotizing enterocolitis and death in preterm or very low-birth-weight infants (level 2 [mid-level] evidence) o based on systematic review without assessment of allocation concealment o systematic review of 20 randomized trials comparing probiotics to placebo for prevention of severe necrotizing enterocolitis in 3,816 preterm infants born at < 34 weeks gestation or with birth weight < 1,500 g (3.3 lbs) o probiotic was Bifidobacterium infantis in 8 trials, Lactobacillus acidophilus in 4 trials, Bifidobacterium infantis plus Lactobacillus acidophilus in 6 trials, and Saccharomyces or multicomponent probiotic (> 2) in 2 trials o any probiotics associated with significant decrease in  necrotizing enterocolitis ≥ stage II in analysis of 20 trials with 3,816 infants  risk ratio (RR) 0.33 (95% CI 0.24-0.46)  NNT 19-27, with 7% having necrotizing enterocolitis in placebo group  mortality in analysis of 13 trials with 3,003 infants  RR 0.56 (95% CI 0.43-0.73)  NNT 20-42, with 9% mortality in placebo group o in analyses of specific probiotics  significant reduction in mortality associated with lactobacillus in analysis of 4 trials with 1,205 infants and lactobacillus plus bifidobacteria in analysis of 5 trials with 1,313 infants  no significant difference in mortality comparing bifidobacteria alone to placebo in analysis of 3 trials with 340 infants o no significant difference in incidence of culture-positive sepsis in analysis of 14 trials with 3,090 infants, results limited by significant heterogeneity o Reference - J Pediatr Surg 2012 Jan;47(1):241

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enteral probiotics (Lactobacillus acidophilus plus Bifidobacterium infantis) reduce risk of death, necrotizing enterocolitis and sepsis in very low-birthweight infants (level 1 [likely reliable] evidence) o based on 2 randomized trials (these are 2 of the 4 high-quality trials in Cochrane review) o high-quality randomized trial of 367 very low-birth-weight infants (< 1,500 g) who started to feed enterally and survived to age 7 days randomized to Infloran (Lactobacillus acidophilus and Bifidobacterium infantis) 125 mg/kg twice daily with breast milk until discharged vs. breast milk alone  comparing Infloran plus breast milk vs. breast milk alone  5% vs. 12.8% reached primary endpoint of death or necrotizing enterocolitis of at least stage 2 severity (NNT 13)  3.9% vs. 10.7% died (NNT 15)  1.1% vs. 5.3% had necrotizing enterocolitis of at least stage 2 severity (NNT 24)  0 vs. 3.2% had severe necrotizing enterocolitis (stage 3), 12.2% vs. 19.3% had culture-proven sepsis (NNT 14)  Reference - Pediatrics 2005 Jan;115(1):1 , editorial can be found in Pediatrics 2005 Jan;115(1):171, commentary can be found in Pediatrics 2005 Aug;116(2):522), Pediatrics 2005 May;115(5):1442, Pediatrics 2005 Jul;116(1):293 o randomized trial without intention-to-treat analysis  434 very low-birth-weight infants (< 1,500 g) born at gestational age < 34 weeks who survived to feed enterally were randomized to Infloran 125 mg/kg twice daily with breast milk or mixed feeding (breast milk and formula) vs. breast milk or mixed feeding alone for 6 weeks  comparing Infloran plus breast milk/mixed feeding vs. breast milk/mixed feeding alone  death or necrotizing enterocolitis in 1.8% vs. 9.2% (p = 0.002, NNT 14)  necrotizing enterocolitis ≥ stage 2 severity in 1.8% vs. 6.5% (p = 0.02, NNT 22)  death attributable to necrotizing enterocolitis in 0.9% vs.

1.4% (not significant)  death not attributable to necrotizing enterocolitis in 0% vs.

2.8% (p = 0.04)  Reference - Pediatrics 2008 Oct;122(4):693 probiotic (Lactobacillus casei and Bifidobacterium breve) associated with decreased risk of necrotizing enterocolitis in very low-birth-weight preterm infants (level 2 [mid-level] evidence) o based on randomized trial with unplanned early trial termination o 243 preterm infants with very low birth weight (750 g-1,499 g) randomized to human milk plus L. casei and B. breve vs. human milk alone started on second day of life and given until day 30, diagnosis of necrotizing enterocolitis, discharge from hospital or death

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recruitment interrupted by external study committee before goal of 282 infants due to "major benefit" observed with probiotic 12 children in serious condition at admission died after randomization and before intervention comparing probiotic vs. control  necrotizing enterocolitis stage ≥ 2 in 0 vs. 3.5% (p = 0.05, NNT 29)  mean time to reach full enteral feeding 15.2 days vs. 17.4 days in control (p = 0.02) Reference - Am J Clin Nutr 2011 Jan;93(1):81

Prevention of atopic dermatitis: 

Lactobacillus given prenatally through infancy may reduce incidence of atopic dermatitis or eczema in infants at risk for allergic disease (level 2 [mid-level] evidence) o based on 9 randomized trials with inconsistent findings o 6 trials reported statistically significant differences  high quality randomized trial in 159 pregnant women  159 mothers with family history of atopic disease (mother, father, or older sibling with atopic eczema, allergic rhinitis, or asthma) were randomized to 2 capsules of 10 billion colonyforming units of Lactobacillus GG vs. placebo orally once daily for 2-4 weeks before expected delivery then continued postnatally for 6 months (to mother if breastfeeding and infant if not), blinded follow-up for 2 years  atopic eczema defined as pruritus, facial or extensor involvement, and chronic relapsing course (for example, eczema for 1 month at 24-month study visit and on at least one previous visit)  132 children (83%) followed up at 2 years, 23% vs. 46% had atopic eczema (p = 0.008, NNT 5)  Reference - Lancet 2001 Apr 7;357(9262):1076), editorial can be found in Lancet 2001 Apr 7;357(9262):1057, commentary can be found in ACP J Club 2001 NovDec;135(3):106  DynaMed commentary  using intention-to-treat analysis with extreme assumptions favoring placebo, 36% vs. 38% had atopic eczema, so loss to follow-up may affect magnitude of effect but protective effect appears likely if definition of atopic eczema accepted  Lactobacillus GG products are not "drugs" so doses are not standardized  4-year follow-up of 107 infants (67%) from this trial found 26% Lactobacillus vs. 46% placebo group had developed atopic eczema (NNT 5) (Lancet 2003 May

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31;361(9372):1869), commentary can be found in Lancet 2003 Aug 9;362(9382):496  brand name for Lactobacillus GG 10 billion bacteria/capsule is Culturelle (Prescriber's Letter 2006 Jul;13(7):40) randomized trial without intention-to-treat analysis in 1,233 pregnant women  1,233 pregnant women carrying children at increased risk for allergy were randomized to receive probiotic preparation vs. placebo 2-4 weeks before delivery, their infants received same intervention for 6 months and were assessed at 2 years  probiotic preparation included Lactobacillus rhamnosus (GG) 5 × 109 CFU, L. rhamnosus (LC705) 5 × 109 CFU, B. breve (Bb99) 2 × 108 CFU and P. freudenreichii subspecies shermanii (JS) 2 × 109 cfu  mothers received probiotic or placebo orally twice daily  infants received 1 opened capsule containing same probiotics mixed with 20 drops of sugar syrup containing 0.8 g of galactooligosaccharides once daily  comparing probiotics preparation vs. placebo  eczema in 26% vs. 32.3% (odds ratio 0.74, p = 0.035, NNT 16)  atopic eczema in 12.4% vs. 17.7%, p = 0.025, NNT 19)  allergic disease in 31.5% vs. 35.1% (not significant)  immunoglobulin E (IgE)-associated allergic disease in 14.% vs. 18.8% (not significant)  Reference - J Allergy Clin Immunol 2007 Jan;119(1):192 randomized trial without intention-to-treat analysis in 512 pregnant women  512 pregnant women were randomized to receive Lactobacillus rhamnosus 6 x 109 colony-forming units/day vs. B. animalis subspecies lactis 9 x 109 colony-forming units/day vs. placebo orally once daily from 35 weeks gestation to 6 months if breastfeeding, and 474 of their infants received same intervention from median 6 days post birth until 2 years  eligible infants had ≥ 1 parent with history of treated asthma, eczema or hay fever  comparing L. rhamnosus vs. placebo from birth to 2 years  eczema prevalence in 14.8% vs. 26.8% (hazard ratio 0.51, p = 0.01, NNT 9)  eczema severity score SCORAD ≥ 10 (excludes trivial rash) in 24% vs. 38.7% (hazard ratio 0.57, p = 0.009, NNT 7)  IgE associated eczema in 9.9% vs. 18.5% (hazard ratio 0.51, p - 0.04, NNT 12)

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B. animalis subspecies lactis had no significant effect on eczema prevalence or severity  neither L. rhamnosus nor B. animalis subspecies lactis had significant effect on atopy to any allergen including food  Reference - J Allergy Clin Immunol 2008 Oct;122(4):788 randomized trial with high dropout rate in 112 pregnant women  112 pregnant women with family history of allergic diseases randomized to probiotic mixture (Bifidobacterium bifidum BGN4, B. lactis AD011 and Lactobacillus acidophilus AD031) vs. placebo starting 4-8 weeks before delivery and ending 6 months after delivery  infants breast-fed exclusively through 3 months (breast milk or cow's milk formula at 4-6 months)  68 infants completed study  comparing probiotic mixture vs. placebo at 1-year follow-up  eczema prevalence 18.2% vs. 40% (p = 0.048, NNT 5)  cumulative eczema incidence 36.4% vs. 62.9% (p = 0.029, NNT 4)  no difference in serum total IgE or food allergen sensitization  Reference - Pediatr Allergy Immunol 2010 Mar;21(2 Pt 2):e386 randomized trial without intention-to-treat analysis in 241 pregnant women  241 pregnant women with allergic disease and atopic sensitization randomized to 1 of 3 interventions from 2 months before delivery through first 2 months of breastfeeding  L. rhamnosus LPR plus Bifidobacterium longum BL999  Lactobacillus paracasei ST11 plus B. longum BL999  placebo  children were followed to age 2 years  15% did not complete trial and were excluded from analyses  eczema rates in children  29% with L. rhamnosus LPR plus B. longum BL999 (p < 0.001 vs. placebo, NNT 3)  29% with L. paracasei ST11 plus B. longum BL999 (p < 0.001 vs. placebo, NNT 3)  71% with placebo  Reference - J Allergy Clin Immunol 2012 Dec;130(6):1355 randomized trial with baseline differences in 62 pregnant women  62 pregnant women from atopic families who were willing to breast-feed for at least 3 months were randomized to probiotics (Lactobacillus rhamnosus strain GG) vs. placebo during pregnancy 4 weeks prenatally and lactation 3 months postpartum

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15% infants of mothers receiving probiotics vs. 47% control infants had chronic relapsing eczema during first 2 years of life (NNT 4) based on analysis of 92% infants (8% had "missing data")  no adverse effects  Reference - J Allergy Clin Immunol 2002 Jan;109(1):119 in Altern Ther Health Med 2002 May-Jun;8(3):111  DynaMed commentary  baseline differences may account for some of the effects in this trial as 60% treated mothers and 75% placebo mothers had atopic disease  costs and availability in United States not stated  larger study without baseline differences needed for conclusive evidence 3 trials reported no significant differences  randomized trial with unclear allocation concealment in 253 newborns  253 Asian infants with family history of allergic disease were randomized to cow's milk formula with probiotic supplementation vs. cow's milk formula alone for first 6 months of life  infants evaluated at age 1, 3, 6 and 12 months  probiotic supplementation included Bifidobacterium longum (1 x 107 colony forming units per gram (CFU/g) and Lactobacillus rhamnosus (2 x 107 CFU/g)  no significant differences at 12 months in  incidence of eczema  median atopic dermatitis scores  prevalence of sensitization to common allergies  total IgE geometric mean  atopic eczema (with sensitization)  Reference - Clin Exp Allergy 2009 Apr;39(4):571  randomized trial without intention-to-treat analysis and with low follow-up rate in 231 newborns  231 newborns of women with allergy were randomized to L. acidophilus 3 x 109 vs. placebo orally daily from birth to 6 months and were assessed at 6 and 12 months  comparing L. acidophilus vs. placebo at 12 months  doctor-diagnosed atopic dermatitis in 43% vs. 39% (not significant)  skin prick test positive for atopic dermatitis in 26% vs. 14% (p = 0.045, NNH 9)  skin prick test positive for any allergen in 40% vs.

24% (p = 0.03, NNH 7)  Reference - J Allergy Clin Immunol 2007 Jan;119(1):184  randomized trial with wide confidence intervals and without intention-to-treat analysis 105 pregnant women

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105 pregnant women from families with ≥ 1 member (parent or child) with atopic dermatitis were randomized to Lactobacillus GG (5 x 109 CFU) twice daily vs. placebo Lactobacillus GG given  4-6 weeks prenatally  for 3 months postnatally to breastfeeding mothers (if not breastfeeding infants received supplement)  to infants only, months 4-6 89.5% completed trial no significant difference in frequency (28% vs. 27.3%) or severity of atopic dermatitis between groups at 2 years of age recurrent (≥ 5 episodes) wheezing bronchitis more likely in probiotic group (26% vs. 9.1%, p = 0.03, NNH 2) Reference - Pediatrics 2008 Apr;121(4):e850

Prevention of Pseudomonas aeruginosa: 

oral Lactobacillus casei rhamnosus may delay colonization with Pseudomonas aeruginosa in patients in intensive care units (level 3 [lacking direct] evidence) o based on randomized trial without intention-to-treat analysis o 208 patients (mean age 57 years) hospitalized on the intensive care ward with nasogastric feeding randomized to 109 colony-forming units of L. casei rhamnosus vs. placebo twice daily, starting day 3 to discharge o comparing occurrence of P. aeruginosa in placebo vs. L. casei rhamnosus  median difference in delay of respiratory colonization and or infection 11 days vs. 50 days (p = 0.01)  ventilator-associated pneumonia due to P. aeruginosa 7.5% vs. 2.9% (not significant) o Reference - Crit Care 2008;12(3):R69

Prevention of infections in critically ill patients: 

probiotics appear to reduce infectious complications but not mortality or length of hospital stay in critically ill patients (level 2 [mid-level] evidence) o based on systematic review limited by clinical heterogeneity o systematic review of 23 randomized trials comparing probiotics to placebo or no treatment in 2,153 critically ill patients o analyses limited by clinical heterogeneity in patient populations, probiotic therapies used, and outcomes (definition of infectious complications as defined by primary authors) o probiotics associated with reduced  infectious complications in analysis of 11 trials with 981 patients  risk ratio 0.82 (95% CI 0.69-0.99), but results limited by significant heterogeneity  NNT 7-218 with infectious complications in 46% of controls  ventilator-associated pneumonia in analysis of 7 trials with 1,193 patients

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risk ratio 0.75 (95% CI 0.59-0.97) NNT 10-134 with ventilator-associated pneumonia in 25% of controls no significant differences in  in-hospital mortality (14 trials with 1,266 patients) or intensive care unit (ICU) mortality (6 trials with 569 patients)  hospital or intensive care unit length of stay increased magnitude of benefit for reduced infectious complications in lower-quality trials compared to higher-quality trials in sensitivity analysis Reference - Crit Care Med 2012 Dec;40(12):3290

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probiotics may reduce ICU-acquired pneumonia and ICU length of stay in critically ill adults (level 2 [mid-level] evidence) o based on systematic review limited by clinical heterogeneity o systematic review of 13 randomized trials comparing probiotics (and/or prebiotics or synbiotics) vs. control (placebo or other) on ICU and hospital mortality rates in 1,439 critically ill adults o treatment regimens consisted of single probiotic (Lactobacillus plantarum 299 in 4 studies, and Lactobacillus rhamnosus GG in 1 study) or a combination of several probiotic strains in 8 studies (all including Lactobacillus) 9 11 o daily quantity of probiotics varied from 2 × 10 to 9 × 10 colony-forming units o analyses limited by clinical heterogeneity in patient population, and probiotic strains, doses, and treatment durations o probiotics associated with reduced  ICU-acquired pneumonia (odds ratio 0.58, 95% CI 0.42-0.79) in analysis of 10 trials with 1,218 patients  ICU length of stay (mean difference 1.5 days, 95% CI 0.9-2.1 days) in analysis of 7 trials with 802 patients, results limited by significant heterogeneity o no significant difference in  all-cause ICU mortality in analysis of 9 trials with 1,119 patients  all-cause hospital mortality in analysis of 8 trials with 841 patients  ICU-acquired infections in analysis of 9 trials with 969 patients, results limited by significant heterogeneity  diarrhea in analysis of 5 trials with 648 patients  duration of mechanical ventilation in analysis of 4 trials with 624 patients, results limited by significant heterogeneity  hospital length of stay in analysis of 6 trials with 685 patients o Reference - Chest 2013 Mar 1;143(3):646

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Lactobacillus rhamnosus GG associated with reduced ventilator associated pneumonia (level 3 [lacking direct] evidence) o based on randomized trial without clinical outcomes o 146 patients on mechanical ventilation randomized to enteral probiotics with L. rhamnosus GG vs. placebo twice daily

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comparing probiotics vs. placebo  microbiologically confirmed ventilator associated pneumonia in 40% vs. 19.1% (p = 0.007, NNT 5)  Clostridium difficile associated diarrhea in 18.6% vs. 5.8% (p = 0.02, NNT 8) o Reference - Am J Respir Crit Care Med 2010 Oct 15;182(8):1058 synbiotic composition of pre- and probiotics reduces infections in patients having liver transplantation (level 1 [likely reliable] evidence) o based on randomized trial o 66 adults (mean age 50 years) having liver transplant randomized to synbiotic composition by feeding tube or orally plus 4 fibers vs. 4 fibers alone twice daily from day of operation to day 14 o synbiotic composition included Pediacoccus pentosaceus, Leuconostoc mesenteroides, Lactobacillus paracasei, L. plantarum o all patients received prophylactic antibiotics including cefuroxime 1.5 g plus metronidazole 500 mg twice daily for 36 hours starting 30 minutes before surgery o comparing synbiotic composition vs. fiber alone  antibiotics required for 0.1 days vs. 3.8 days (p < 0.05)  infection in 3% vs. 48% (p < 0.05, NNT 3) o Reference - Am J Transplant 2005 Jan;5(1):125, commentary can be found in Hepatology 2006 Aug;44(2):507 probiotics may decrease risk of Candida colonization in critically ill infants and children receiving antibiotics (level 3 [lacking direct] evidence) o based on randomized trial without clinical outcomes o 150 patients aged 3 months to 12 years in pediatric intensive care unit and receiving broad spectrum antibiotics for ≥ 48 hours randomized to probiotic mix twice daily vs. placebo for 7 days o probiotics mix contained Lactobacillus acidophilus, Lactobacillus rhamnosus, Bifidobacterium longum, Bifidobacterium bifidum, Saccharomyces boulardii, Saccharomyces thermophilus, and fructooligosaccharides o Candida prevalence comparing probiotics vs. placebo at 14 days  rectal colonization in 31.3% vs. 50% (p = 0.02)  growth in urine in 17.3% vs. 37.3% (p = 0.006)  growth in blood in 1.6% vs. 6.35% (not significant) o Reference - Crit Care Med 2013 Feb;41(2):565

Prevention of preterm delivery: 

probiotics do not appear to prevent preterm delivery (level 2 [mid-level] evidence) o based on Cochrane review with limited evidence o systematic review of 3 randomized trials evaluating prevention of preterm labor through use of probiotics (to treat or prevent genital infections) in 344 women

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only 1 randomized trial (with unclear allocation concealment and wide confidence intervals) evaluated preterm delivery  256 pregnant women in first trimester were randomized to dietary intervention plus probiotics once daily vs. dietary intervention plus placebo vs. placebo alone for duration of pregnancy and until end of exclusive breastfeeding  no significant differences between groups in duration of pregnancy or rates of preterm delivery (but rates of preterm delivery ≤ 2%)  Reference - Br J Nutr 2010 Jun;103(12):1792 probiotics significantly reduced genital infection in analysis of 2 trials with 88 women (risk ratio 0.19 [95% CI 0.08-0.48], NNT 2-4 assuming 52% infection in control group) Reference - Cochrane Database Syst Rev 2010 Nov 10;(11):CD005941

Treatment of Diarrhea Treatment of acute diarrhea: 

probiotics may reduce duration of acute infectious diarrhea (level 2 [mid-level] evidence) o based on Cochrane review with unexplained heterogeneity o systematic review of 63 randomized and quasi-randomized trials evaluating probiotics in 8,014 patients with acute diarrhea proven or suspected to be of infectious origin o 56 trials recruited infants or young children o in overall analyses probiotics reduced  duration of diarrhea (mean difference -24.76 hours, 95% CI -33.61 to -15.91 hours) in analysis of 25 trials with 4,555 patients  diarrhea lasting ≥ 4 days in analysis of 29 trials with 2,853 patients  risk ratio (RR) 0.41 (95% CI 0.32-0.53)  NNT 4-5 assuming diarrhea for ≥ 4 days in 45% of controls o all results limited by significant heterogeneity o effect size differences among trials could not be explained by trial quality, location, probiotic strain, number of different strains, organism viability, dosage, causes or severity of diarrhea o among 10 high-quality trials, 7 found significant benefit with probiotics and 3 found no significant benefit o in subgroup analyses by probiotic strains (where > 3 trials provided data for key outcomes)  for live Lactobacillus casei strain GG  reduced duration of diarrhea (mean difference -26.69 hours, 95% CI -40.5 to -12.88 hours) in analysis of 11 trials with 2,072 patients, analysis limited by heterogeneity with 8 trials finding benefit and 3 trials finding no effect  reduced rate of diarrhea lasting ≥ 4 days in analysis of 4 trials with 572 patients  RR 0.59 (95% CI 0.4-0.87)

NNT 4-15 assuming diarrhea for ≥ 4 days in 53% of controls  analysis limited by heterogeneity with 3 trials finding benefit and 1 trial finding no effect  reduced mean stool frequency on day 2 in analysis of 6 trials with 1,135 patients, analysis limited by heterogeneity with 3 trials finding benefit and 3 trials finding no effect  for Enterococcus LAB SF68  reduced rate of diarrhea lasting ≥ 4 days in analysis of 4 trials with 333 patients  RR 0.21 (95% CI 0.08-0.52)  NNT 2-4 assuming diarrhea for ≥ 4 days in 62% of controls  analysis limited by heterogeneity but all 4 trials suggested benefit  for Saccharomyces boulardii  reduced rate of diarrhea lasting ≥ 4 days in analysis of 6 trials with 606 patients  RR 0.37 (95% CI 0.21-0.65)  NNT 4-8 assuming diarrhea for ≥ 4 days in 40% of controls  analysis limited by heterogeneity but all 6 trials suggested benefit  none of these 6 trials met all quality criteria o Reference - Cochrane Database Syst Rev 2010 Dec 8;(12):CD003048 some probiotics but not others may reduce duration of acute diarrhea in young children (level 2 [mid-level] evidence) o based on randomized trial without blinding of parents o 571 children aged 3-36 months with diarrhea (3 or more loose or liquid stools/day) for < 48 hours were treated with oral rehydration solution for 3-6 hours, then fed with full-strength formula, and were also randomized to 1 of 6 groups  oral rehydration alone  L. casei subspecies rhamnosus GG (Dicoflor 60) twice daily for 5 days  S. boulardii (Codex) twice daily for 5 days  Bacillus clausii (Enterogermina) twice daily for 5 days  Enterococcus faecium SF 68 (Bioflorin) twice daily for 5 days  mixture of L. delbrueckii var bulgaricus, L. acidophilus, Streptococcus thermophilus and B. bifidum (Lactogermina) twice daily for 5 days o median duration of diarrhea  115.5 hours with oral rehydration solution alone  118 hours with Enterogermina (not significant)  115 hours with Bioflorin (not significant)  105 hours with Codex (not significant)  78.5 hours with Dicoflor 60 (p < 0.001)  70 hours with Lactogermina (p < 0.001) o study not funded by industry, authors declare no competing interests 

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Reference - BMJ 2007 Aug 18;335(7615):340 , commentary can be found in BMJ 2007 Sep 1;335(7617):414 Lactobacillus preparations o Lactobacillus therapy may reduce duration and frequency of acute infectious diarrhea in children (level 2 [mid-level] evidence)  based on systematic review without trial quality assessment  systematic review and meta-analysis of 9 randomized placebocontrolled trials of Lactobacillus  at least 3 different Lactobacillus strains evaluated  summary point estimates show  reduction in diarrhea duration of 0.7 days (95% CI 0.3-1.2 days, based on 7 trials)  reduction in diarrhea frequency of 1.6 stools on day 2 of treatment (95% CI 0.7-2.6 fewer stools, based on 3 trials)  preplanned subanalysis suggests dose-effect relationship  Reference - Pediatrics 2002 Apr;109(4):678 , commentary can be found in ACP J Club 2002 Nov-Dec;137(3):96 o Lactobacillus therapy may reduce length of hospital stay in children admitted for acute diarrhea (level 2 [mid-level] evidence)  based on randomized trial with allocation concealment not stated  69 children hospitalized for acute diarrhea were randomized to Lactobacillus (L. rhamnosus 19070-2 [1,010 CFU] and L. reuteri DSM 12246 [1,010 CFU]) vs. placebo orally twice daily for 5 days  comparing Lactobacillus vs. placebo  duration of diarrhea 82 vs. 101 hours (p = 0.07)  10% vs. 33% had loose stools at end of study (p = 0.03, NNT 5)  comparing Lactobacillus vs. placebo among patients treated within 60 hours of onset of diarrhea  duration of diarrhea 80 vs. 130 hours  duration of hospitalization 1.7 vs. 3.5 days  Reference - Pediatr Dis Infect J 2002 May;21(5):411 in Altern Ther Health Med 2002 Nov-Dec;8(6):102 o live L. casei strain GG may reduce duration of acute diarrhea (level 2 [mid-level] evidence)  based on meta-analysis of 11 randomized trials with heterogeneity  Reference - see Cochrane review CD003048 summarized above o Lactobacillus reuteri may reduce duration and relapse of acute diarrhea in children (level 2 [mid-level] evidence)  based on randomized trial without intention-to-treat analysis  74 children aged 6-36 months hospitalized for acute diarrhea with clinical signs of mild to moderate dehydration randomized to Lactobacillus reuteri DSM 17938 (4 × 108 colony-forming units) orally once daily vs. placebo for 7 days  oral rehydration solution given during first 4 hours, then subsequent fecal losses replaced as needed  69 children (93%) included in analysis

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comparing L. reuteri vs. placebo  diarrhea on day 3 in 73% vs. 46% (p < 0.03, NNT 4)  mean duration of diarrhea 2.1 days vs. 3.3 days (p < 0.03)  relapse of diarrhea in 15% vs. 42% (p < 0.03, NNT 4)  vomiting in 35% vs. 55% (not significant)  Reference - Aliment Pharmacol Ther 2012 Aug;36(4):363 o Lactobacillus paracasei strain ST11 (ST11) does not improve rotaviral diarrhea (level 1 [likely reliable] evidence) but may reduce duration of nonrotaviral diarrhea in children (level 2 [mid-level] evidence)  based on randomized trial  230 boys ages 4-24 months with acute watery diarrhea (4 or more liquid stools within 24 hours) for < 2 days in Bangladesh admitted to metabolic research unit and randomized to ST11 (5 billion colonyforming units) vs. placebo twice daily for 5 days  24 children with vibrios subsequently excluded, 3 children did not have rotavirus testing  in overall cohort, no significant differences in daily or cumulative stool output, stool frequency, oral rehydration solution intake or cessation of diarrhea  among 140 boys with positive rotaviral testing, no significant differences in daily or cumulative stool output, stool frequency, oral rehydration solution intake or cessation of diarrhea  among 63 boys with negative rotaviral testing, ST11 associated with lower cumulative oral rehydration solution intake (mean 180 vs. 331 mL/kg over 6 days), lower cumulative stool output (mean 225 vs.

381 g/kg over 6 days), higher rate of diarrhea cessation within 6 days (70% vs. 47%, NNT 5)  Reference - Pediatrics 2005 Aug;116(2):e221 o Lactobacillus GG probiotic may not reduce duration of diarrhea in infants and children < 2 years old hospitalized for acute diarrhea (level 2 [mid-level] evidence)  based on randomized trial with inadequate statistical power  64 Australian Aboriginal infants and young children (aged 4 months to 2 years) admitted to hospital with acute diarrhea were randomized to Lactobacillus GG (5 x 109 colony-forming units) vs. placebo orally 3 times daily for 3 days  no significant differences in duration of diarrhea or total diarrheal stools  Reference - J Pediatr Gastroenterol Nutr 2010 Jun;50(6):619 o Lactobacillus acidophilus reduced mean duration of diarrhea (from 63.4 hours to 39.5 hours, p < 0.01) in randomized trial in 80 children (mean age 10 months) (Pediatrics 2007 Oct;120(4):e795) S. boulardii o live S. boulardii may reduce rate of diarrhea lasting ≥ 4 days (level 2 [mid-level] evidence)  based on meta-analysis of 6 randomized trials with methodologic limitations

 Reference - see Cochrane review CD003048 summarized above S. boulardii may reduce duration of diarrhea in infants and children  based on systematic review and small randomized trial  systematic review of 5 randomized trials of S. boulardii with 619 children with acute infectious diarrhea  meta-analysis of 4 trials comparing S. boulardii vs. control  significantly reduced duration of diarrhea (weighted mean difference -1.1 days, 95% CI -1.3 to -0.8 days)  significantly reduced risk of diarrhea on days 3, 6 and 7  S. boulardii significantly reduced risk of diarrhea lasting > 7 days in 1 trial with 88 patients (NNT 5, 95% CI 3-20)  Reference - Aliment Pharmacol Ther 2007 Feb 1;25(3):257  small randomized trial without blinding  55 children (mean age 21 months) with acute nonbloody diarrhea randomized to S. boulardii vs. yogurt fluid  diarrhea resolution on day 3 in 48.5% with S. boulardii vs.

25.5% with yogurt fluid (p < 0.05, NNT 5)  no significant differences in  mean duration of diarrhea  hospital stay  Reference - Am J Trop Med Hyg 2010 Mar;82(3):488 o S. boulardii may reduce duration of diarrhea in children (level 2 [midlevel] evidence)  based on randomized trial with unclear method of randomization  186 children aged 6-48 months hospitalized within 72 hours of onset of acute diarrhea randomized to S. boulardii 200 mg orally twice daily for 5 days vs. placebo  S. boulardii associated with reduced duration of diarrhea (p < 0.05)  Reference - J Pediatr Gastroenterol Nutr 2011 Nov;53(5):497 E. coli strain Nissle 1917 reduces acute diarrhea in infants and toddlers (level 1 [likely reliable] evidence) o based on 2 randomized trials by same authors o randomized trial in 113 children  113 children aged 2-47 months with acute diarrhea randomized to E. coli Nissle 1917 vs. placebo suspension 1-3 mL/day orally  response defined as reduction of stool frequency to ≤ 3 watery or loose stools/day for at least 2 consecutive days  comparing E. coli Nissle 1917 vs. placebo  response rate 94.5% vs. 67.2% (NNT 4)  median time to response 2.5 days vs. 4.8 days (p = 0.0007)  Reference - Eur J Pediatr 2007 Apr;166(4):311 o randomized trial in 151 children  151 children aged 1-47 months with nonspecific diarrhea for 4-14 days randomized to E. coli Nissle 1917 vs. placebo suspension 1-3 mL/day orally for 21 days  comparing E. coli Nissle 1917 vs. placebo o

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7-day response rate 78.7% vs. 59.2% (NNT 6) 14-day response rate 93.3% vs. 65.8% (NNT 4) 21-day response rate 98.7% vs. 71.1% (NNT 4) median time to response 2.4 days vs. 5.7 days (p < 0.0001)  Reference - Pediatr Infect Dis J 2008 Jun;27(6):494 Bio-three probiotics associated with decreased duration of diarrhea and length of stay among children hospitalized with acute infectious diarrhea (level 2 [mid-level] evidence) o based on randomized trial with allocation concealment not stated o 304 children aged 3 months to 6 years hospitalized for acute diarrhea randomized to Bio-three (mixture of Bacillus mesentericus, Enterococcus faecalis, and Clostridium butyricum) vs. placebo orally 3 times daily for 7 days o comparing probiotics vs. placebo  mean duration of diarrhea after therapy was 60.1 vs. 86.3 hours (p = 0.003)  length of hospital stay was 2.9 vs. 4.2 days (p = 0.009) o Reference - Pediatr Infect Dis J 2010 Feb;29(2):135 Lactobacillus paracasei may be more effective than L. casei subspecies Rhamnosus in decreasing symptoms of acute diarrhea (level 2 [mid-level] evidence) o based on randomized trial with low adherence o 174 patients with acute diarrhea randomized to 2 daily sachets of L. paracasei B 21060 vs. L. casei ssp Rhamnosus for 10 days o protocol violations in 17% with L. paracasei vs. 23% with L. casei subspecies Rhamnosus o physician-judged overall efficacy in 92% with L. paracasei vs. 84% with L. casei subspecies Rhamnosus (p = 0.003) o L. paracasei associated with decreased abdominal pain and diarrhea over multiple time points (p = 0.05) o Reference - J Clin Gastroenterol 2010 Sep;44 Suppl 1:S35 o DynaMed commentary -- outcome results of abdominal pain and diarrhea not stated in absolute numbers, so unable to distinguish if effect statistically or clinically significant at any individual time point

Treatment of chronic diarrhea: 

probiotics reduce persistent diarrhea in children (level 1 [likely reliable] evidence) o based on Cochrane review o systematic review of 4 randomized trials comparing probiotic agent with placebo or no probiotic in 464 children with persistent diarrhea (duration ≥ 14 days) o probiotics associated with reduced  duration of persistent diarrhea (weighted mean difference 4.02 days, 95% CI 4.61-3.43 days) in analysis of 2 trials 324 children

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hospital stay in 1 trial (7.3 days with probiotics vs. 15.5 days with oral rehydration, p < 0.05) Reference - Cochrane Database Syst Rev 2010 Nov 10;(11):CD007401, commentary can be found in Evid Based Med 2011 Jun;16(3):83, Int J Epidemiol 2012 Apr;41(2):390

Treatment of Clostridium difficile-associated diarrhea: 

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insufficient evidence to evaluate addition of probiotics to antibiotic therapy for treatment of Clostridium difficile colitis o based on Cochrane review of trials with methodologic limitations o systematic review of 4 randomized trials evaluating probiotics for treatment of recurrence or initial episode of documented C. difficile colitis in adults o all trials evaluated addition of probiotics to conventional antibiotics (vancomycin or metronidazole) o trials were small and had methodologic limitations (2 trials did not randomize patients to antibiotic therapy, 1 trial did not use intention-to-treat analysis, and 1 trial had unclear allocation concealment and blinding) o Saccharomyces boulardii (probiotic) plus antibiotics associated with reduced risk of recurrence of C. difficile diarrhea in 1 trial, described below o no benefit of probiotics treatment found in other 3 trials o Reference - Cochrane Database Syst Rev 2008 Jan 23;(1):CD004611 insufficient evidence to support use of probiotics to prevent or treat C. difficileassociated diarrhea o systematic review of 4 randomized placebo-controlled trials of prevention (1 trial) or treatment (3 trials) of C. difficile-associated diarrhea o 2 trials showed benefit only in subgroups with severe C. difficile-associated diarrhea and increased use of vancomycin o 2 trials were too methodologically flawed to draw conclusions o 4 additional trials of prevention of antibiotic-associated diarrhea (with C. difficile-associated diarrhea as secondary outcome) had too few numbers of C. difficile-associated diarrhea cases to draw conclusions o Reference - CMAJ 2005 Jul 19;173(2):167 , correction can be found in CMAJ 2005 Aug 16;173(4):345, commentary can be found in CMAJ 2006 Jan 3;174(1):65 Saccharomyces boulardii has limited and inconsistent evidence for efficacy in patients with recurrent C. difficile-associated diarrhea (level 2 [mid-level] evidence) o based on 2 randomized trials with significant differences limited to subgroup analyses o addition of S. boulardii to antibiotics for 4 weeks may reduce recurrence rate in patients with recurrent C. difficile-associated diarrhea (level 2 [mid-level] evidence)  based on subgroup analysis of randomized trial  124 patients hospitalized with active C. difficile-associated diarrhea (64 initial, 60 recurrent) were randomized to oral S. boulardii 1 g daily vs. placebo for 4 weeks

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o

o

all patients given standard antibiotic (vancomycin or metronidazole) for 4 weeks  comparing S. boulardii vs. placebo at 8 weeks  recurrence rate 19.3% vs. 24.2% in patients with initial C. difficile-associated diarrhea (not significant)  recurrence rate 34.6% vs. 64.7% in patients with recurrent C. difficile-associated diarrhea (p = 0.04, NNT 4)  Reference - JAMA 1994 Jun 22-29;271(24):1913, correction can be found in JAMA 1994 Aug 17;272(7):518 S. boulardii for 28 days appears ineffective for reducing recurrences in patents with recurrent C. difficile-associated diarrhea (level 2 [midlevel] evidence)  based on randomized trial with uncertain statistical power  168 adults with recurrent C. difficile-associated diarrhea were treated with 1 of 3 antibiotic regimens for 10 days  vancomycin 2 g/day in 32 patients  vancomycin 500 mg/day in 85 patients  metronidazole 1 g/day in 53 patients  antibiotic choice was not randomized  patients randomized to S. boulardii (500 mg twice daily) vs. placebo starting on day 7 of antibiotic treatment and continued for 28 days  recurrence rates comparing S. boulardii vs. placebo  16.7% vs. 50% in subgroup taking vancomycin 2 g/day (p = 0.05, NNT 3)  51.1% vs. 44.7% in subgroup taking vancomycin 500 mg/day (not significant)  48.1% vs. 50% in subgroup taking metronidazole 1 g/day (not significant)  Reference - Clin Infect Dis 2000 Oct;31(4):1012  DynaMed commentary -- this trial which did not find efficacy for S. boulardii in the overall trial was reported as positive by focusing on the subgroup of 32 patients (19%) given vancomycin 2 g/day S. boulardii but not other probiotics may be associated with reduction in recurrence of C. difficile-positive diarrhea (level 3 [lacking direct] evidence)  based on systematic review with heterogeneity  systematic review of 6 randomized trials of probiotics with 354 patients who had C. difficile disease  trials varied in study population, type of probiotic, dose of probiotic, duration of treatment, and concomitant antibiotic regimen  only 2 trials rated as good quality  C. difficile disease defined as C. difficile positive diarrhea within 1 month of a previous C. difficile diarrhea episode  only 2 trials (both evaluating S. boulardii) reported significant reduction in recurrent C. difficile disease  S. boulardii associated with significant reduction in recurrences of C. difficile disease in analysis of 2 trials

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1 of these trials was interpreted as having 32 patients so was actually reporting a subgroup analysis (see DynaMed commentary above) no significant reductions in recurrence rates with L. rhamnosus GG, L. plantarum 299v, or probiotic mixture (L. acidophilus plus B. bifidum) Reference - Am J Gastroenterol 2006 Apr;101(4):812, commentary can be found in Am J Gastroenterol 2007 Jan;102(1):201, ACP J Club 2006 Sep-Oct;145(2):46

Treatment of Other Gastrointestinal Disease Irritable bowel syndrome:        



most conclusions about probiotics for irritable bowel syndrome (IBS) are based on single trials Bifidobacterium bifidum MIMBb75 improves symptoms and quality of life in patients with IBS (level 1 [likely reliable] evidence) Bifidobacterium infantis 35624 may reduce some IBS symptoms (ACG Grade 2C, level 2 [mid-level] evidence) Lactobacillus rhamnosus GG reduces abdominal pain in children with IBS (level 1 [likely reliable] evidence) evidence for benefit in IBS is limited for Lactobacillus acidophilus or Lactobacillus plantarum Escherichia coli preparation may reduce core symptoms of IBS (level 2 [mid-level] evidence) some probiotic mixtures may reduce symptoms of IBS (ACG Grade 2C, level 2 [mid-level] evidence) transgalactooligosaccharide prebiotic may improve symptoms (level 2 [mid-level] evidence) and stimulate bifidobacteria (level 3 [lacking direct] evidence) in patients with IBS see Probiotics for irritable bowel syndrome for details

Constipation: 

some probiotics may be effective for treatment of constipation in adults (level 2 [mid-level] evidence) o based on systematic review of randomized trials with methodologic limitations o 3 randomized trials found evaluating probiotics for treatment of constipation including 231 adults  all 3 trials had unclear allocation concealment, 1 lacked blinding, 1 lacked intention-to-treat analysis  each trial used a different probiotic o E. coli Nissle 1917 associated with increased mean number of stools/week in 1 trial

o

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Lactobacillus casei Shirota associated with reduction in severity of chronic constipation in 1 trial summarized below o B. lactis DN-173 010 plus S. thermophilus and L. bulgaricus associated with increased mean number of stools/week and improved stool consistency in 1 trial o Reference - World J Gastroenterol 2010 Jan 7;16(1):69 o probiotic beverage may reduce severity of chronic constipation in adults (level 2 [mid-level] evidence)  based on randomized trial with allocation concealment not stated  70 patients aged 18-70 years in a naturopathic practice with chronic idiopathic constipation were randomized to beverage containing Lactobacillus casei Shirota vs. placebo 65 mL/day for 4 weeks  probiotic beverage significantly improved self-reported severity of constipation and stool consistency at 2-4 weeks, no significant differences in flatulence or bloating  comparing L. casei Shirota vs. placebo  severe or moderately severe constipation at baseline in 97% vs. 88% (not significant)  severe or moderate constipation at end of treatment in 34% vs. 83% (p < 0.001, NNT 2-3)  median weekly defecation frequency at baseline 3 vs. 3 (not significant)  median weekly defecation frequency after treatment 6 vs. 5 (p = 0.004)  ≤ 3 defecations per week in 4% vs. 15% (not significant)  "distinct improvement" reported in 17% vs. 0 (NNT 6)  Reference - Can J Gastroenterol 2003 Nov;17(11):655  DynaMed commentary -- probiotic beverage group had slightly higher percentage of patients in "good general condition" at baseline compared with placebo group, but differences were not statistically significant Lactobacillus paracasei associated with decreased constipation (level 2 [midlevel] evidence) o based on small randomized crossover trial o 20 patients (mean age 38.8 years) with constipation randomized to L. paracasei-enriched artichokes 180 g/day vs. artichokes 180 g/day alone for 15 days o probiotics associated with  decrease in constipation (p = 0.032)  increase in patient-rated symptom relief and preference (p ≤ 0.011 for both) o Reference - Aliment Pharmacol Ther 2012 Feb;35(4):441 for constipation in children o evidence for probiotic supplementation for constipation in children is limited and inconsistent  based on systematic review with limited evidence

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o

systematic review of 5 randomized trials evaluating probiotics vs. placebo or no treatment in 266 adults and 111 children with constipation  treatment success rates in children (defined as ≥ 3 spontaneous bowel movements/week and no fecal soiling) comparing treatment vs. placebo  68% vs. 72% at 12 weeks (not significant) and 65% vs. 64% at 24 weeks (not significant) in 1 trial with 84 children aged 2-18 years evaluating 70% lactulose plus 109 colony forming units of Lactobacillus rhamnosus GG 1 mL/kg/day orally for 12 weeks  78% of 18 children vs. 11% of 9 children (risk ratio 7, 95% CI 1.1-45, NNT 2) in 1 trial in children < 10 years old evaluating Lactobacillus casei rhamnosus Lcr35 orally for 4 weeks  studies in adults suggested favorable effect on defecation frequency and stool consistency with Bifidobacterium lactis DN-173 010, Lactobacillus casei Shirota, and Escherichia coli Nissle 1917  Reference - World J Gastroenterol 2010 Jan 7;16(1):69 Bifidobacterium lactis not associated with significant increase in stool frequency in children with constipation (level 2 [mid-level] evidence)  based on randomized trial with possible differences in secondary outcomes  159 children aged 3-16 years with constipation by Rome III criteria for past 2 months randomized to fermented dairy product containing B. lactis strain DN-173 010 (Activia) vs. control twice daily for 3 weeks  11 children were lost to follow-up, had no outcome data during follow-up, and were excluded from analysis  primary end point was change in stool frequency  secondary end points included success (defined as ≥ 3 bowel movements per week and no fecal incontinence episodes in last 2 weeks) and response (defined as ≥ 3 bowel movements in last week)  comparing probiotic vs. control  mean stool frequency at baseline 1.6 vs. 1.3 per week (not significant)  mean stool frequency at 3 weeks 4.5 vs. 3.9 per week (not significant)  mean increase in stool frequency 2.9 vs. 2.6 per week (not significant)  success rate 38% vs. 24% (p = 0.06)  response rate 72% vs. 64% (not significant)  flatulence in 23.6% vs. 34.7% (p = 0.02, NNT 9)  no serious adverse events reported  Reference - Pediatrics 2011 Jun;127(6):e1392

o

Lactobacillus reuteri supplement associated with increased stool frequency but no change in inconsolable crying in infants with constipation (level 2 [mid-level] evidence)  based on small randomized trial  44 infants ≥ 6 months old with functional chronic constipation were randomized to L. reuteri supplement vs. placebo for 8 weeks  L. reuteri associated with significantly increased bowel movement frequency but no differences in stool consistency or episodes of inconsolable crying  Reference - J Pediatr 2010 Oct;157(4):598

Ulcerative colitis: 

VSL#3 may increase remission rates in ulcerative colitis (level 2 [mid-level] evidence), other probiotics have limited evidence o based on 2 systematic reviews with heterogeneity and 3 randomized trials o 2010 systematic review  systematic review of 7 randomized trials evaluating remission rate with probiotics vs. non-probiotics treatment in 399 patients with ulcerative colitis  DynaMed commentary -- overall meta-analysis reported but unclear that statistical combination of trials with placebo control and active comparator (effective therapy control) provides meaningful conclusion  remission rate significantly increased with probiotics compared with placebo (odds ratio [OR] 2, 95% CI 1.35-2.96)  2 trials evaluating VSL#3 (both published in 2009) suggested benefit, both summarized below  remission rate comparing probiotics with active control (generally 5aminosalicylic acid drugs) was not significantly different (OR 1, 95% CI 0.85-1.18)  Reference - World J Gastroenterol 2010 Apr 21;16(15):1908 o 2007 Cochrane review  systematic review of 4 randomized trials comparing probiotics vs. standard treatments for induction of remission in patients with active ulcerative colitis  meta-analysis not done due to differences in probiotics, outcomes and trial methodology  no significant differences in remission or clinical improvement rates comparing probiotics vs. control in  2 trials comparing probiotics vs. placebo  1 trial comparing probiotic vs. mesalazine  1 trial evaluating addition of probiotic to balsalazide  Reference - systematic review last updated 2007 Jul 4 (Cochrane Library 2007 Issue 4:CD005573) o 3 trials supporting remission induction or clinical response with VSL#3

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VSL#3 may increase clinical response and remission rate in adults with mild-to-moderately active ulcerative colitis (level 2 [mid-level] evidence)  based on randomized trial with high dropout rate  147 adults with mild-to-moderately active ulcerative colitis randomized to VSL#3 (3.6 x 1012 colony-forming units) vs. placebo orally twice daily for 12 weeks  84 patients (57%) completed the trial  comparing VSL#3 vs. placebo in intention-to-treat analysis  > 50% improvement in disease activity index at 6 weeks in 32.5% vs. 10% (p = 0.001, NNT 5)  remission at 12 weeks in 42.9% vs. 15.7% (p < 0.001, NNT 4)  Reference - Clin Gastroenterol Hepatol 2009 Nov;7(11):1202 addition of VSL#3 to oral 5-aminosalicylic acid (5-ASA) and/or immunosuppressants appears to reduce disease activity scores in patients with relapsing mild-to-moderate ulcerative colitis (level 2 [mid-level] evidence)  based on randomized trial with allocation concealment not stated  144 adults with mild-to-moderate relapsing ulcerative colitis receiving stable dose of oral 5-ASA or immunosuppressants or both were randomized to VSL#3 (3.6 x 1012 colonyforming units) vs. placebo for 8 weeks  5-ASA fixed at stable dose ≥ 4 weeks before trial entry (mesalazine ≥ 1.6 g/day or balsalazide ≥ 4.5 g/day)  immunosuppressants fixed at stable dose ≥ 3 months before trial entry (azathioprine ≥ 1.5 mg/kg/day or 6mercaptopurine ≥ 1 mg/kg/day)  remission defined as Ulcerative Colitis Disease Activity Index (UCDAI) score ≤ 2 points (0-12 point scale)  mean UCDAI at baseline was 5.5 points  comparing VSL#3 vs. placebo at 8 weeks  ≥ 50% improvement in UCDAI score in 63.1% vs.

40.8%. (p = 0.01, NNT 5)  ≥ 3-point decrease in UCDAI score in 60% vs. 43.9% (p = 0.017, NNT 7)  remission in 47.7% vs. 32.4% (p = 0.07)  Reference - Am J Gastroenterol 2010 Oct;105(10):2218 VSL#3 may improve remission rate in children with ulcerative colitis (level 2 [mid-level] evidence)  based on small randomized trial  29 consecutive children (mean age 9.8 years) with newly diagnosed ulcerative colitis receiving steroid induction and mesalamine maintenance treatment randomized to VSL#3

o

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(weight-based dose, range 450-1,800 billion bacteria/day) vs. placebo  children evaluated at 1, 2, 6 and 12 months, or at time of relapse  comparing VSL#3 group vs. placebo group  remission in 92.8% vs. 36.4% (p < 0.001, NNT 2)  relapse within 1 year in 21.4% vs. 73.3% (p = 0.014, NNT 2)  no adverse effect related to VSL#3 reported  Reference - Am J Gastroenterol 2009 Feb;104(2):437 VSL#3 reported to not be cost-effective as adjunctive therapy in pediatric ulcerative colitis (J Pediatr Gastroenterol Nutr 2011 Nov;53(5):489)

some probiotics may maintain remission in ulcerative colitis and may be as effective as mesalamine (level 2 [mid-level] evidence) o based on 2 systematic reviews with heterogeneity and Cochrane review of trials with unclear allocation concealment o 2010 systematic review of 8 randomized trials  systematic review of 8 randomized trials evaluating relapse rate with probiotics vs. nonprobiotics treatment in 709 patients with ulcerative colitis in remission  DynaMed commentary -- overall meta-analysis reported but unclear that statistical combination of trials with placebo control and active comparator (effective therapy control) provides meaningful conclusion  relapse rate significantly decreased with probiotics compared with placebo (OR 0.25, 95% CI 0.12-0.51)  relapse rate comparing probiotics with active control (generally 5aminosalicylic acid drugs) was not significantly different (OR 0.92, 95% CI 0.75-1.14), analysis limited by heterogeneity  Reference - World J Gastroenterol 2010 Apr 21;16(15):1908 o 2010 systematic review of 5 randomized trials  systematic review of 5 randomized trials of probiotics for maintaining remission of ulcerative colitis in 771 adults  data not pooled due to inadequate study design and statistical analysis  E. coli Nissle 1917 and mesalazine reported to have similar relapse rates in 3 trials  Lactobacillus rhamnosus GG (alone or with mesalazine) showed significant increase in time to relapse vs. mesalazine alone in 1 trial  Bifidobacteria-fermented milk supplements reported significant reductions in ulcerative colitis exacerbations vs. no supplements in 1 trial  probiotics appear well tolerated, with similar adverse event rates as other treatments  Reference - Ann Pharmacother 2010 Mar;44(3):565 o 2011 Cochrane review of 4 randomized trials

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systematic review of 4 randomized trials evaluating probiotics for maintaining remission of ulcerative colitis in 587 patients 3 trials compared probiotics to mesalazine; no significant differences in  relapse rates in analysis of 3 trials with 555 patients  adverse events in analysis of 2 trials with 430 patients 1 trial with 32 patients compared probiotics to placebo  no significant difference in relapse rates at 1 year (75% vs.

92%) but wide confidence intervals (odds ratio 0.27, 95% CI 0.03-2.68)  similar number of adverse events reported in each group Reference - Cochrane Database Syst Rev 2011 Dec 7;(12):CD007443

VSL#3 is effective for maintenance of remission in chronic pouchitis and prevention of chronic pouchitis after ileal pouch-anal anastomosis for ulcerative colitis (level 1 [likely reliable] evidence) o based on Cochrane review o systematic review of 11 randomized trials evaluating interventions for treatment or prevention of pouchitis in adults after ileal pouch-anal anastomosis, of which 5 trials evaluated probiotics o for induction of remission in acute pouchitis, no significant difference between Lactobacillus GG and placebo in 1 trial with 20 patients o for maintenance of remission in chronic pouchitis VSL#3 effective in analysis of 2 high-quality trials with 76 patients (OR 25, 95% CI 10-62, NNT 2 to prevent 1 relapse) o for prevention of pouchitis  VSL #3 effective in 1 high-quality trial with 40 patients (20% vs.

40%, p = 0.03, NNT 5)  VSL #3 not associated with significant difference in 1 open-label trial with 28 patients (0% vs. 8.3%, p = 0.25) o Reference - Cochrane Database Syst Rev 2010 Jun 16;(6):CD001176 E. coli Nissle 1917 may be as effective as mesalamine in inducing and maintaining remission (level 2 [mid-level] evidence) o based on 2 randomized trials with non-significant differences o nonpathogenic E. coli Nissle 1917 sold in Germany as Mutaflor o in trial of 116 patients with active ulcerative colitis  patients randomized to E. coli Nissle 1917 vs. mesalamine 800 mg 3 times daily for 1 year  both groups received "standard medical therapy" and gentamicin orally for 1 week  no significant difference in remission rates comparing probiotic (68%) vs. mesalamine (75%)  Reference - Lancet 1999 Aug 21;354(9179):635, commentary can be found in Lancet 1999 Dec 4;354(9194):2000 o in trial of 327 patients with ulcerative colitis in remission

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patients randomized to E. coli Nissle 1917 (200 mg orally once daily) vs. mesalamine (500 mg orally 3 times daily) for 1 year  no significant difference in relapse rates comparing probiotic (45%) vs. mesalamine (37%) in intention-to-treat analysis  no significant differences in relapse rates (36% vs. 34%) in perprotocol analysis with 222 (68%) patients  Reference - Gut 2004 Nov;53(11):1617 , commentary can be found in Am Fam Physician 2005 May 15;71(10):1990 o DynaMed commentary -- although both trials report E. coli Nissle 1917 to be as effective as mesalamine, absolute differences favoring mesalamine might be considered clinically relevant Lactobacillus GG may be as effective as mesalamine in maintaining remission (level 2 [mid-level] evidence) o based on randomized trial without blinding o 187 patients with ulcerative colitis in remission were randomized to Lactobacillus GG 18 billion viable bacteria/day vs. mesalamine 800 mg 3 times daily vs. both for 1 year o all 3 treatments appear equally effective in maintaining remission o sustained remission rates comparing probiotic alone vs. mesalamine alone vs. both  at 6 months 91% vs. 87% vs. 94% (not significant)  at 12 months 85% vs. 80% vs. 84% (not significant) o Lactobacillus GG reported to be more effective than mesalamine in prolonging relapse-free time (p < 0.05) based on tendency for earlier relapse in mesalamine alone group o Reference - Aliment Pharmacol Ther 2006 Jun 1;23(11):1567 Bifidobacterium longum probiotic, psyllium and combination of both reported to be similarly effective or similarly ineffective for improving quality of life in patients with ulcerative colitis (level 3 [lacking direct] evidence) o based on randomized trial without direct comparisons of randomized groups o 120 outpatients with ulcerative colitis randomized to 1 of 3 groups for 4 weeks 9  B. longum 2 x 10 colony-forming units once daily (probiotic)  psyllium 8 g once daily (called prebiotic)  combination of probiotic plus psyllium (called synbiotic) o 26 patients (22%) with incomplete questionnaires not analyzed o Inflammatory Bowel Disease Questionnaires (quality of life) scores improved by 7 points with probiotic, by 8 points with psyllium and by 8 points with combination o Reference - Nutrition 2009 May;25(5):520

Crohn's disease: 

insufficient evidence to evaluate probiotics for inducing remission of Crohn's disease o based on Cochrane review

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systematic review of randomized trials evaluating probiotics for induction of remission in Crohn's disease o only 1 small trial with 11 patients included  trial had unclear allocation concealment and unclear how outcomes were assessed  both groups concurrently treated with corticosteroids  remission achieved in 4 of 5 probiotic (80%) vs. 5 of 6 placebo patients (83%) (not significant) o Reference - Cochrane Database Syst Rev 2008 Jul 16;(3):CD006634 no evidence to support probiotics for maintenance of remission of Crohn's disease o based on Cochrane review and subsequent randomized trial o systematic review of 7 randomized trials of probiotics for maintenance of remission of Crohn's disease o no statistically significant benefits but all trials were small and unable to rule out benefit o trials too variable to be combined in meta-analysis o Reference - systematic review last updated 2006 Jul 25 (Cochrane Library 2006 Issue 4:CD004826) o no significant differences in clinical or endoscopic relapse rates reported in systematic review of 8 randomized placebo-controlled trials of probiotics for maintenance of remission of Crohn's disease (Dig Dis Sci 2008 Sep;53(9):2524) Bifidobacterium longum and Synergy 1 synbiotic may improve Crohn's activity scores but not associated with self-reported symptom improvement in patients with active Crohn's disease (level 2 [mid-level] evidence) o based on small randomized trial without intention-to-treat analysis o 35 patients with active Crohn's disease randomized to synbiotic (B. longum and Synergy 1) vs. placebo twice daily for 6 months o 46% lost to follow-up o synbiotic associated with  improvement in Crohn's disease activity scores from baseline (p = 0.02)  improvement in mean histological scores (p = 0.018)  no significant difference in bowel habits or patient questionnaire o Reference - Aliment Pharmacol Ther 2010 Oct;32(7):872 no evidence to support probiotics for preventing postoperative recurrence of Crohn's disease o probiotics not associated with preventing postoperative recurrence of Crohn's disease  based on systematic review 5 randomized trials comparing probiotics vs. placebo and 2 trials comparing antibiotics vs. placebo for treatment of postoperative recurrence of Crohn's disease  probiotic treatment not associated with reduced clinical or endoscopic recurrence  nitroimidazole antibiotics associated with reduced risk of clinical and endoscopic recurrence

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 Reference - Aliment Pharmacol Ther 2010 Apr;31(8):802 Lactobacillus johnsonii LA1 does not appear to reduce recurrence rate after surgical resection for Crohn's disease (level 2 [mid-level] evidence)  based on randomized trial with limited number of clinical outcomes  98 patients within 21 days of intestinal resection of Crohn's disease were randomized to lyophilized L. johnsonii LA1 (109 CFU/packet) vs. placebo twice daily for 6 months  comparing probiotic vs. placebo  clinical recurrence in 4 cases vs. 3 cases  endoscopic recurrence (among 90 patients with endoscopic follow-up) in 49% vs. 64% (not significant, p = 0.15)  Reference - Gut 2006 Jun;55(6):842 Lactobacillus GG does not appear to reduce recurrence rate after surgical resection for Crohn's disease (level 2 [mid-level] evidence)  based on small randomized trial  45 patients who had surgical resection for Crohn's disease were randomized to Lactobacillus GG (6 x 109 CFU/2.46 g bag) vs. placebo twice daily for 1 year  8 patients excluded due to noncompliance or protocol violations  comparing probiotic vs. placebo  clinical recurrence in 8.5% vs. 7%  endoscopic recurrence (among patients in clinical remission) in 60% vs. 35% (not significant)  Reference - Gut 2002 Sep;51(3):405

Helicobacter pylori infection: 

probiotics may reduce side effects during Helicobacter pylori eradication therapy (level 2 [mid-level] evidence) but effect on eradication rates uncertain o based on systematic reviews with clinical heterogeneity o probiotics may reduce side effects during H. pylori eradication therapy (level 2 [mid-level] evidence) without affecting eradication rates (level 3 [lacking direct] evidence)  based on systematic review of dissimilar products, limited to placebo-controlled trials  systematic review of 4 randomized double-blind placebo-controlled trials evaluating addition of probiotics to H. pylori eradication regimens in 318 patients  further evaluation of trial quality not reported  each trial evaluated different probiotics  3 of 4 trials reported significant reductions in side effects during treatment  diarrhea reduced in 3 trials  nausea reduced in 2 trials  taste disturbance reduced in 2 trials  epigastric pain reduced in 1 trial  no significant differences in adverse effects in 1 trial

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all 4 trials found no significant differences in eradication rates Reference - Ann Pharmacother 2011 Jul;45(7-8):960 o probiotics may increase H. pylori eradication rates and reduce side effects (level 2 [mid-level] evidence)  based on systematic review with meta-analysis of possibly dissimilar probiotics  systematic review of 14 randomized trials of addition of probiotics to H. pylori eradication regimens in 1,671 patients  comparing probiotics vs. no probiotics  pooled H. pylori eradication rates 83.6% vs. 74.8% (NNT 12)  total side effect rates 24.7% vs. 38.5% (NNT 8)  taste disturbance in 25% vs. 46% (NNT 5)  diarrhea in 6.1% vs. 16% (NNT 11)  nausea in 16% vs. 25% (NNT 12)  epigastric pain in 16% vs. 23% (NNT 14)  Reference - Aliment Pharmacol Ther 2007 Jan 15;25(2):155, commentary can be found in ACP J Club 2007 May-Jun;146(3):63 addition of Saccharomyces boulardii to triple eradication therapy may increase eradication rates and reduce side effects (level 2 [mid-level] evidence) o based on systematic review of trials with methodologic limitations o systematic review of 5 randomized trials evaluating addition of S. boulardii vs. placebo to triple eradication therapy or no intervention for H. pylori infection in 1,307 patients o methodologic limitations include  lack of blinding  unclear allocation concealment o S. boulardii associated with  increased eradication in analysis of 4 trials with 915 patients  relative risk (RR) 1.13 (95% CI 1.05-1.21)  NNT 7-28 assuming eradication in 71% of controls  reduced H. pylori therapy related adverse events in analysis of 5 trials with 1,305 patients  RR 0.46 (95% CI 0.3-0.7)  NNT 6-14 assuming adverse events in 24.4% of controls  reduced diarrhea in analysis of 4 trials with 1,215 patients  RR 0.47 (95% CI 0.32-0.69)  NNT 13-27 assuming diarrhea in 12% of controls o Reference - Aliment Pharmacol Ther 2010 Nov;32(9):1069 o addition of S. boulardii to triple eradication therapy for H. pylori infection may reduce side effects (level 2 [mid-level] evidence)  based on randomized trial without blinding (included in systematic review above)  90 symptomatic children aged 3-18 years receiving triple eradication therapy for H. pylori infection were randomized to S. boulardii 250 mg twice daily for 4 weeks vs. no S. boulardii  triple eradication therapy included omeprazole/esomeprazole, amoxicillin, and clarithromycin for 7-10 days

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comparing S. boulardii vs. control  side effects of treatment (most commonly bloating, taste disturbance, nausea) in 8.3% vs. 30.9% (p = 0.047, NNT 5)  H. pylori eradication in 93.8% vs. 80.9% (not significant)  Reference - Acta Paediatr 2009 Jan;98(1):127 outcomes with specific probiotic regimens in randomized trials o addition of kefir to triple therapy associated with increased H. pylori eradication and fewer treatment side effects (level 2 [mid-level] evidence)  based on randomized trial with unclear method of randomization and allocation concealment  82 patients with symptoms of dyspepsia and H. pylori infection confirmed by urea breath test randomized to lansoprazole 30 mg plus amoxicillin 1,000 mg plus clarithromycin 500 mg twice daily for 14 days plus addition of either kefir (fermented milk drink containing probiotics) vs. milk containing placebo 250 mg twice daily  side effects questionnaire completed at 15 days, and repeat urea breath test at 45 days following initiation of treatment  comparing triple therapy plus kefir vs. triple therapy plus placebo  H. pylori eradication rate 78.2% vs. 50% (p = 0.026, NNT 4)  diarrhea in 23.9% vs. 50% (p = 0.001, NNT 4)  headache in 4.3% vs. 33.3% (p = 0.008, NNT 4)  nausea in 24.3% vs. 41.6% (p = 0.029, NNT 6)  abdominal pain in 26% vs. 69.4% (p < 0.001, NNT 3)  Reference - J Med Food 2011 Apr;14(4):344 o yogurt containing Lactobacillus and Bifidobacterium  probiotic yogurt supplementation may improve eradication rates and decrease gastrointestinal side effects in patients taking triple therapy (level 2 [mid-level] evidence)  based on randomized trial without blinding  160 H. pylori-infected patients with dyspepsia were randomized to triple therapy for 1 week plus yogurt (containing Lactobacillus acidophilus La5 and Bifidobacterium lactis Bb12) 200 mL twice daily for 5 weeks vs. triple therapy alone  eradication rates comparing triple therapy plus yogurt vs. triple therapy alone  91% vs. 78% by intention-to-treat analysis (NNT 8)  93.5% vs. 89% by per-protocol analysis (not statistically significant)  side effects had lower rate with yogurt (19% vs. 66%, p < 0.05, NNT 3) with differences in vomiting, constipation, diarrhea, and metallic taste  Reference - Aliment Pharmacol Ther 2002 Sep;16(9):1669  probiotic yogurt supplementation may improve eradication rates in patients taking quadruple therapy after failed triple therapy (level 3 [lacking direct] evidence)

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based on randomized trial without clinical outcome 138 patients with dyspepsia and H. pylori infection which persisted after 1 week triple therapy were randomized to quadruple therapy for 1 week plus yogurt (containing L. acidophilus La5, B. lactis Bb12, Lactobacillus bulgaricus, and Streptococcus thermophilus) 200 mL twice daily for 5 weeks vs. quadruple therapy alone  eradication rates comparing quadruple therapy plus yogurt vs. quadruple therapy alone  85.5% vs. 71.1% by intention-to-treat analysis (NNT 7)  90.8% vs. 76.6% by per-protocol analysis (NNT 7)  Reference - Am J Clin Nutr 2006 Apr;83(4):864 inactivated L. acidophilus culture may improve eradication rates but may not decrease gastrointestinal side effects in patients taking triple therapy (level 2 [mid-level] evidence)  based on randomized trial without blinding  120 asymptomatic patients with positive screening for H. pylori were randomized to eradication therapy for 7 days plus Lacteol Fort 3 times daily for 10 days vs. eradication therapy for 7 days alone  eradication therapy was rabeprazole 20 mg twice daily, clarithromycin 250 mg 3 times daily, and amoxicillin 500 mg 3 times daily for 7 days 9  Lacteol Fort contains heat-killed L. acidophilus 5 x 10 organisms (80 mg), lactose monohydrate 50 mg, calcium carbonate 5 mg, silicic acid 20 mg, talc 7 mg, magnesium stearate 3 mg, and anhydrous lactose 35 mg  comparing Lacteol Fort vs. control  H. pylori eradication rate in intention-to-treat analysis 87% vs. 70% (p = 0.02, NNT 6)  H. pylori eradication rate in per-protocol analysis 88% vs.

72% (p = 0.03, NNT 7)  side effects in 10% vs. 10% (not significant)  Reference - Aliment Pharmacol Ther 2000 Dec;14(12):1625 addition of Bacillus subtilis and Streptococcus faecium to triple therapy may be associated with improved eradication rates and reduced side effects (level 2 [mid-level] evidence)  based on randomized trial without blinding  352 H. pylori-infected patients were randomized to triple therapy for 1 week plus probiotics for 8 weeks vs. triple therapy for 1 week only  comparing triple therapy plus probiotics vs. triple therapy only  eradication rate 83.5% vs. 73.3% (p = 0.027, NNT 10)  diarrhea and overall side effects more common in triple therapy only group (p < 0.05)  Reference - Hepatogastroenterology 2007 Oct-Nov;54(79):2032

o

acidified milk with L. acidophilus does not appear to increase eradication rates with antibiotic monotherapy (level 3 [lacking direct] evidence)  based on randomized trial without clinical outcome  53 volunteers with H. pylori infection randomized to L. acidophilus (johnsonii La1 strain)-acidified milk vs. placebo 180 mL twice daily for 3 weeks  all participants given clarithromycin 500 mg twice daily for last 2 weeks  no significant difference in 26% H. pylori eradication rate  Reference - Eur J Gastroenterol Hepatol 2001 Jan;13(1):25

Chronic liver disease: 

probiotic yogurt associated with improved symptoms in patients with chronic liver disease (level 2 [mid-level] evidence) o based on randomized trial without blinding, allocation concealment, or intention-to-treat analysis o 85 patients aged 18-65 years with chronic liver disease (liver cirrhosis or chronic severe hepatitis) were randomized to probiotic yogurt 1 cup within 2 hours of meal 3 times daily vs. no probiotic yogurt for 14 days o 81 patients analyzed o probiotic yogurt contained Bacillus bifidus, Lactobacillus acidophilus, Lactobacillus bulgaricus, and Streptococcus thermophilus o probiotic yogurt associated with (all p < 0.05)  improved debilitation  improved food intake  improved appetite  reduced abdominal distension  reduced ascitic fluid o Reference - Nurs Res 2010 Nov-Dec;59(6):426 o DynaMed commentary -- caution warranted due to lack of evidence for safety of probiotics in cirrhosis, especially in decompensated cirrhosis

Hepatic encephalopathy: 

probiotics have limited and inconclusive evidence for effect on recovery rates in patients with hepatic encephalopathy o based on Cochrane review limited by clinical heterogeneity and trials with methodologic limitations o systematic review of 7 randomized trials evaluating probiotics in 550 patients with hepatic encephalopathy o number and type of probiotics varied across trials (each trial used a different preparation) and duration ranged from 10 to 180 days o all trials had methodologic limitations; no trial had adequate allocation concealment, only 1 trial had complete blinding o limited data reported in terms of analyses of specific probiotics

o

o

o

4 trials compared probiotics to placebo or no treatment  for outcome of no recovery (incomplete resolution of clinical symptoms)  no significant difference at 1 month in 2 trials with 101 patients  probiotics associated with lower risk at 2-3 months in 2 different trials with 105 patients  no significant differences in  all-cause mortality in analysis of 2 trials with 105 patients  adverse events in analysis of 3 trials with 145 patients  quality of life in 1 trial with 40 patients  change of or withdrawal from treatment in analysis of 3 trials with 175 patients  probiotics associated with significantly lower plasma ammonia concentration at 1 month and 3 months 3 trials compared probiotics to lactulose; no significant differences in  lack of recovery in analysis of 3 trials with 173 patients  adverse events in analysis of 2 trials with 111 patients  change of or withdrawal from treatment in analysis of 3 trials with 190 patients Reference - Cochrane Database Syst Rev 2011 Nov 9;(11):CD008716

Spondyloarthritis: 

probiotics do not appear to improve symptoms or quality of life in patients with spondyloarthritis (level 2 [mid-level] evidence) o based on randomized trial with inadequate statistical power o 63 patients with active spondyloarthritis randomized to oral probiotic vs. placebo for 12 weeks o small improvements on symptom and quality of life scales in both groups (difference not significant between groups) o Reference - J Rheumatol 2010 Oct;37(10):2118

Treatment of Atopic Dermatitis 

evidence for efficacy of probiotics for children with eczema is limited and inconsistent (level 2 [mid-level] evidence) o based on 2 systematic reviews with heterogeneity (and differing conclusions regarding results of subgroup analyses to explore heterogeneity) o Cochrane review  systematic review of 12 randomized trials evaluating live orally ingested microorganisms (probiotics) for treatment of eczema in 781 children  11 trials used Lactobacillus species (L. rhamnosus GG in 10 trials) alone or with other probiotics, 1 trial used Bifidobacteria  4 trials had adequate randomization method, allocation concealment and blinding

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no trial reported intention-to-treat analysis statistical heterogeneity occurred between individual trials, may be attributed to use of different probiotic strains  no significant differences comparing probiotic vs. placebo in overall meta-analyses of  patient- or parent-rated symptom scores in analysis of 5 trials with 313 children (but 3 trials suggested efficacy and 1 trial suggested harm)  patient- or parent-rated overall eczema severity in analysis of 3 trials with 150 children (but 2 trials suggested efficacy)  investigator-rated eczema severity in analysis of 7 trials with 588 children (but 3 trials suggested efficacy and 1 trial suggested harm)  similar results in subgroup analyses by age, eczema severity, presence of atopy, and presence of food allergy  in meta-analyses by probiotic strain  L. rhamnosus GG, alone or with other probiotic bacteria, associated with WORSE outcomes in terms of global eczema severity in analysis of 3 trials (p = 0.02, mean difference in total SCORAD score 3.37, 95% CI 0.55-6.2)  other Lactobacillus strains, alone or with other probiotic bacteria, associated with BETTER outcomes in terms of global eczema severity in analysis of 4 trials (p < 0.01, mean difference in total SCORAD score -7.64, 95% CI -11.65 to 3.62)  probiotics associated with some case reports of infections and bowel ischemia  Reference - Cochrane Database Syst Rev 2008 Oct 8;(4):CD006135 systematic review of 10 randomized trials evaluating probiotics for atopic dermatitis in 678 children  children ranged in age from 1 month to 13 years  outcomes were changes in Scoring for Atopic Dermatitis (SCORAD) score  individually 2 trials suggested significant benefit, 4 trials suggested no significant benefit, 4 trials were inconclusive  in overall meta-analysis probiotics associated with greater reduction in SCORAD score compared to control (weighted mean difference 3.01, p = 0.01, 95% CI -5.36 to -0.66)  authors question clinical impact of 3-point SCORAD difference  overall results were not more informative in subgroup analyses by probiotic strain  subgroup analyses by severity of atopic dermatitis  probiotics associated with greater reduction in SCORAD score in children with moderate-to-severe dermatitis (baseline SCORAD ≥ 25) (weighted mean difference -3.02, p = 0.01) in meta-analysis of 9 trials with 431 children

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no significant difference in SCORAD score for children with mild dermatitis (baseline SCORAD < 25) in meta-analysis of 7 trials with 236 children  Reference - Ann Allergy Asthma Immunol 2008 Nov;101(5):508 daily supplementation with Lactobacillus sakei may reduce severity of atopic eczema-dermatitis in children (level 2 [mid-level] evidence) o based on randomized trial with differential loss to follow-up o 88 children (aged 2-10 years) with atopic eczema-dermatitis syndrome (SCORAD score ≥ 25) randomized to L. sakei supplements vs. placebo for 12 weeks o dropout in 9% with L. sakei supplements vs. 21% with placebo o L. sakei significantly associated with  reduced severity (SCORAD) scores (mean improvement 13.1 points vs. 5.2 points, p = 0.008)  improved disease activity scores  increased rate of patients achieving > 30% or > 50% improvement o Reference - Ann Allergy Asthma Immunol 2010 Apr;104(4):343

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Lactobacillus plantarum may reduce severity of atopic dermatitis in children (level 2 [mid-level] evidence) o based on randomized trial with high dropout rate o 118 children (aged 1-13 years) with atopic dermatitis randomized to L. plantarum 0.5 x 1010 colony-forming units vs. placebo 2 times/day for 12 weeks o 30% did not complete trial but patients were included in intention-to-treat analyses o mean SCORAD score decreased by 9.1 with L. plantarum vs. 1.8 with placebo (p = 0.004) o no significant difference in total topical corticosteroid use o Reference - Pediatr Allergy Immunol 2012 Nov;23(7):667

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addition of Lactobacillus salivarius to fructooligosaccharide associated with reduced severity of atopic dermatitis in children and adolescents (level 2 [midlevel] evidence) o based on small randomized trial o 60 patients aged 2-14 years with moderate or severe atopic dermatitis (SCORAD score > 25) randomized to L. salivarius plus fructooligosaccharide orally twice daily vs. fructooligosaccharide orally twice daily for 8 weeks and followed until 10 weeks o comparing L. salivarius plus fructooligosaccharide vs. fructooligosaccharide  mean SCORAD scores at 8 weeks 27.4 vs. 36.3 (p = 0.022)  mild atopic dermatitis at 8 weeks in 52% vs. 30% (p = 0.024, NNT 5) o L. salivarius plus fructooligosaccharide associated with significantly reduced atopic dermatitis intensity and medication use frequency at 8 weeks o Reference - Br J Dermatol 2012 Jan;166(1):129

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Lactobacillus salivarius reported to reduce severity of atopic dermatitis in adults (level 3 [lacking direct] evidence) o based on small randomized trial without direct comparison of groups as randomized o 38 patients aged 18-46 years with atopic dermatitis randomized to L. salivarius vs. placebo for 4 months o L. salivarius associated with significant reductions in disease severity and disability compared to baseline o statistical comparison of L. salivarius vs. placebo not reported o Reference - J Clin Gastroenterol 2012 Oct;46 Suppl:S56

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Lactobacillus salivarius plus Bifidobacterium breve reported to reduce severity of atopic dermatitis in adults (level 3 [lacking direct] evidence) o based on small randomized trial without direct comparison of groups as randomized for clinical outcomes o 48 adults (mean age 32 years) with atopic dermatitis randomized to L. salivarius plus B. breve vs. placebo for 3 months o L. salivarius plus B. breve associated with significant reductions in disease severity and disability compared to baseline o statistical comparisons of L. salivarius plus B. breve vs. placebo for disease severity and disability not reported o Reference - J Clin Gastroenterol 2012 Oct;46 Suppl:S33

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Lactobacillus infections rare, and association with probiotics limited to case reports (BMJ 2006 Nov 11;333(7576):1006), commentary can be found in BMJ 2006 Dec 16;333(7581):1272

Treatment of Other Illnesses Bacterial vaginosis: 

probiotics for eradication of bacterial vaginosis (BV) o oral or intravaginal Lactobacillus each may be effective for BV in nonpregnant women (level 3 [lacking direct] evidence)  based on Cochrane review without clinical outcomes  systematic review of 24 randomized trials evaluating antimicrobial agents for BV in 4,422 nonpregnant women  primary outcome was treatment failure, defined as ≥ 3 Amsel criteria  23 trials studied symptomatic women  3 trials evaluated Lactobacillus  lower treatment failure rates with  Lactobacillus vaginal capsules for 5 nights (vs. metronidazole 0.75% vaginal gel twice daily for 5 nights) in 1 trial with 40 women (NNT 3)  Lactobacillus orally for 30 days plus metronidazole 500 mg orally twice daily for 5 days (vs. metronidazole regimen alone) in 1 trial with 125 women

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both of these trials conducted by same authors and used Lactobacillus GR-1 and RC-14  no significant differences comparing vaginal Lactobacilli tampons vs. placebo (both groups received treatment with clindamycin vaginal ovules 100 mg) in 1 trial  Reference - Cochrane Database Syst Rev 2009 Jul 8;(3):CD006055 insufficient evidence to recommend for or against use of probiotics for treatment of bacterial vaginosis (BV)  based on Cochrane review of trials with methodologic limitations  systematic review of 4 randomized trials evaluating probiotics alone or in combination with other agents for BV  oral probiotic plus metronidazole vs. metronidazole alone in 1 trial with 106 patients  probiotic vaginal capsule vs. metronidazole vaginal gel in 1 trial with 35 patients  probiotic tampon vs. placebo after clindamycin treatment (3 days) in 1 trial with 224 patients  probiotic vaginal tablet with estriol vs. placebo in 1 trial with 17 patients  methodologic limitations included lack of blinding and high dropout rate  no meta-analysis due to heterogeneity of interventions  microbiologic cure assessed by Nugent criteria  probiotic plus metronidazole associated with microbiologic cure  probiotic with estriol associated with microbiologic cure and physician-reported clinical cure  no significant differences in patient-reported symptom resolution or microbiologic cure for  probiotic vaginal capsule vs. metronidazole vaginal gel  probiotic tampon vs. placebo after clindamycin treatment  Reference - Cochrane Database Syst Rev 2009 Oct 7;(4):CD006289 addition of daily probiotic supplement to single dose tinidazole associated with increased cure rate in women with BV (level 2 [midlevel] evidence)  based on small randomized trial with borderline statistical significance for clinical outcomes  64 women with BV taking single dose tinidazole 2 g were randomized to probiotics 2 capsules orally once daily vs. placebo for 4 weeks  probiotic capsules contained L. rhamnosus GR-1 and L. reuteri RC14  comparing probiotic vs. placebo  cure rate by Amsel criteria 87.5% vs. 50% (p = 0.001, NNT 3)  "normal" vaginal microbiota in 75% vs. 34.4% (p = 0.011, NNT 3)

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cure rates accounting for self-reported recurrent BV and objective testing 75% vs. 57.1% (not significant)  self-reported bad vaginal odor in 9.4% vs. 28.1% (p = 0.055)  vulvovaginal candidiasis in 3.1% vs. 12.5% (not significant)  Reference - Can J Microbiol 2009 Feb;55(2):133 probiotics for reducing recurrence of bacterial vaginosis (BV) o vaginal probiotic may reduce recurrence of BV in women with recurring BV (level 2 [mid-level] evidence)  based on randomized trial with allocation concealment not stated  120 women with history of recurrent BV randomized to probiotic capsule (with L. rhamnosus, Lactobacillus acidophilus, and Streptococcus thermophilus) vs. placebo vaginally daily for 14 days (over two 7-day periods with 7-day break in between)  evaluation completed in 91% at 2 months and 78% at 11 months  comparing probiotic vs. placebo  recurrence of BV within 2 months in 16% vs. 45% (p < 0.001, NNT 4)  recurrence of BV between 2-11 months in 10% vs. 27% (p = 0.04, NNT 6)  Gardnerella vaginalis within 2 months in 3.5% vs. 18.3% (p = 0.02, NNT 7)  Reference - Am J Obstet Gynecol 2010 Aug;203(2):120.e1, commentary can be found in J Fam Pract 2011 Feb;60(2):91 o daily oral yogurt with L. acidophilus might prevent recurrent BV (level 2 [mid-level] evidence)  based on small randomized trial  46 women with ≥ 4 documented episodes of vaginal candidiasis or BV during previous year were randomized to 150 mL of yogurt enriched with L. acidophilus vs. 150 mL of pasteurized yogurt daily for 2 months  23 women had BV, 8 women had both vaginal conditions  rates of BV comparing Lactobacillus-enriched yogurt vs. control yogurt (extrapolated from figure 3)  56% vs. 70% at baseline (46 patients analyzed)  24% vs. 53% at 1 month (40 patients analyzed)  7% vs. 43% at 2 months (28 patients analyzed)  study protocol then had 2-month washout and 2-month crossover treatment but only 7 women completed study  Reference - Arch Fam Med 1996 Nov-Dec;5(10):593 PDF  DynaMed commentary -- progressive decrease in number of participants over time questions how well patients will comply with daily yogurt o vaginal Lactobacillus casei rhamnosus may restore vaginal flora by Nugent score after standard antibiotic treatment (level 3 [lacking direct] evidence)  based on randomized trial without clinical outcomes

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190 women with bacterial vaginosis diagnosed by Nugent score 7-10 and treated with clindamycin 300 mg orally twice daily for 7 days were randomized to live L. casei rhamnosus capsule vs. placebo intravaginally once daily for 7 days with follow-up at 4 weeks  reduction in Nugent score by at least 5 grades in 83% with Lactobacillus vs. 35% with placebo (p < 0.001, NNT 2)  Reference - BJOG 2008 Oct;115(11):1369 intravaginal yogurt has been promoted as treatment for vaginitis but evidence limited o yogurt douches during pregnancy may restore normal vaginal flora (level 3 [lacking direct] evidence)  based on small randomized trial without clinical outcomes  64 pregnant women with bacterial vaginitis were randomized to open-label yogurt douches vs. acetic acid tampons twice daily during first trimester  proportion of women free of bacterial vaginitis 2 months after treatment 88% with yogurt douche vs. 38% with control  5% of 20 women refusing treatment were free of bacterial vaginitis at 2 months  Reference - Acta Obstet Gynecol Scand 1993 Jan;72(1):17 o vaginally delivered yogurt via douching associated with eradication of BV (level 3 [lacking direct] evidence  based on case series  11 women with bacterial vaginosis treated with commercial yogurt intravaginally for 3 days  bacteriologic eradication in 55%  Reference - Jpn J Antibiot 1995 Mar;48(3):432 [Japanese]

Infectious mastitis: 

lactobacilli probiotics associated with decreased pain and fewer recurrences in women with infectious mastitis (level 2 [mid-level] evidence) o based on randomized trial without blinding o 352 women with infectious mastitis randomized to antibiotic therapy vs. 9 log10 colony-forming units (CFU) of L. fermentum CECT5716 vs. L salivarius CECT5713 for 3 weeks o antibiotics included clavulanic acid (38.6%), amoxicillin (22.8%), cotrimoxazole (18.8%), cloxacillin (17.8%), and erythromycin (2%) o mean pain score at day 21 (intense pain 0-4, discomfort with breastfeeding 5-7, complete recovery 8-10)  5.81 for antibiotic therapy  8.68 for L. fermentum CECT5716 (p < 0.05 vs. antibiotic therapy)  8.61 for L salivarius CECT5713 (p < 0.05 for antibiotic therapy) o mean bacterial counts in milk samples on day 21  3.28 log10 colony-forming units (CFU)/mL for antibiotic therapy  2.61 log10 CFU/mL for L. fermentum CECT5716 (p < 0.05 vs. antibiotic therapy)

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2.33 log10 CFU/mL for L salivarius CECT5713 (p < 0.05 for antibiotic therapy) recurrence (new episode mastitis over 3-month follow-up) in  30.7% with antibiotic therapy  10.5% with L. fermentum CECT5716 (p < 0.05 vs. antibiotic therapy, NNT 5 )  7.1% with L salivarius CECT5713 (p < 0.05 for antibiotic therapy, NNT 5 ) Reference - Clin Infect Dis 2010 Jun 15;50(12):1551 full text

Chronic fatigue syndrome: 

supplementation with lactic-acid producing bacteria reported to be beneficial (level 3 [lacking direct] evidence) o based on case series of 15 patients taking probiotic supplement for 4 weeks o 40% patients reported improved symptoms at 8 weeks follow-up o Reference - Nutr J 2009 Jan 26;8:4

Hypercholesterolemia: 

daily probiotic yogurt consumption may be associated with reduced total cholesterol at 8 weeks (level 3 [lacking direct] evidence) o based on small randomized crossover trial o 14 adults aged 40-64 years with serum total cholesterol 5.17-7.76 mmol/L (200-300 mg/dL) were randomized in crossover fashion to probiotic yogurt vs. standard yogurt 300 g/day for 6 weeks with 4-week washout between o probiotic yogurt consumption associated with reduced serum total cholesterol (-0.32 vs. +0.36 mmol/L in standard yogurt group) (-12 vs. +14 mg/dL) (p = 0.041) o Reference - Ann Nutr Metab 2009;54(1):22

Asthma: 

Lactobacillus not associated with symptom improvement (level 2 [mid-level] evidence) but may improve pulmonary function in children with asthma and allergic rhinitis (level 3 [lacking direct] evidence) o based on randomized trial with allocation concealment not stated o 118 children aged 6-12 years with mild-to-moderate persistent asthma and allergic rhinitis randomized to Lactobacillus gasseri A5 twice daily vs. placebo for 8 weeks o no significant difference in nighttime asthmatic and allergic rhinitis symptoms or physician-evaluated severity and asthma control o Lactobacillus associated with greater improvement at 10 weeks in  forced expiratory volume (FEV) (p = 0.028)  forced vital capacity (FVC) (p = 0.035)  FEV/FVC (p = 0.007)  bronchodilator dilation test (p < 0.001)

 peak expiratory flow rates (p < 0.05) Reference - Pediatr Pulmonol 2010 Nov;45(11):1111 Lactobacillus casei may not reduce symptoms in children with asthma but may reduce rhinitis episodes in children with rhinitis (level 2 [mid-level] evidence) o based on randomized trial with low compliance rate o 187 children aged 2-5 years with allergic asthma and/or rhinitis randomized to fermented milk with Lactobacillus casei 100 mL daily vs. placebo for 12 months o compliance in 70%-74% o no significant differences in 119 children with asthma in  time free from asthma/rhinitis  number of asthma/rhinitis episodes  fever episodes  diarrhea episodes  change in serum immunoglobulin o Lactobacillus casei associated with significant improvements in 131 children with rhinitis in  annual number of rhinitis episodes  mean duration of diarrhea episode o no significant differences in other outcomes in children with rhinitis o Reference - Pediatr Res 2007 Aug;62(2):215 o

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Infantile colic: 

probiotic Lactobacillus reuteri supplement may reduce crying in infants with colic (level 2 [mid-level] evidence) o based on 3 randomized trials with methodologic or statistical limitations o randomized trial with baseline differences  82 infants < 5 months old with infantile colic (crying episodes lasting ≥ 3 hours/day, ≥ 3 times/week) randomized to L. reuteri DSM 17938 (108 colony-forming units) vs. placebo orally once daily for 21 days  median duration of crying time at baseline 240 minutes/day in both groups  family history of allergy higher in probiotic group (52.5%) than placebo group (17.5%) at baseline  comparing L. reuteri vs. placebo at 28 days  reduction in mean daily crying time ≥ 50% in 100% vs.

62.5% (p < 0.001, NNT 3 [95% CI 2-5])  median duration of crying time 52 minutes/day vs. 120 minutes/day (p < 0.0001)  probiotics associated with improved parental perception of severity and family quality of life on days 7, 21, and 28  Reference - J Pediatr 2013 Feb;162(2):257 o randomized trial without blinding  90 exclusively breastfed infants with colic symptoms (> 3 hours crying on > 3 days in the week) for mean 6 days were randomized to L. reuteri vs. simethicone for 28 days

L. reuteri given at 108 colony-forming units in 5 drops of oil suspension, 30 minutes after feeding, once daily for 28 days  simethicone 60 mg/day given as 15 drops twice daily after feeding for 28 days  82 infants analyzed  comparing L. reuteri vs. simethicone  at baseline, median crying times 197 minutes/day vs. 197 minutes/day  at day 7, median crying times 159 minutes/day vs. 177 minutes/day (p = 0.005)  at day 28, median crying times 51 minutes/day vs. 145 minutes/day (p < 0.001)  at day 28, 95% vs. 7% were responders defined as ≥ 50% decrease in crying time from baseline  Reference - Pediatrics 2007 Jan;119(1):e124 o small randomized trial  50 exclusively breastfed infants with colic (according to modified Wessel criteria) randomized to L. reuteri vs. placebo for 21 days  46 infants completed the trial  comparing L. reuteri vs. placebo  median total daily crying time was 370 minutes/day vs. 300 minutes/day at baseline (not significant)  median total daily crying time was 35 minutes/day vs. 90 minutes/day on day 21 (p = 0.022)  L. reuteri associated with greater response (50% reduction in crying time from baseline) on days 7, 14, and 21 (all p > 0.01)  Reference - Pediatrics 2010 Sep;126(3):e526 Lactobacillus rhamnosus and Propionibacterium freudenreichii not associated with significant decrease in crying compared to placebo in 1 small trial with 18 infants (pilot trial summary in systematic review [Pediatrics 2011 Apr;127(4):720 ]) 

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