Probiotics to
Prevent Antibiotic
Associated Diarrhea
By Jens Langsjoen
Outline
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Background of probiotics and AAD
Efficacy of probiotics to prevent AAD
Safety of probiotics
UNMH inpatient probiotics
Recommendations
Background on Probiotics
• “Live microorganisms, which when adminstered in
adequate amounts, confer a health benefit on the
host” -FAO/WHO
• Can be Bacteria or Fungi
• Common OTC supplement
• Have been studied in AAD, IBD, IBS, C diff, Cancer,
allergies
Origins
• “Bacterium Lactis” 1st Bacteria ever discovered…
in souring milk
o Joseph Lister 1857
Causes of AAD
• Killing Anaerobic bacteria
o They normally digest carbohydrates
o This causes an Osmotic diarrhea
• Altering gut flora overgrowth of pathogens
o Like C diff!!!
o More alteration of gut flora = more diarrhea
• Pro-motility
o erythromycin
1. Doron SI, Hibberd PL, Gorbach SL. Probiotics for prevention of antibioticassociated diarrhea, J Clin Gastroenterol 2008;42 Suppl 2:S58-63.
Frequency of AAD
• Frequency range: 5-34%,
• Can occur between initiation of abx and 2 months
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





Hospitalized patients
Sicker patients, old and young.
Broad spectrum antibiotics.
B-Lactams, cephalosporins, clindamycin.
Longer Antibiotic Duration
History of AAD
AAD Frequency
Clinical Trials
Population Age
Country
# pts
Frequency
Inpatient
>50 yrs
UK
56
33.9%
Inpatient
>18yrs
USA
134
29.9%
Inpatient
Children
Japan
455
22.6
Outpatient
>1yrs
UK
120
14%
In/out
<14yrs
Poland
127
23%
2. Wistrom J, Norrby SR, Myhre EB, Eriksson S, Granstrom G, Lagergren L, Englund G, Nord CE,
Svenungsson B. Frequency of antibiotic-associated diarrhoea in 2462 antibiotic-treated
hospitalized patients: a prospective study, J Antimicrob Chemother 2001;47:43-50.
AAD Frequency
Population Studies
Population
Age
Country
# pts
Frequency
Inpatient
>12yrs
Sweden
2462
4.9%
Outpatient
<15yrs
France
650
11%
Outpatient
<14.5yrs Thailand
225
6.2%
Ambulatory
Adults
358,389
0.0012%
USA
Clostridium Difficile
• 10-25% of AAD are C diff infections6
• Extended LOS: between 3-7days
• Increased subsequent infections: 20-65%
6. Al-Eidan FA, McElnay JC, Scott MG, Kearney MP. Clostridium difficile-associated diarrhoea
in hospitalised patients, J Clin Pharm Ther 2000;25:101-109.
Probiotic MOA
• We only have theories…
• Suppression of pathogenic bacterial growth
• Improving intestinal barrier function
o inducing protective cytokines
• Immune system modulation
o Suppressing pro-inflammatory cytokines
Metanalyses
of Probiotics for AAD
• All Probiotics
o
o
o
o
o
o
Avadhani
Johnston
Cremonini
D’Souza
McFarland
Videlock
8 RCTs
9 RCTs
9 RCTs
22 RCTs
25 RCTs
34 RCTs
• ALL SHOW PROBIOTICS
TO BE EFFECTIVE
• S. Boulardii
o McFarland 10 RCTs
o Szajewska 6 RCTs
• Lactobacillus
o Kale-Pradham 10 RCTs
o Sazawal
19 RCTs
Meta-analysis:
McFarland
• 2006 American Journal of Gastroenterology
• 31 RCTs on AAD prevention and C diff tx.
• 25 RCTs on AAD: 2810 patients, all settings, all ages
• 6 RCTs on C diff diarrhea tx and prevension.
4. McFarland LV. Meta-analysis of probiotics for the prevention of antibiotic associated
diarrhea and the treatment of Clostridium difficile disease, Am J Gastroenterol 2006;101:812822.
RR 0.43
CI (0.31-0.58)
Meta-analysis:
McFarland
• 13 of 25 trials (52%) showed  AAD
• Prevention of AAD: RR 0.43 (0.31-0.58)
• NNT~8
• High heterogeneity
Multiple subgroup analyses done to assess.
No difference in adults vs peds.
Most (90%) of studies were underpowered
Likely 2/2 differences in population (age) and
intervention (dose, strains)
Metanalysis:
Videlock
• April 2012-Alimentary Pharmacology & Therapeutics
• 34 double-blind RCTs, 4138 pts:
o All ages, all settings, pts on abx given probiotics for AAD prevention
o Includes 20/25 studies from McFarland.
• Thorough search strategy (Cochrane methodology)
5. Videlock EJ, Cremonini F. Meta-analysis: probiotics in antibiotic-associated diarrhoea,
Aliment Pharmacol Ther 2012.
Results:
Videlock
• Pooled data for AAD prevention
RR 0.53 (0.44 to 0.63)
NNT: 8 (using pooled raw data)
o diffucult to interpret given heterogeniety
• Significant heterogeneity
• multiple subgroup analyses and metaregressions
performed
Subgroup Analyses:
Videlock
• All 34 trials: Pooled data RR 0.53 (0.44 to 0.63)
• 24 adult trials: RR 0.53 (0.43-0.66)
• 10 pediatric: RR 0.48 (0.35 to 0.65)
• 13 Adult inpatient: RR 0.52 (0.38 to 0.72)
Subgroup AnalysesRisk of Bias
• 14 Low risk : RR 0.48 (0.35-0.68)
• 10 Unclear risk: RR 0.48 (0.37-0.63)
• 10 High risk: RR 0.62 (0.46-0.84)
How to Explain the
Heterogeniety?
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Efficacy by Dose
Efficacy by treatment duration
Efficacy by Probiotic strain
Efficacy for inpatient adults
Efficacy by Dose
• Gao et al. 7
RCT with 235 pts, using L. Acidophilus + L Casei
placebo vs 50 billion vs 100 billion CFUs
Assessed AAD and C diff recurrence.
7. Gao XW, Mubasher M, Fang CY, Reifer C, Miller LE. Dose-response efficacy of a proprietary
probiotic formula of Lactobacillus acidophilus CL1285 and Lactobacillus casei LBC80R for antibioticassociated diarrhea and Clostridium difficile-associated diarrhea prophylaxis in adult patients, Am J
Gastroenterol 2010;105:1636-1641.
Dose Response: Gao
AAD
50 Billion
CFUs
100 Billion
CFUs
Dose Response: Gao
C diff
50 Billion
CFUs
100 Billion
CFUs
Efficacy by Dose
• Johnston et al.8
Subgroup analysis <5b vs >5b CFUs/day
for >5b: RR 0.53 (0.29-0.55)
for <5b: RR 0.80 (0.53-1.21)
Interaction p=0.01
• McFarland
 >10 billion CFU dose more effective
 8/12 (67%) high dose trials Efficacious vs
2/12 (17%) non-efficacious
8. Johnston BC, Goldenberg JZ, Vandvik PO, Sun X, Guyatt GH. Probiotics for the prevention of
pediatric antibiotic-associated diarrhea, Cochrane Database Syst Rev 2011;(11):CD004827.
Efficacy by treatment
duration
• McFarland
Tx duration range 5d-8wks
NS difference
• Videlock
16 trials- Equal to abx duration: RR 0.49 (0.38-0.63)
12 trials- 7d longer than abx: RR 0.53 (0.38-0.75)
Efficacy by Probiotic
Strain
• McFarlandOnly L. Rhamnosus GG, S. Boulardii and probiotic
mixtures were effective
• Johnston
Only LGG, L Coagulans, and S. Boulardii effective
• VidelockSimilar RR across all probiotic strains
o
o
o
o
L. GG 8 trials 847 pts: RR 0.40 (0.20-0.81)
S. Boulardii 7 trials 1007 pts: RR 0.46 (0.30-0.70)
Any lactobacilli 24 trials 2817 pts: RR 0.56 (0.45-0.69)
Bifidobacteria 10 trials 602 pts: RR 0.55(0.37-0.82)
Lactobacilli
Efficacy
• Videlock
Any lactobacilli 24 trials 2817 pts RR 0.56 (0.45-0.69)
• Kale-Pradhan- Lactobacilli meta-analysis9
10 RCTs, 1862 pts
doses of 2-40 billion CFUs
in Adults- RR 0.24 (0.08-0.75)
9. Kale-Pradhan PB, Jassal HK, Wilhelm SM. Role of Lactobacillus in the prevention of antibioticassociated diarrhea: a meta-analysis, Pharmacotherapy 2010;30:119-126.
Saccharomyces Boulardii
Efficacy
• Szajewska, 2005 Meta-analysis
5 RCTs, 1076 pts
RR= 0.43 (0.23-0.78)  NNT of 10
• McFarland, 2010 Meta-analysis10
10 RCTs, pooled RR: 0.47 (0.35-0.63)
• Videlock 2012- S. Boulardii Subgroup11
7 RCTs 1007 pts: RR 0.46 (0.30-0.70)
10. McFarland LV. Systematic review and meta-analysis of Saccharomyces boulardii in adult patients,
World J Gastroenterol 2010;16:2202-2222.
11. Szajewska H, Mrukowicz J. Meta-analysis: non-pathogenic yeast Saccharomyces boulardii in the
prevention of antibiotic-associated diarrhoea, Aliment Pharmacol Ther 2005;22:365-372.
S. BoulardiiMcFarland 2010
RR: 0.47
(0.35-0.63)
Efficacy in Hospitalized
Adult Patients
• Avadhani: meta-analysis of Inpatient adults. 8 RCTs
AAD 1220 pts RR 0.56 (0.44–0.71)
C diff 471 pts RR 0.29 (0.18–0.46)
• Videlock : subgroup- 13 adult inpatient trials
AAD 1693 pts: RR 0.52 (0.38 to 0.72)
• 6 more inpatient trials currently ongoing
What do the experts
think?
• American College of Gastroenterology formed
“Yale Workshop on Probiotics” 12
2011 update, Probiotics for AAD: level A
recommendation for S. boulardii, LGG, and
combo of L. casei, L. bulgaricus,
• World Gastrenterology Association 2008
“In AAD, there is strong evidence of efficacy for S.
boulardii or L. rhamnosus GG in adults”
12. Floch MH, Walker WA, Madsen K, Sanders ME, Macfarlane GT, Flint HJ, Dieleman LA, Ringel Y,
Guandalini S, Kelly CP, Brandt LJ. Recommendations for probiotic use-2011 update, J Clin
Gastroenterol 2011;45 Suppl:S168-71.
Safety:
Population Studies
• Salminen et al.13
Finland, 1990: L. Rhamnosus introduced into dairy
3 Trillion CFUs/person/year
11 cases of Lactobacillus bacteremia from
1990-2000
No increased incidence
• Saxelin et al.14
4 year study in South Finland.
No relation between Lacto. Bcx strains and those
used buy food industry
13. Salminen MK, Lactobacillus bacteremia during a rapid increase in probiotic use of Lactobacillus
rhamnosus GG in Finland, Clin Infect Dis 2002;35:1155-1160.
14. Saxelin M, Chuang NH, Chassy B, Rautelin H, Makela PH, Salminen S, Gorbach SL. Lactobacilli and
bacteremia in southern Finland, 1989-1992, Clin Infect Dis 1996;22:564-566.
Safety:
Clinical Trials
• From 61-98’ 143 probiotic trials, 7,526 pts
no adverse effects.
no fungemia or bacteremia
• Videlock 2012 Meta-analysis
4138 pts no adverse events
• Wolf et al. Blinded safety RCT on 39 HIV pts15
no adverse events.
15. Wolf BW, Wheeler KB, Ataya DG, Garleb KA. Safety and tolerance of Lactobacillus reuteri
supplementation to a population infected with the human immunodeficiency virus, Food Chem Toxicol
1998;36:1085-1094.
Safety:
Case Reports
• Bacteremia: 6 cases
4 in children with short gut syndrome
• Fungemia: 29 cases to date.
24 in ICUs, had CVCs, or immunosuppressed.
1 report of 2 neighbors being infected by fungus.
16. Boyle RJ, Robins-Browne RM, Tang ML. Probiotic use in clinical practice: what are the risks? Am J
Clin Nutr 2006;83:1256-64; quiz 1446-7.
Summary
• Efficacy: Works for AAD prevention. NNT 5-10
• Dose: in the billions, more (>5-50 billion) is better
• Duration: for duration of Abx therapy
• Strains: Best evidence for S. Boulardii, LGG, and
Mixed strains.
• Safety: potentially fungemia- S. Boulardii in ICU pts,
pts with central lines, and the immunosuppressed.
Products Available
Inpatient UNMH
• Lactinex (L. Acidophilus and L. Bulgaricus)
• Florastor (S. Boulardii)
• Yoplait (commercial yogurt)
Lactinex
• L. Acidophilus and L Bulgaricus
•
•
•
•
1 tab: 1 million CFUs
1 pack granules: 100 million CFUs,
100 tabs= 1 granule pack.
Cost of granules: $13 per 5 days, $0.86 per packet
• 2 trials on Lactinex for AAD prevention
Gotz (1979): 79 inpatient Adults. NS
Tankanow (1990): 38 outpatient peds. NS
Florastor
• Saccharomyces Boulardii
• 5 Billion CFUs per 250mg capsule
• Cost: $8 per 5 days, $0.79 per pill
• Restricted to pediatric use only.
• Great efficacy data
Yoplait
• Comercial Yogurt
• One serving contains around 280 million CFUs
of L. Acidophilus and S. Thermophilus17
• Cost: at 3 a day; $15 per 5 days…?
• 2 RCTs on comercial Yogurt: 1 positive, 1 negative
17. Dunlap BS, Yu H, Elitsur Y. The probiotic content of commercial yogurts in west virginia, Clin Pediatr
(Phila) 2009;48:522-527.
Saving the Hospital
Money
• Hickson et al. 18
Cost to prevent 1 AAD: $100
Cost to prevent 1 C diff: $120
• Kyne et al. 3
Cost per pt to treat C diff: $3,669
Cost of C diff in 2008: $3.2 billion
3. Kyne L, Hamel MB, Polavaram R, Kelly CP. Health care costs and mortality associated with
nosocomial diarrhea due to Clostridium difficile, Clin Infect Dis 2002;34:346-353.
18. Hickson M, D'Souza AL, Muthu N, Rogers TR, Want S, Rajkumar C, Bulpitt CJ. Use of probiotic
Lactobacillus preparation to prevent diarrhoea associated with antibiotics: randomised double blind
placebo controlled trial, BMJ 2007;335:80.
Recommendations
• Get S. Boulardii approved for adults.
• Once approved, use in all patients on antibiotics
except those with central lines, the
immunosuppressed, and ICU patients.
• In the meantime, use Lactinex granules 2 packets
TID mixed with Yogurt TID
 ~1.5 billion CFUs/day
Pro-bios
or
Anti-bios?
1. Doron SI, Hibberd PL, Gorbach SL. Probiotics for prevention of antibiotic-associated diarrhea, J Clin Gastroenterol 2008;42 Suppl
2:S58-63.
2. Wistrom J, Norrby SR, Myhre EB, Eriksson S, Granstrom G, Lagergren L, Englund G, Nord CE, Svenungsson B. Frequency of
antibiotic-associated diarrhoea in 2462 antibiotic-treated hospitalized patients: a prospective study, J Antimicrob Chemother
2001;47:43-50.
3. Kyne L, Hamel MB, Polavaram R, Kelly CP. Health care costs and mortality associated with nosocomial diarrhea due to
Clostridium difficile, Clin Infect Dis 2002;34:346-353.
4. McFarland LV. Meta-analysis of probiotics for the prevention of antibiotic associated diarrhea and the treatment of Clostridium
difficile disease, Am J Gastroenterol 2006;101:812-822.
5. Videlock EJ, Cremonini F. Meta-analysis: probiotics in antibiotic-associated diarrhoea, Aliment Pharmacol Ther 2012.
6. Al-Eidan FA, McElnay JC, Scott MG, Kearney MP. Clostridium difficile-associated diarrhoea in hospitalised patients, J Clin Pharm
Ther 2000;25:101-109.
7. Gao XW, Mubasher M, Fang CY, Reifer C, Miller LE. Dose-response efficacy of a proprietary probiotic formula of Lactobacillus
acidophilus CL1285 and Lactobacillus casei LBC80R for antibiotic-associated diarrhea and Clostridium difficile-associated diarrhea
prophylaxis in adult patients, Am J Gastroenterol 2010;105:1636-1641.
8. Johnston BC, Goldenberg JZ, Vandvik PO, Sun X, Guyatt GH. Probiotics for the prevention of pediatric antibiotic-associated
diarrhea, Cochrane Database Syst Rev 2011;(11):CD004827.
9. Kale-Pradhan PB, Jassal HK, Wilhelm SM. Role of Lactobacillus in the prevention of antibiotic-associated diarrhea: a metaanalysis, Pharmacotherapy 2010;30:119-126.
10. McFarland LV. Systematic review and meta-analysis of Saccharomyces boulardii in adult patients, World J Gastroenterol
2010;16:2202-2222.
11. Szajewska H, Mrukowicz J. Meta-analysis: non-pathogenic yeast Saccharomyces boulardii in the prevention of antibioticassociated diarrhoea, Aliment Pharmacol Ther 2005;22:365-372.
12. Floch MH, Walker WA, Madsen K, Sanders ME, Macfarlane GT, Flint HJ, Dieleman LA, Ringel Y, Guandalini S, Kelly CP, Brandt
LJ. Recommendations for probiotic use-2011 update, J Clin Gastroenterol 2011;45 Suppl:S168-71.
13. Salminen MK, Tynkkynen S, Rautelin H, Saxelin M, Vaara M, Ruutu P, Sarna S, Valtonen V, Jarvinen A. Lactobacillus bacteremia
during a rapid increase in probiotic use of Lactobacillus rhamnosus GG in Finland, Clin Infect Dis 2002;35:1155-1160.
14. Saxelin M, Chuang NH, Chassy B, Rautelin H, Makela PH, Salminen S, Gorbach SL. Lactobacilli and bacteremia in southern
Finland, 1989-1992, Clin Infect Dis 1996;22:564-566.
15. Wolf BW, Wheeler KB, Ataya DG, Garleb KA. Safety and tolerance of Lactobacillus reuteri supplementation to a population
infected with the human immunodeficiency virus, Food Chem Toxicol 1998;36:1085-1094.
16. Boyle RJ, Robins-Browne RM, Tang ML. Probiotic use in clinical practice: what are the risks? Am J Clin Nutr 2006;83:1256-64;
quiz 1446-7.
17. Dunlap BS, Yu H, Elitsur Y. The probiotic content of commercial yogurts in west virginia, Clin Pediatr (Phila) 2009;48:522-527.
18. Hickson M, D'Souza AL, Muthu N, Rogers TR, Want S, Rajkumar C, Bulpitt CJ. Use of probiotic Lactobacillus preparation to
prevent diarrhoea associated with antibiotics: randomised double blind placebo controlled trial, BMJ 2007;335:80.