PROBIOTICS NEGATIVE ASPECTS

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1 PROBIOTICS NEGATIVE ASPECTS Dr Ismail Moola Department of Medical Gastroenterology CMJAH University of Witwatersrand

2 Putative Benefits of Probiotics Modulate Immune Intestinal Function Increase secretory IgA Reduce Pro Inflammatory Cytokines Promote epithelial homeostasis Neuromodulatory Effects Block effects of Pathogenetic Bacteria Nutritional Effects Energy Recovery from indigestible foodstuffs

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4 Issues Surrounding Probiotics Do they work? Are they Cost Effective? Are there any Negative Side Effects?

5 Antibiotic Associated Diarrhoea 2 Issues Antibiotic Associated Diarrhoea C. Diff Associated Infection 2 major Meta analyses LANCET JAMA

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7 Results and Methodology Meta analysis of 63 RCTs participants, Probiotic administration associated with reduction in AAD Relative risk 0.58 NNT = 13

8 Sub Group Analyses 14 RCTs participants aged 18 to 65 years RR of 0.54 (95% CI, 0.34 to 0.85) NNT 13 3 RCT studies were identified exclusively in elderly adults > 65 with AAD RR of 0.81 NNT 25

9 Rates of AAD Diarrhoea Rates: 5 10 % Ampicillin % Amoxicillin Clavulanate, 15 to 20 % Cefixime, 2 to 5 % treated with other Cephalosporins, Fluoroquinolones, Azithromycin, Clarithromycin, Erythromycin, and Tetracycline. Equal rates of diarrhoea between parental and oral antibiotics

10 Implications of this data Absolute Risk appears to be small NNT may probiotics non cost effective Potentially less efficacious in Elderly Data not helpful in determining which probiotic strains and doses are best in preventing AAD

11 PLACIDE TRIAL

12 PLACIDE TRIAL Multicentre, randomised, double-blind, placebocontrolled trial of inpatients Age > 65 years and exposure to 1 Antibiotic (oral or parenteral) Multistrain preparation Lactobacilli and bifidobacteria 1 Daily / 21 days VS Placebo

13 PLACIDE TRIAL Primary outcomes Occurrence of AAD within 8 weeks C difficile diarrhoea (CDD) within 12 weeks patients screened, 1470 TREATMENT GROUP 1471 PLACEBO GROUP

14 Meta Analyses for Antibiotic Associated Diarrhoea

15 Meta Analyses for Antibiotic Associated Diarrhoea AAD (including CDD) 159 (10.8%) participants in the microbial preparation group 153 (10.4%) participants in the placebo group RR 1.04; (95% CI ; p=0.71). CDD was an uncommon cause of AAD: 12 Participants (0.8%) Microbial preparation group 17 participants (1.2%) in the Placebo group

16 RESULTS NO SIGNIFICANT DIFFERENCES BETWEEN GROUPS

17 CONCLUSIONS COMMONLY USED PROBIOTICS ARE NOT EFFECTIVE IN REDUCTION OF C DIFF INFECTION PREVENTION OF AAD IS THIS A COST EFFECTIVE INTERVENTION IN THE SETTING OF BROAD USAGE OF ANTIBIOTICS?

18 VSL#3 VSL#3 is a high-concentration probiotic preparation Contains 225 billion live bacteria (DS also available) 8 live freeze-dried bacterial species 4 strains of Lactobacilli (Lactobacillus casei, L. plantarum, L. acidophilus and L. delbrueckii subsp. bulgaricus), 3 strains of Bifidobacteria (Bifidobacterium longum, B. breve and B. infantis) Streptococcus salivarius subsp. thermophilus.

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20 UC, IAPA and PROBIOTICS Reasonable evidence of VSL#3 for prevention of POUCHITIS Patients with UC AND IAPA Reduction by 75 % Small trial 40 patients (20 TREAT VS 20 PLACEBO) Good study design ( Placebo Control Trial and length of F/U 52 weeks) Gastroenterology May;124(5): Prophylaxis of pouchitis onset with probiotic therapy: a double-blind, placebo-controlled trial. Gionchetti P Et al

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22 IMPLICATIONS OF THIS STUDY Adjunct VSL#3 therapy does not provide sufficient additional benefits over the lifetimes of children with UC to justify its added costs. FUNDERS WILL NOT reimburse VSL#3 expenses TREATMENT WITH VSL#3 probiotic available ONLY AS AN OUT OF POCKET EXPENSE Findings also make a strong economic case for advising physicians to prescribe STANDARD TREATMENT ALONE

23 CROHNS DISEASE What is the evidence for PROBIOTICS: INDUCTION of Remission? MAINTENANCE of Remssion?

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25 Probiotics for induction of remission in Crohn's disease Cochrane Database of Systematic Reviews 16 JUL 2008 DOI: / CD pub2

26 Risks of Probiotics DO PROBIOTICS CAUSE HARM?

27 Probiotic prophylaxis in predicted severe acute pancreatitis: a randomised, double-blind, placebo-controlled trial Lancet 2008 Besselink et al Probiotics, Pancreatitis and Adverse Outcomes Randomised Placebo Control Trial 298 patients with Acute Pancreatitis Infectious complications similar Probiotic 30% vs Placebo 28 % RR 1.06 Death 16% Probiotic vs 9 % Placebo RR Patients probiotics group developed bowel ischaemia (8 Fatalities ) none in the placebo group (p=0 004).

28 Conclusions Equivocal evidence Nil IN Crohn s Disease Nil In C Diff Some benefit in UC and AAD Cost Expensive Potentially on a long term basis Potentially harmful Acute Pancreatitis Benefits overstated vs CAM industry claims