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Three Part Question

In [adult patients taking antibiotics] does the [co-administration of probiotics] [reduce the incidence of antibiotic-associated diarrhoea]?

Clinical Scenario

Your relative has returned from their general practitioner with a prescription for antibiotics. They ask you if there is anything they could take to prevent diarrhoea following the antibiotics, as, on occasions, it has resulted in them stopping the antibiotics early. You have some recollection regarding the use of probiotics and wonder whether there is evidence to support their use in this manner.

Search Strategy

Medline 1950 - November week 1 2009 using the OvidSP interface


[(exp Anti-Bacterial Agents/OR antibiotic$.mp.) AND (exp Probiotics/OR probiotic$.mp. OR exp Lactobacillus/OR Lactobacill$.mp. OR exp Saccharomyces/OR Saccharomyc$.mp.) AND (exp Clostridium/OR exp Clostridium difficile/OR clostridium difficile.mp. OR exp Diarrhea/OR Diarrh$.mp.)] LIMIT to abstracts and English language and humans and ‘all adult (19 plus years)’. The Cochrane database of systematic reviews.

Search Outcome

This MEDLINE search returned 104 papers, of which 13 answered the question.

Of these 13 papers: one was excluded because it was a pilot study, of very small numbers (Safdar et al, 2008); a second was excluded because it pooled data from both adults and paediatric patients (Conway et al, 2007) and three others as they were included in the meta-analysis (Lewis et al, 1998; McFarland et al, 1995 and Gotz et al, 1979).

The Cochrane database of systematic reviews did not return any relevant articles.

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Wenus et al 2008 Norway	All adult inpatients that were prescribed antibiotics of at least 7 days duration were randomised to recieve a probiotic milk drink or placebo.	Randomised, double-blind, placebo-controlled study.	Primary end point criterion was diarrhoea, defined as at least three fluid stools/day for at least 2 days during the test period	87 patients were randomized to probiotic (n=46) or placebo (n=41) treatment. Eight (27.6%) patients in the placebo group, and two (5.9%) patients in the probiotic group experienced AAD (P=0.035).	Small sample size High drop out rate (12 in each group). Calculations based on per-protocol analysis and not intention-to-treat.
Koning CJ et al, 2008 Netherlands	41 healthy volunteers were given 500 mg amoxycillin twice daily for 7 days and were randomized to either 5 g of a multispecies probiotic, Ecologic, or placebo, twice daily for 14 days.	Randomised, double-blind, placebo-controlled study.	Main outcome measures were intestinal microbiota composition, bowel frequency and consistency according to the Bristol stool scale	Bowel movements with a frequency >or=3 per day for at least 2 days and/or a consistency >or=5 for at least 2 days were reported less frequently in the probiotic compared to the placebo group (48%vs 79%, P < 0.05)	The use of healthy volunteers may not make this study transferable to those acutely unwell. Small sample size.
Beausoleil et al, 2007 Canada	All hospitalized patients, who were anticipated to take at least three days of any systemic antibiotic, were randomly assigned to receive either a lactobacilli-fermented milk or a placebo.	Randomised, double-blind, placebo-control study.	The primary outcome of the present study was the incidence of AAD during the study period	Among 89 randomized patients, antibiotic-associated diarrhea occurred in seven of 44 patients (15.9%) in the lactobacilli group and in 16 of 45 patients (35.6%) in the placebo group (OR 0.34, 95% CI 0.125 to 0.944; P=0.05).	Hugely underpowered. Large proportion excluded (1306 of 1422 screened). Lack of generalisability of subjects as all hospitalised.
Hickson et al, 2007 UK	135 hospitalised patients taking antibiotics randomised to receive either probiotic drink or placebo.	Randomised, double-blind, placebo-controlled study.	Primary outcome: occurrence of AAD. Secondary outcome: presence of CDAD	7/57 (12%) of the probiotic group developed diarrhoea associated with antibiotic use compared with 19/56 (34%) in the placebo group (p=0.007). No one in the probiotic group and 9/53 (17%) in the placebo group had diarrhoea caused by CDAD (p=0.001)	Analysis did not follow the intention to treat model. High exclusion rate (1625/1760) questioning generalisability. High numbers (16%) lost to follow up.
Can M et al, 2006 Turkey	151 inpatients randomised to recieve antibiotics plus either S. boulardii or placebo	Randomised, double-blind, placebo-controlled study.	Rate of AAD in both groups	The rate of AAD was 9% in the placebo group and 1.4% in the S. boulardii group (p<0.05)	Outcome measures not defined. No power calculation performed. No consort diagram. No intention to treat model.
Cremonini et al, 2002 Italy	7 randomised, control studies that included 881 patients.	Meta-analysis	Whether probiotics reduce AAD	Three studies showed significantly less AAD with a combined relative risk of 0.397 (95% CI 0.275 to 0.571)	Studies included children Poor homogeneity
Thomas MR et al, 2001 USA	302 hospitalised patients recieving antibiotics were randomly allocated to receive Lactobacillus GG or placebo for 14 days.	Prospective, randomised, double-blind, placebo-controlled trial.	Proportion of patients who developed diarrhoea	ADD occurrence rate was 39/133 (29.3%) in those receiving Lactobacillus and 40/134 (29.9%) in those receiving placebo (p=0.93)	Only abstract available from publishers.

Editor Comment

AAD, antibiotic-associated diarrhoea; CDAD, Clostridium difficile-associated diarrhoea

Clinical Bottom Line

The evidence supports probiotics for reducing antibiotic-associated diarrhoea.

References

1. Wenus C, Goll R, Loken E, et al. Prevention of antibiotic-associated diarrhoea by a fermented probiotic milk drink European Journal of Clinical Nutrition (2008) 62, 299–301.
2. Koning C, Jonkers D, Stobberingh E, et al. The effect of a multispecies probiotic on the intestinal microbiota and bowel movements in healthy volunteers taking the antibiotic amoxycillin. American Journal of Gastroenterology 2008 Jan, 103(1):178-89,
3. Beausoleil M, Fortier N, Guenette S, et al. Effect of a fermented milk combining Lactobacillus acidophilus CL1285 and Lactobacillus casei in the prevention of antibiotic-associated diarrhea: A randomized, double-blind, placebo-controlled trial Canadian Journal of Gastroenterology 2007;21(11):732-736.
4. Hickson M, D'Souza A, Muthu N, et al. Use of probiotic Lactobacillus preparation to prevent diarrhoea associated with antibiotics: randomised double blind placebo controlled trial British Medical Journal 2007;335:80-3.
5. Can M, Besirbellioglu B, Avci I, et al. Prophylactic Saccharomyces boulardii in the prevention of antibiotic-associated diarrhea: A prospective study Med Sci Monit 2006;12:19–22.
6. Cremonini F, Di Caro S, Nista E, et al. Meta-analysis: the effect of probiotic administration on antibioticassociated diarrhoea Alimentary, Pharmacology and Therapeutics 2002; 16: 1461–1467.
7. Thomas M, Litin S, Osmon D, et al.(abstract only available). Lack of effect of Lactobacillus GG on antibiotic-associated diarrhea: a randomized, placebo-controlled trial. Mayo Clinic Proceedings 2001 Sep; 76(9):883-9.