GIT

Does taking probiotics routinely with antibioticsprevent antibiotic associated diarrhoea?

BMJ 21 February 2012
د. حسين محمد جمعه
اختصاصي الامراض الباطنة
البورد العربي
كلية طب الموصل
2012

Diarrhoea develops in association with antibiotic treatment in 1% to 44% of cases, and ranges from mild episodes that resolve when antibiotics are stopped to serious complications such as toxic megacolon, bowel perforation, and death. Risk is
increased with extremes of age, co-morbidity, oral broad spectrum antibiotics (particularly clindamycin, β-lactams, and third generation cephalosporins), prolonged antibiotic duration, previous antibiotic associated diarrhoea, and hospitalisation.

Probiotics—live microorganisms that, when administered in adequate amounts, confer a health benefit on the host—are present in products available in shops as foodstuffs, and in
formulations used for specific therapeutic purposes.

Probiotics are thought to combat antibiotic associated diarrhoea through restoring resistance to colonisation by pathogenic bacteria after
the normal colonic microflora have been damaged by antibiotics, by breaking down non-absorbable compounds into absorbable products, by interfering with pathogenic toxins, and by enhancing immunity. Effects of probiotics vary by strain owing to differing resistance to gastric acid and bile, ability to colonise mucosa, and susceptibility to antibiotics.


Probiotics carry theoretical risks, including infection beyond the gut and transfer of antibiotic resistant genes. However, so far, there have been no reports of bacteraemia or fungaemia attributable to the probiotics in trials included in published systematic reviews.

Lactobacillus bacteraemia is rare and has a low mortality rate.

Cancer, diabetes, broad spectrum antibiotic therapy, organ transplantation, and abscess may be risk factors for lactobacillus bacteraemia. Twelve cases of lactobacillus bacteraemia have
been reported in patients taking a probiotic and 24 cases of fungaemia associated with the probiotic Saccharomyces boulardii.

However, many lactobacillus strains are human

commensals and a review identified only five well documented published cases where the consumed probiotic strain was the same as a clinical isolate. Mild to moderate gastrointestinal side effects and rash are generally no more common than in patients on placebo probiotic.
Probiotics may therefore be an attractive option for preventing antibiotic associated diarrhoea because they are cheap (the cost of preventing one case in selected hospital patients may be as low as £50; €60, $79)12 and safe.

What is the evidence of uncertainty?

We conducted a review of meta-analyses, updated with subsequent randomised controlled trials. We searched PubMed, EMBASE, the Cochrane Library, and Clinical Evidence in
October 2011 for meta-analyses published in the past five years in English and trials published after their search dates on probiotics to prevent antibiotic associated diarrhoea using the
search terms “probiotic” and “antibiotic associated diarrhoea [or diarrhea]”.

We excluded prevention studies, small pilot

studies, studies that were not placebo controlled, studies published only in abstract form, studies focusing on antibiotic associated diarrhoea caused by a single organism (such as Clostridium difficile), and systematic reviews without meta-analysis.

The commonest outcome measure was diarrhoea, defined as three loose stools in a 24 hour or 48 hour period.⇓ The type of probiotic tested, study populations, and effect sizes varied widely
between studies, with both statistically significant2 and non-significant findings for the primary outcome and widely differing rates of antibiotic associated diarrhoea.


Many of the trials identified in the systematic reviews were of poor quality. Reasons included poor allocation concealment, inadequate power, possible publication bias, variation in outcome measures, lack of intention to treat analyses, variation in follow-up duration, lack of cost-benefit data, variation in illness severity, and the small proportion of eligible patient enrolled. We found no head to head comparisons of probiotic strains.

Is ongoing research likely to provide relevant evidence?

We searched the Current Controlled Trials database (www. controlled-trials.com) for ongoing randomised controlled trials using the previously described search terms. Six placebo controlled trials are in progress examining the effect of probiotics in preventing antibiotic associated diarrhoea in hospitalised patients.

Three (ISRCTN57305201,

ISRCTN10768531, and isrctn19604441) are investigating the
effect of a mixed probiotic, VSL#3, containing eight species of
bacteria licensed for use in irritable bowel syndrome, with one
recruiting exclusively from intensive care units
(ISRCTN10768531). One trial (NCT01087892) is investigating
the effect of Actimel, which contains three species
(Lactobacillus casei DN 114 001, Lactobacillus bulgaricus,
and Streptococcus thermophilus) and one (ISRCTN70017204)
is investigating the effect of a probiotic that contains two strains
of Lactobacillus acidophilus (National Collection of Industrial,
Food and Marine Bacteria (NCIMB) 30157 and 30156),
Bifidobacterium bifidum (NCIMB 30153) and Bifidobacterium
lactis (NCIMB 30172). One (ISRCTN86623192) is investigating
the effect of S boulardii. These studies will provide information
on probiotics to prevent antibiotic associated diarrhoea in a
wider range of hospitalised patients and may be large enough
to provide information on which subgroups of patients are at
greatest risk and are most likely to benefit.


No randomised controlled trials have specifically assessed the use of probiotics with antibiotics in care homes. Robust data are lacking on levels of antibiotic use and on frequency and severity of associated diarrhoea this setting. Our Probiotics for Antibiotic Associated Diarrhoea (PAAD) Study
(ISRCTN79548440) is in an observational phase to determine whether a trial of probiotics to prevent antibiotic associated diarrhoea is justified and feasible in care homes.

There is an absence or insufficiency of high quality evidence to support routine use of probiotics to prevent antibiotic associated diarrhoea in all people, regardless of age, comorbidity, and care setting. For example, few trials have been done in primary care, and we found none from intermediate and social care settings. We found no pragmatic, open
implementation studies.

What should we do in the light of uncertainty?

Good evidence exists to support using probiotics with S boulardii and Lactococcus rhamnosus GG (ATCC 53103) to prevent antibiotic associated diarrhoea, with emerging evidence for certain mixed strains that include L casei or L acidophilus. Probiotics also seem to be more effective at higher doses.

However, because insufficient evidence exists to

support routinely using probiotics for this purpose, and because of the low incidence and generally mild severity of antibiotic associated diarrhoea in otherwise healthy people, we recommend against routine use of probiotics in all people taking antibiotics to prevent antibiotic associated diarrhoea.

Not all probiotics evaluated as part of clinical trials are commercially available in the United Kingdom. Nevertheless, probiotics are cheap and safe, so routine use with antibiotics is justified in frail patients
in hospital and possibly in children.
Those who have previouslyhad antibiotic associated diarrhoea should be offered probiotics when they are treated with antibiotics, regardless of setting, but probiotics should be avoided in people who are seriously immunocompromised.

As probiotics seem more effective at higher doses, doses of at least 50 billion colony forming units should be used; probiotics should be taken for the duration of antibiotic treatment and continued for a week thereafter.
Evidence about the effectiveness of many strains is absent or insufficient.
Head to head studies of probiotic strains are needed,as well as more studies to identify groups of patients at greatest risk and most likely to benefit, especially in the community and in intermediate care.