Our meta-analysis of trials that used live organisms to prevent diarrhoea associated with antibiotics shows that probiotics may be effective in preventing antibiotic associated diarrhoea. We had only a small number of trials in our meta-analysis, and it should be noted that the different antibiotics used in the trials may have altered the risk of patients getting diarrhoea and their response to the probiotics. Although probiotics have been used to prevent or treat diarrhoea of other causes—namely traveller's diarrhoea and infantile infectious diarrhoea—we did not include trials that investigated probiotics in these indications; however, most of these studies showed positive results, and some reviews have been encouraging.43
The way in which probiotics affect the gut has drawn much interest. To combat the problems of gastrointestinal infection, a probiotic must be non-pathogenic and must act against pathogens by different mechanisms from antibiotics—for example, by competition. More importantly, they should have a fairly rapid onset of action and survive the challenges of gastric acid, bile, or concurrent antibiotics. It is also desirable that they modify immune processes to destroy the invading organism. Saccharomyces boulardii and lactobacilli display these common properties.
A few live organisms have been used in many trials. S boulardii
, a non-pathogenic yeast, is one such organism. It has a growth temperature of 37°C, rapidly colonises the bowel, does not alter the normal gut flora, and is cleared from the colon after treatment is discontinued.44
Of the four yeast trials, two studies individually showed significant benefit,31,33,37
but one did not38
; differences in the dose and duration of treatment with S boulardii
and variations in the period of follow up may explain this disparity. Interestingly, S boulardii
can also destroy the receptor site for C difficile
toxin A and B by producing a protease47
; this could explain how S boulardii
was noted to reduce the frequency of toxin B positivity.40
This finding was criticised,45
but it was also supported.46
The other probiotic agent used widely in clinical trials is the Lactobacillus
species. The mechanism of action of lactobacilli may be through multiple means: Lactobacillus
GG has shown beneficial effects on intestinal immunity, it increases the numbers of cells that secrete immunoglobulin G and other immunoglobulins in the intestinal mucosa, and it stimulates the local release of interferon.48
It also facilitates antigen transport to underlying lymphoid cells, and shows increased uptake in Peyer's patches.48 Lactobacillus
GG has also been shown to produce an antimicrobial substance that inhibits the growth of Escherichia coli,
streptococci, C difficile, Bacteroides fragilis
, and Salmonella
.49 L casei shirota
also showed good survival in the gut in separate studies, and mucosal antibody titres (specific to lactobacilli) were increased in the presence of this agent.50,51
Although there was no discernible change to the numbers of clostridia or enterococci, there was an increase in the numbers of excreted bifidobacteria—a normal bowel anaerobe.50,51
It is possible that this increase in bifidobacteria interferes with the pathogenic potential of C difficile
Advantages of S boulardii
over current clinical practice include its ready availability in the form of brewer's yeast, its easy administration, and the remarkable cost effectiveness of its use compared with vancomycin when infection occurs.11
However, there is a risk of fungaemia in immunocompromised patients52
and further large trials to document safety are needed before use of this agent will be accepted widely. Some papers report the development of septicaemia in immunocompromised patients and of endocarditis in those with damaged or artificial heart valves who have been treated with lactobacilli53,54
; it would seem prudent to avoid using lactobacilli in such patients.
Probiotics are a possible solution in the prevention of antibiotic associated diarrhoea. Clostridium difficile
infection is increasingly prevalent in today's hospital setting, particularly in elderly patients, in whom 10-20% of such cases occur.55
The incidence of antibiotic associated diarrhoea depends on the antibiotic used and each individual patient's risk factors. The standard regimens to treat colitis associated with Clostridium difficile
are metronidazole and vancomycin; although these drugs are successful in 80% of cases, about 20% of patients suffer from recurrence.56
In light of the need to control costs in these days of managed health care, we must re-examine the benefits of using live organisms. Whether the use of probiotics can actually reduce the length of hospital stay by reducing the incidence of infection with C difficile
and the need to use antibiotics such as metronidazole and vancomycin are issues that need to be addressed in a clinical trial.
Our meta-analysis of nine trials shows that biotherapeutic agents may be useful in preventing antibiotic associated diarrhoea, but it provides little support for a role of probiotics in the treatment of such diarrhoea.
The increasing availability, lower costs, and relative lack of side effects of probiotics contrast with the problems associated with current antibiotic regimens. Commercially available strains are being marketed in capsules and yoghurt based drinks, but their potential benefit needs further investigation. It would be wrong to credit the proved benefits of one strain to an untested but closely related strain.57
Data from trials have provided us with clear evidence on the efficacy of some strains in the gut, but we still need to see confirmation of their clinical benefit.