How Good is Your Probiotic for Antibiotic-Associated Diarrhea?

The enthusiasm for probiotics is generally greater than expected based on the data available to support their use for many indications.  This has been discussed several times on this blog (see below).  The reasons why probiotics are sometimes not effective can be related to being poorly regulated/lack rigorous production standards; even in conditions in which there is some effectiveness (eg. antibiotic-associated diarrhea [AAD]), the number of persons needed to treat for one person to benefit is fairly high. Furthermore, as a recent study (A Olek et al. J Pediatr 2017; 186: 82-6) shows, even in conditions like AAD in which probiotics have proven efficacy, the effects may be strain-specific and/or dose-related.

Olek et al showed that Lactobacillus planatarum DSM9843 (LP299V) was NOT beneficial compared to placebo in reducing the incidence of loose/watery stools or mean number of stools among 438 children receiving outpatient antibiotic therapy.

Specifics: This was a prospective, double-blind, randomized, placebo-controlled parallel-group study.  The treatment group received LP299V during antibiotic therapy and for 1 week afterwards.  In addition to monitoring the number of stools, the authors determined the frequency of AAD which they defined according to WHO guidelines (>3 loose/watery stools/24 hours after initiation of antibiotics).  In this study, AAD was confined to study duration rather than over 2 months.

  • Overall, 44.5% of children developed loose/watery stools among placebo group and 39% among probiotic group
  • 4.1% developed AAD among placebo group and 2.8% among LP299V
  • LP299V showed no significant beneficial effects in reducing AAD or loose/watery stools

The authors note that LP299V has been effective in studies involving adult hospitalized patients.  They question whether healthy children, therefore, may be less likely to benefit from probiotics and whether a higher dose could have been more effective.

My take: “Data from clinical studies on probiotics are conflicting” for many conditions, including antibiotic-associated diarrhea.

Lovers Leap, near Ashville (Appalachian Trail)

 

 

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Pushback on Probiotics

I had not paid much attention to a study last year (Lancet 2013; 382: 1249-57) titled, “Lactobacilli and bifidobacteria in the prevention of antibiotic-associated diarrhea and Clostridium difficile diarrhea in older patients (PLACIDE): a randomized, double-blind, placebo-controlled, multcentre trial.”

A useful review (Gastroenterol 2014; 146: 1822-23) of this study provides some useful insight into the use of probiotics.  The authors state that “in the last decade, medical and non medical professionals have endorsed the use of probiotics as a means of preventing AAD through a dogma that adding ‘good bacteria’ will prevent dysbiosis caused by ‘bad bacteria.'”  They note that several meta-analysis have supported a positive benefit for probiotics in this setting; yet, the “results merit cautious interpretation owing to a high risk of bias and notable heterogeneity of included studies.”

The PLACIDE study overcomes many of the previous limitations in this well-designed study design which enrolled a large cohort of 2,981 patients (≥65 years old).  The probiotics used in this trial were lactobacillus acidophilus along with bidodbacterium bifidum and lactis.  Ultimately, “patients receiving probiotics were as likely to develop AAD as patients in the placebo arm (relative risk 1.04).”  The rate of C difficile infection was ~1% and lower than expected.

While this study did not demonstrate any benefit from probiotics, there was no significant harm identified from probiotics; though, patients receiving probiotics were more likely to develop flatus and bloating in comparison to placebo.

Take-home message: “This study now also points away from probiotics being of benefit…probiotics use will not diminish as a result of this trial.  Parties will, argue rightly or wrongly, that the wrong strains were chosen…However, what the PLACIDE trial does point is that there is no clear evidence for use of probiotics in this setting until high-quality RCTs are conducted.”

Another probiotic reference:

JAMA Pediatr 2014; 168: 228-33.  This randomized double-blind, controlled trial conducted in 9 neonatal units in Italy compared L reuteri DSM 17938 to placebo for prevention of colic.  Mean duration of daily crying was 38 min in probiotic group compared with 71 min in placebo-treated patients, though these measures were with a nonvalidated diary.  Conclusions of authors: “prophylactic use of L reuteri DSM 17938 during the first 3 months of life reduced the magnitude of crying and functional gastrointestinal disorders.”

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