Probiotics Fail to Impact Antibiotic Associated Diarrhea in Lancet Study

The study “Lactobacilli and bifidobacteria in the prevention of antibiotic-associated diarrhoea and Clostridium difficile diarrhoea in older inpatients (PLACIDE): a randomised, double-blind, placebo-controlled, multicentre trial” was published online in the Lancet on August 8, 2013. The study authors (Allen et al. from the College of Medicine, Swansea University in the UK) look to have done this study right:

  • Used a high dose (6 × 10¹⁰ total dose) of probiotic with defined strains deposited into an international culture collection [Lactobacillus acidophilus CUL60 (National Collection of Industrial, Food and Marine Bacteria [NCIMB] 30157), L. acidophilus CUL21 (NCIMB 30156), Bifidobacterium bifidum CUL20 (NCIMB 30153) and Bifidobacterium lactis CUL34 (NCIMB 30172)] (provided by Cultech UK).
  • Targeted a large number of subjects (2,981 subjects randomized)
  • Registered the trial
  • Followed CONSORT guidelines for reporting the trial, including:
    • Clear statement of primary outcomes (occurrence of AAD within 8 weeks and CDD within 12 weeks of recruitment)
    • Clear definition of study population (inpatients aged 65 years or older and exposed to one or more oral or intravenous antibiotics in the preceding 7 days, or about to start antibiotic treatment)
    • Clear reporting of adverse incidents
    • Clear “Figure 1:  Trial profile” delineating the fate of every person contacted for the study
    • Clear definition of diarrhea [3 or more loose stools (consistency 5–7 on the Bristol Stool Form Scale) in a 24 h period or as stools described as looser than normal in participants unable to use the scale]

But the results did not show any impact on incidence of antibiotic associated diarrhea (AAD) or C. difficile infection (CD).

How do we reconcile the lack of probiotic impact observed in this study with meta-analyses – summarizing all available data – that conclude that probiotics are effective (Hempel et al. 2012; Goldenberg et al. 2013; Johnston et al. 2012)? Some thoughts:

  • The low incidence of AAD and CD may have prevented seeing a positive effect (about 10% occurrence of AAD compared with a prediction of 20%; 1% occurrence of CD compared with a prediction of 4%).
  • Probiotic was administered for 21 days, but diarrhea incidence was tracked for 8 weeks post recruitment. Post-hoc analysis identified that 73% of episodes of AAD (195/266) and 76% of CDD (22/29) occurred within 4 weeks of recruitment. This means that at least 27% of episodes of AAD and 24% of episodes of CDD occurred after probiotic administration was stopped. Would more extended administration of probiotic have prevented any of these additional cases? Personal communication with the author indicates he is going to evaluate incidence during the antibiotic-only period as an exploratory outcome.
  • This study allowed probiotics to be started 7 days after antibiotics. Effectiveness of probiotics was shown to increase when the probiotic was given close to the first antibiotic dose. A late start to probiotic treatment may have rendered the probiotic ineffective. (Bullet point added March 30, 2017)
  • The study reported testing active capsules at conclusion of the study, confirming that they contained the expected level of live probiotic (at least 1·62×10¹⁰), and placebo capsules were sterile. But if a recovery period was used as part of the enumeration method, injured cells could have made up a significant portion of the probiotic. (The study did span 3 years and the age of the product was not disclosed in the study.) These injured cells might not have been hardy enough to survive intestinal transit.
  • Perhaps the strain blend used for this study was not correct. A preliminary human study was conducted with this blend (Plummer et al. 2005), but no pilot study on AAD endpoint was conducted.

Null studies are a fact of life when doing human studies. Kudos to the authors and to Lancet for publishing these results. Such studies must be considered within the context of the full body of data. This study does not negate other positive studies. In fact, an analysis done as part of a commentary (Daneman, 2013) indicated that adding the Allen study to a recreated forest plot from a previous meta-analysis “barely shifts the risk reduction estimate.” But the Allen et al. study is a reminder that not all populations will necessarily benefit from all probiotics, and this strain blend appears to have no impact on AAD in this setting. Not all antibiotics work on all infections and it isn’t surprising that not all probiotics will work for AAD.

References:

Allen SJ, Wareham K, Wang D, Bradley C, Hutchings H, Harris W, Dhar A, Brown H, Foden A, Gravenor MB, Mack D.  Lactobacilli and bifidobacteria in the prevention of antibiotic-associated diarrhoea and Clostridium difficile diarrhoea in older inpatients (PLACIDE): a randomised, double-blind, placebo-controlled, multicentre trial. Lancet. 2013 Aug 7. doi:pii: S0140-6736(13)61218-0. 10.1016/S0140-6736(13)61218-0. [Epub ahead of print]

Daneman N. A probiotic trial: tipping the balance of evidence? Lancet. 2013 Aug 7. doi:pii: S0140-6736(13)61571-8. 10.1016/S0140-6736(13)61571-8. [Epub ahead of print]

Goldenberg JZ, Ma SS, Saxton JD, Martzen MR, Vandvik PO, Thorlund K, Guyatt GH, Johnston BC. Probiotics for the prevention of Clostridium difficile-associated diarrhea in adults and children. Cochrane Database Syst Rev. 2013 May 31;5:CD006095. doi: 10.1002/14651858.CD006095.pub3.

Hempel S, Newberry SJ, Maher AR, Wang Z, Miles JN, Shanman R, Johnsen B, Shekelle PG. Probiotics for the prevention and treatment of antibiotic-associated diarrhea: a systematic review and meta-analysis. JAMA. 2012 May 9;307(18):1959-69. doi: 10.1001/jama.2012.3507.

Johnston BC, Ma SS, Goldenberg JZ, Thorlund K, Vandvik PO, Loeb M, Guyatt GH. Probiotics for the prevention of Clostridium difficile-associated diarrhea: a systematic review and meta-analysis. Ann Intern Med. 2012 Dec 18;157(12):878-88.

Plummer SF, Garaiova I, Sarvotham T, Cottrell SL, Le Scouiller S, Weaver MA, Tang J, Dee P, Hunter J. Effects of probiotics on the composition of the intestinal microbiota following antibiotic therapy. Int J Antimicrob Agents. 2005 Jul;26(1):69-74).