Efficacy and Safety of Lactobacillus plantarum DSM 9843 (LP299V) in the Prevention of Antibiotic-Associated Gastrointestinal Symptoms in Children - Randomized, Double-Blind, Placebo-Controlled Study

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Olek A, et al. "Efficacy and Safety of Lactobacillus plantarum DSM 9843 (LP299V) in the Prevention of Antibiotic-Associated Gastrointestinal Symptoms in Children-Randomized, Double-Blind, Placebo-Controlled Study". The Journal of Pediatrics. 2017. 186:82-86.
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Clinical Question

In pediatric patients newly prescribed antibiotic therapy, does the probiotic strain Lactobacillus plantarum (LP299V) compared to placebo, decrease the rate of antibiotic-associated gastrointestinal symptoms while remaining safe?

Bottom Line

It appears that concurrent probiotic therapy with Lactobacillus plantarum (LP299V) during antibiotic therapy in children is ineffective in preventing loose/watery stools, mean number of loose/watery stools, and abdominal symptoms compared to placebo. However, it is safe and well-tolerated.

Major Points

Treatment with antibiotics have been shown to cause gastrointestinal (GI) side effects, notably diarrhea, due to their negative effects on the natural gut microbiota. Therefore, the health benefits of probiotics are necessary to explore because they have been shown to reduce these GI side effects caused by antibiotics.(1) Strains that are used for this purpose include Lactobacillus, Bifidobacterium, and Saccharomyces.(2) A Cochrane review of 23 studies testing the probiotics strains Lactobacilli spp., Bifidobacterium spp., Streptococcus spp., and Saccharomyces boulardii for Antibiotic-Associated Diarrhea (AAD) prevention in children found that Lactobacillus rhamnosus or Saccharomyces boulardii at 5-40 billion colony forming units per day may be an effective approach. The incidence of AAD in the treatment group was 8% versus 19% in the control group.(3)

In a study conducted by Lonnermark, et al in 2010,adult patients treated at an infectious diseases clinic who took Lactobacillus plantarum (LP299V) during antibiotic therapy were significantly less likely to develop all cases of diarrhea as compared to those patients not taking the probiotic (P = 0.012). However, there was no significant difference when it came to the specific development of AAD.(4)

Overall, there has been conflicting evidence on the use of probiotics for the prevention of GI side effects of antibiotics. It is necessary to see what place this specific strain of probiotic has in preventing antibiotic-associated diarrhea and other adverse gastrointestinal effects associated with antibiotics in children.(5)

Guidelines

The American College of Gastroenterology and ESPGHAN Working Group for Probiotics/Prebiotics recommend S. boulardii or L. rhamnosus GG in adults or children who are receiving antibiotic therapy to prevent antibiotic-associated diarrhea.(6)(8)(9) L. casei DN-114 001 may be effective in hospitalized adult patients for preventing antibiotic-associated diarrhea and C. difficile diarrhea.6 There is low quality evidence supporting S. boulardii for preventing C.difficile diarrhea.(8) Overall, there is insufficient evidence that probiotics prevent C. difficile infection.(7) There is also insufficient evidence behind the use of the following probiotics for antibiotic-associated diarrhea prevention: Bacillus clausii (single strain), bacillus lactis/streptococcus thermophilus, L acidophilus/L bulgaricus, L acidophilus/Bifidobacterium infantis, L acidophilus/Bifidobacterium breve, L rhamnosus GG/Bb-12/L acidophilus La-5, B longum PL03/L rhamnosus KL53A/L plantarum PL02, L rhamnosus E/N, Oxy, Pen, L acidophilus/L rhamnosus/L bulgaricus/L casei/Str thermophilus/B infantis/B breve.(8)

Design

  • Prospective, randomized, double-blind, placebo-controlled, multicenter, and parallel-group trial
  • N=438
    • Probiotics (n=218)
    • Placebo (n=220)
  • Setting: Outpatient primary care.
  • Enrollment: Dec. 2013- Apr. 2014
  • Final Study Visit varied, 15-28 days
  • Analysis: available data and per-protocol
  • Primary outcomes:
    • Incidence of loose/watery stools (type 6 or 7 according to Bristol Stool Scale) during the total length of the study.


Population

Inclusion Criteria

  • Outpatients Age 1-11
  • Starting antibiotic therapy


Exclusion Criteria

  • Chronic intestinal disease
  • Current immunodeficiency or immunosuppressive treatment
  • Chronic or acute diarrheal disease
  • Usage of laxatives the week before inclusion into the study
  • Known hypersensitivity to any of the ingredients in the probiotic product or the placebo
  • Regular intake of any probiotics for the last 2 weeks before inclusion into the study


Baseline Characteristics

From the LP299V group. Groups were similar.

  • Demographics: Age 5.1 + 2.6 years, male 48.1%, BMI 16.
  • Prestudy characteristics: abdominal pain 19%, abdominal distention 5%, vomiting 16%, flatulence 11%.
  • Diarrhea during previous antibiotic therapy: 35 total children (LP299V 17; placebo 18)
  • Reason for therapy: RTI 53%, throat infection 30%, ear infection 14%, and UTI 3%.
  • Antibiotics: Penicillin 44%, cephalosporin 24%, sulfamethoxazole and trimethoprim 8%, and macrolides 25%
  • Duration (days): 22.1 + 3.6
  • Duration of Phases (days):
    • Antibiotic+LP299V/placebo: 8.1 ± 2.0
    • LP299V/placebo: 6.7 ± 1.7
    • Treatment free follow-up: 7.2 ± 2.4


Interventions

  • Participants were randomized to a group:
    • Probiotic: Freeze-dried Lactobacillus plantarum (LP299V) at 1 × 10^10 colony forming units per capsule
    • Placebo: Potato Starch
  • One tablet was taken once daily 2-3 hours after antibiotic dose during duration of therapy and for one week after.


Outcomes

Comparisons are LP299V vs. placebo.

Primary Outcomes

  • Incidence of loose/watery stools (type 6 or 7 according to Bristol Stool Scale) during the total length of the study.
    • 39% vs. 44.5% (P = 0.26) NS
  • Not related to type of antibiotic prescribed.

Secondary Outcomes

  • Mean number of loose/watery stools
    • 3.9 ± 3.5 vs 4.7 ± 6.3 (P = 0.9) NS
  • Not related to type of antibiotic prescribed.


  • AAD
    • > 3 loose/watery stools/24 hours after initiation of antibiotic treatment (Defined by WHO guidelines)
    • 2.8% vs. 4.1% (P = 0.4) NS
  • Abdominal Symptoms'
    • Similar in both groups
    • Looking at: Pain, distention, vomiting, flatulence


Adverse Events

  • Any Adverse events
    • 155 adverse events in 99 children reported by parents
    • 17.9% (LP299V) vs 27.3% (Placebo) (P=0.02)
    • Most frequent: pyrexia, headache, rash, anorexia, cough viral infection, and ear pain.


Criticisms

  • Homogenous population
    • Applicability outside a scandinavian country, based off of differing diets and lifestyle habits.
  • Suspect of recall bias due to subjects’ parents recording bowel habits and adverse events.
  • Short treatment duration
    • Observation period defined by WHO (2 hours-2 months after initiation of antibiotic treatment). (5)(10)
  • Would appreciate a post-hoc analysis to describe;
    • Percentage of patients with a specific treatment duration, and effect of that distribution on outcomes.
  • Probable conflicts of interest
    • Employees of funding body, though research did not show it to be any different than placebo, once should still be aware.


Funding

Probi AB Sölvegatan.

Further Reading

1. Hill C, Guarner F, Reid G, et al. The International Scientific Association for Probiotics and Prebiotics consensus statement on the scope and appropriate use of the term probiotic. Nat Rev Gastroenterol Hepatol 2014;11:506-14.

2. Bardowski J, Fordymacka A, Szajewska H, et al. Microbiological and genetic analysis of probiotic products licensed for medicinal purposes. Med Sci Monit 2004;10:346-50.

3. Goldenberg JZ, Lytvyn L, Steurich J, et al. Probiotics for the prevention of pediatric antibiotic-associated diarrhea. Cochrane Database of Systematic Reviews 2015, Issue 12. Art. No.: CD004827. DOI: 10.1002/14651858.CD004827.pub4

4. Lönnermark E, Friman V, Lappas G, et al. Intake of Lactobacillus plantarum reduces certain gastrointestinal symptoms during treatment with antibiotics. J Clin Gastroenterol 2010;44:106-12.

5. Ahrén I, Kierkuś J, Olek A, et al. Efficacy and safety of lactobacillus plantarum DSM 9843 (LP299V) in the prevention of antibiotic-associated gastrointestinal symptoms in children—randomized, double-blind, placebo-controlled study. J Pediatr. 2017;186:82-86

6. Farthing M, Lindberg G, Salam M, et al. Acute Diarrhea in Adults and Children. Journal of Clinical Gastroenterology [Internet]. 2013 [cited 24 Aug 2017];47(1):12-20. Available from: http://www.worldgastroenterology.org/UserFiles/file/guidelines/acute-diarrhea-english-2012.pdf

7. Brandt L, Binion D, Surawicz C, et al. Guidelines for diagnosis, treatment, and prevention of clostridium difficile infections. The American Journal of Gastroenterology [Internet]. 2013 [cited 24 Aug 2017];108(4):478-498. Available from: https://gi.org/guideline/diagnosis-and-management-of-c-difficile-associated-diarrhea-and-colitis/

8. Berni Canani R, Guarino A, Szajewska H, et al. Probiotics for the prevention of antibiotic-associated diarrhea in children [Internet].; 2015 [cited 25 Aug 2017]. Available from: http://www.espghan.org/fileadmin/user_upload/guidelines_pdf/Hep_Nutr/Probiotics_for_the_Prevention_of.31__1_.pdf

9. Connor B, DuPont H, Riddle M, et al. . ACG clinical guideline: diagnosis, treatment, and Prevention of Acute Diarrheal Infections in Adults. The American Journal of Gastroenterology [Internet]. 2016 [cited 24 Aug 2017];111(5):602-622. Available from: http://acgblog.org/wp-content/uploads/2016/04/ACG-Guidelines-Acute-Diarrheal-Infections-in-Adults-AJG-2016.pdf

10. Barbut F, Maynerd J. Managing antibiotic associated diarrhoea. BMJ [Internet]. 2002 [cited 24 Aug 2017];324(7350):1345-1346. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1123310/