title: A high-dose preparation of lactobacilli and bifidobacteria in the prevention of antibiotic-associated and Clostridium difficile diarrhoea in older people admitted to hospital: a multicentre, randomised, double-blind, placebo-controlled, parallel arm trial (PLACIDE).
abstract: BACKGROUND
  Antibiotic-associated diarrhoea (AAD) occurs most commonly in older people admitted to hospital and within 12 weeks of exposure to broad-spectrum antibiotics. Although usually a mild and self-limiting illness, the 15-39% of cases caused by Clostridium difficile infection [C. difficile diarrhoea (CDD)] may result in severe diarrhoea and death. Previous research has shown that probiotics, live microbial organisms that, when administered in adequate numbers, are beneficial to health, may be effective in preventing AAD and CDD.
  
  
  OBJECTIVE
  To determine the clinical effectiveness and cost-effectiveness of a high-dose, multistrain probiotic in the prevention of AAD and CDD in older people admitted to hospital.
  
  
  METHODS
  A multicentre, randomised, double-blind, placebo-controlled, parallel-arm trial.
  
  
  METHODS
  Medical, surgical and elderly care inpatient wards in five NHS hospitals in the UK.
  
  
  METHODS
  Eligible patients were aged ≥ 65 years, were exposed to one or more oral or parenteral antibiotics and were without pre-existing diarrhoeal disorders, recent CDD or at risk of probiotic adverse effects. Out of 17,420 patients screened, 2981 (17.1%) were recruited. Participants were allocated sequentially according to a computer-generated random allocation sequence; 1493 (50.1%) were allocated to the probiotic and 1488 (49.9%) to the placebo arm.
  
  
  METHODS
  Vegetarian capsules containing two strains of lactobacilli and two strains of bifidobacteria (a total of 6 × 10(10) organisms per day) were taken daily for 21 days. The placebo was inert maltodextrin powder in identical capsules.
  
  
  METHODS
  The occurrence of AAD within 8 weeks and CDD within 12 weeks of recruitment was determined by participant follow-up and checking hospital laboratory records by research nurses who were blind to arm allocation.
  
  
  RESULTS
  Analysis based on the treatment allocated included 2941 (98.7%) participants. Potential risk factors for AAD at baseline were similar in the two study arms. Frequency of AAD (including CDD) was similar in the probiotic (159/1470, 10.8%) and placebo arms [153/1471, 10.4%; relative risk (RR) 1.04; 95% confidence interval (CI) 0.84 to 1.28; p = 0.71]. CDD was an uncommon cause of AAD and occurred in 12/1470 (0.8%) participants in the probiotic and 17/1471 (1.2%) in the placebo arm (RR 0.71; 95% CI 0.34 to 1.47; p = 0.35). Duration and severity of diarrhoea, common gastrointestinal symptoms, serious adverse events and quality of life measures were also similar in the two arms. Total health-care costs per patient did not differ significantly between the probiotic (£8020; 95% CI £7620 to £8420) and placebo (£8010; 95% CI £7600 to £8420) arms.
  
  
  CONCLUSIONS
  We found no evidence that probiotic administration was effective in preventing AAD. Although there was a trend towards reduced CDD in the probiotic arm, on balance, the administration of this probiotic seems unlikely to benefit older patients exposed to antibiotics. A better understanding of the pathogenesis of AAD and CDD and the strain-specific effects of probiotics is needed before further clinical trials of specific microbial preparations are undertaken. Evaluation of the effectiveness of other probiotics will be difficult where other measures, such as antibiotic stewardship, have reduced CDD rates.
  
  
  BACKGROUND
  This trial is registered as ISRCTN70017204.
  
  
  BACKGROUND
  This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 17, No. 57. See the NIHR Journals Library website for further project information.
authors.affiliation: College of Medicine, Swansea University, Swansea, UK.
authors.forename: S J
authors.initials: SJ
authors.lastname: Allen
authors.forename: K
authors.initials: K
authors.lastname: Wareham
authors.forename: D
authors.initials: D
authors.lastname: Wang
authors.forename: C
authors.initials: C
authors.lastname: Bradley
authors.forename: B
authors.initials: B
authors.lastname: Sewell
authors.forename: H
authors.initials: H
authors.lastname: Hutchings
authors.forename: W
authors.initials: W
authors.lastname: Harris
authors.forename: A
authors.initials: A
authors.lastname: Dhar
authors.forename: H
authors.initials: H
authors.lastname: Brown
authors.forename: A
authors.initials: A
authors.lastname: Foden
authors.forename: M B
authors.initials: MB
authors.lastname: Gravenor
authors.forename: D
authors.initials: D
authors.lastname: Mack
authors.forename: C J
authors.initials: CJ
authors.lastname: Phillips
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000900:Anti-Bacterial Agents / Q000009:adverse effects* / Q000145:classification / Q000191:economics; D001644:Bifidobacterium / Q000502:physiology*; D016360:Clostridioides difficile; D015897:Comorbidity; D003362:Cost-Benefit Analysis; D003967:Diarrhea / Q000139:chemically induced / Q000191:economics / Q000382:microbiology / Q000517:prevention & control*; D004311:Double-Blind Method; D004761:Enterocolitis, Pseudomembranous / Q000139:chemically induced / Q000191:economics / Q000517:prevention & control*; D005260:Female; D006801:Humans; D007297:Inpatients / Q000706:statistics & numerical data; D007778:Lactobacillus / Q000502:physiology*; D008297:Male; D017063:Outcome Assessment, Health Care; D019936:Probiotics / Q000008:administration & dosage* / Q000009:adverse effects / Q000191:economics; D011446:Prospective Studies; D019057:Quality-Adjusted Life Years; D006113:United Kingdom
chemical_list: D000900:Anti-Bacterial Agents