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.
BACKGROUND
Antibiotic-associated diarrhoea (AAD) occurs most frequently in older (≥65 years) inpatients exposed to broad-spectrum antibiotics. When caused by Clostridium difficile, AAD can result in life-threatening illness. Although underlying disease mechanisms are not well understood, microbial preparations have been assessed in the prevention of AAD. However, studies have been mostly small single-centre trials with varying quality, providing insufficient data to reliably assess effectiveness. We aimed to do a pragmatic efficacy trial in older inpatients who would be representative of those admitted to National Health Service (NHS) and similar secondary care institutions and to recruit a sufficient number of patients to generate a definitive result.


METHODS
We did a multicentre, randomised, double-blind, placebo-controlled, pragmatic, efficacy trial of inpatients aged 65 years and older and exposed to one or more oral or parenteral antibiotics. A computer-generated randomisation scheme was used to allocate participants (in a 1:1 ratio) to receive either a multistrain preparation of lactobacilli and bifidobacteria, with a total of 6 × 10(10) organisms, one per day for 21 days, or an identical placebo. Patients, study staff, and specimen and data analysts were masked to assignment. The primary outcomes were occurrence of AAD within 8 weeks and C difficile diarrhoea (CDD) within 12 weeks of recruitment. Analysis was by modified intention-to-treat. This trial is registered, number ISRCTN70017204.


RESULTS
Of 17,420 patients screened, 1493 were randomly assigned to the microbial preparation group and 1488 to the placebo group. 1470 and 1471, respectively, were included in the analyses of the primary endpoints. AAD (including CDD) occurred in 159 (10·8%) participants in the microbial preparation group and 153 (10·4%) participants in the placebo group (relative risk [RR] 1·04; 95% CI 0·84-1·28; p=0·71). CDD was an uncommon cause of AAD and occurred in 12 (0·8%) participants in the microbial preparation group and 17 (1·2%) participants in the placebo group (RR 0·71; 95% CI 0·34-1·47; p=0·35). 578 (19·7%) participants had one or more serious adverse event; the frequency of serious adverse events was much the same in the two study groups and none was attributed to participation in the trial.


CONCLUSIONS
We identified no evidence that a multistrain preparation of lactobacilli and bifidobacteria was effective in prevention of AAD or CDD. An improved understanding of the pathophysiology of AAD is needed to guide future studies.


BACKGROUND
Health Technology Assessment programme; National Institute for Health Research, UK.
College of Medicine, Swansea University, Swansea, UK. s.j.allen@swansea.ac.uk
Stephen J
SJ
Allen
Kathie
K
Wareham
Duolao
D
Wang
Caroline
C
Bradley
Hayley
H
Hutchings
Wyn
W
Harris
Anjan
A
Dhar
Helga
H
Brown
Alwyn
A
Foden
Michael B
MB
Gravenor
Dietrich
D
Mack
D000368:Aged; D000369:Aged, 80 and over; D000900:Anti-Bacterial Agents / Q000009:adverse effects*; D001644:Bifidobacterium; D016360:Clostridioides difficile; D003967:Diarrhea / Q000517:prevention & control*; D004311:Double-Blind Method; D004761:Enterocolitis, Pseudomembranous / Q000517:prevention & control*; D005260:Female; D006801:Humans; D007778:Lactobacillus; D007902:Length of Stay; D008297:Male; D055118:Medication Adherence; D019936:Probiotics / Q000008:administration & dosage*
D000900:Anti-Bacterial Agents