Title: Probiotic to Reduce Infections iN CarE home reSidentS (PRINCESS)
Funder: Department of Health and Social Care

Abstract: AIMS: To evaluate the effect of a dose of daily oral probiotics on cumulative antibiotic administration days (CAAD) for all-cause infections. Evaluate daily oral probiotic on gastrointestinal colonisation with antimicrobial resistant (AMR) bacteria and on ex-vivo immune response to pathogenic challenge. HYPOTHESIS (Primary): Daily oral probiotic reduces CAAD for infection vs placebo in Care Home Resident (CHR). HYPOTHESIS (Mechanisms): Daily oral probiotic reduces gastrointestinal colonisation with AMR bacteria, enhances influenza vaccine response and modulates ex-vivo cytokine response to Toll Like Receptor (TLR) agonists vs placebo in CHR. DESIGN: Double blind, individually randomised, 2 arm efficacy, placebo controlled trial. DURATION: 12 months. POPULATION: CHR from Cardiff and Oxford. Inclusion: Currently living in a care home setting (residential, nursing or mixed); Participant is willing and able to give informed consent for participation in the trial OR if the participant lacks capacity, a consultee is willing to complete a consultee declaration form; Aged 65 years or older. Exclusion: The CHR may not enter the trial if ANY of the following apply: Is known to be immunocompromised (requiring immunosuppressants, long term high dose oral, intramuscular or intravenous steroids); Is currently taking regular probiotics and is not willing to adapt to trial protocol; Is a temporary care home resident (i.e. less than 1 month of planned transitional/respite residential care); Death is thought to be imminent; Lactose intolerant. INTERVENTIONS: Probiotics containing Lactobacillus rhamnosus, LGG and Bifidobacterium animalis subsp. lactis, BB-12 vs. placebo. OUTCOMES: Primary: CAAD for all-cause infections over 12 months. Secondary: CAAD for five sub-categories of CID (RTI, UTI, skin, GI unexplained fever); number, site, duration (mean and cumulative) of infection; EQ-5D (health utility), ICECAP-O (wellbeing); GP visits, A&E visits and hospitalisations; death; Antimicrobial resistance (AMR) (Culture and antibiotic sensitivity of Gram-negative Enterobacteriaceae and VRE from stool sample and presence of probiotic species in stool to explore adherence and contamination); Antibiotic consumption. Mechanistic measures: Blood – FBC; Vitamin D; influenza vaccine response - Haemagglutination inhibition assay; immunology - TLR ligand stimulated (TLR2 and TLR4) cytokines/chemokines, receptor expression (circulating immune cells TLR2 and TLR4) Saliva – presence of oral Candida species Stool – presence of probiotic bacteria Lactobacillus rhamnosus, LGG and Bifidobacterium animalis subsp. lactis, BB-12, plus presence of AMR bacteria and C. difficile Tertiary outcome: To determine if level of vitamin D correlate with colonisation of AMR bacteria in faecal isolates ASSESSMENTS: Blood, saliva, stool samples collected at baseline, 3 month (no blood) and 12 month. Study nurses will attend regularly to record infections and antibiotic prescribing (MAR sheets). SAMPLE SIZE: Our previous study predicts 17.4 days on antibiotics/CHR/year. We will recruit 330 CHR (165/arm; 90% power, 5% significance) to detect a 10% relative reduction in CAPD between arms (absolute reduction to 15.6 days) allowing 30% loss to follow-up. RECRUITMENT: We will approach 660 residents from 15 homes (assuming 50% CHR recruitment from homes with >50 eligible CHR). ANALYSIS: The primary analysis will be by intention-to-treat, and will consist of a between-group comparison of the mean cumulative antibiotic administration days (CAAD) using Poisson regression. As the randomisation will be stratified by care home, the regression model will control for the care home a participant was recruited from. Negative binomial regression will be used in the presence of over-dispersed count data. For secondary outcomes, depending on the type of data, a mixture of Poisson, linear, logistic and Cox models will be used to appropriately compare trial arms with respect to rates, means, proportions and time to events. TIMELINE: The study will begin in 09/2015 and last 39 months; After an 8 month set-up phase, a 3/12 feasibility phase will confirm viable recruitment and retention rates prior to further funding, followed by the substantive trial commencing 09/2016.

Lay abstract: Care home residents (CHR) are prescribed far more antibiotics than the general population because of the high burden of infections they bear, caused by weakened immunity, close-proximity living and multi morbidity (1). In our previous research in care homes, we found CHR took antibiotics for an average of 17.4 days per year (2). High antibiotic use increases the risk of reservoirs of antimicrobial resistance (AMR) in care homes that can spread within care homes and to hospitals and the community (1). This will intensify as the population ages. Infections in CHR cost the NHS >£54 M/year in hospitalisation alone (3) and infections are the commonest reason for CHR to be hospitalised. AMR infections are generally more serious and costly, particularly in older people. Reduction in antibiotic use and AMR could improve quality of life, save money, and help preserve the usefulness of existing antibiotics. Other than vaccination and hygiene methods, there are few interventions proven to prevent infection in CHR. Probiotics are live bacteria that may confer health benefit by improving immune function and reducing carriage of potentially harmful bacteria. Probiotics are safe and cheap and are available as supplements. Probiotics may mediate positive changes in gut bacteria and therefore decrease immunity decline and infection. Reviews of studies found that probiotics reduced antibiotic use and risk of respiratory tract infections in adults (4) and reduced antibiotic associated diarrhoea (AAD) (5). Probiotics also reduced carriage of AMR bacteria in a review of critically ill patients, and have reduced duration of CID (6) and enhanced immune response, including to flu vaccination (7). However, research in CHR is currently lacking. The PRINCESS trial will trial a probiotic preparation containing Lactobacillus rhamnosus, LGG and Bifidobacterium animalis subsp. lactis, BB-12 to determine whether this product prevents infections over a 12 month period. Other probiotic species have not shown benefit in respiratory tract infection (RTI) or immune function in older people (8). We will assess total days on antibiotics for infections (including RTI, urinary tract infection (UTI), skin and gastro-intestinal infection (GI)), immune parameters (including influenza vaccine response), and changes in AMR in bowel flora. We will explore mechanisms, and test if probiotics reduce cumulative antibiotic prescribing days by 10% or more. To detect this we will recruit 330 CHR from care homes in Wales and England into an individually randomised trial of probiotic vs placebo, and follow them up for 12 months. We will seek informed consent from CHR with capacity, and consult with next of kin/representative for those lacking capacity.

Research activity codes: 6.1 PHARMACEUTICALS
Health categories: INFECTION