PLACIDE

Published

Allen SJ, et al. "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". The Lancet. 2013. 382(9900):1249-1257.
PubMed • Full text • PDF

Clinical Question

In hospitalized, elderly patients treated with antibiotics, does a microbial preparation containing lactobacilli and bifidobacteria prevent Clostridium difficile- or antibiotic-associated diarrhea?

Bottom Line

Probiotics containing a combination of Lactobacillus acidophilus, Bifidobacterium bifidum, and Bifidobacterium lactis do not appear to prevent Clostridium difficile- or antibiotic-associated diarrhea in hospitalized elderly patients treated with antibiotics.

Major Points

The frequency of antibiotic-associated diarrhea (AAD) depends on the type of antibiotic, ranging from 2-20% with cephalosporins, fluoroquinolones, macrolides, or tetracycline, 5-10% with ampicillin, and 10-25% with amoxicillin-clavulanate. Clostridium difficile-associated diarrhea (CDAD), a potentially severe infection, accounts for 15-39% of AAD. AAD is thought to occur as a result of disruption of gut microbiota, subsequent changes in metabolism of carbohydrates, short-chain fatty acids, and bile acids, and impaired resistance to pathogens. Probiotics are speculated to prevent pathogenic bacterial infection through introduction of non-pathogenic bacteria. This may also assist in restoring the normal gut microbiome and prevent changes in metabolism and adherence of pathogens.

A 2012 meta-analysis found a small but statistically significant reduction in AAD with probiotics. A 2013 Cochrane review found that moderate quality evidence supported the use of probiotics for the prevention of CDAD. The trials included in the meta-analyses were small and of variable quality. No large placebo-controlled trial had been performed.

In the PLACIDE trial, 2,941 elderly inpatients taking antibiotics or beginning antibiotic therapy were given a probiotic preparation of Lactobacillus acidophilus, Bifidobacterium bifidum, and Bifidobacterium lactis (n=1,470) or placebo (n=1,471) for 21 days. At 8 weeks, the probiotic preparation did not reduce the incidence of AAD (10.8% vs. 10.4%) or CDAD (0.8% vs. 1.2%). The significant findings of the Cochrane review remained significant likely due to the low event rate in PLACIDE.

Guidelines

As of April 2015, no guidelines have been published that reflect the results of this trial.

Design

• Multicenter, randomized, allocation concealed, double-blind, placebo-controlled trial
• N=2,941
  • Probiotics (n=1,470)
  • Placebo (n=1,471)
• Setting: 3 hospitals in South Wales and 2 hospitals in Northeast England
• Enrollment: 2008-2012
• Follow up at 4, 8, and 12 weeks
• Analysis: modified intention-to-treat
• Primary outcomes:
  • AAD within 8 weeks
  • CDAD within 12 weeks

Population

Inclusion Criteria

• Inpatients age ≥65 years
• Exposed ≥1 PO or IV antibiotics in the prior 7 days or about to start antibiotic treatment

Exclusion Criteria

• Diarrhea at baseline
• Immunocompromised state requiring isolation or barrier nursing
• Severity of illness requiring ICU or high-dependency care
• Prosthetic heart valve
• CDAD in the prior 3 months
• IBD requiring treatment in the prior 12 months
• Suspected acute pancreatitis defined by abdominal pain with amylase or lipase >3x ULN
• Known disease or abnormality of mesenteric vessels or celiac axis
• J-tube or receiving jejunal feeds
• Any adverse reaction to probiotics
• Unwilling to discontinue current probiotics
• NPO status
• Severely ill and not expected to survive the study duration

Baseline Characteristics

From the probiotic group. Groups were similar.

• Demographics: Age 77 years, male 53%, white 99.9%
• Admission details: During winter (October-March) 57%, from home 92%, from residential care facility 4, from other hospital 3%, other 2%, admission in past 8 weeks 33%, live bacteria in past 2 weeks (defined by bacteria, probiotics, live yogurt)
• PMH: HTN 53%, COPD 24%, DM 24%, asthma 16%, renal disease 9%, dementia 4%, other illness 67%, cigarette smoker 9.5%, alcohol drinker 31%
• PSH: Any GI 14%
• NGT in place: 0.3%
• Antibiotics: Penicillin 72% (antipseudomonal 9%), cephalosporin 24%, carbapenem or other beta-lactam 2%, clindamycin 1%, quinolone 13%
  • Classes used: One 21%, two 28%, ≥three 51%
  • Duration: Single dose 9%, 1-6 days 28%, 7-13 days 29%, ≥14 days 34%

Interventions

• Participants were randomized to a group:
  • Probiotic: Lyophilised powder with 6×10¹⁰ live bacteria
    • Two strains of Lactobacillus acidophilus and two strains of Bifidobacterium (B. bifidum and B. lactis)
  • Placebo: Maltodextrin powder
• One tablet was taken once daily for 21 days, preferentially given with food and between doses of antibiotics

Outcomes

Comparisons are probiotic vs. placebo.

Primary Outcome

AAD within 8 weeks

Diarrhea defined as 3 or more loose stools (consistency 5-7 on the Bristol Stool Form Scale) in a 24 hours period or as stools described as looser than normal in participants unable to use the scale.

10.8% vs. 10.4% (RR 1.04; 95% CI 0.84-1.28; P=0.71)

CDAD within 12 weeks

0.8% vs. 1.2% (RR 0.71; 95% CI, 0.34-1.47; p=0.35)

Secondary Outcomes

Diarrhea severity and frequency of abdominal symptoms

Similar in both groups

Length of hospital stay

Similar in both groups

QOL

Similar in both groups

Additional Analyses

Flatus

12.5% vs. 10.2% (OR 1.26; 95% CI 1.00-1.59; P=0.045)

Percentage of ADD that was from CDAD

Of the 58.5% and 57.5% of participants in each group with ADD that gave stool samples.

0.99% overall, no difference between groups (RR 0.71; 95% CI 0.34-1.47; P=0.35)

Took all 21 doses

53.1% vs. 52.3%

Patients assessed for inclusion who were recruited, overall

17.1%

Adverse Events

Adverse events

Any serious: 19.7% overall, no difference between groups

Criticisms

• Little ethnic diversity
• Low recruitment rate
• Low adherence to treatment
• Low incidence of ADD and CDAD
• Probiotics may not be effective unless started before antibiotics
• The power calculation assumed a greater placebo effect than was noted so a false negative result cannot be ruled out
• Unclear if other probiotic strains would provide benefit

Funding

• Health Technology Assessment programme of the National Institute for Health Research, UK
• The County Durham & Tees Valley and NIHR Comprehensive Local Research Network
• The funding institutions had no role in study design, data collection, data analysis, data interpretation, or writing of the report
• There was no reported funding from external manufacturers or other commercial companies