PLACIDE

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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.
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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.[1] A 2013 Cochrane review found that moderate quality evidence supported the use of probiotics for the prevention of CDAD.[2] 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.[3]

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[4]
  • Probiotics may not be effective unless started before antibiotics[5]
  • The power calculation assumed a greater placebo effect than was noted so a false negative result cannot be ruled out[5]
  • Unclear if other probiotic strains would provide benefit[4]

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

Further Reading

  1. Hempel S, et al. "Probiotics for the prevention and treatment of antibiotic-associated diarrhea: A systematic review and meta-analysis." JAMA. 2012;307(18):1959-1969.
  2. Goldenberg JZ, et al. "Probiotics for the prevention of Clostridium difficile-associated diarrhea in adults and children." Cochrane Database of Systematic Reviews. 2013;31(5):CD005095.
  3. Daneman N. "A probiotic trial: Tipping the balance of evidence?" The Lancet. 2013;382(9900):1228-1230.
  4. 4.0 4.1 Allen SJ, et al. "ACP Journal Club: A microbial preparation did not reduce diarrhea in older inpatients receiving antibiotics." Annals of Internal Medicine. 2013;159(10):JC9.
  5. 5.0 5.1 Multiple authors. "Correspondence: Probiotics and antibiotic-associated diarrhoea." The Lancet. 2014;383(9911):29-30.