Therapeutics
Probiotics did not prevent antibioticassociated or C. difficile diarrhea in hospitalized older patients
Allen SJ, Wareham K, Wang D, et al. 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). Health Technol Assess. 2013;17:1-140.
Clinical impact ratings: F ★★★★★★✩ h ★★★★★✩✩ g ★★★★★★✩ I ★★★★★★✩ Question
Conclusion
Does a high-dose, multistrain probiotic prevent antibiotic-associated diarrhea (AAD) and Clostridium difficile diarrhea (CDD) in hospitalized older patients?
In hospitalized older patients who were receiving antibiotics, probiotics did not prevent antibiotic-associated or Clostridium difficile diarrhea compared with placebo.
Methods
*Information provided by author.
Design: Randomized placebo-controlled trial (Probiotic Lactobacilli and Bifidobacteria in Antibiotic-associated Diarrhoea and Clostridium Difficile Diarrhoea in the Elderly [PLACIDE] trial). Current Controlled Trials ISRCTN70017204 and European Clinical Trials Database 2007-002876-32. Allocation: {Concealed}*.† Blinding: Blinded† (patients, research team, and outcome assessors). Follow-up period: 8 weeks (AAD) and 12 weeks (CDD). Setting: Inpatient wards in 5 National Health Service hospitals in the UK. Patients: 2981 inpatients ≥ 65 years of age (median age 77 y, 50% women) who received ≥ 1 oral or parenteral antibiotic in the past 7 days or were about to start antibiotics. Exclusion criteria included diarrhea in the past 24 hours, CDD in the past 3 months, immunocompromise with need for isolation, or previous adverse reactions to probiotics. Intervention: Vegetarian probiotic capsule containing 6 x 1010 live bacteria, with 2 strains of Lactobacillus acidophilus and 2 of Bifidobacterium bifidum (n = 1493), or placebo (n = 1488), each taken daily for 21 days. Outcomes: AAD (diarrhea associated with antibiotic use and without diarrheal pathogens identified on routine laboratory tests or alternative explanations), CDD (AAD with C. difficile toxins identified on routine laboratory tests), and serious adverse events (SAEs). 2974 patients were needed to detect a 50% reduction in CDD from 4% in the placebo group (80% power, α = 0.05) and in AAD from 20% in the placebo group (> 99% power, α = 0.05), allowing for 20% dropouts or loss to follow-up. Patient follow-up: {99%}* (intention-to-treat analysis).
Main results 79% of patients received antibiotics from ≥ 1 class: 72% used penicillins, and 24% used cephalosporins. 59% of patients who had diarrhea had stool samples tested for pathogens. Probiotics and placebo did not differ for AAD or SAEs at 8 weeks (Table), CDD at 12 weeks (Table), or SAEs resulting in death (5.4% vs 4.4%, relative risk increase 24%, 95% CI −10 to 70). Probiotics vs placebo in hospitalized older patients who received antibiotics‡ Outcomes
Probiotics
AAD at 8 wk
11%
CDD at 12 wk SAE at 8 wk§
0.8% 20%
Placebo 10% 1.2% 19%
RRI/RRR (95% CI)
NNH/NNT (CI)
RRI 4% (−16 to 28)
Not significant
RRR 29% (−47 to 66)
Not significant
RRI 4% (−10 to 20)
Not significant
‡AAD = antibiotic-associated diarrhea; CDD = Clostridium difficile diarrhea; SAE = serious adverse event; other abbreviations defined in Glossary. RRI, RRR, and CI calculated from relative risk or event rates in article. §Follow-up period for SAEs provided by author.
JC6
†See Glossary.
Source of funding: National Institute for Health Research Health Technology Assessment programme. For correspondence: Dr. S.J. Allen, Swansea University, Swansea, Wales, UK. E-mail [email protected]. ■
Commentary Allen and colleagues did a large multicenter, randomized placebocontrolled trial evaluating the use of multistrain probiotics to prevent AAD and CDD in older hospitalized patients in the UK. They concluded that probiotics are unlikely to reduce CDD or AAD in that population. Strengths of the trial included rigorous methodology, large sample size, and a specific focus on older patients. C. difficile is the most common cause of acute infectious diarrhea in hospital settings and long-term care facilities and disproportionately affects older persons; however, randomized data are rare or underpowered to detect treatment differences. The study results argue against routine use of probiotics in older hospitalized patients receiving antibiotics. In contrast, a recent Cochrane review pooled data from pediatric and adult patients and found a reduction in CDD with probiotics compared with placebo or no treatment (pooled relative risk 0.36, CI 0.26 to 0.51) (1). In subgroup analysis, the protective effect of probiotics remained in adults and inpatients, although no stratification was made for age > 65 years. However, the review allowed for varied definitions of CDD based on individual included studies (1). Allen and colleagues used a high-dose preparation of lactobacilli and bifidobacteria because multistrain schemes may be preferred to prevent transmission and reinfections. Moreover, prolonged administration may be needed to document benefit, as patients with nosocomial infections usually receive short courses (53% completed the 21-d course). It is unclear whether results would be the same in the USA, where C. difficile epidemiology and antibiotic exposure may be different. Rigorous methodology and the sample size of Allen and colleagues’ study add value to the findings against indiscriminate use of probiotics in older patients. However, the results do not preclude future use of probiotics in other high-risk groups or as part of a multifaceted approach that includes antibiotic stewardship and restriction of proton-pump inhibitors, which have been associated with C. difficile infection. P.D. Ziakas, MD E. Mylonakis, MD Warren Alpert Medical School of Brown University Providence, Rhode Island, USA Reference 1. Goldenberg JZ, Ma SS, Saxton JD, et al. Probiotics for the prevention of Clostridium difficile-associated diarrhea in adults and children. Cochrane Database Syst Rev. 2013;5:CD006095.
© 2014 American College of Physicians
Downloaded From: http://annals.org/ by a University of California San Diego User on 12/25/2016
17 June 2014 | ACP Journal Club | Volume 160 • Number 12
Probiotics did not prevent antibioticassociated or C. difficile diarrhea in hospitalized older patients
Allen SJ, Wareham K, Wang D, et al. 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). Health Technol Assess. 2013;17:1-140.
Clinical impact ratings: F ★★★★★★✩ h ★★★★★✩✩ g ★★★★★★✩ I ★★★★★★✩ Question
Conclusion
Does a high-dose, multistrain probiotic prevent antibiotic-associated diarrhea (AAD) and Clostridium difficile diarrhea (CDD) in hospitalized older patients?
In hospitalized older patients who were receiving antibiotics, probiotics did not prevent antibiotic-associated or Clostridium difficile diarrhea compared with placebo.
Methods
*Information provided by author.
Design: Randomized placebo-controlled trial (Probiotic Lactobacilli and Bifidobacteria in Antibiotic-associated Diarrhoea and Clostridium Difficile Diarrhoea in the Elderly [PLACIDE] trial). Current Controlled Trials ISRCTN70017204 and European Clinical Trials Database 2007-002876-32. Allocation: {Concealed}*.† Blinding: Blinded† (patients, research team, and outcome assessors). Follow-up period: 8 weeks (AAD) and 12 weeks (CDD). Setting: Inpatient wards in 5 National Health Service hospitals in the UK. Patients: 2981 inpatients ≥ 65 years of age (median age 77 y, 50% women) who received ≥ 1 oral or parenteral antibiotic in the past 7 days or were about to start antibiotics. Exclusion criteria included diarrhea in the past 24 hours, CDD in the past 3 months, immunocompromise with need for isolation, or previous adverse reactions to probiotics. Intervention: Vegetarian probiotic capsule containing 6 x 1010 live bacteria, with 2 strains of Lactobacillus acidophilus and 2 of Bifidobacterium bifidum (n = 1493), or placebo (n = 1488), each taken daily for 21 days. Outcomes: AAD (diarrhea associated with antibiotic use and without diarrheal pathogens identified on routine laboratory tests or alternative explanations), CDD (AAD with C. difficile toxins identified on routine laboratory tests), and serious adverse events (SAEs). 2974 patients were needed to detect a 50% reduction in CDD from 4% in the placebo group (80% power, α = 0.05) and in AAD from 20% in the placebo group (> 99% power, α = 0.05), allowing for 20% dropouts or loss to follow-up. Patient follow-up: {99%}* (intention-to-treat analysis).
Main results 79% of patients received antibiotics from ≥ 1 class: 72% used penicillins, and 24% used cephalosporins. 59% of patients who had diarrhea had stool samples tested for pathogens. Probiotics and placebo did not differ for AAD or SAEs at 8 weeks (Table), CDD at 12 weeks (Table), or SAEs resulting in death (5.4% vs 4.4%, relative risk increase 24%, 95% CI −10 to 70). Probiotics vs placebo in hospitalized older patients who received antibiotics‡ Outcomes
Probiotics
AAD at 8 wk
11%
CDD at 12 wk SAE at 8 wk§
0.8% 20%
Placebo 10% 1.2% 19%
RRI/RRR (95% CI)
NNH/NNT (CI)
RRI 4% (−16 to 28)
Not significant
RRR 29% (−47 to 66)
Not significant
RRI 4% (−10 to 20)
Not significant
‡AAD = antibiotic-associated diarrhea; CDD = Clostridium difficile diarrhea; SAE = serious adverse event; other abbreviations defined in Glossary. RRI, RRR, and CI calculated from relative risk or event rates in article. §Follow-up period for SAEs provided by author.
JC6
†See Glossary.
Source of funding: National Institute for Health Research Health Technology Assessment programme. For correspondence: Dr. S.J. Allen, Swansea University, Swansea, Wales, UK. E-mail [email protected]. ■
Commentary Allen and colleagues did a large multicenter, randomized placebocontrolled trial evaluating the use of multistrain probiotics to prevent AAD and CDD in older hospitalized patients in the UK. They concluded that probiotics are unlikely to reduce CDD or AAD in that population. Strengths of the trial included rigorous methodology, large sample size, and a specific focus on older patients. C. difficile is the most common cause of acute infectious diarrhea in hospital settings and long-term care facilities and disproportionately affects older persons; however, randomized data are rare or underpowered to detect treatment differences. The study results argue against routine use of probiotics in older hospitalized patients receiving antibiotics. In contrast, a recent Cochrane review pooled data from pediatric and adult patients and found a reduction in CDD with probiotics compared with placebo or no treatment (pooled relative risk 0.36, CI 0.26 to 0.51) (1). In subgroup analysis, the protective effect of probiotics remained in adults and inpatients, although no stratification was made for age > 65 years. However, the review allowed for varied definitions of CDD based on individual included studies (1). Allen and colleagues used a high-dose preparation of lactobacilli and bifidobacteria because multistrain schemes may be preferred to prevent transmission and reinfections. Moreover, prolonged administration may be needed to document benefit, as patients with nosocomial infections usually receive short courses (53% completed the 21-d course). It is unclear whether results would be the same in the USA, where C. difficile epidemiology and antibiotic exposure may be different. Rigorous methodology and the sample size of Allen and colleagues’ study add value to the findings against indiscriminate use of probiotics in older patients. However, the results do not preclude future use of probiotics in other high-risk groups or as part of a multifaceted approach that includes antibiotic stewardship and restriction of proton-pump inhibitors, which have been associated with C. difficile infection. P.D. Ziakas, MD E. Mylonakis, MD Warren Alpert Medical School of Brown University Providence, Rhode Island, USA Reference 1. Goldenberg JZ, Ma SS, Saxton JD, et al. Probiotics for the prevention of Clostridium difficile-associated diarrhea in adults and children. Cochrane Database Syst Rev. 2013;5:CD006095.
© 2014 American College of Physicians
Downloaded From: http://annals.org/ by a University of California San Diego User on 12/25/2016
17 June 2014 | ACP Journal Club | Volume 160 • Number 12
