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Meta-Analysis
. 2017 Dec 19;12(12):CD006095.
doi: 10.1002/14651858.CD006095.pub4.

Probiotics for the prevention of Clostridium difficile-associated diarrhea in adults and children

Joshua Z Goldenberg  1 , Christina Yap, Lyubov Lytvyn, Calvin Ka-Fung Lo, Jennifer Beardsley, Dominik Mertz, Bradley C Johnston
Affiliations
Meta-Analysis

Probiotics for the prevention of Clostridium difficile-associated diarrhea in adults and children

Joshua Z Goldenberg et al. Cochrane Database Syst Rev. .

Abstract

Background: Antibiotics can disturb gastrointestinal microbiota which may lead to reduced resistance to pathogens such as Clostridium difficile (C. difficile). Probiotics are live microbial preparations that, when administered in adequate amounts, may confer a health benefit to the host, and are a potential C. difficile prevention strategy. Recent clinical practice guidelines do not recommend probiotic prophylaxis, even though probiotics have the highest quality evidence among cited prophylactic therapies.

Objectives: To assess the efficacy and safety of probiotics for preventing C.difficile-associated diarrhea (CDAD) in adults and children.

Search methods: We searched PubMed, EMBASE, CENTRAL, and the Cochrane IBD Group Specialized Register from inception to 21 March 2017. Additionally, we conducted an extensive grey literature search.

Selection criteria: Randomized controlled (placebo, alternative prophylaxis, or no treatment control) trials investigating probiotics (any strain, any dose) for prevention of CDAD, or C. difficile infection were considered for inclusion.

Data collection and analysis: Two authors (independently and in duplicate) extracted data and assessed risk of bias. The primary outcome was the incidence of CDAD. Secondary outcomes included detection of C. difficile infection in stool, adverse events, antibiotic-associated diarrhea (AAD) and length of hospital stay. Dichotomous outcomes (e.g. incidence of CDAD) were pooled using a random-effects model to calculate the risk ratio (RR) and corresponding 95% confidence interval (95% CI). We calculated the number needed to treat for an additional beneficial outcome (NNTB) where appropriate. Continuous outcomes (e.g. length of hospital stay) were pooled using a random-effects model to calculate the mean difference and corresponding 95% CI. Sensitivity analyses were conducted to explore the impact of missing data on efficacy and safety outcomes. For the sensitivity analyses, we assumed that the event rate for those participants in the control group who had missing data was the same as the event rate for those participants in the control group who were successfully followed. For the probiotic group, we calculated effects using the following assumed ratios of event rates in those with missing data in comparison to those successfully followed: 1.5:1, 2:1, 3:1, and 5:1. To explore possible explanations for heterogeneity, a priori subgroup analyses were conducted on probiotic species, dose, adult versus pediatric population, and risk of bias as well as a post hoc subgroup analysis on baseline risk of CDAD (low 0% to 2%; moderate 3% to 5%; high > 5%). The overall quality of the evidence supporting each outcome was independently assessed using the GRADE criteria.

Main results: Thirty-nine studies (9955 participants) met the eligibility requirements for our review. Overall, 27 studies were rated as either high or unclear risk of bias. A complete case analysis (i.e. participants who completed the study) among trials investigating CDAD (31 trials, 8672 participants) suggests that probiotics reduce the risk of CDAD by 60%. The incidence of CDAD was 1.5% (70/4525) in the probiotic group compared to 4.0% (164/4147) in the placebo or no treatment control group (RR 0.40, 95% CI 0.30 to 0.52; GRADE = moderate). Twenty-two of 31 trials had missing CDAD data ranging from 2% to 45%. Our complete case CDAD results proved robust to sensitivity analyses of plausible and worst-plausible assumptions regarding missing outcome data and results were similar whether considering subgroups of trials in adults versus children, inpatients versus outpatients, different probiotic species, lower versus higher doses of probiotics, or studies at high versus low risk of bias. However, in a post hoc analysis, we did observe a subgroup effect with respect to baseline risk of developing CDAD. Trials with a baseline CDAD risk of 0% to 2% and 3% to 5% did not show any difference in risk but trials enrolling participants with a baseline risk of > 5% for developing CDAD demonstrated a large 70% risk reduction (interaction P value = 0.01). Among studies with a baseline risk > 5%, the incidence of CDAD in the probiotic group was 3.1% (43/1370) compared to 11.6% (126/1084) in the control group (13 trials, 2454 participants; RR 0.30, 95% CI 0.21 to 0.42; GRADE = moderate). With respect to detection of C. difficile in the stool pooled complete case results from 15 trials (1214 participants) did not show a reduction in infection rates. C. difficile infection was 15.5% (98/633) in the probiotics group compared to 17.0% (99/581) in the placebo or no treatment control group (RR 0.86, 95% CI 0.67 to 1.10; GRADE = moderate). Adverse events were assessed in 32 studies (8305 participants) and our pooled complete case analysis indicates probiotics reduce the risk of adverse events by 17% (RR 0.83, 95% CI 0.71 to 0.97; GRADE = very low). In both treatment and control groups the most common adverse events included abdominal cramping, nausea, fever, soft stools, flatulence, and taste disturbance.

Authors' conclusions: Based on this systematic review and meta-analysis of 31 randomized controlled trials including 8672 patients, moderate certainty evidence suggests that probiotics are effective for preventing CDAD (NNTB = 42 patients, 95% CI 32 to 58). Our post hoc subgroup analyses to explore heterogeneity indicated that probiotics are effective among trials with a CDAD baseline risk >5% (NNTB = 12; moderate certainty evidence), but not among trials with a baseline risk ≤5% (low to moderate certainty evidence). Although adverse effects were reported among 32 included trials, there were more adverse events among patients in the control groups. The short-term use of probiotics appears to be safe and effective when used along with antibiotics in patients who are not immunocompromised or severely debilitated. Despite the need for further research, hospitalized patients, particularly those at high risk of CDAD, should be informed of the potential benefits and harms of probiotics.

PubMed Disclaimer

Conflict of interest statement

Joshua Z Goldenberg: None known

Christina Yap: None known

Lyubov Lytvyn: None known

Calvin Ka‐Fung Lo: None known

Jennifer Beardsley: None known

Dominik Mertz: None known

Bradley Johnston: None known

Figures

1
1
Study flow diagram.
2
2
Risk of bias summary: review authors' judgements about each risk of bias item for each included study. Blanks cells indicate that this outcome was not assessed in the study.
3
3
Forest plot of comparison: 1 C. difficile associated diarrhea, outcome: 1.1 Incidence CDAD: complete case.
4
4
Forest plot of comparison: 1 Probiotics versus control, outcome: 1.24 Adverse Events: complete case.
5
5
Funnel plot of comparison: 1 C. difficile associated diarrhea, outcome: 1.1 Incidence CDAD: complete case.
6
6
Funnel plot of comparison: 1 Probiotics versus control, outcome: 1.24 Adverse Events: complete case.
1.1
1.1. Analysis
Comparison 1 Probiotics versus control, Outcome 1 Incidence CDAD: complete case.
1.2
1.2. Analysis
Comparison 1 Probiotics versus control, Outcome 2 Incidence CDAD: complete case ‐ fixed effects.
1.3
1.3. Analysis
Comparison 1 Probiotics versus control, Outcome 3 Incidence CDAD: Sensitivity (1.5:1).
1.4
1.4. Analysis
Comparison 1 Probiotics versus control, Outcome 4 Incidence CDAD: Sensitivity (2:1).
1.5
1.5. Analysis
Comparison 1 Probiotics versus control, Outcome 5 Incidence CDAD: Sensitivity (3:1).
1.6
1.6. Analysis
Comparison 1 Probiotics versus control, Outcome 6 Incidence CDAD: Sensitivity (5:1).
1.7
1.7. Analysis
Comparison 1 Probiotics versus control, Outcome 7 Incidence CDAD: Subgroup: Inpatient versus outpatient populations.
1.8
1.8. Analysis
Comparison 1 Probiotics versus control, Outcome 8 Incidence CDAD: Subgroup: Species: all.
1.9
1.9. Analysis
Comparison 1 Probiotics versus control, Outcome 9 Incidence CDAD: Subgroup: Species: LGG versus SB.
1.10
1.10. Analysis
Comparison 1 Probiotics versus control, Outcome 10 Incidence CDAD: Subgroup: Species: LGG versus LA + LC.
1.11
1.11. Analysis
Comparison 1 Probiotics versus control, Outcome 11 Incidence CDAD: Subgroup: Risk of Bias.
1.12
1.12. Analysis
Comparison 1 Probiotics versus control, Outcome 12 Incidence CDAD: Subgroup: Adult versus child.
1.13
1.13. Analysis
Comparison 1 Probiotics versus control, Outcome 13 Incidence CDAD: Baseline Risk.
1.14
1.14. Analysis
Comparison 1 Probiotics versus control, Outcome 14 Incidence CDAD: worst case.
1.15
1.15. Analysis
Comparison 1 Probiotics versus control, Outcome 15 Incidence CDAD: 0‐2% baseline risk RoB.
1.16
1.16. Analysis
Comparison 1 Probiotics versus control, Outcome 16 Incidence CDAD: 3‐5% baseline risk RoB.
1.17
1.17. Analysis
Comparison 1 Probiotics versus control, Outcome 17 Incidence CDAD: >5% baseline risk RoB.
1.18
1.18. Analysis
Comparison 1 Probiotics versus control, Outcome 18 Incidence of infection: complete case.
1.19
1.19. Analysis
Comparison 1 Probiotics versus control, Outcome 19 Incidence of infection: Subgroup: Risk of Bias.
1.20
1.20. Analysis
Comparison 1 Probiotics versus control, Outcome 20 Incidence of infection: Inpatient versus outpatient.
1.21
1.21. Analysis
Comparison 1 Probiotics versus control, Outcome 21 Incidence of infection: Species: all.
1.22
1.22. Analysis
Comparison 1 Probiotics versus control, Outcome 22 Incidence of infection: Subgroup: Species: LGG versus SB.
1.23
1.23. Analysis
Comparison 1 Probiotics versus control, Outcome 23 Incidence of infection: Adult versus child.
1.24
1.24. Analysis
Comparison 1 Probiotics versus control, Outcome 24 Adverse Events: complete case.
1.25
1.25. Analysis
Comparison 1 Probiotics versus control, Outcome 25 Adverse Events: Subgroup: Risk of Bias.
1.26
1.26. Analysis
Comparison 1 Probiotics versus control, Outcome 26 Adverse Events: Sensitivity 1.5:1.
1.27
1.27. Analysis
Comparison 1 Probiotics versus control, Outcome 27 Adverse Events: Sensitivity 2:1.
1.28
1.28. Analysis
Comparison 1 Probiotics versus control, Outcome 28 Adverse Events: Sensitivity 3:1.
1.29
1.29. Analysis
Comparison 1 Probiotics versus control, Outcome 29 Adverse Events: Sensitivity 5:1.
1.30
1.30. Analysis
Comparison 1 Probiotics versus control, Outcome 30 Adverse Events: Species: all.
1.31
1.31. Analysis
Comparison 1 Probiotics versus control, Outcome 31 Adverse Events: Species: LGG versus SB.
1.32
1.32. Analysis
Comparison 1 Probiotics versus control, Outcome 32 Adverse Events: Species: LGG versus LA + LC.
1.33
1.33. Analysis
Comparison 1 Probiotics versus control, Outcome 33 Adverse Events: Inpatient versus outpatient.
1.34
1.34. Analysis
Comparison 1 Probiotics versus control, Outcome 34 Adverse Events: Adult versus child.
1.35
1.35. Analysis
Comparison 1 Probiotics versus control, Outcome 35 Incidence AAD: complete case.
1.36
1.36. Analysis
Comparison 1 Probiotics versus control, Outcome 36 Incidence AAD: Subgroup: Risk of Bias.
1.37
1.37. Analysis
Comparison 1 Probiotics versus control, Outcome 37 Incidence AAD: sensitivity (1.5:1).
1.38
1.38. Analysis
Comparison 1 Probiotics versus control, Outcome 38 Incidence AAD: sensitivity (2:1).
1.39
1.39. Analysis
Comparison 1 Probiotics versus control, Outcome 39 Incidence AAD: sensitivity (3:1).
1.40
1.40. Analysis
Comparison 1 Probiotics versus control, Outcome 40 Incidence AAD: sensitivity (5:1).
1.41
1.41. Analysis
Comparison 1 Probiotics versus control, Outcome 41 Incidence AAD: Patient population.
1.42
1.42. Analysis
Comparison 1 Probiotics versus control, Outcome 42 Incidence AAD: Species: all.
1.43
1.43. Analysis
Comparison 1 Probiotics versus control, Outcome 43 Incidence AAD: Species: LGG versus SB.
1.44
1.44. Analysis
Comparison 1 Probiotics versus control, Outcome 44 Incidence AAD: Species: LGG versus LA + LC.
1.45
1.45. Analysis
Comparison 1 Probiotics versus control, Outcome 45 Incidence AAD: Adult versus child.
1.46
1.46. Analysis
Comparison 1 Probiotics versus control, Outcome 46 Incidence AAD: Adult (RoB).
1.47
1.47. Analysis
Comparison 1 Probiotics versus control, Outcome 47 Incidence AAD: Child (RoB).
1.48
1.48. Analysis
Comparison 1 Probiotics versus control, Outcome 48 Length of Hospital Stay: complete case.
See this image and copyright information in PMC

Update of

References

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References to studies excluded from this review

Agarwal 2003 {published data only}
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