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Probiotics in hospitalized adult patients: a systematic review of economic evaluations

  • Vincent I. LauEmail author
  • Bram Rochwerg
  • Feng Xie
  • Jennie Johnstone
  • John Basmaji
  • Jana Balakumaran
  • Alla Iansavichene
  • Deborah J. Cook
Review Article/Brief Review

Abstract

Purpose

Probiotics may prevent healthcare-associated infections, such as ventilator-associated pneumonia, Clostridioides difficile-associated diarrhea, and other adverse outcomes. Despite their potential benefits, there are no summative data examining the cost-effectiveness of probiotics in hospitalized patients. This systematic review summarized studies evaluating the economic impact of using probiotics in hospitalized adult patients.

Methods

We searched MEDLINE, EMBASE, CENTRAL, ACP Journal Club, and other EBM reviews (inception to January 31, 2019) for health economics evaluations examining the use of probiotics in hospitalized adults. Independently and in duplicate, we extracted data study characteristics, risk of bias, effectiveness and total costs (medications, diagnostics/procedures, devices, personnel, hospital) associated with healthcare-associated infections (ventilator-associated pneumonia, Clostridioides difficile-associated diarrhea and antibiotic-associated diarrhea). We used Grading of Recommendations Assessment, Development and Evaluation methods to assess certainty in the overall cost-effectiveness evidence.

Results

Of 721 citations identified, we included seven studies. For the clinical outcomes of interest, there was one randomized-controlled trial (RCT)-based health economic evaluation, and six model-based health economic evaluations. Probiotics showed favourable cost-effectiveness in six of seven (86%) economic evaluations. Three of the seven studies were manufacturer-supported, all which suggested cost-effectiveness. Certainty of cost-effectiveness evidence was very low because of risk of bias, imprecision, and inconsistency.

Conclusion

Probiotics may be an economically attractive intervention for preventing ventilator-associated pneumonia, Clostridioides difficile-associated diarrhea, and antibiotic-associated diarrhea in hospitalized adult patients. Nevertheless, certainty about their cost-effectiveness evidence is very low. Future RCTs examining probiotics should incorporate cost data to inform bedside practice, clinical guidelines, and healthcare policy.

Trial registration: PROSPERO CRD42019129929; Registered 25 April, 2019.

Les probiotiques pour les patients adultes hospitalisés : une revue systématique des évaluations économiques

Résumé

Objectif

Les probiotiques pourraient prévenir les infections nosocomiales, telles que la pneumonie acquise sous ventilation, la diarrhée associée au Clostridioides difficile, et d’autres atteintes néfastes. Malgré leurs bienfaits potentiels, il n’existe aucune donnée sommative examinant la rentabilité des probiotiques chez des patients hospitalisés. Cette revue systématique a résumé les études évaluant l’impact économique de l’utilisation de probiotiques chez des patients adultes hospitalisés.

Méthode

Nous avons effectué des recherches dans les bases de données MEDLINE, EMBASE, CENTRAL, ACP Journal Club et d’autres ressources médicales fondées sur des données probantes (de leur création jusqu’au 31 janvier 2019) pour en extraire les évaluations économiques examinant l’utilisation de probiotiques auprès d’adultes hospitalisés. Nous avons extrait, de façon indépendante et en double, les caractéristiques des données des études, le risque de biais, l’efficacité et les coûts totaux (médicaments, diagnostics et interventions, dispositifs, personnel et hôpitaux) associés aux infections nosocomiales (pneumonie acquise sous ventilation, diarrhée associée au Clostridioides difficile et diarrhée associée aux antibiotiques). Nous avons utilisé l’échelle GRADE (Grading of Recommendations Assessment, Development and Evaluation) afin d’évaluer le degré de certitude des données probantes globales de rentabilité.

Résultats

Parmi les 721 citations identifiées, sept études ont été incluses. En ce qui touchait aux critères d’évaluation présélectionnés, on comptait une évaluation économique de la santé basée sur une étude randomisée contrôlée (ERC) et six évaluations économiques de la santé fondées sur des modèles. Les probiotiques ont démontré une rentabilité favorable dans six des sept (86 %) évaluations économiques. Trois des sept études étaient financées par l’industrie, suggérant toutes la rentabilité des probiotiques. Le degré de certitude des données probantes de rentabilité était très faible en raison du risque de biais, d’imprécision et d’incohérence.

Conclusion

Les probiotiques pourraient constituer une intervention séduisante d’un point de vue économique pour prévenir la pneumonie acquise sous ventilation, la diarrhée associée au Clostridioides difficile et la diarrhée associée aux antibiotiques chez les patients adultes hospitalisés. Toutefois, le degré de certitude quant aux données probantes de rentabilité est très faible. Davantage d’ERC examinant les probiotiques devraient intégrer les données de coûts afin de guider la pratique au chevet, les recommandations cliniques et les politiques de soins de santé.

Enregistrement de l’étude : PROSPERO CRD42019129929; enregistrée le 25 avril 2019.

Notes

Author contributions

Vincent Lau, Bram Rochwerg, Feng Xie, John Basmaji, Jana Balakumaran, Alla Iansavichene, Jennie Johnstone, and Deborah Cook made substantial contributions to study conception and design, and acquisition, analysis and interpretation of data; and drafted the submitted article and revised it critically for important intellectual content. Conception: Lau, Rochwerg, Xie, Cook. Background: Vincent Lau, Feng Xie, Bram Rochwerg, Alla Iansavichene, Jennie Johnstone, and Deborah Cook. Design: Vincent Lau, Bram Rochwerg, Feng Xie, and Deborah Cook. Acquisition of data: Vincent Lau, Jana Balakumaran, John Basmaji, Bram Rochwerg, Feng Xie, Alla Iansavichene, Jennie Johnstone, and Deborah Cook. Drafting the manuscript: Vincent Lau, Bram Rochwerg, Feng Xie, John Basmaji, Jana Balakumaran, Alla Iansavichene, Jennie Johnstone, and Deborah Cook. Revising the manuscript: Vincent Lau, Bram Rochwerg, Feng Xie, John Basmaji, Jana Balakumaran, Alla Iansavichene, Jennie Johnstone, and Deborah Cook.

Acknowledgements

We are grateful to the Canadian Critical Care Trials Group and the Canadian Institute of Health Research who have supported PROSPECT. We also thank Juanita Meyer (Library Services, London Health Sciences Center) for her assistance with the full-text acquisition and search strategy.

Competing interests

Several co-authors (Drs. Deborah Cook, Jennie Johnstone, Bram Rochwerg) are co-investigators in PROSPECT (Probiotics: Prevention of Severe Pneumonia and Endotracheal Colonization Trial) NCT01782755.

Funding statement

D Cook holds a Canada Research Chair in Knowledge Translation in Intensive Care Medicine from the Canadian Institutes of Health Research.

Editorial responsibility

This submission was handled by Dr. Sangeeta Mehta, Associate Editor, Canadian Journal of Anesthesia.

Supplementary material

12630_2019_1525_MOESM1_ESM.pdf (105 kb)
Supplementary material 1 (PDF 105 kb) eAppendix 1 Search strategy
12630_2019_1525_MOESM2_ESM.pdf (85 kb)
Supplementary material 2 (PDF 85 kb) eAppendix 2 Data extraction form (change to a form)
12630_2019_1525_MOESM3_ESM.pdf (78 kb)
Supplementary material 3 (PDF 78 kb) eAppendix 3 Risk of bias (ROB) assessment methods
12630_2019_1525_MOESM4_ESM.pdf (145 kb)
Supplementary material 4 (PDF 145 kb) eAppendix 4A-B Risk of bias table 4A) Risk of bias assessment for source clinical studies utilized in health economic analysis of probiotics (randomized-controlled trials); 4B) Risk of Bias Assessment for Source Clinical Studies Utilized in Health Economic Analysis of Probiotics (Observational Studies – Utilizing the Newcastle-Ottawa Quality Assessment Scale for Cohort Studies); 4C) Risk of Bias Assessment for Source Clinical Studies Utilized in Health Economic Analysis of Probiotics (Observational Studies – Utilizing the Newcastle-Ottawa Quality Assessment Scale for Case-Control Studies); 4D) Risk of Bias Assessment for Source Clinical Studies Utilized in Health Economic Analysis of Probiotics (Evidence Partners and CLARITY for Risk of Bias of Surveys)
12630_2019_1525_MOESM5_ESM.pdf (175 kb)
Supplementary material 5 (PDF 175 kb) eAppendix 5 Costing data (natural units, unit costs, and/or total costs)

References

  1. 1.
    World Health Organization. Diarrhoea. Available from URL: http://www.who.int/topics/diarrhoea/en/ (accessed September 2019).
  2. 2.
    Marshall JC. Gastrointestinal flora and its alterations in critical illness. Curr Opin Clin Nutr Metab Care 1999; 2: 405-11.CrossRefGoogle Scholar
  3. 3.
    Brenchley JM, Douek DC. Microbial translocation across the GI tract. Annu Rev Immunol 2012; 30: 149-73.CrossRefGoogle Scholar
  4. 4.
    Hao Q, Lu Z, Dong BR, Huang CD, Wu T. Probiotics for preventing acute upper respiratory tract infections. Cochrane Database Syst Rev 2011; 9: CD006895.Google Scholar
  5. 5.
    Hempel S, Newberry SJ, Maher AR, et al. Probiotics for the prevention and treatment of antibiotic-associated diarrhea: a systematic review and meta-analysis. JAMA 2012; 307: 1959-69.CrossRefGoogle Scholar
  6. 6.
    Manzanares W, Lemieux M, Langlois PL, Wischmeyer PE. Probiotic and synbiotic therapy in critical illness: a systematic review and meta-analysis. Crit Care 2016; .  https://doi.org/10.1186/s13054-016-1434-y.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Safdar N, Dezfulian C, Collard HR, Saint S. Clinical and economic consequences of ventilator-associated pneumonia: a systematic review. Crit Care Med 2005; 33: 2184-93.CrossRefGoogle Scholar
  8. 8.
    Goldenberg JZ, Yap C, Lytvyn L, et al. Probiotics for the prevention of Clostridium difficile-associated diarrhea in adults and children. Cochrane Database Syst Rev 2017; 12: CD006095.Google Scholar
  9. 9.
    Nanwa N, Kendzerska T, Krahn M, et al. The economic impact of Clostridium difficile infection: a systematic review. Am J Gastroenterol 2015; 110: 511-9.CrossRefGoogle Scholar
  10. 10.
    Gomersall JS, Jadotte YT, Xue Y, Lockwood S, Riddle D, Preda A. Conducting systematic reviews of economic evaluations. Int J Evid Based Healthc 2015; 13: 170-8.CrossRefGoogle Scholar
  11. 11.
    Husereau D, Drummond M, Petrou S, et al. Consolidated Health Economic Evaluation Reporting Standards (CHEERS) statement. BMJ 2013; .  https://doi.org/10.1136/bmj.f1049.CrossRefPubMedGoogle Scholar
  12. 12.
    The World Bank. Official exchange rate (LCU per US$, period average). Available from URL: https://data.worldbank.org/indicator/PA.NUS.FCRF (accessed September 2019).
  13. 13.
    Higgins JP, Altman DG, Gøtzsche PC, et al. The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials. BMJ 2011; .  https://doi.org/10.1136/bmj.d5928.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Wells GA, Shea B, O’Connell D, et al. The Ottawa Hospital Research Institute. The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses. Available from URL: http://www.ohri.ca/programs/clinical_epidemiology/oxford.asp (accessed September 2019).
  15. 15.
    Agarwal A, Guyatt G, Busse J. Evidence Partners. Methods commentary: risk of bias in cross-sectional surveys of attitudes and practices. Available from URL: https://www.evidencepartners.com/resources/methodological-resources/risk-of-bias-cross-sectional-surveys-of-attitudes-and-practices/ (accessed September 2019).
  16. 16.
    Moher D, Liberati A, Tetzlaff J, Altman DG; PRISMA Group. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. J Clin Epidemiol 2009; 62: 1006-12.Google Scholar
  17. 17.
    Schünemann H, Brożek J, Guyatt G, Oxman A. GRADE Handbook; 2013. Available from URL: https://gdt.gradepro.org/app/handbook/handbook.html (accessed September 2019).
  18. 18.
    Branch-Elliman W, Wright SB, Howell MD. Determining the ideal strategy for ventilator-associated pneumonia prevention. Cost-benefit analysis. Am J Respir Crit Care Med 2015; 192: 57-63.CrossRefGoogle Scholar
  19. 19.
    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.CrossRefGoogle Scholar
  20. 20.
    Kamdeu Fansi AA, Guertin JR, LeLorier J. Savings from the use of a probiotic formula in the prophylaxis of antibiotic-associated diarrhea. J Med Econ 2012; 15: 53-60.CrossRefGoogle Scholar
  21. 21.
    Leal JR, Heitman SJ, Conly JM, Henderson EA, Manns BJ. Cost-effectiveness analysis of the use of probiotics for the prevention of Clostridium difficile–associated diarrhea in a provincial healthcare system. Infect Control Hosp Epidemiol 2016; 37: 1079-86.CrossRefGoogle Scholar
  22. 22.
    Lenoir-Wijnkoop I, Nuijten MJ, Craig J, Butler CC. Nutrition economic evaluation of a probiotic in the prevention of antibiotic-associated diarrhea. Front Pharmacol 2014; DOI:  https://doi.org/10.3389/fphar.2014.00013.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Shen NT, Leff JA, Schneider Y, et al. Cost-effectiveness analysis of probiotic use to prevent Clostridium difficile infection in hospitalized adults receiving antibiotics. Open Forum Infect Dis 2017; DOI:  https://doi.org/10.1093/ofid/ofx148.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Vermeersch SJ, Vandenplas Y, Tanghe A, Elseviers M, Annemans L. Economic evaluation of S. boulardii CNCM I-745 for prevention of antibioticassociated diarrhoea in hospitalized patients. Acta Gastroenterol Belg 2018; 81: 269-76.Google Scholar
  25. 25.
    Kuntz JL, Polgreen PM. The importance of considering different healthcare settings when estimating the burden of Clostridium difficile. Clin Infect Dis 2015; 60: 831-6.CrossRefGoogle Scholar
  26. 26.
    Elseviers MM, Van Camp Y, Nayaert S, et al.) Prevalence and management of antibiotic associated diarrhea in general hospitals. BMC Infect Dis 2015; DOI:  https://doi.org/10.1186/s12879-015-0869-0.
  27. 27.
    ISPOR. Good Research Practices for Measuring Drug Costs in Cost-Effectiveness Analyses: A Societal Perspective; 2010. Available from URL: https://www.ispor.org/heor-resources/good-practices-for-outcomes-research/article/good-research-practices-for-measuring-drug-costs-in-cost-effectiveness-analyses-a-societal-perspective (accessed September 2019).
  28. 28.
    Salminen MK, Tynkkynen S, Rautelin H, et al. Lactobacillus bacteremia during a rapid increase in probiotic use of Lactobacillus rhamnosus GG in Finland. Clin Infect Dis 2002; 35: 1155-60.CrossRefGoogle Scholar
  29. 29.
    Song X, Bartlett JG, Speck K, Naegeli A, Carroll K, Perl TM. Rising economic impact of clostridium difficile-associated disease in adult hospitalized patient population. Infect Control Hosp Epidemiol 2008; 29: 823-8.CrossRefGoogle Scholar
  30. 30.
    Miller MA, Hyland M, Ofner-Agostini M, et al. Morbidity, mortality, and healthcare burden of nosocomial Clostridium difficile-associated diarrhea in Canadian hospitals. Infect Control Hosp Epidemiol 2002; 23: 137-40.CrossRefGoogle Scholar
  31. 31.
    Kyne L, Hamel MB, Polavaram R, Kelly CP. Health care costs and mortality associated with nosocomial diarrhea due to Clostridium difficile. Clin Infect Dis 2002; 34: 346-53.CrossRefGoogle Scholar
  32. 32.
    Pepin J, Alary ME, Valiquette L, et al. Increasing risk of relapse after treatment of Clostridium difficile colitis in Quebec. Canada. Clin Infect Dis 2005; 40: 1591-7.CrossRefGoogle Scholar
  33. 33.
    van Walraven C. The Hospital-patient One-year Mortality Risk score accurately predicted long-term death risk in hospitalized patients. J Clin Epidemiol 2014; 67: 1025-34.CrossRefGoogle Scholar
  34. 34.
    Lessa FC, Mu Y, Bamberg WM, et al. Burden of Clostridium difficile infection in the United States. N Engl J Med 2015; 372: 825-34.CrossRefGoogle Scholar
  35. 35.
    Dubberke ER, Reske KA, Olsen MA, McDonald LC, Fraser VJ. Short- and long-term attributable costs of Clostridium difficile-associated disease in nonsurgical inpatients. Clin Infect Dis 2008; 46: 497-504.CrossRefGoogle Scholar
  36. 36.
    Lawrence SJ, Puzniak LA, Shadel BN, Gillespie KN, Kollef MH, Mundy LM. Clostridium difficile in the intensive care unit: epidemiology, costs, and colonization pressure. Infect Control Hosp Epidemiol 2007; 28: 123-30.CrossRefGoogle Scholar
  37. 37.
    Riley TV, Codde JP, Rouse IL. Increased length of hospital stay due to Clostridium difficile associated diarrhoea. Lancet 1995; 345: 455-6.CrossRefGoogle Scholar
  38. 38.
    Ananthakrishnan AN, McGinley EL, Binion DG. Excess hospitalisation burden associated with Clostridium difficile in patients with inflammatory bowel disease. Gut 2008; 57: 205-10.CrossRefGoogle Scholar
  39. 39.
    Kofsky P, Rosen L, Reed J, Tolmie M, Ufberg D. Clostridium difficile–a common and costly colitis. Dis Colon Rectum 1991; 34: 244-8.CrossRefGoogle Scholar
  40. 40.
    Wassenberg MW, Kluytmans JA, Box AT, et al. Rapid screening of methicillin-resistant Staphylococcus aureus using PCR and chromogenic agar: a prospective study to evaluate costs and effects. Clin Microbiol Infect 2010; 16: 1754-61.CrossRefGoogle Scholar
  41. 41.
    Henrich TJ, Krakower D, Bitton A, Yokoe DS. Clinical risk factors for severe Clostridium difficile-associated disease. Emerg Infect Dis 2009; 15: 415-22.CrossRefGoogle Scholar
  42. 42.
    Sunenshine RH, McDonald LC. Clostridium difficile-associated disease: new challenges from an established pathogen. Cleve Clin J Med 2006; 73: 187-97.CrossRefGoogle Scholar
  43. 43.
    Magill SS, Edwards JR, Bamberg W, et al. Multistate point-prevalence survey of health care-associated infections. N Engl J Med 2014; 370: 1198-208.CrossRefGoogle Scholar
  44. 44.
    Sullivan PW, Ghushchyan V. Preference-based EQ-5D index scores for chronic conditions in the United States. Med Decis Making 2006; 26: 410-20.CrossRefGoogle Scholar
  45. 45.
    Bauer MP, Notermans DW, van Benthem BH, et al. Clostridium difficile infection in Europe: a hospital-based survey. Lancet 2011; 77: 63-73.CrossRefGoogle Scholar
  46. 46.
    Brunetti M, Shemilt I, Pregno S, et al. GRADE guidelines: 10. Considering resource use and rating the quality of economic evidence. J Clin Epidemiol 2013; 66: 140-50.CrossRefGoogle Scholar
  47. 47.
    Dick AW, Perencevich EN, Pogorzelska-Maziarz M, Zwanziger J, Larson EL, Stone PW. A decade of investment in infection prevention: a cost effectiveness analysis. Am J Infect Control 2015; 43: 4-9.CrossRefGoogle Scholar
  48. 48.
    Herzer KR, Niessen L, Constenla DO, Ward WJ Jr, Pronovost PJ. Cost-effectiveness of a quality improvement programme to reduce central line-associated bloodstream infections in intensive care units in the USA. BMJ Open 2014; DOI: 0.1136/bmjopen-2014-006065.Google Scholar
  49. 49.
    Jayaraman SP, Jiang Y, Resch S, Askari R, Klompas M. Cost-effectiveness of a model infection control program for preventing multi-drug-resistant organism infections in critically ill surgical patients. Surg Infect (Larchmt) 2016; 17: 589-95.CrossRefGoogle Scholar
  50. 50.
    Kelly RE, Cohen LJ, Semple RJ, et al. Relationship between drug company funding and outcomes of clinical psychiatric research. Psychol Med 2006; 36: 1647-56.CrossRefGoogle Scholar
  51. 51.
    Yaphe J, Edman R, Knishkowy B, Herman J. The association between funding by commercial interests and study outcome in randomized controlled drug trials. Fam Pract 2001; 18: 565-8.CrossRefGoogle Scholar

Copyright information

© Canadian Anesthesiologists' Society 2019

Authors and Affiliations

  • Vincent I. Lau
    • 1
    • 3
    • 8
    Email author
  • Bram Rochwerg
    • 2
    • 3
  • Feng Xie
    • 3
  • Jennie Johnstone
    • 4
    • 5
  • John Basmaji
    • 1
  • Jana Balakumaran
    • 6
  • Alla Iansavichene
    • 7
  • Deborah J. Cook
    • 2
    • 3
  1. 1.Department of Medicine, Division of Critical Care MedicineWestern UniversityLondonCanada
  2. 2.Department of Medicine, Division of Critical Care MedicineMcMaster UniversityHamiltonCanada
  3. 3.Department of Health Research Methods, Evidence & ImpactMcMaster UniversityHamiltonCanada
  4. 4.Public Health OntarioTorontoCanada
  5. 5.Dalla Lana School of Public HealthUniversity of TorontoTorontoCanada
  6. 6.Michael G. DeGroote School of MedicineMcMaster UniversityHamiltonCanada
  7. 7.Library ServicesLondon Health Sciences CenterLondonCanada
  8. 8.Department of Medicine, Division of Critical Care, Schulich School of Medicine and DentistryWestern UniversityLondonCanada

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