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Effect of Probiotics on Incident Ventilator-Associated Pneumonia in Critically Ill PatientsA Randomized Clinical Trial

Educational Objective
To understand the role of probiotic treatments for patients who are critically ill.
1 Credit CME
Key Points

Question  Does the probiotic Lactobacillus rhamnosus GG prevent ventilator-associated pneumonia (VAP) among critically ill patients?

Findings  In this randomized trial involving 2650 patients, no significant difference in VAP incidence was found among patients treated with probiotics compared with placebo (21.9% vs 21.3%, respectively; hazard ratio 1.03; 95% CI 0.87-1.22).

Meaning  These findings do not support the use of Lactobacillus rhamnosus GG for prevention of ventilator-associated pneumonia in critically ill patients requiring mechanical ventilation.


Importance  Growing interest in microbial dysbiosis during critical illness has raised questions about the therapeutic potential of microbiome modification with probiotics. Prior randomized trials in this population suggest that probiotics reduce infection, particularly ventilator-associated pneumonia (VAP), although probiotic-associated infections have also been reported.

Objective  To evaluate the effect of Lactobacillus rhamnosus GG on preventing VAP, additional infections, and other clinically important outcomes in the intensive care unit (ICU).

Design, Setting, and Participants  Randomized placebo-controlled trial in 44 ICUs in Canada, the United States, and Saudi Arabia enrolling adults predicted to require mechanical ventilation for at least 72 hours. A total of 2653 patients were enrolled from October 2013 to March 2019 (final follow-up, October 2020).

Interventions  Enteral L rhamnosus GG (1 × 1010 colony-forming units) (n = 1321) or placebo (n = 1332) twice daily in the ICU.

Main Outcomes and Measures  The primary outcome was VAP determined by duplicate blinded central adjudication. Secondary outcomes were other ICU-acquired infections including Clostridioides difficile infection, diarrhea, antimicrobial use, ICU and hospital length of stay, and mortality.

Results  Among 2653 randomized patients (mean age, 59.8 years [SD], 16.5 years), 2650 (99.9%) completed the trial (mean age, 59.8 years [SD], 16.5 years; 1063 women [40.1%.] with a mean Acute Physiology and Chronic Health Evaluation II score of 22.0 (SD, 7.8) and received the study product for a median of 9 days (IQR, 5-15 days). VAP developed among 289 of 1318 patients (21.9%) receiving probiotics vs 284 of 1332 controls (21.3%; hazard ratio [HR], 1.03 (95% CI, 0.87-1.22; P = .73, absolute difference, 0.6%, 95% CI, –2.5% to 3.7%). None of the 20 prespecified secondary outcomes, including other ICU-acquired infections, diarrhea, antimicrobial use, mortality, or length of stay showed a significant difference. Fifteen patients (1.1%) receiving probiotics vs 1 (0.1%) in the control group experienced the adverse event of L rhamnosus in a sterile site or the sole or predominant organism in a nonsterile site (odds ratio, 14.02; 95% CI, 1.79-109.58; P < .001).

Conclusions and Relevance  Among critically ill patients requiring mechanical ventilation, administration of the probiotic L rhamnosus GG compared with placebo, resulted in no significant difference in the development of ventilator-associated pneumonia. These findings do not support the use of L rhamnosus GG in critically ill patients.

Trial Registration  ClinicalTrials.gov Identifier: NCT02462590

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Article Information

Corresponding Author: Deborah Cook, MD, MSc, Methods Center, St Joseph’s Healthcare, 50 Charlton Ave E, Room H327, Hamilton, ON, Canada L9H 4A6 (debcook@mcmaster.ca).

Accepted for Publication: July 23, 2021.

Author Contributions: Drs Cook and Heels-Ansdell had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Johnstone, Meade, Lauzier, Marshall, Duan, Dionne, Arabi, Thabane, Lamarche, Surrette, Zytaruk, Cook.

Acquisition, analysis, or interpretation of data: Johnstone, Meade, Lauzier, Marshall, Duan, Dionne, Arabi, Heels-Ansdell, Thabane, Lamarche, Surette, Zytaruk, Mehta, McIntyre, English, Rochwerg, Karachi, Henderson, Wood, Ovakim, Herridge, Granton, Wilcox, Goffi, Stelfox, Niven, Muscedere, Lamontagne, D'Aragon, St.-Arnaud, Ball, Nagpal, Girard, Aslanian, Charbonney, Williamson, Sligl, Friedrich, Adhikari, Marquis, Archambault, Khwaja, Kristof, Kutsogiannis, Zarychanski, Reeve, Lellouche, Hosek, Tsang, Binnie, Trop, Loubani, Hall, Cirone, Reynolds, Lysecki, Golan, Cartin-Ceba, Taylor, Cook.

Drafting of the manuscript: Johnstone, Meade, Lauzier, Marshall, Duan, Dionne, Lamarche, Zytaruk, Cook.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Dionne, Heels-Ansdell, Thabane, Zytaruk, Cook.

Obtained funding: Johnstone, Meade, Lauzier, Duan, Dionne, Zytaruk, Ball, Aslanian, Charbonney, Williamson, Kutsogiannis, Hall, Cook.

Administrative, technical, or material support: Lauzier, Duan, Dionne, Arabi, Lamarche, Surette, Zytaruk, Mehta, English, Rochwerg, Karachi, Henderson, Wood, Herridge, Granton, Wilcox, Stelfox, Niven, D'Aragon, St.-Arnaud, Ball, Nagpal, Aslanian, Williamson, Sligl, Marquis, Archambault, Kutsogiannis, Zarychanski, Reeve, Lellouche, Hosek, Tsang, Binnie, Reynolds, Lysecki, Golan, Cartin-Ceba, Cook.

Supervision: Lauzier, Duan, Arabi, Thabane, Zytaruk, Henderson, Lamontagne, D'Aragon, St-Arnaud, Girard, Aslanian, Sligl, Archambault, Khwaja, Lellouche, Trop, Hall, Cirone, Lysecki, Cook.

Conflict of Interest Disclosures: Dr Lauzier reported being the recipient of a Research Career Award from the Fonds de la Recherché du Québec-Santé. Dr Marshall reported receiving personal fees from AM Pharma, serving as a consultant to Gilead, being an associate editor for Critical Care Medicine, and holding the Unity Health Chair in Trauma Research. Dr Dionne reported being a recipient of a Career Award from Physician Services Incorporated of Ontario. Dr. Surette reported holding a Canada Research Chair in Interdisciplinary Microbiome Research. Dr Lamontagne reported being a recipient of a Research Career Award from the Fonds de la Recherché du Québec-Santé. Dr D’Aragon reported being a recipient of a Research Career Award from the Fonds de la Recherché du Québec-Santé. Dr Zarychanski reports holding the Lyonel G. Israels Research Chair in Hematology (University of Manitoba). Dr Lellouche reported cofounding and serving as a member of the board of directors of Oxynov and having a patent for automated oxygen. Dr Cook reported being a recipient of a Research Chair in Intensive Care Medicine from the Canadian Institutes for Health Research. No other disclosures were reported.

Funding/Support: This trial was funded by the Canadian Institute for Health Research, Canadian Frailty Network, Physician Services Incorporated, Hamilton Academic Health Sciences Organization, Academic Medical Organization of Southwestern Ontario, St Joseph's Healthcare Hamilton, and McMaster University. I-Health donated active study product and placebo for the conduct of the trial.

Role of the Funders/Sponsors: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Writing Committee Members: Dr Johnstone (coprincipal investigator), Meade, Lauzier, Marshall, Heels-Ansdell, Thabane, Arabi, Dionne, and Duan, Zytaruk, Lamarche, Surette, and Cook (coprincipal investigator).

Data Monitoring Committee: Drs Andreas Laupacis (chair), Roberts, and Brun-Buisson.

Pneumonia and other Infection Adjudication Committee: Drs Johnstone, Francois Lauzier, and Cook (main) and Drs Duan, Dionne, Rochwerg, Centofanti, Oczkowski, and Cook (pilot).

C difficile Infection Adjudication Committee: Drs Dionne, Duan, and Johnstone.

Translational Science Committee: Drs Lamarche, Surette, and Bowdish

Group Information: The PROSPECT Investigators and the Canadian Critical Care Trials Group members are listed in Supplement 3.

Data Sharing Statement: See Supplement 4.

Additional Contributions: We thank the patients and families participating in this trial, as well as the collaborating research coordinators and investigators, and bedside clinicians who supported this work. The trial was designed by the PROSPECT steering committee, the PROSPECT investigators and research coordinators, and the Canadian Critical Care Trials Group. We thank the PROSPECT methods center staff for their expertise and data management, including Lois Saunders, Mary Copland, BA, Shelley Anderson-White, BA, Alyson Takaoka, MSc, France Clarke, RRT, Lori Hand, RRT, Megan Davis, BSc, Melissa Shears, MD, and Kristine Wachmann, RN. We thank Drs Kho, and Fowler, for their review of this manuscript for the Canadian Critical Care Trials Group. None mentioned herein were compensated.

Additional Information: Pharmacy Consultants: Christine Wallace, BSc, St Joseph’s Healthcare Hamilton, and Gita Sobi, BSc, Phm, Hamilton Health Sciences Center, Hamilton.

Relman  DA .  The human microbiome and the future practice of medicine.   JAMA. 2015;314(11):1127-1128. doi:10.1001/jama.2015.10700PubMedGoogle ScholarCrossref
Bassetti  M , Bandera  A , Gori  A .  Therapeutic potential of the gut microbiota in the management of sepsis critical care.   Crit Care. 2020;24(1):105. doi:10.1186/s13054-020-2780-3PubMedGoogle ScholarCrossref
Panigrahi  P , Parida  S , Nanda  NC ,  et al.  A randomized synbiotic trial to prevent sepsis among infants in rural India.   Nature. 2017;548(7668):407-412. doi:10.1038/nature23480PubMedGoogle ScholarCrossref
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(18):1959-1969. doi:10.1001/jama.2012.3507PubMedGoogle Scholar
Johnston  BC , Lytvyn  L , Lo  CK ,  et al.  Microbial preparations (probiotics) for the prevention of Clostridium difficile infection in adults and children: an individual patient data meta-analysis of 6,851 participants.   Infect Control Hosp Epidemiol. 2018;39(7):771-781. doi:10.1017/ice.2018.84PubMedGoogle ScholarCrossref
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(12):CD006095. doi:10.1002/14651858.CD006095.pub4PubMedGoogle Scholar
Allen  SJ , Wareham  K , Wang  D ,  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.   Lancet. 2013;382(9900):1249-1257. doi:10.1016/S0140-6736(13)61218-0PubMedGoogle ScholarCrossref
Hempel  S , Newberry  S , Ruelaz  A ,  et al.  Safety of probiotics used to reduce risk and prevent or treat disease.   Evid Rep Technol Assess (Full Rep). 2011;200(200):1-645.PubMedGoogle Scholar
Bafeta  A , Koh  M , Riveros  C , Ravaud  P .  Harms reporting in randomized controlled trials of interventions aimed at modifying microbiota: a systematic review.   Ann Intern Med. 2018;169(4):240-247. doi:10.7326/M18-0343PubMedGoogle ScholarCrossref
Manzanares  W , Lemieux  M , Langlois  PL , Wischmeyer  PE .  Probiotic and synbiotic therapy in critical illness: a systematic review and meta-analysis.   Crit Care. 2016;19:262. doi:10.1186/s13054-016-1434-yPubMedGoogle Scholar
Batra  P , Soni  KD , Mathur  P .  Efficacy of probiotics in the prevention of VAP in critically ill ICU patients: an updated systematic review and meta-analysis of randomized control trials.   J Intensive Care. 2020;8:81. doi:10.1186/s40560-020-00487-8PubMedGoogle ScholarCrossref
Branch-Elliman  W , Wright  SB , Howell  MD .  Determining the ideal strategy for ventilator-associated pneumonia prevention.   Am J Respir Crit Care Med. 2015;192(1):57-63. doi:10.1164/rccm.201412-2316OCPubMedGoogle ScholarCrossref
McClave  SA , Taylor  BE , Martindale  RG ,  et al; Society of Critical Care Medicine; American Society for Parenteral and Enteral Nutrition.  Guidelines for the provision and assessment of nutrition support therapy in the adult critically ill patient: Society of Critical Care Medicine (SCCM) and American Society for Parenteral and Enteral Nutrition (ASPEN).   JPEN J Parenter Enteral Nutr. 2016;40(2):159-211. doi:10.1177/0148607115621863PubMedGoogle ScholarCrossref
McDonald  D , Ackermann  G , Khailova  L ,  et al.  Extreme dysbiosis of the microbiome in critical illness.   mSphere. 2016;1(4):e00199-e16. doi:10.1128/mSphere.00199-16PubMedGoogle ScholarCrossref
Kitsios  GD , Morowitz  MJ , Dickson  RP , Huffnagle  GB , McVerry  BJ , Morris  A .  Dysbiosis in the intensive care unit: microbiome science coming to the bedside.   J Crit Care. 2017;38:84-91. doi:10.1016/j.jcrc.2016.09.029PubMedGoogle ScholarCrossref
Johnstone  J , Meade  M , Marshall  J ,  et al; PROSPECT Investigators and the Canadian Critical Care Trials Group.  Probiotics: Prevention of Severe Pneumonia and Endotracheal Colonization Trial-PROSPECT: protocol for a feasibility randomized pilot trial.   Pilot Feasibility Stud. 2015;1:19. doi:10.1186/s40814-015-0013-3PubMedGoogle ScholarCrossref
Cook  DJ , Johnstone  J , Marshall  JC ,  et al; PROSPECT Investigators and the Canadian Critical Care Trials Group.  Probiotics: prevention of severe pneumonia and endotracheal colonization Trial-PROSPECT: a pilot trial.   Trials. 2016;17:377. doi:10.1186/s13063-016-1495-xPubMedGoogle ScholarCrossref
Johnstone  J , Heels-Ansdell  D , Thabane  L ,  et al; PROSPECT Investigators and the Canadian Critical Care Trials Group.  Evaluating probiotics for the prevention of ventilator-associated pneumonia: a randomised placebo-controlled multicentre trial protocol and statistical analysis plan for PROSPECT.   BMJ Open. 2019;9(6):e025228. doi:10.1136/bmjopen-2018-025228PubMedGoogle Scholar
Lamarche  D , Rossi  L , Shah  M ,  et al. Quality control in the conduct of a probiotic randomized trial. Abstract presented at: Critical Care Canada Forum; October 28, 2014: Toronto, ON. Accessed August 25, 2021. https://criticalcarecanada.com/abstracts/2014/quality_control_in_the_conduct_of_a_probiotic_randomized_trial.pdf
Grossman  RF , Fein  A .  Evidence-based assessment of diagnostic tests for ventilator-associated pneumonia. Executive summary.   Chest. 2000;117(4)(suppl 2):177S-181S. doi:10.1378/chest.117.4_suppl_2.177SPubMedGoogle ScholarCrossref
Morrow  LE , Kollef  MH , Casale  TB .  Probiotic prophylaxis of ventilator-associated pneumonia: a blinded, randomized, controlled trial.   Am J Respir Crit Care Med. 2010;182(8):1058-1064. doi:10.1164/rccm.200912-1853OCPubMedGoogle ScholarCrossref
Heyland  D , Muscedere  J , Wischmeyer  PE ,  et al; Canadian Critical Care Trials Group.  A randomized trial of glutamine and antioxidants in critically ill patients.   N Engl J Med. 2013;368(16):1489-1497. doi:10.1056/NEJMoa1212722PubMedGoogle ScholarCrossref
Calandra  T , Cohen  J ; International Sepsis Forum Definition of Infection in the ICU Consensus Conference.  The International Sepsis Forum Consensus Conference on definitions of infection in the intensive care unit.   Crit Care Med. 2005;33(7):1538-1548. doi:10.1097/01.CCM.0000168253.91200.83PubMedGoogle ScholarCrossref
Pugin  J , Auckenthaler  R , Mili  N , Janssens  JP , Lew  PD , Suter  PM .  Diagnosis of ventilator-associated pneumonia by bacteriologic analysis of bronchoscopic and nonbronchoscopic “blind” bronchoalveolar lavage fluid.   Am Rev Respir Dis. 1991;143(5 Pt 1):1121-1129. doi:10.1164/ajrccm/143.5_Pt_1.1121PubMedGoogle Scholar
Horan  TC , Andrus  M , Dudeck  MA .  CDC/NHSN surveillance definition of health care-associated infection and criteria for specific types of infections in the acute care setting.   Am J Infect Control. 2008;36(5):309-332. doi:10.1016/j.ajic.2008.03.002PubMedGoogle ScholarCrossref
Cohen  SH , Gerding  DN , Johnson  S ,  et al; Society for Healthcare Epidemiology of America; Infectious Diseases Society of America.  Clinical practice guidelines for Clostridium difficile infection in adults: 2010 update by the Society for Healthcare Epidemiology of America (SHEA) and the Infectious Diseases Society of America (IDSA).   Infect Control Hosp Epidemiol. 2010;31(5):431-455. doi:10.1086/651706PubMedGoogle ScholarCrossref
World Health Organization. Accessed November 29, 2020. https://www.who.int/news-room/fact-sheets/detail/diarrhoeal-disease
Lewis  SJ , Heaton  KW .  Stool form scale as a useful guide to intestinal transit time.   Scand J Gastroenterol. 1997;32(9):920-924. doi:10.3109/00365529709011203PubMedGoogle ScholarCrossref
Thibault  R , Graf  S , Clerc  A ,  et al.  Diarrhea in the intensive care unit.   Crit Care. 2013;17:R153. doi:10.1186/cc12832PubMedGoogle ScholarCrossref
Petrof  EO , Dhaliwal  R , Manzanares  W , Johnstone  J , Cook  D , Heyland  DK .  Probiotics in the critically ill: a systematic review of the randomized trial evidence.   Crit Care Med. 2012;40(12):3290-3302. doi:10.1097/CCM.0b013e318260cc33PubMedGoogle ScholarCrossref
Fine  JP , Gray  RJ .  A proportional hazards model for the subdistribution of a competing risk.   J Am Stat Assoc. 1999;94(446):496-509. doi:10.1080/01621459.1999.10474144Google ScholarCrossref
Rockwood  K , Song  X , MacKnight  C ,  et al.  A global clinical measure of fitness and frailty in elderly people.   CMAJ. 2005;173(5):489-495. doi:10.1503/cmaj.050051PubMedGoogle ScholarCrossref
Haybittle  JL .  Repeated assessment of results in clinical trials of cancer treatment.   Br J Radiol. 1971;44(526):793-797. doi:10.1259/0007-1285-44-526-793PubMedGoogle ScholarCrossref
Peto  R , Pike  MC , Armitage  P ,  et al.  Design and analysis of randomized control trials requiring prolonged observations of each patient, I: introduction and design.   British J Cancer. 1976;34:585. doi:10.1038/bjc.1976.220PubMedGoogle ScholarCrossref
Li  G , Taljaard  M , Van den Heuvel  ER ,  et al.  An introduction to multiplicity issues in clinical trials: the what, why, when and how.   Int J Epidemiol. 2017;46(2):746-755.PubMedGoogle Scholar
Yelin  I , Flett  KB , Merakou  C ,  et al.  Genomic and epidemiological evidence of bacterial transmission from probiotic capsule to blood in ICU patients.   Nat Med. 2019;25(11):1728-1732. doi:10.1038/s41591-019-0626-9PubMedGoogle ScholarCrossref
Lamarche  D , Johnstone  J , Zytaruk  N ,  et al; PROSPECT Investigators; Canadian Critical Care Trials Group; Canadian Critical Care Translational Biology Group.  Microbial dysbiosis and mortality during mechanical ventilation: a prospective observational study.   Respir Res. 2018;19(1):245. doi:10.1186/s12931-018-0950-5PubMedGoogle ScholarCrossref
Salminen  MK , Rautelin  H , Tynkkynen  S ,  et al.  Lactobacillus bacteremia, clinical significance, and patient outcome, with special focus on probiotic L. rhamnosus GG.   Clin Infect Dis. 2004;38(1):62-69. doi:10.1086/380455PubMedGoogle ScholarCrossref
Schandelmaier  S , Briel  M , Varadhan  R ,  et al.  Development of the Instrument to assess the Credibility of Effect Modification Analyses (ICEMAN) in randomized controlled trials and meta-analyses.   CMAJ. 2020;192(32):E901-E906. doi:10.1503/cmaj.200077PubMedGoogle ScholarCrossref
Yi  SH , Jernigan  JA , McDonald  LC .  Prevalence of probiotic use among inpatients: a descriptive study of 145 US hospitals.   Am J Infect Control. 2016;44(5):548-553, 548-553. z. doi:10.1016/j.ajic.2015.12.001PubMedGoogle ScholarCrossref
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