Effect of Probiotics on Incident Ventilator-Associated Pneumonia in Critically Ill Patients
Authors: Jennie Johnstone, Maureen Meade, François Lauzier, John Marshall, Erick Duan, Joanna Dionne, Yaseen M. Arabi, Diane Heels-Ansdell, Lehana Thabane, Daphnee Lamarche, Michael Surette, Nicole Zytaruk, Sangeeta Mehta, Peter Dodek, Lauralyn McIntyre, Shane English, Bram Rochwerg, Tim Karachi, William Henderson, Gordon Wood, Daniel Ovakim, Margaret Herridge, John Granton, M. Elizabeth Wilcox, Alberto Goffi, Henry T. Stelfox, Daniel Niven, John Muscedere, François Lamontagne, Frédérick D’Aragon, Charles St.-Arnaud, Ian Ball, Dave Nagpal, Martin Girard, Pierre Aslanian, Emmanuel Charbonney, David Williamson, Wendy Sligl, Jan Friedrich, Neill K. Adhikari, François Marquis, Patrick Archambault, Kosar Khwaja, Arnold Kristof, James Kutsogiannis, Ryan Zarychanski, Bojan Paunovic, Brenda Reeve, François Lellouche, Paul Hosek, Jennifer Tsang, Alexandra Binnie, Sébastien Trop, Osama Loubani, Richard Hall, Robert Cirone, Steve Reynolds, Paul Lysecki, Eyal Golan, Rodrigo Cartin-Ceba, Robert Taylor, Deborah Cook, Christine Wallace, Gita Sobhi, Jennie Johnstone, François Lauzier, Deborah Cook, Erick Duan, Joanna Dionne, Bram Rochwerg, John Centoanti, Simon Oczkowski , Daphne Lamarche, Michael Surette, Dawn Bowdish, Andreas Laupacis, Robin Roberts, Christian Brun-Buisson, Steve Reynolds, Sue Willems, Tina Sekhon, Peter Dodek, Najib Ayas, Maria Agda, Victoria Alcuaz, Betty-Jean Ashley, Kelsey Brewer, Janice Palmer, Glen Brown, Mara Pavan, William Henderson, Donald Greisdale, Mypinder Sekhon, Denise Foster, Suzie Logie, Judy Yip, Gordon Wood, Daniel Ovakim, Fiona Auld, Gayle Carney, Ralph Fleming, Jennifer Good, Mandeep Manhas, Karin Boyd, Jane Dheere, Tom Stelfox, Philippe Couillard, Christopher Doig, Ken Parhar, Joshua Booth, Cassidy Codan, Stacy Ruddell, Candice Cameron, Rhonda Edison, Anne Martin, Breanna Mina, Daniel Niven, Luc Berthiaume, Jonathan Gaudet, Jim Kutsiogiannis, Raiyan Chowdhury, Jon Davidow, Curt Johnston, Richard Johnston, Kim Macala, Sam Marcushamer, Darren Markland, Doug Matheson, Damian Payton-Gay, David Zygun, Tayne Hewer, Pat Thompson, Maggie Ge, Janny Hall, Sharon Matenchuk, Wendy Sligl, Sean Bagshaw, Nadia Baig, Lorena McCoshen, Katrina Alexandropoulos, Sherri Bain, Michelle Brandt, Cathy Constable, Kari Douglas, Shaleen Maharaj, Sabrina Travers, Ryan Zarychanski, Bojan Paunovic, Justin Lys, Nicole Marten, Audrey Bhairo, Halyna Ferenes, Beata Kozak, Debra Verrier, Dawn-Lee McLaughlin, Maria Valente, Marcus Blouw, Kendiss Olafson, Heather Smith, Oliver Gutieror, Sherri Lynn Wingfield, Marnie Boyle, Debbie Hrabi, Chantal MacDonald, Brenda Reeve, Karen Bento, Megan Davis, William Dechert, Barbara Longo, Courtney Mullen, Elysia Skrzpek, Laurenne Wierenga, Wesam Abuzaiter, Lynda Amorim, Rosemarie Bauer, Rachel Damota, Hoang Thoa Ho, Nicole Macdougall, Mary Thornewell, Lara Tran, Jennifer Visocchi, Paul Hosek, Bill Plaxton, Catherine Armstong, Janelle Ellis, Kayla Fisk, Melissa Gabnouri, Emilie Gordon, Rebecca Haegens, Lisa Halford, Brooklyn Hillis, Rebecca Jesso, Jennifer McLaren, Elliot McMillan, Mariska Pelkmans, Matthew Rekman, Sylvia Sinkovitis, Monica Truong, Michelle White, Noah Bates, Susan Bryden-Cromwell, Colleen Cameron, Aminah Deen, Sheri DiGiovanni, Anders Foss, Esther Lee, Heidi MacGregor, Esther Galbraith, Robyn McArthur, Julie McGregor, Keith Miller, Sharon Morris, Shelley Parker, Candice Smith, Joanna Stoglow, Jennifer Tung, Melissa Vos, Maureen Meade, Emilie Belley-Cote, Lori Hand, Lisa Klotz, Alexandra Sabev, Nevena Savija, Paige Guyatt, Deanna Cosentino, Diane Lourenco, Julie Misina, Paul Lysecki, Joseph Berlingieri, Sameer Shaikh, Steven Skitch, Tracy Campbell, Hala Basheer, Kathy Bruder, Jane Cheng, Kaiser Qureshi, Celeste Infantino, Timothy Karachi, Mashari Alghuroba, Alia Khaled, Tina Millen, Ryan Vaisler, Maya Biljan, Deane Cosentino, Brittany Marriott, John Muscedere, Gordon Boyd, Christine D`Arsigny, John Drover, Jason Erb, David Maslove, Chris Parker, Stephanie Sibley, Tracy Boyd, Ilinca Georgescu, Miranda Hunt, Danielle Muscedere, Cathy Baker, Jennifer Engel, Jennifer Fleming, Lisa Roderick, Shelley Silk, Marcy Spencer, Michelle Tryon, Dave Nagpal, Ian Ball, Michael Sharpe, Karen J Bosma, Tracey Bentall, Jessica Sturt-Smith, Michelle Alexander, Tammy Ellis, Mindy Muylaert, Cindy Paczkowski, Eileen Campbell, Susie Imervoski, Athena Ovsenek, Rebecca Rondinelli, Teresa Longfield, Amy Moyer, Faith Norris, Janice Sumpton, Karina Teterycz, Sangeeta Mehta, Stephen Lapinsky, Laveena Munshi, Maedean Brown, Brittany Giacomino, Marnie Jakab, Alan Kraguiljac, Sumesh Shah, Erik Tamberg, Doret Cheng, Gagan Grewal, Andrew Han, Holly Leung, Ioanna Mantas, Hilary Rodrigues, Andew Wyllie, Jennifer LY Tsang, Mercedes Carmargo, Beverly Richter, Rita Caporuscio, Rachel Kressner Falvo, Dimitra Fleming, Carmelina Maxwell, Karmen Plantic, Lauralyn McIntyre, Giuseppe Pagliarello, Gianni D`Egidio, Shane English, Mike Hartwick, Jonathan Hooper, Dal Kubelik, Kwadwo Kyeremanteng, Hilary Meggison, David Neilipovitz, Rakesh Patel, Joseph Po, Erin Rosenberg, Brigette Gomes, Lianne Leclair, Rebecca Porteous, Shawna Reddie, Irene Watpool, Marianne Cox, Kathy Fraser, Jennifer Kuhn, Rob Macleod, Susanne Richard, Dawn Rose, Sherry Weir, Pierre Cardinal, Gwynne Jones, John Kim, Sherissa Microys, Aimee Sarti, Andrew Seely, Shelley Acres, Sydney Mietitis, Kaitlyn Montroy, Amanda Van Beinum, Wendy Aikens, Anne-Marie Dugal, Susan Fetzer, Mark Soth, Waleed Alhazanni, France Clarke, Mary Copland, Neala Hoad, Melissa Sheers, Alyson Takaoka, Nicole Zytaruk, Christa Connolly, Denise Davis, Catherine Eaton, Tracy Gallinas, Jean Lee-Yoo, Connie Lukinuk, Leia Musielak, Nancy Pavunkovic, Joy Pelayo, Kaitlyn Phillips, Catherine Pracsovics, Julia Raimondo, Vida Stankus, Angela Wright, Crystal Young, Rob Cirrone, Kanthi Kavikondala, Axelle Pellerin, Laura Tomat, Jeff Carter, Jiten Jani, Brendan Yaets, John Marshall, Jan Friedrich, Jennifer Hodder, Imrana Khalid, Julie Lee, Yoon Lee, Kurtis Salway, Gyan Sandhu, Marlene Santos, Orla Smith, Melissa Wang, Norman Dewhurst, Ann Dowbenka, Ann Kosinski, Laura Parsons, Johanna Proceviat, Gitana Ramonas, Mae Yuen, Neill Adhikari, Andre Amaral, Brian H Cuthbertson, Rob Fowler, Damon Scales, Navjot Kaur, Nicole Marinoff, Adic Perez, Jane Wang, Katrina Hatzifilalithis, John Iazzetta, Chrys Kolos, Ingrid Quinton, Margaret Herridge, Eyal Golan, John Granton, Jaimie Archer, Daniel Chen, Brooke Fraser, Cheryl Geen-Smith, Andrea Matte, Priscilla Robles, Cristian Urrea, Jane Ascroft, Fatima Haji, Jie Ming, Matthew Suen, Muhammad Walid, Jill Westlund, Alberto Goffi, Victoria McCredie, Elizabeth Wilcox, Paulina Farias, Barbara Kosky, Christina Pugliese, Lia Stenyk, Karolina Walczak, Kyung Ae, Rajvinder Kaur, Jane Lui, Sophia Mateo, Nga Pham, Tam Pham, Sebastien Trop, Alexandra Binnie, Ronald Heslegrave, Zaynab Panchbhaya, Kim Sharman, Rakhi Goel, Kim Kozluk, Julianne Labelle, Hina Marsonia, Cecillia Scott, Martin Girard, Pierrre Aslanian, Sylvain Belisle, François-Martin Carrier, Michaël Chassé, André Denault, Jean-Gilles Guimond, Antoine Halwagi, Paul Hébert, Christopher Kolan, Jordi Mancebo, Nicholas Robillard, Fatna Benettaib, Dounia Boumahni, Casey Bourdeau Caporuscio, Marie-Ève Cantin, Virginy Côté-Gravel, Ali Ghamraoui, Martine Lebrasseur, Lancelot Legendre Courville, Stéphanie Lorio, Maria Trinidad Madrid, Nicole Poitras, Romain Rigal, Maya Salame, Valérie Tran, Katie Bacon, Nathalie Boudreau, Cecilia Carvajal, Lyne Gauthier, Julie Gendron, Karine Jean, Louise Laforest, Antonietta Lembo, Sothun Lim, Jennifer Morrissette, France Pagé, Lucie Pelletier, Marie-Christine Rodrigue, Patrick Archambault, Jean-François Bellemare, Simon Bordeleau, Christine Drouin, Benoit Duhaime, Ann Laberge, Philippe Lechance, Estel Deblois, Maude Dionne, Lise Lavoie, Isabelle Michel, Alexandre Pépin, Sandrine Poulin, Sarah Anctil, Louis-Étienne Marchand, Robin Roy, François Lamontagne, Charles St-Arnaud, Frédérick D'Aragon, Hector Quiroz, Dominique Bérard, Marc-Andre Léclair, Virginie Bolduc, Elaine Carbonneau, Joannie Marchand, Marie-Hélène Masse, Sylvie Cloutier, Marianne Guay, Line Morin, Jessie Nicolson, Isabelle Paquette, France Théberge, Emmanuel Charbonney, Yoan Lamarche, Soazig Leguillan, Karim Serri, Colin Verdant, Yanick Beaulieu, Patrick Bellemare, Philippe Rico, Francis Bernard, Marc Giasson, Véronique Brunette, Alexandros Cavayas, Émilie Lévesque, Halina Labikova, Julia Lainer Palacios, Marie-Ève Langlois, Virginie Williams, Thuy Anh Nguyen, Valérie Phaneuf, David Williamson, François Marquis, Han Tin Wang, Francis Toupin, Stephane Ahern, Brian Laufer, Marc Brosseau, Pauline Dul, Johanne Harvey, Lotthida Inthanavong, Danae Tassy, Helen Assayag, Maude Bachand, Marysa Betournay, Karine Daoust, Kristine Goyette, Ariane Lessard, Marceline Quach, Alexis Turgeon, Danny Barriault, David Bellemare, Anick Boivin, Sarah-Judith Breton, Ève Cloutier, Marjorie Daigle, Charles Delisle-Thibeault, Panagiota Giannakouros, Stéphanie Grenier, Gabrielle Guilbault, Caroline Léger, Catherine Ouellet, Marie-Claude Trembley, Julie Gaudreau, Claire Grégoire, Véronique Labbé, Ariane Laprise-Rochette, Caroline Ouellet, Mélanie Samson, Marie-David Simoneau, Virginie Tourcotte, Tuong-Vi Tran, François Lellouche, Ying Tung Sia, Mathieu Simon, Pierre-Alexandre Bouchard, Patricia Lizotte, Nathalie Chateauvert, Thérèse Grenier, Kosar Khwaja, Dan Deckelbaum, Jeremy Grushka, Ash Gursahaney, David Hornstein, Dev Jayaraman, Tarek Razek, Robert Salasidis, Patrizia Zanelli, Norine Alam, Laura Garcia, Tonia Doerksen, Gilbert Matte, Marie-France Robert, Arnold S Kristof, Peter Goldberg, Roupen Hatzakorzian, Sheldon Magder, Jason Shahin, Salman Qureshi, Josie Campisi, Vasilica Botan, Anissa Capilnean, Alyssa Corey, Annick Gagné, Jasmine Mian, Kathleen Normandin, Osama Loubani, Rick Hall, Robert Green, Diana Gillis, Lisa Julien, Laura Lee Magennis, Tamara Mitterer, Joanna Arsenault, Kim Bruce-Payne, Patti Gallant, Rodrigo Cartin-Ceba, Richard Oeckler, Brenda Anderson, Lavonne Liedl, Laurie Meade, Sueanne Weist, Anna Bartoo, Debbie Bauer, Vince Brickley, Shaun Bridges, Greg Brunn, Jennifer Eickstaedt, Jill Bergerson, Sandy Showalter, Erin Stern, Melissa Manley, Robert Taylor, Margaret Cryton, Kim Fowler, Katie Krause, Jackie O`Brien, Marianne Tow, John Ma, Kaitlin MS Moore, Yaseen Arabi, Abdulaziz Al-Dawood, Haytham Tlayjeh, Alaaeldien Ghanem, Ahmad Hassanien, Mohamed Hegazy, Ashraf El Sharkawi, Felwa Bin Humaid, Hala Alanizi, Nadyah Alanizy, Njoud Al Bogami, Mohammed Muhaidib, Jawaher Gramish, Randa Alsomali, Nora Devera, Marjane Villafranca
Journal: JAMA (2021)

<h3>Importance</h3> 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. <h3>Objective</h3> To evaluate the effect of<i>Lactobacillus rhamnosus</i>GG on preventing VAP, additional infections, and other clinically important outcomes in the intensive care unit (ICU). <h3>Design, Setting, and Participants</h3> 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). <h3>Interventions</h3> Enteral<i>L rhamnosus</i>GG (1 × 10<sup>10</sup>colony-forming units) (n = 1321) or placebo (n = 1332) twice daily in the ICU. <h3>Main Outcomes and Measures</h3> The primary outcome was VAP determined by duplicate blinded central adjudication. Secondary outcomes were other ICU-acquired infections including<i>Clostridioides difficile</i>infection, diarrhea, antimicrobial use, ICU and hospital length of stay, and mortality. <h3>Results</h3> 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;<i>P</i> = .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<i>L rhamnosus</i>in a sterile site or the sole or predominant organism in a nonsterile site (odds ratio, 14.02; 95% CI, 1.79-109.58;<i>P</i> &lt; .001). <h3>Conclusions and Relevance</h3> Among critically ill patients requiring mechanical ventilation, administration of the probiotic<i>L rhamnosus</i>GG compared with placebo, resulted in no significant difference in the development of ventilator-associated pneumonia. These findings do not support the use of<i>L rhamnosus</i>GG in critically ill patients. <h3>Trial Registration</h3> ClinicalTrials.gov Identifier:NCT02462590