Continuous vs Intermittent β-Lactam Antibiotic Infusions in Critically Ill Patients With Sepsis
Authors: Joel M. Dulhunty, Stephen J. Brett, Jan J. De Waele, Dorrilyn Rajbhandari, Laurent Billot, Menino O. Cotta, Joshua S. Davis, Simon Finfer, Naomi E. Hammond, Serena Knowles, Xiaoqiu Liu, Shay McGuinness, Jayanthi Mysore, David L. Paterson, Sandra Peake, Andrew Rhodes, Jason A. Roberts, Claire Roger, Charudatt Shirwadkar, Therese Starr, Colman Taylor, John A. Myburgh, Jeffrey Lipman, Rinaldo Bellomo, Glenn Eastwood, Leah Peck, Helen Young, Andrew Cheng, Luke Lau, Magdalena Luciuk, Margaret Muteitha, Manoj Saxena, Catherine Boschert, Timothy Chimunda, Cameron Knott, Julie Smith, Kiran Nand, Treena Sara, Peter Chan, Graeme Duke, John Dyett, Kym Gellie, Stephanie Hunter, Melissa Kaufman, Owen Roodenburg, Joseph Veto, Julia Affleck, Mahesh Ramanan, Megan Ratcliffe, Alexis Tabah, Timothy Warhurst, Maimoonbe Gough, Maree Houbert, Julie Pitman, Mandy Tallott, James Winearls, Shelley Donovan, Katrina Ellis, Atul Gaur, Mary Keehan, Amy Kelty, Elisha Turner, Cynthia Bierl, Gail Brinkerhoff, Dustin Bush, Amber-Louise Poulter, Krishna Sunkara, Melanie Cooper, Lynette Morrison, Sunil Sane, Joanne Sutton, Hayden White, Vishwanath Biradar, Milind Sanap, Natalie Soar, Megan Davis, Meg Harward, Cassie Jones, Josie Mackay, Niki McGuinness, Jason Meye, Emma Saylor, Adam Suliman, Alex Tabah, Ellen Venz, James Walsham, Krista Wetzig, Catherine Kurenda, Patricia Williams, Stuart Baker, Maree Duroux, Kylie Jacobs, Hamish Pollock, Sam Shone, Jenie Butler, Cheryl Fourie, Marianne Kirrane, Melissa Lassig-Smith, Daisy Lindsay, Amelia Livermore, Bree-Yana McConnochie, Lynn Murray, Georgina Peacock, Janine Stuart, Sidharth Agarwal, Margaret Phillips, Kirsty Smyth, David Cooper, Rick McAllister, Yasmine Ali Abdelhamid, Deborah Barge, Kathleen Byrne, Adam Deane, Sarah Doherty, Simon Iles, Brie Jelbart, Thomas Rechnitzer, Angela Ashelford, Frances Bass, Celia Bradford, Anthony Delaney, Jonathan Gatward, Roger Harris, Pierre Janin, Richard Lee, Elizabeth Limbrey, Sharon Mar, Naomi Pallas, Julia Pilowsky, Melanie Ross, Wade Stedman, Miyuki Tokumitsu, Elizabeth Yarad, Maryam Alborzi, Heidi Buhr, Jennifer Coles, David Gattas, Deborah Inskip, Asako Ito, Jennene Miller, Claire Reynolds, Sam Rudham, Alison Bone, Claire Cattigan, Tania Elderkin, Tania Salerno, Jeremy Cohen, Amanda Davie, Amy Owens, Roslyn Purcell, Balasubramanian Venkatesh, David Bowen, Peter Clark, Mohammad Hamidi, Jenyfer Joy, Jing Kong, Vineet Nayyar, Kaatje Cruysberghs, Philippe Jorens, Petra Vertongen, Marc Diltoer, Marie Claire Van Malderen, Anne Joosten, Maxime Van Cutsem, Caroline Abbenhuijs, Dominique Durand, Nancy Matumikina, Fabio Taccone, Stephanie Bracke, Lesley De Coster, Luc De Crop, Anouska De Smeytere, Jolien Van Hecke, Daisy Vermeiren, Jan Heerman, Steffi Ryckaert, Annelies Van Damme, Nicolas De Schryver, Anne Thirifays, Els Fannes, Niels Van Regenmortel, Corentine Alauzet, Thibaut Belveyre, Jessica Breistroff, Aurélie Gutehrle, Emmanuel Novy, Maximilien Saint Gilles, Marie Bonnefoy, Audrey Clavier, Pierre Ducq, Antoine Frouin, Sébastien Moschietto, Marion Touzet, Claire Dahyot-Fizelier, Angéline Jamet, Angela Kostencovska, Quentin Saint Genis, Sami Alaya, Ali Mofredj, Caroline Boutin, Loubna Elotmani, Martin Mahul, Laurent Muller, Nicolas Perin, Sanihah Che Omar, Suki Ismet, Noor Iellieya Maisarah Jamaludin, Md Fadhil Mat Amin, Mohd Zulfakar Mazlan, Husna Mohd Nor, Nabila Mohd Sukri, Nurul Amira Nizar, Mahamarowi Omar, Era Nabilah Roslan, Zeti Norfidiyati Salmuna, Tuan Zulfadli Syazwan Tuan Mohd Adnan, W Mohd Nazarudin W Hassan, Halimatun Arwa Yaakub, Mohd Shahnaz Hasan, Marhainie Mohamad, Mohamad Irfan Othman Jailani, Helmi Sulaiman, Farisha Ali, Magdalena Butler, Keri-Anne Cowdrey, Eileen Gilder, Jane Hallion, Immanuel Hennessy, Philippa Neal, Karina O’Connor, Rachael Parke, Samantha Ryan, Melissa Woollett (now Robertson), Yan Chen, Colin McArthur, Rachael McConnochie, Caroline O’Connor, Catherine Simmonds, Brandon Burke, Tara Doyle, Jan Mehrtens, Stacey Morgan, Anna Morris, Kym Van Der Heyden, Dinu Girijadevi, Vivian Lai, Rima Song, Tony Williams, Amelia Butler, Caitriona Fiske, Annette Forrest, Erin Furborough, Robert Martynoga, Renesh Nair, Sarah Rogers, Livia Schischka, Kara Trask, April Aguilar, Colin Barnes, Ben Barry, Niña Beehre, Kirsha Delaney, Dick Dinsdale, Kim Grayson, Deb Hendry, Anna Hunt, April Jane, Harriet Judd, Charlotte Latimer-Bell, Cassie Lawrence, Eden Lesona, Rosie Martin, Agnes Mckay Vucago, Alex Millington, James Moore, Leanlove Navarra, Shaanti Olatunji, Alex Psirides, Yve Robertson, Hannah Smellie, Rhoze Sol Cruz, Raulle Sol Cuz, Shawn Sturland, Kate Tietjens, Bob Ure, Lawrence Walker, Jason Wright, Chelsea Young, Sara Andertun, Martin Annborn, Maria Nelderup, Lisa Boström, Susann Schrey, Marina Larsson, Fredrik Sjövall, Maria Alvarez Corral, Anthony Ashton, Nicholas J Cortes, Denise Griffin, Nycola Muchenje, McDonald Mupudzi, Dawn Trodd, Leonie Benham, Zena Bradshaw, Gemma Brown, Janette Brown, Jason Cupitt, Lisa Elawamy, Alan Fahey, James Glen, Shamina Hankinson, Gareth Hardy, Jazmine McCooey, Sam Remnant, Ella Riedel, Emma Stoddard, Bhagawathi Suryanarayanan, Lauren Thornborough, Emma Ward, Scott Warden, Conor Wilkinson, Jeremy Bewley, Anna Chillingworth, Georgia Efford, Zoe Garland, Lisa Grimmer, Rebekah Johnson, Katie Sweet, Denise Webster, Kim Kim Wright, Mandy Austin, Vallish Bhardwaj, Stacey Cotterell, Fiona McNeela, Victoria Mead, Lauren Perkins, Jayachandran Radhakrishnan, Sue Smolen, Christopher Westall, David Antcliffe, Ziortza Fernandez, Eleanor Jepson, Roceld Rojo, Anita Tamang Gurung, Maie Templeton, Delores Beach, Melanie Colegrove, Maria Faulkner, Laura McKay, Jos Wickett, Laurence Wilson, Zakaulla Belagodu, Ryan Coe, Katy Collins, Charlotte Kamundi, Naomi Oakley, Carmel Stuart, Nikitas Nikitas, Ana Sanchez-Rodriguez, Kayleigh Spencer, Liana Stapleton, Bethan Stowe, Colin Wells, Sarah Doyle, Stephanie Dukes, Sarah Horton, James Rees, Mark Shortland, Ruth Thomas, Sophie Webber, Trish Williams, Lauren Butler, Leigh Dunn, Arti Gulati, Jonathan Shelton, Yvonne Bland, Lianne Chapman, Rozzie Dolman, George Evetts, Danni Greener, Istvan Kajtor, Stephen Lewis, Cat Lumby, Helen Rayner, Susanne Cathcart, Pamela MacTavish, Kathryn Puxty, Christine Aitken, Elizabeth Boyd, Julie Buckley, Charlene Hamilton, Ilkin Kasmani, Thomas Keast, Phil McCall, Ruth McLaren, Ben Shelley, Sonia Sousa Arias, Jenny Wong, Susan Anderson, Eleanor Andrews, Janine Birch, Emma Collins, Mark Forrest, Surpreet Grewal, Kate Hammerton, Andrew Holland, Robin Jootun, Ryan O’Leary, Kyaw Pyae Soan, Carl Stevenson, Samantha Summers, Laura Troth, Louise Foster, Andrew Gratrix, Matthew Hines, Victoria Martinson, Vanessa Rivers, Elizabeth Stones, Sarah Bartholomew, Stephanie Bell, Kate Turner, Karen Winter, Uwe Franke, Evie Headlam, Keith Hugill, Jessica Jones, Abigail List, Joanne Morley, Tracy Ruddick, Amy Thompson, Nikkita Adams, Emma Clarey, Maeve Cockrell, Ele Corcoran, Maria Depante, Clare Finney, Aparna George, Philip Hopkins, Nauman Hussain, Reena Mehta, Kevin O'Reilly, Mandeep Phull, John Smith, Mandy Gill, Jill Kirk, Pulak Paul, Sarah Shelton, Hanan Abdullise, Samantha Bacciarelli, Julia Balcioglu, Isabel Bradley, Sabrina Carta, Rebecca Crowe, Marion Gillespie, Margaret Grout, Rosaleen Herdman-Grant, Olumayowa Ogunwemimo, Nicole Richard, Kathryn Sollesta, Andrew Swain, Joan Willis, Miriam Davey, Rebecca Seaman, James Wood, Iram Ahmed, Rebecca Collins, Tessa Glazebrook, Paul Hayden, Thyra Khyere Diaborr, Robert Musalagani, Linda Ofori, Vonganyi Ogbeide, Sandra Sowah, Rebecca Squires, Louise Mew, James Pocock, Richard Stewart, Sara Beth Sutherland, Pauline Austin , Louise Cabrelli, Matthew Casey, Susan Chapman, Hayley McKie, Jessica Reynolds, Tracy Smith, Gail Waddell, Jack Wilkinson, Bryan Yates, Ali Alayan, Andrew Ashcroft, Sarah Buckley, Elizabeth Denis, Lucy Gurr, Amy Major, Alex Metcalfe, Alice Poole, Alistair Rose, Brendan Sloan, Sharwend Supermanian, Nicola Thompson, Katie Wilson, Julie Camsooksai, Yasmin De’Ath, Sarah Jenkins, Emma Langridge, Rebecca Miln, Sarah Patch, Magda Pomichowska, Henrik Reschreiter, Suzanne Roffe, Sarah Savage, Harriet Noble, Helen Claridge, Aimi Collins, Zoe Daly, Dovy Domingo, James McNicholas, Angie Nown, Steve Rose, Mansoor Bangash, Colin Bergin, Ronald Carrera, Amy Clark, Lauren Cooper, Natalie Dooley, Karen Ellis, Emma Fellows, Stephanie Goundry, Samantha Harkett, Saffron King, Tracy Mason, Aoife Neal, Alex Newton-Cox, Dhruv Parekh, Jaimin Patel, Christopher Sheridan, Hazel Smith, Elaine Spruce, Sam Bosompem, Parveen Dugh, Mariha Khalid, Lace Paulyn Rosaroso, Mandeep K Phull, Tatiana Pogreban, Saima Ashraf, Marc Chikhani, Louise Conner, Martin Dent, Daniel Harvey, Treesa Joseph, Megan Meredith, Lucy Morris, Cecilia Peters, Lucy Ryan, Julia Sampson, Anju Thomas, Catherine Walton, Shauna Bartley, Parminder Bhuie, Sabi Gurung Rai, Nicola Jacques, Andrew Walden, Madhu Balasubramaniam, Hugo Buckley, Scott Latham, Emily Bevan, Arthur Goldsmith, Irina Grecu, Jane Martin, Simon Williams, Caroline Wrey Brown, Amaia Arrieta, Maria Fernandez, Alex Fowler, Ryan Haines, Mareena Joseph, Tim Martin, Filipa Santos, Fatima Seidu, Ruzena Uddin, Parjam Zolfaghari, Claudio Addari, Sekina Bakare, Lauren Barraclough, Thomas Bemand, Ethel Black, Matt Clayton, Arnold Dela Rosa, Luke Edwards, Hugh Furness, Richard Gordon-Williams, Nicole Greenshields, Natalie Hester, Francesca Holden, Ryan Howle, Emma Hunt, Aatif Husain, Sultan Iqbal, Venkateswaran Jambunathan, Shaman Jhanji, Ahalya Kadirvelarasan, Harriet Kemp, Suzannah Lant, Sarah Loftus, Sam Maese, Laura Matthews, Olivia Morley, Kshiteeja Naik, Isabel Norris, Nicola Ocean, Luke Parker, Amee Patel, Shivali Patel, Ravishankar Raobaikady, Martin Shao Foong Chong, William Sherwood, Sam Smith, Prakhar Srilastava, Sharjeel Tahir, Shamil Tanna, Kate Tatham, Benjamin Thomas, Pete Thomas, Shree Voralia, Kritchai Vutipongsatorn, Zoszka Webb, Tanith Westerman, Alasdair Wills, Hafsana Ali, Michele Bossy, Naomi Boyer, Letitia Bullman, Dorota Burda, Paula Carveli, Sandra Chmielewska, Daniel Cottam, Nichalus Dawson, Jeanny Del Socorro, Lui Forni, James Hilton, Sherin John, Justin Kirk-Bayley, Donna May Sanga, Kathryn Mcintosh, Jame McKinley, Rugaia Montaser, Tahir Nasser, Razan Nour, Elizabeth Poter, Stephanie Rouse, Armorel Salberg, Joe Tooley, Emma Tyson, Jerik Verula, Eva Wilson, Waldtraud Wutte, Emma Boxall, Kathryn Cawley, Joy Dearden, Reece Doonan, John MacDonald, Danielle McLaughlan, Alice Baker, Clare Bolger, Rachel Burnish, Michael Carter, Rebecca Cusack, Susan Jackson, Karen Salmon, Lijun Ding, Sarah Farnell Ward, Helen Farrah, Geraldine Gray, Pamela Kabungo, Susannah Leaver, Romina Pepermans Saluzzio, Christine Sicat, Maria Thanasi, Vince Ventura, Nikki Yun, Dorota Banach, Anthony Gordon, Amal Mohammed, Ehsan Ahmadnia, Mike Barker, Aneta Bociek, Lynda Cameron, Fabiola D’Amato, Fraser Hanks, Sarah Khorshid, Rosario Lim, Shelley Lorah, Kyma Morera, Marlies Ostermann, Gill Radcliffe, Chris Remmington, Natasha Thaladi, Duncan Wyncoll, Judith Abrams, Oliver Dare, Geraldine Hambrook, Katarina Manso, Elizabeth McKerrow, Pradeep Shanmugasundaram, Sarah Cornell, Alistair Roy, Lindsey Woods, Hayley Dolan, Thomas Billyward, Pamela Bremmer, Carl Hawkins, Sophie Jackson, Geraldine Ward, Michele Clark, Vijay Jagannathan, Sarah Purvis, Pam Race, Thomas Robb, Simon Sinclair, Jenny Brooks, Jade Cole, Michelle Davies, Rhys Davies, Helen Hill, Matt Morgan, Craig Spencer, Emma Thomas, Angharad Williams, Chiara Ellis, Elvira Hoxha, Valerie Page, Xiaobei Zhao, Nick Ivin, Rachel Johnston, Louise Ma, Anezka Pratley, Aine Ruttledge, Kathryn Simpson, Greg Barton, Anthony Cochrane, Clare Harrop, Chelcie Jewitt, Charlotte Preston, Karen Shuker
Journal: JAMA (2024)

Importance Whether β-lactam antibiotics administered by continuous compared with intermittent infusion reduces the risk of death in patients with sepsis is uncertain. Objective To evaluate whether continuous vs intermittent infusion of a β-lactam antibiotic (piperacillin-tazobactam or meropenem) results in decreased all-cause mortality at 90 days in critically ill patients with sepsis. Design, Setting, and Participants An international, open-label, randomized clinical trial conducted in 104 intensive care units (ICUs) in Australia, Belgium, France, Malaysia, New Zealand, Sweden, and the United Kingdom. Recruitment occurred from March 26, 2018, to January 11, 2023, with follow-up completed on April 12, 2023. Participants were critically ill adults (≥18 years) treated with piperacillin-tazobactam or meropenem for sepsis. Intervention Eligible patients were randomized to receive an equivalent 24-hour dose of a β-lactam antibiotic by either continuous (n = 3498) or intermittent (n = 3533) infusion for a clinician-determined duration of treatment or until ICU discharge, whichever occurred first. Main Outcomes and Measures The primary outcome was all-cause mortality within 90 days after randomization. Secondary outcomes were clinical cure up to 14 days after randomization; new acquisition, colonization, or infection with a multiresistant organism or Clostridioides difficile infection up to 14 days after randomization; ICU mortality; and in-hospital mortality. Results Among 7202 randomized participants, 7031 (mean [SD] age, 59 [16] years; 2423 women [35%]) met consent requirements for inclusion in the primary analysis (97.6%). Within 90 days, 864 of 3474 patients (24.9%) assigned to receive continuous infusion had died compared with 939 of 3507 (26.8%) assigned intermittent infusion (absolute difference, −1.9% [95% CI, −4.9% to 1.1%]; odds ratio, 0.91 [95% CI, 0.81 to 1.01]; P = .08). Clinical cure was higher in the continuous vs intermittent infusion group (1930/3467 [55.7%] and 1744/3491 [50.0%], respectively; absolute difference, 5.7% [95% CI, 2.4% to 9.1%]). Other secondary outcomes were not statistically different. Conclusions and Relevance The observed difference in 90-day mortality between continuous vs intermittent infusions of β-lactam antibiotics did not meet statistical significance in the primary analysis. However, the confidence interval around the effect estimate includes the possibility of both no important effect and a clinically important benefit in the use of continuous infusions in this group of patients. Trial Registration ClinicalTrials.gov Identifier: NCT03213990