Continuous vs Intermittent β-Lactam Antibiotic Infusions in Critically Ill Patients With Sepsis: The BLING III Randomized Clinical Trial. Dulhunty, J. M., Brett, S. J., De Waele, J. J., Rajbhandari, D., Billot, L., Cotta, M. O., Davis, J. S., Finfer, S., Hammond, N. E., Knowles, S., Liu, X., McGuinness, S., Mysore, J., Paterson, D. L., Peake, S., Rhodes, A., Roberts, J. A., Roger, C., Shirwadkar, C., Starr, T., Taylor, C., Myburgh, J. A., Lipman, J., BLING III Study Investigators, Bellomo, R., Eastwood, G., Peck, L., Young, H., Cheng, A., Lau, L., Luciuk, M., Muteitha, M., Saxena, M., Boschert, C., Chimunda, T., Knott, C., Smith, J., Nand, K., Sara, T., Chan, P., Duke, G., Dyett, J., Gellie, K., Hunter, S., Kaufman, M., Roodenburg, O., Veto, J., Affleck, J., Ramanan, M., Ratcliffe, M., Tabah, A., Warhurst, T., Gough, M., Houbert, M., Pitman, J., Tallott, M., Winearls, J., Donovan, S., Ellis, K., Gaur, A., Keehan, M., Kelty, A., Turner, E., Bierl, C., Brinkerhoff, G., Bush, D., Poulter, A., Sunkara, K., Cooper, M., Morrison, L., Sane, S., Sutton, J., White, H., Biradar, V., Sanap, M., Soar, N., Davis, M., Harward, M., Jones, C., Mackay, J., McGuinness, N., Meye, J., Saylor, E., Suliman, A., Tabah, A., Venz, E., Walsham, J., Wetzig, K., Kurenda, C., Williams, P., Baker, S., Duroux, M., Jacobs, K., Pollock, H., Shone, S., Butler, J., Fourie, C., Kirrane, M., Lassig-Smith, M., Lindsay, D., Livermore, A., McConnochie, B., Murray, L., Peacock, G., Stuart, J., Agarwal, S., Phillips, M., Smyth, K., Cooper, D., McAllister, R., Ali Abdelhamid, Y., Barge, D., Byrne, K., Deane, A., Doherty, S., Iles, S., Jelbart, B., Rechnitzer, T., Ashelford, A., Bass, F., Bradford, C., Delaney, A., Gatward, J., Harris, R., Janin, P., Lee, R., Limbrey, E., Mar, S., Pallas, N., Pilowsky, J., Ross, M., Stedman, W., Tokumitsu, M., Yarad, E., Alborzi, M., Buhr, H., Coles, J., Gattas, D., Inskip, D., Ito, A., Miller, J., Reynolds, C., Rudham, S., Bone, A., Cattigan, C., Elderkin, T., Salerno, T., Cohen, J., Davie, A., Owens, A., Purcell, R., Venkatesh, B., Bowen, D., Clark, P., Hamidi, M., Joy, J., Kong, J., Nayyar, V., Cruysberghs, K., Jorens, P., Vertongen, P., Diltoer, M., Van Malderen, M. C., Joosten, A., Van Cutsem, M., Abbenhuijs, C., Durand, D., Matumikina, N., Taccone, F., Bracke, S., De Coster, L., De Crop, L., De Smeytere, A., Van Hecke, J., Vermeiren, D., Heerman, J., Ryckaert, S., Van Damme, A., De Schryver, N., Thirifays, A., Fannes, E., Van Regenmortel, N., Alauzet, C., Belveyre, T., Breistroff, J., Gutehrle, A., Novy, E., Saint Gilles, M., Bonnefoy, M., Clavier, A., Ducq, P., Frouin, A., Moschietto, S., Touzet, M., Dahyot-Fizelier, C., Jamet, A., Kostencovska, A., Saint Genis, Q., Alaya, S., Mofredj, A., Boutin, C., Elotmani, L., Mahul, M., Muller, L., Perin, N., Che Omar, S., Ismet, S., Jamaludin, N. I. M., Mat Amin, M. F., Mazlan, M. Z., Mohd Nor, H., Mohd Sukri, N., Nizar, N. A., Omar, M., Roslan, E. N., Salmuna, Z. N., Tuan Mohd Adnan, T. Z. S., W Hassan, W M. N., Yaakub, H. A., Hasan, M. S., Mohamad, M., Othman Jailani, M. I., Sulaiman, H., Ali, F., Butler, M., Cowdrey, K., Gilder, E., Hallion, J., Hennessy, I., Neal, P., O’Connor, K., Parke, R., Ryan, S., Woollett (Now Robertson), M., Chen, Y., McArthur, C., McConnochie, R., O’Connor, C., Simmonds, C., Burke, B., Doyle, T., Mehrtens, J., Morgan, S., Morris, A., Van Der Heyden, K., Girijadevi, D., Lai, V., Song, R., Williams, T., Butler, A., Fiske, C., Forrest, A., Furborough, E., Martynoga, R., Nair, R., Rogers, S., Schischka, L., Trask, K., Aguilar, A., Barnes, C., Barry, B., Beehre, N., Delaney, K., Dinsdale, D., Grayson, K., Hendry, D., Hunt, A., Jane, A., Judd, H., Latimer-Bell, C., Lawrence, C., Lesona, E., Martin, R., Mckay Vucago, A., Millington, A., Moore, J., Navarra, L., Olatunji, S., Psirides, A., Robertson, Y., Smellie, H., Sol Cruz, R., Sol Cuz, R., Sturland, S., Tietjens, K., Ure, B., Walker, L., Wright, J., Young, C., Andertun, S., Annborn, M., Nelderup, M., Boström, L., Schrey, S., Larsson, M., Sjövall, F., Alvarez Corral, M., Ashton, A., Cortes, N. J, Griffin, D., Muchenje, N., Mupudzi, M., Trodd, D., Benham, L., Bradshaw, Z., Brown, G., Brown, J., Cupitt, J., Elawamy, L., Fahey, A., Glen, J., Hankinson, S., Hardy, G., McCooey, J., Remnant, S., Riedel, E., Stoddard, E., Suryanarayanan, B., Thornborough, L., Ward, E., Warden, S., Wilkinson, C., Bewley, J., Chillingworth, A., Efford, G., Garland, Z., Grimmer, L., Johnson, R., Sweet, K., Webster, D., Kim Wright, K., Austin, M., Bhardwaj, V., Cotterell, S., McNeela, F., Mead, V., Perkins, L., Radhakrishnan, J., Smolen, S., Westall, C., Antcliffe, D., Fernandez, Z., Jepson, E., Rojo, R., Tamang Gurung, A., Templeton, M., Beach, D., Colegrove, M., Faulkner, M., McKay, L., Wickett, J., Wilson, L., Belagodu, Z., Coe, R., Collins, K., Kamundi, C., Oakley, N., Stuart, C., Nikitas, N., Sanchez-Rodriguez, A., Spencer, K., Stapleton, L., Stowe, B., Wells, C., Doyle, S., Dukes, S., Horton, S., Rees, J., Shortland, M., Thomas, R., Webber, S., Williams, T., Butler, L., Dunn, L., Gulati, A., Shelton, J., Bland, Y., Chapman, L., Dolman, R., Evetts, G., Greener, D., Kajtor, I., Lewis, S., Lumby, C., Rayner, H., Cathcart, S., MacTavish, P., Puxty, K., Aitken, C., Boyd, E., Buckley, J., Hamilton, C., Kasmani, I., Keast, T., McCall, P., McLaren, R., Shelley, B., Sousa Arias, S., Wong, J., Anderson, S., Andrews, E., Birch, J., Collins, E., Forrest, M., Grewal, S., Hammerton, K., Holland, A., Jootun, R., O’Leary, R., Pyae Soan, K., Stevenson, C., Summers, S., Troth, L., Foster, L., Gratrix, A., Hines, M., Martinson, V., Rivers, V., Stones, E., Bartholomew, S., Bell, S., Turner, K., Winter, K., Franke, U., Headlam, E., Hugill, K., Jones, J., List, A., Morley, J., Ruddick, T., Thompson, A., Adams, N., Clarey, E., Cockrell, M., Corcoran, E., Depante, M., Finney, C., George, A., Hopkins, P., Hussain, N., Mehta, R., O'Reilly, K., Phull, M., Smith, J., Gill, M., Kirk, J., Paul, P., Shelton, S., Abdullise, H., Bacciarelli, S., Balcioglu, J., Bradley, I., Carta, S., Crowe, R., Gillespie, M., Grout, M., Herdman-Grant, R., Ogunwemimo, O., Richard, N., Sollesta, K., Swain, A., Willis, J., Davey, M., Seaman, R., Wood, J., Ahmed, I., Collins, R., Glazebrook, T., Hayden, P., Khyere Diaborr, T., Musalagani, R., Ofori, L., Ogbeide, V., Sowah, S., Squires, R., Mew, L., Pocock, J., Stewart, R., Sutherland, S. B., Austin, P., Cabrelli, L., Casey, M., Chapman, S., McKie, H., Reynolds, J., Smith, T., Waddell, G., Wilkinson, J., Yates, B., Alayan, A., Ashcroft, A., Buckley, S., Denis, E., Gurr, L., Major, A., Metcalfe, A., Poole, A., Rose, A., Sloan, B., Supermanian, S., Thompson, N., Wilson, K., Camsooksai, J., De’Ath, Y., Jenkins, S., Langridge, E., Miln, R., Patch, S., Pomichowska, M., Reschreiter, H., Roffe, S., Savage, S., Noble, H., Claridge, H., Collins, A., Daly, Z., Domingo, D., McNicholas, J., Nown, A., Rose, S., Bangash, M., Bergin, C., Carrera, R., Clark, A., Cooper, L., Dooley, N., Ellis, K., Fellows, E., Goundry, S., Harkett, S., King, S., Mason, T., Neal, A., Newton-Cox, A., Parekh, D., Patel, J., Sheridan, C., Smith, H., Spruce, E., Bosompem, S., Dugh, P., Khalid, M., Paulyn Rosaroso, L., Phull, M. K, Pogreban, T., Ashraf, S., Chikhani, M., Conner, L., Dent, M., Harvey, D., Joseph, T., Meredith, M., Morris, L., Peters, C., Ryan, L., Sampson, J., Thomas, A., Walton, C., Bartley, S., Bhuie, P., Gurung Rai, S., Jacques, N., Walden, A., Balasubramaniam, M., Buckley, H., Latham, S., Bevan, E., Goldsmith, A., Grecu, I., Martin, J., Williams, S., Wrey Brown, C., Arrieta, A., Fernandez, M., Fowler, A., Haines, R., Joseph, M., Martin, T., Santos, F., Seidu, F., Uddin, R., Zolfaghari, P., Addari, C., Bakare, S., Barraclough, L., Bemand, T., Black, E., Clayton, M., Dela Rosa, A., Edwards, L., Furness, H., Gordon-Williams, R., Greenshields, N., Hester, N., Holden, F., Howle, R., Hunt, E., Husain, A., Iqbal, S., Jambunathan, V., Jhanji, S., Kadirvelarasan, A., Kemp, H., Lant, S., Loftus, S., Maese, S., Matthews, L., Morley, O., Naik, K., Norris, I., Ocean, N., Parker, L., Patel, A., Patel, S., Raobaikady, R., Shao Foong Chong, M., Sherwood, W., Smith, S., Srilastava, P., Tahir, S., Tanna, S., Tatham, K., Thomas, B., Thomas, P., Voralia, S., Vutipongsatorn, K., Webb, Z., Westerman, T., Wills, A., Ali, H., Bossy, M., Boyer, N., Bullman, L., Burda, D., Carveli, P., Chmielewska, S., Cottam, D., Dawson, N., Del Socorro, J., Forni, L., Hilton, J., John, S., Kirk-Bayley, J., May Sanga, D., Mcintosh, K., McKinley, J., Montaser, R., Nasser, T., Nour, R., Poter, E., Rouse, S., Salberg, A., Tooley, J., Tyson, E., Verula, J., Wilson, E., Wutte, W., Boxall, E., Cawley, K., Dearden, J., Doonan, R., MacDonald, J., McLaughlan, D., Baker, A., Bolger, C., Burnish, R., Carter, M., Cusack, R., Jackson, S., Salmon, K., Ding, L., Farnell Ward, S., Farrah, H., Gray, G., Kabungo, P., Leaver, S., Pepermans Saluzzio, R., Sicat, C., Thanasi, M., Ventura, V., Yun, N., Banach, D., Gordon, A., Mohammed, A., Ahmadnia, E., Barker, M., Bociek, A., Cameron, L., D’Amato, F., Hanks, F., Khorshid, S., Lim, R., Lorah, S., Morera, K., Ostermann, M., Radcliffe, G., Remmington, C., Thaladi, N., Wyncoll, D., Abrams, J., Dare, O., Hambrook, G., Manso, K., McKerrow, E., Shanmugasundaram, P., Cornell, S., Roy, A., Woods, L., Dolan, H., Billyward, T., Bremmer, P., Hawkins, C., Jackson, S., Ward, G., Clark, M., Jagannathan, V., Purvis, S., Race, P., Robb, T., Sinclair, S., Brooks, J., Cole, J., Davies, M., Davies, R., Hill, H., Morgan, M., Spencer, C., Thomas, E., Williams, A., Ellis, C., Hoxha, E., Page, V., Zhao, X., Ivin, N., Johnston, R., Ma, L., Pratley, A., Ruttledge, A., Simpson, K., Barton, G., Cochrane, A., Harrop, C., Jewitt, C., Preston, C., & Shuker, K. JAMA, June, 2024.
Paper doi abstract bibtex 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
@article{dulhunty_continuous_2024,
title = {Continuous vs {Intermittent} β-{Lactam} {Antibiotic} {Infusions} in {Critically} {Ill} {Patients} {With} {Sepsis}: {The} {BLING} {III} {Randomized} {Clinical} {Trial}},
issn = {0098-7484},
shorttitle = {Continuous vs {Intermittent} β-{Lactam} {Antibiotic} {Infusions} in {Critically} {Ill} {Patients} {With} {Sepsis}},
url = {https://jamanetwork.com/journals/jama/fullarticle/2819971},
doi = {10.1001/jama.2024.9779},
abstract = {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},
language = {en},
urldate = {2024-08-11},
journal = {JAMA},
author = {Dulhunty, Joel M. and Brett, Stephen J. and De Waele, Jan J. and Rajbhandari, Dorrilyn and Billot, Laurent and Cotta, Menino O. and Davis, Joshua S. and Finfer, Simon and Hammond, Naomi E. and Knowles, Serena and Liu, Xiaoqiu and McGuinness, Shay and Mysore, Jayanthi and Paterson, David L. and Peake, Sandra and Rhodes, Andrew and Roberts, Jason A. and Roger, Claire and Shirwadkar, Charudatt and Starr, Therese and Taylor, Colman and Myburgh, John A. and Lipman, Jeffrey and {BLING III Study Investigators} and Bellomo, Rinaldo and Eastwood, Glenn and Peck, Leah and Young, Helen and Cheng, Andrew and Lau, Luke and Luciuk, Magdalena and Muteitha, Margaret and Saxena, Manoj and Boschert, Catherine and Chimunda, Timothy and Knott, Cameron and Smith, Julie and Nand, Kiran and Sara, Treena and Chan, Peter and Duke, Graeme and Dyett, John and Gellie, Kym and Hunter, Stephanie and Kaufman, Melissa and Roodenburg, Owen and Veto, Joseph and Affleck, Julia and Ramanan, Mahesh and Ratcliffe, Megan and Tabah, Alexis and Warhurst, Timothy and Gough, Maimoonbe and Houbert, Maree and Pitman, Julie and Tallott, Mandy and Winearls, James and Donovan, Shelley and Ellis, Katrina and Gaur, Atul and Keehan, Mary and Kelty, Amy and Turner, Elisha and Bierl, Cynthia and Brinkerhoff, Gail and Bush, Dustin and Poulter, Amber-Louise and Sunkara, Krishna and Cooper, Melanie and Morrison, Lynette and Sane, Sunil and Sutton, Joanne and White, Hayden and Biradar, Vishwanath and Sanap, Milind and Soar, Natalie and Davis, Megan and Harward, Meg and Jones, Cassie and Mackay, Josie and McGuinness, Niki and Meye, Jason and Saylor, Emma and Suliman, Adam and Tabah, Alex and Venz, Ellen and Walsham, James and Wetzig, Krista and Kurenda, Catherine and Williams, Patricia and Baker, Stuart and Duroux, Maree and Jacobs, Kylie and Pollock, Hamish and Shone, Sam and Butler, Jenie and Fourie, Cheryl and Kirrane, Marianne and Lassig-Smith, Melissa and Lindsay, Daisy and Livermore, Amelia and McConnochie, Bree-Yana and Murray, Lynn and Peacock, Georgina and Stuart, Janine and Agarwal, Sidharth and Phillips, Margaret and Smyth, Kirsty and Cooper, David and McAllister, Rick and Ali Abdelhamid, Yasmine and Barge, Deborah and Byrne, Kathleen and Deane, Adam and Doherty, Sarah and Iles, Simon and Jelbart, Brie and Rechnitzer, Thomas and Ashelford, Angela and Bass, Frances and Bradford, Celia and Delaney, Anthony and Gatward, Jonathan and Harris, Roger and Janin, Pierre and Lee, Richard and Limbrey, Elizabeth and Mar, Sharon and Pallas, Naomi and Pilowsky, Julia and Ross, Melanie and Stedman, Wade and Tokumitsu, Miyuki and Yarad, Elizabeth and Alborzi, Maryam and Buhr, Heidi and Coles, Jennifer and Gattas, David and Inskip, Deborah and Ito, Asako and Miller, Jennene and Reynolds, Claire and Rudham, Sam and Bone, Alison and Cattigan, Claire and Elderkin, Tania and Salerno, Tania and Cohen, Jeremy and Davie, Amanda and Owens, Amy and Purcell, Roslyn and Venkatesh, Balasubramanian and Bowen, David and Clark, Peter and Hamidi, Mohammad and Joy, Jenyfer and Kong, Jing and Nayyar, Vineet and Cruysberghs, Kaatje and Jorens, Philippe and Vertongen, Petra and Diltoer, Marc and Van Malderen, Marie Claire and Joosten, Anne and Van Cutsem, Maxime and Abbenhuijs, Caroline and Durand, Dominique and Matumikina, Nancy and Taccone, Fabio and Bracke, Stephanie and De Coster, Lesley and De Crop, Luc and De Smeytere, Anouska and Van Hecke, Jolien and Vermeiren, Daisy and Heerman, Jan and Ryckaert, Steffi and Van Damme, Annelies and De Schryver, Nicolas and Thirifays, Anne and Fannes, Els and Van Regenmortel, Niels and Alauzet, Corentine and Belveyre, Thibaut and Breistroff, Jessica and Gutehrle, Aurélie and Novy, Emmanuel and Saint Gilles, Maximilien and Bonnefoy, Marie and Clavier, Audrey and Ducq, Pierre and Frouin, Antoine and Moschietto, Sébastien and Touzet, Marion and Dahyot-Fizelier, Claire and Jamet, Angéline and Kostencovska, Angela and Saint Genis, Quentin and Alaya, Sami and Mofredj, Ali and Boutin, Caroline and Elotmani, Loubna and Mahul, Martin and Muller, Laurent and Perin, Nicolas and Che Omar, Sanihah and Ismet, Suki and Jamaludin, Noor Iellieya Maisarah and Mat Amin, Md Fadhil and Mazlan, Mohd Zulfakar and Mohd Nor, Husna and Mohd Sukri, Nabila and Nizar, Nurul Amira and Omar, Mahamarowi and Roslan, Era Nabilah and Salmuna, Zeti Norfidiyati and Tuan Mohd Adnan, Tuan Zulfadli Syazwan and W Hassan, W Mohd Nazarudin and Yaakub, Halimatun Arwa and Hasan, Mohd Shahnaz and Mohamad, Marhainie and Othman Jailani, Mohamad Irfan and Sulaiman, Helmi and Ali, Farisha and Butler, Magdalena and Cowdrey, Keri-Anne and Gilder, Eileen and Hallion, Jane and Hennessy, Immanuel and Neal, Philippa and O’Connor, Karina and Parke, Rachael and Ryan, Samantha and Woollett (Now Robertson), Melissa and Chen, Yan and McArthur, Colin and McConnochie, Rachael and O’Connor, Caroline and Simmonds, Catherine and Burke, Brandon and Doyle, Tara and Mehrtens, Jan and Morgan, Stacey and Morris, Anna and Van Der Heyden, Kym and Girijadevi, Dinu and Lai, Vivian and Song, Rima and Williams, Tony and Butler, Amelia and Fiske, Caitriona and Forrest, Annette and Furborough, Erin and Martynoga, Robert and Nair, Renesh and Rogers, Sarah and Schischka, Livia and Trask, Kara and Aguilar, April and Barnes, Colin and Barry, Ben and Beehre, Niña and Delaney, Kirsha and Dinsdale, Dick and Grayson, Kim and Hendry, Deb and Hunt, Anna and Jane, April and Judd, Harriet and Latimer-Bell, Charlotte and Lawrence, Cassie and Lesona, Eden and Martin, Rosie and Mckay Vucago, Agnes and Millington, Alex and Moore, James and Navarra, Leanlove and Olatunji, Shaanti and Psirides, Alex and Robertson, Yve and Smellie, Hannah and Sol Cruz, Rhoze and Sol Cuz, Raulle and Sturland, Shawn and Tietjens, Kate and Ure, Bob and Walker, Lawrence and Wright, Jason and Young, Chelsea and Andertun, Sara and Annborn, Martin and Nelderup, Maria and Boström, Lisa and Schrey, Susann and Larsson, Marina and Sjövall, Fredrik and Alvarez Corral, Maria and Ashton, Anthony and Cortes, Nicholas J and Griffin, Denise and Muchenje, Nycola and Mupudzi, McDonald and Trodd, Dawn and Benham, Leonie and Bradshaw, Zena and Brown, Gemma and Brown, Janette and Cupitt, Jason and Elawamy, Lisa and Fahey, Alan and Glen, James and Hankinson, Shamina and Hardy, Gareth and McCooey, Jazmine and Remnant, Sam and Riedel, Ella and Stoddard, Emma and Suryanarayanan, Bhagawathi and Thornborough, Lauren and Ward, Emma and Warden, Scott and Wilkinson, Conor and Bewley, Jeremy and Chillingworth, Anna and Efford, Georgia and Garland, Zoe and Grimmer, Lisa and Johnson, Rebekah and Sweet, Katie and Webster, Denise and Kim Wright, Kim and Austin, Mandy and Bhardwaj, Vallish and Cotterell, Stacey and McNeela, Fiona and Mead, Victoria and Perkins, Lauren and Radhakrishnan, Jayachandran and Smolen, Sue and Westall, Christopher and Antcliffe, David and Fernandez, Ziortza and Jepson, Eleanor and Rojo, Roceld and Tamang Gurung, Anita and Templeton, Maie and Beach, Delores and Colegrove, Melanie and Faulkner, Maria and McKay, Laura and Wickett, Jos and Wilson, Laurence and Belagodu, Zakaulla and Coe, Ryan and Collins, Katy and Kamundi, Charlotte and Oakley, Naomi and Stuart, Carmel and Nikitas, Nikitas and Sanchez-Rodriguez, Ana and Spencer, Kayleigh and Stapleton, Liana and Stowe, Bethan and Wells, Colin and Doyle, Sarah and Dukes, Stephanie and Horton, Sarah and Rees, James and Shortland, Mark and Thomas, Ruth and Webber, Sophie and Williams, Trish and Butler, Lauren and Dunn, Leigh and Gulati, Arti and Shelton, Jonathan and Bland, Yvonne and Chapman, Lianne and Dolman, Rozzie and Evetts, George and Greener, Danni and Kajtor, Istvan and Lewis, Stephen and Lumby, Cat and Rayner, Helen and Cathcart, Susanne and MacTavish, Pamela and Puxty, Kathryn and Aitken, Christine and Boyd, Elizabeth and Buckley, Julie and Hamilton, Charlene and Kasmani, Ilkin and Keast, Thomas and McCall, Phil and McLaren, Ruth and Shelley, Ben and Sousa Arias, Sonia and Wong, Jenny and Anderson, Susan and Andrews, Eleanor and Birch, Janine and Collins, Emma and Forrest, Mark and Grewal, Surpreet and Hammerton, Kate and Holland, Andrew and Jootun, Robin and O’Leary, Ryan and Pyae Soan, Kyaw and Stevenson, Carl and Summers, Samantha and Troth, Laura and Foster, Louise and Gratrix, Andrew and Hines, Matthew and Martinson, Victoria and Rivers, Vanessa and Stones, Elizabeth and Bartholomew, Sarah and Bell, Stephanie and Turner, Kate and Winter, Karen and Franke, Uwe and Headlam, Evie and Hugill, Keith and Jones, Jessica and List, Abigail and Morley, Joanne and Ruddick, Tracy and Thompson, Amy and Adams, Nikkita and Clarey, Emma and Cockrell, Maeve and Corcoran, Ele and Depante, Maria and Finney, Clare and George, Aparna and Hopkins, Philip and Hussain, Nauman and Mehta, Reena and O'Reilly, Kevin and Phull, Mandeep and Smith, John and Gill, Mandy and Kirk, Jill and Paul, Pulak and Shelton, Sarah and Abdullise, Hanan and Bacciarelli, Samantha and Balcioglu, Julia and Bradley, Isabel and Carta, Sabrina and Crowe, Rebecca and Gillespie, Marion and Grout, Margaret and Herdman-Grant, Rosaleen and Ogunwemimo, Olumayowa and Richard, Nicole and Sollesta, Kathryn and Swain, Andrew and Willis, Joan and Davey, Miriam and Seaman, Rebecca and Wood, James and Ahmed, Iram and Collins, Rebecca and Glazebrook, Tessa and Hayden, Paul and Khyere Diaborr, Thyra and Musalagani, Robert and Ofori, Linda and Ogbeide, Vonganyi and Sowah, Sandra and Squires, Rebecca and Mew, Louise and Pocock, James and Stewart, Richard and Sutherland, Sara Beth and Austin, Pauline and Cabrelli, Louise and Casey, Matthew and Chapman, Susan and McKie, Hayley and Reynolds, Jessica and Smith, Tracy and Waddell, Gail and Wilkinson, Jack and Yates, Bryan and Alayan, Ali and Ashcroft, Andrew and Buckley, Sarah and Denis, Elizabeth and Gurr, Lucy and Major, Amy and Metcalfe, Alex and Poole, Alice and Rose, Alistair and Sloan, Brendan and Supermanian, Sharwend and Thompson, Nicola and Wilson, Katie and Camsooksai, Julie and De’Ath, Yasmin and Jenkins, Sarah and Langridge, Emma and Miln, Rebecca and Patch, Sarah and Pomichowska, Magda and Reschreiter, Henrik and Roffe, Suzanne and Savage, Sarah and Noble, Harriet and Claridge, Helen and Collins, Aimi and Daly, Zoe and Domingo, Dovy and McNicholas, James and Nown, Angie and Rose, Steve and Bangash, Mansoor and Bergin, Colin and Carrera, Ronald and Clark, Amy and Cooper, Lauren and Dooley, Natalie and Ellis, Karen and Fellows, Emma and Goundry, Stephanie and Harkett, Samantha and King, Saffron and Mason, Tracy and Neal, Aoife and Newton-Cox, Alex and Parekh, Dhruv and Patel, Jaimin and Sheridan, Christopher and Smith, Hazel and Spruce, Elaine and Bosompem, Sam and Dugh, Parveen and Khalid, Mariha and Paulyn Rosaroso, Lace and Phull, Mandeep K and Pogreban, Tatiana and Ashraf, Saima and Chikhani, Marc and Conner, Louise and Dent, Martin and Harvey, Daniel and Joseph, Treesa 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Kadirvelarasan, Ahalya and Kemp, Harriet and Lant, Suzannah and Loftus, Sarah and Maese, Sam and Matthews, Laura and Morley, Olivia and Naik, Kshiteeja and Norris, Isabel and Ocean, Nicola and Parker, Luke and Patel, Amee and Patel, Shivali and Raobaikady, Ravishankar and Shao Foong Chong, Martin and Sherwood, William and Smith, Sam and Srilastava, Prakhar and Tahir, Sharjeel and Tanna, Shamil and Tatham, Kate and Thomas, Benjamin and Thomas, Pete and Voralia, Shree and Vutipongsatorn, Kritchai and Webb, Zoszka and Westerman, Tanith and Wills, Alasdair and Ali, Hafsana and Bossy, Michele and Boyer, Naomi and Bullman, Letitia and Burda, Dorota and Carveli, Paula and Chmielewska, Sandra and Cottam, Daniel and Dawson, Nichalus and Del Socorro, Jeanny and Forni, Lui and Hilton, James and John, Sherin and Kirk-Bayley, Justin and May Sanga, Donna and Mcintosh, Kathryn and McKinley, Jame and Montaser, Rugaia and Nasser, Tahir and Nour, Razan and Poter, Elizabeth and Rouse, Stephanie and 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Katarina and McKerrow, Elizabeth and Shanmugasundaram, Pradeep and Cornell, Sarah and Roy, Alistair and Woods, Lindsey and Dolan, Hayley and Billyward, Thomas and Bremmer, Pamela and Hawkins, Carl and Jackson, Sophie and Ward, Geraldine and Clark, Michele and Jagannathan, Vijay and Purvis, Sarah and Race, Pam and Robb, Thomas and Sinclair, Simon and Brooks, Jenny and Cole, Jade and Davies, Michelle and Davies, Rhys and Hill, Helen and Morgan, Matt and Spencer, Craig and Thomas, Emma and Williams, Angharad and Ellis, Chiara and Hoxha, Elvira and Page, Valerie and Zhao, Xiaobei and Ivin, Nick and Johnston, Rachel and Ma, Louise and Pratley, Anezka and Ruttledge, Aine and Simpson, Kathryn and Barton, Greg and Cochrane, Anthony and Harrop, Clare and Jewitt, Chelcie and Preston, Charlotte and Shuker, Karen},
month = jun,
year = {2024},
}
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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: 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= {Continuous vs {Intermittent} β-{Lactam} {Antibiotic} {Infusions} in {Critically} {Ill} {Patients} {With} {Sepsis}: {The} {BLING} {III} {Randomized} {Clinical} {Trial}},\n\tissn = {0098-7484},\n\tshorttitle = {Continuous vs {Intermittent} β-{Lactam} {Antibiotic} {Infusions} in {Critically} {Ill} {Patients} {With} {Sepsis}},\n\turl = {https://jamanetwork.com/journals/jama/fullarticle/2819971},\n\tdoi = {10.1001/jama.2024.9779},\n\tabstract = {Importance \n Whether β-lactam antibiotics administered by continuous compared with intermittent infusion reduces the risk of death in patients with sepsis is uncertain. \n \n \n Objective \n 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. \n \n \n Design, Setting, and Participants \n 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. \n \n \n Intervention \n 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. \n \n \n Main Outcomes and Measures \n \n 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 \n Clostridioides difficile \n infection up to 14 days after randomization; ICU mortality; and in-hospital mortality. \n \n \n \n Results \n \n 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]; \n P \n = .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. \n \n \n \n Conclusions and Relevance \n 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. \n \n \n Trial Registration \n \n ClinicalTrials.gov Identifier: \n NCT03213990},\n\tlanguage = {en},\n\turldate = {2024-08-11},\n\tjournal = {JAMA},\n\tauthor = {Dulhunty, Joel M. and Brett, Stephen J. and De Waele, Jan J. and Rajbhandari, Dorrilyn and Billot, Laurent and Cotta, Menino O. and Davis, Joshua S. and Finfer, Simon and Hammond, Naomi E. and Knowles, Serena and Liu, Xiaoqiu and McGuinness, Shay and Mysore, Jayanthi and Paterson, David L. and Peake, Sandra and Rhodes, Andrew and Roberts, Jason A. and Roger, Claire and Shirwadkar, Charudatt and Starr, Therese and Taylor, Colman and Myburgh, John A. and Lipman, Jeffrey and {BLING III Study Investigators} and Bellomo, Rinaldo and Eastwood, Glenn and Peck, Leah and Young, Helen and Cheng, Andrew and Lau, Luke and Luciuk, Magdalena and Muteitha, Margaret and Saxena, Manoj and Boschert, Catherine and Chimunda, Timothy and Knott, Cameron and Smith, Julie and Nand, Kiran and Sara, Treena and Chan, Peter and Duke, Graeme and Dyett, John and Gellie, Kym and Hunter, Stephanie and Kaufman, Melissa and Roodenburg, Owen and Veto, Joseph and Affleck, Julia and Ramanan, Mahesh and Ratcliffe, Megan and Tabah, Alexis and Warhurst, Timothy and Gough, Maimoonbe and Houbert, Maree and Pitman, Julie and Tallott, Mandy and Winearls, James and Donovan, Shelley and Ellis, Katrina and Gaur, Atul and Keehan, Mary and Kelty, Amy and Turner, Elisha and Bierl, Cynthia and Brinkerhoff, Gail and Bush, Dustin and Poulter, Amber-Louise and Sunkara, Krishna and Cooper, Melanie and Morrison, Lynette and Sane, Sunil and Sutton, Joanne and White, Hayden and Biradar, Vishwanath and Sanap, Milind and Soar, Natalie and Davis, Megan and Harward, Meg and Jones, Cassie and Mackay, Josie and McGuinness, Niki and Meye, Jason and Saylor, Emma 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