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