Prolonged vs Intermittent Infusions of β-Lactam Antibiotics in Adults With Sepsis or Septic Shock (2024)

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Original Investigation

Caring for the Critically Ill Patient

June12, 2024

Mohd H.Abdul-Aziz,BPharm, PhD1; Naomi E.Hammond,RN, PhD2,3; Stephen J.Brett,MD4; et al Menino O.Cotta,BPharm, PhD1; Jan J.De Waele,MD, PhD5; AnthonyDevaux,PhD6; Gian LucaDi Tanna,PhD6,7,8; Joel M.Dulhunty,MD, PhD2,9,10,11; HatemElkady,MD12; LarsEriksson,BA13; M. ShahnazHasan,MD14; Ayesha BibiKhan,MD15; JeffreyLipman,MD, DMed1,9,16,17; XiaoqiuLiu,PhD6,18; GiacomoMonti,MD19,20; JohnMyburgh,MD, PhD2,21; EmmanuelNovy,MD22,23; ShahedOmar,MD15; DorrilynRajbhandari,RN2; ClaireRoger,MD, PhD24,25; FredrikSjövall,MD, PhD26,27; IreneZaghi,MD28; AlbertoZangrillo,MD19,20; AnthonyDelaney,MD, PhD2,3; Jason A.Roberts,BPharm, PhD1,9,17,29

Author Affiliations Article Information

¹University of Queensland Centre for Clinical Research (UQCCR), Faculty of Medicine, The University of Queensland, Brisbane, Queensland, Australia
²Critical Care Program, The George Institute for Global Health and University of New South Wales, Sydney, New South Wales, Australia
³Malcolm Fisher Department of Intensive Care, Royal North Shore Hospital, Sydney, New South Wales, Australia
⁴Department of Surgery and Cancer, Imperial College, London, United Kingdom
See Also
β2-microglobulin expression is associated with aggressive histology, activated tumor immune milieu, and outcome in colon carcinoma
⁵Department of Intensive Care Medicine, Ghent University Hospital, Ghent, Belgium
⁶Statistics Division, The George Institute for Global Health and University of New South Wales, Sydney, New South Wales, Australia
⁷Department of Business Economics, Health and Social Care, University of Applied Sciences and Arts of Southern Switzerland, Manno, Switzerland
⁸Department of Clinical Research, University of Bern, Bern, Switzerland
⁹Department of Intensive Care Medicine, Royal Brisbane and Women’s Hospital, Brisbane, Queensland, Australia
¹⁰Redcliffe Hospital, Redcliffe, Queensland, Australia
¹¹Faculty of Medicine, The University of Queensland, Brisbane, Queensland, Australia
¹²Department of Intensive Care Medicine, Westmead Hospital, Sydney, New South Wales, Australia
¹³UQ Library, The University of Queensland, Brisbane, Queensland, Australia
¹⁴Department of Anesthesiology, Faculty of Medicine, University Malaya, Kuala Lumpur, Malaysia
¹⁵Division of Critical Care, University of Witwatersrand, Chris Hani Baragwanath Academic Hospital, Johannesburg, South Africa
¹⁶Jamieson Trauma Institute, Royal Brisbane and Women’s Hospital, Brisbane, Queensland, Australia
¹⁷Division of Anesthesiology Critical Care Emergency and Pain Medicine, Nîmes University Hospital, University of Montpellier, Nîmes, France
¹⁸School of Population Health, University of New South Wales, Sydney, New South Wales, Australia
¹⁹Department of Anesthesia and Intensive Care, IRCCS San Raffaele Scientific Institute, Milan, Italy
²⁰Vita-Salute San Raffaele University, Milan, Italy
²¹Department of Intensive Care, St George Hospital, Kogarah, New South Wales, Australia
²²Service d’anesthésie-réanimation et médicine péri-opératoire Brabois adulte, CHRU de Nancy, Nancy, France
²³Université de Lorraine, SIMPA, Nancy, France
²⁴Département d’anesthésie et réanimation, douleur et médecine d’urgence, CHU Carémeau, Nîmes, France
²⁵UR UM 103IMAGINE, Faculté de Médecine, Montpellier Université, Nîmes, France
²⁶Intensive and Perioperative Care, Skåne University Hospital, Malmö, Sweden
²⁷Department of Clinical Sciences, Lund University, Lund, Sweden
²⁸Department of Diagnostic and Experimental Medicine, University of Bologna, Bologna, Italy
²⁹Herston Infectious Diseases Institute (HeIDI), Metro North Health, Brisbane, Queensland, Australia

JAMA. Published online June 12, 2024. doi:10.1001/jama.2024.9803

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Editorial Resolving the Dilemma on Continuous vs Intermittent β-Lactam Antibiotics in Sepsis
W. JoostWiersinga,MD, PhD, MBA; Michiel A.van Agtmael,MD, PhD

JAMA

Original Investigation Selective Decontamination of the Digestive Tract and Hospital Mortality in Critically Ill Patients
The SuDDICU Investigators for the Australian and New Zealand Intensive Care Society Clinical Trials Group; CatherineBoschert; EmmaBroadfield; TimothyChimunda; JasonFletcher; CameronKnott; SanjayPorwal; JulieSmith; DeepakBhonagiri; MoniqueLeijten; SandhyaNarayan; David Sanchez; PetaSaunders; CarliSherriff; JonathanBarrett; GabrielleHanlon; SarahJelly-Butterworth; JulieO'Donnell; JudithWatson; ShaileshBihari; JuliaBrown; SharonComerford; RussellLaver; JoAnneMcIntyre; TapaswiShrestha; JinXia; SamanthaBates; GerardFennessy; CraigFrench; SathyajithKootayi; FionaMarshall; RebeccaMcEldrew; ForbesMcGain; RebeccaMorgan; JohnMulder; AnnaTippett; MiriamTowns; EllieBarker; ShelleyDonovan; KatrinaEllis; Atul Gaur; HannahGibbons; RebeccaGregory; EloiseHair; MaryKeehan; Jess Naumoff; ElishaTurner; GailBrinkerhoff; DustinBush; FedericaCazzola; KenHavill; PaulHealey; AmberPoulter; KrishnaSunkara; AndersAneman; RachelChoit; KelseyDobell-Brown; KairuiGuo; JillianLee; LienLombardo; ZachariahManalil; JenneneMiller; JordanRogers; AntonyStewart; JanaYanga; RebeccaGresham; JulieLowrey; KristyMasters; ChristinaWhitehead; BeverlyZaratan; MatthewGrigg; MegHarward; CassieJones; JosephineMackay; JasonMeyer; EmmaSaylor; EllenVenz; JamesWalsham; KristaWetzig; NerissaBrown; MarianneChapman; KathleenGlasby; SamuelGluck; TejaswiniMurthy; StephanieO'Connor; EamonRaith; JustineRivett; JoanniesYap; AngelaAshelford; FrancesBass; EmilyFitzgerald; OliverFlower; BernardHudson; PierreJanin; ElizabethLimbrey; SharonMar; AnneO'Connor; MelissaOwen; NaomiPallas; JuliaPilowsky; VeronicaRoach; ElizabethRuse; WadeStedman; MiyukiTokumitsu; ElizabethYarad; DeborahInskip; TheresaJacques; AdelineKintono; CatherineMilner; RebeccaSidoli; CatherineKurenda; SandraPeake; PatriciaWilliams; JeremyCohen; AmandaDavie; AmyOwens; RoslynPurcell; BalasubramanianVenkatesh; CartanCostello; AlanDavey-Quinn; MichaelDavies; Ahmed Elgendy; WenliGeng; VeerendraJagarlamudi; Matthew Mac Partlin; MahadevPatil; AdamPurdon; MartinSterba; Andrea Marshall; Anthony Delaney; MarwaAbdel-All; HayleyClark; NatalieEspinosa; BenjaminFinfer; MirandaHardie; DijlahMoungatonga; ConradNangla; FionaOsbourne; TinaSchneider; PrakritiShrestha; ElizabethWilson; IsabellaSchoeler; ManuelaArmenis; DominicByrne; AmruthaNagarajaiah; PrakeshVelappan; ParisaGlass; KateMyburgh; PhilippaSmith; Martina Bachmaier; Daryll Knowles; MichaelTattersall; John A.Myburgh,MD, PhD; Ian M.Seppelt,MD; FionaGoodman,BN; LaurentBillot,MSc; MaryamCorrea,PhD; Joshua S.Davis,MD, PhD; Anthony C.Gordon,MD; Naomi E.Hammond,PhD; JonIredell,MD, PhD; QiangLi,MBiostat; SharonMicallef,BN; JenneneMiller,BN; JayanthiMysore,MS; ColmanTaylor,PhD; Paul J.Young,MD, PhD; Brian H.Cuthbertson,MD; Simon R.Finfer,MD

JAMA
Original Investigation Continuous vs Intermittent β-Lactam Antibiotic Infusions in Critically Ill Patients With Sepsis
Joel M.Dulhunty,MD, PhD; Stephen J.Brett,MD; Jan J.De Waele,MD, PhD; DorrilynRajbhandari,PGDip(Clinical Nursing); LaurentBillot,MRes; Menino O.Cotta,PhD; Joshua S.Davis,MD, PhD; SimonFinfer,MD; Naomi E.Hammond,RN, PhD; SerenaKnowles,RN, PhD; XiaoqiuLiu,PhD; ShayMcGuinness,MD; JayanthiMysore,MS; David L.Paterson,MD, PhD; SandraPeake,MD, PhD; AndrewRhodes,MD, MD(Res); Jason A.Roberts,BPharm, PhD; ClaireRoger,MD, PhD; CharudattShirwadkar,MD; ThereseStarr,RN; ColmanTaylor,PhD; John A.Myburgh,MD, PhD; JeffreyLipman,MD, DMed(Res); BLING III Study Investigators; RinaldoBellomo; GlennEastwood; LeahPeck; HelenYoung; AndrewCheng; Luke Lau; MagdalenaLuciuk; MargaretMuteitha; ManojSaxena; CatherineBoschert; TimothyChimunda; CameronKnott; JulieSmith; KiranNand; TreenaSara; PeterChan; GraemeDuke; John Dyett; Kym Gellie; StephanieHunter; Melissa Kaufman; OwenRoodenburg; Joseph Veto; JuliaAffleck; MaheshRamanan; MeganRatcliffe; AlexisTabah; TimothyWarhurst; MaimoonbeGough; MareeHoubert; Julie Pitman; MandyTallott; JamesWinearls; ShelleyDonovan; KatrinaEllis; AtulGaur; MaryKeehan; AmyKelty; ElishaTurner; CynthiaBierl; GailBrinkerhoff; DustinBush; Amber-LouisePoulter; KrishnaSunkara; MelanieCooper; LynetteMorrison; SunilSane; JoanneSutton; HaydenWhite; VishwanathBiradar; MilindSanap; NatalieSoar; MeganDavis; MegHarward; CassieJones; JosieMackay; Niki McGuinness; JasonMeye; EmmaSaylor; AdamSuliman; Alex Tabah; EllenVenz; JamesWalsham; KristaWetzig; CatherineKurenda; PatriciaWilliams; StuartBaker; MareeDuroux; KylieJacobs; HamishPollock; SamShone; JenieButler; CherylFourie; MarianneKirrane; MelissaLassig-Smith; DaisyLindsay; AmeliaLivermore; Bree-YanaMcConnochie; Lynn Murray; GeorginaPeaco*ck; Janine Stuart; SidharthAgarwal; MargaretPhillips; KirstySmyth; DavidCooper; RickMcAllister; YasmineAli Abdelhamid; DeborahBarge; KathleenByrne; AdamDeane; SarahDoherty; SimonIles; BrieJelbart; ThomasRechnitzer; AngelaAshelford; FrancesBass; CeliaBradford; AnthonyDelaney; JonathanGatward; RogerHarris; Pierre Janin; RichardLee; ElizabethLimbrey; SharonMar; NaomiPallas; JuliaPilowsky; MelanieRoss; WadeStedman; MiyukiTokumitsu; ElizabethYarad; MaryamAlborzi; HeidiBuhr; JenniferColes; DavidGattas; DeborahInskip; AsakoIto; JenneneMiller; ClaireReynolds; SamRudham; AlisonBone; ClaireCattigan; TaniaElderkin; TaniaSalerno; JeremyCohen; AmandaDavie; AmyOwens; RoslynPurcell; BalasubramanianVenkatesh; DavidBowen; PeterClark; MohammadHamidi; JenyferJoy; JingKong; VineetNayyar; KaatjeCruysberghs; PhilippeJorens; PetraVertongen; MarcDiltoer; Marie ClaireVan Malderen; AnneJoosten; MaximeVan Cutsem; CarolineAbbenhuijs; DominiqueDurand; NancyMatumikina; FabioTaccone; StephanieBracke; LesleyDe Coster; LucDe Crop; AnouskaDe Smeytere; JolienVan Hecke; DaisyVermeiren; JanHeerman; SteffiRyckaert; AnneliesVan Damme ; NicolasDe Schryver; AnneThirifays; ElsFannes; NielsVan Regenmortel; Corentine Alauzet; ThibautBelveyre; JessicaBreistroff; AurélieGutehrle; EmmanuelNovy; MaximilienSaint Gilles; Marie Bonnefoy; 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Continuous vs Intermittent β-Lactam Antibiotic Infusions in Patients With Sepsis

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Key Points

Question Does the administration of β-lactam antibiotics by prolonged infusion reduce 90-day mortality compared with intermittent infusion in adult patients with sepsis or septic shock?

Findings This systematic review and bayesian meta-analysis of 18 randomized trials that included 9108 critically ill adults with sepsis or septic shock reported a 99.1% posterior probability that prolonged infusions were associated with lower 90-day mortality compared with intermittent infusions (risk ratio, 0.86).

Meaning Prolonged infusions of β-lactam antibiotics are associated with a reduced risk of death in critically ill adult patients with sepsis or septic shock compared with intermittent infusions.

Abstract

Importance There is uncertainty about whether prolonged infusions of β-lactam antibiotics improve clinically important outcomes in critically ill adults with sepsis or septic shock.

Objective To determine whether prolonged β-lactam antibiotic infusions are associated with a reduced risk of death in critically ill adults with sepsis or septic shock compared with intermittent infusions.

Data Sources The primary search was conducted with MEDLINE (via PubMed), CINAHL, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), and ClinicalTrials.gov from inception to May 2, 2024.

Study Selection Randomized clinical trials comparing prolonged (continuous or extended) and intermittent infusions of β-lactam antibiotics in critically ill adults with sepsis or septic shock.

Data Extraction and Synthesis Data extraction and risk of bias were assessed independently by 2 reviewers. Certainty of evidence was evaluated with the Grading of Recommendations Assessment, Development and Evaluation approach. A bayesian framework was used as the primary analysis approach and a frequentist framework as the secondary approach.

Main Outcomes and Measures The primary outcome was all-cause 90-day mortality. Secondary outcomes included intensive care unit (ICU) mortality and clinical cure.

Results From 18 eligible randomized clinical trials that included 9108 critically ill adults with sepsis or septic shock (median age, 54 years; IQR, 48-57; 5961 men [65%]), 17 trials (9014 participants) contributed data to the primary outcome. The pooled estimated risk ratio for all-cause 90-day mortality for prolonged infusions of β-lactam antibiotics compared with intermittent infusions was 0.86 (95% credible interval, 0.72-0.98; I² = 21.5%; high certainty), with a 99.1% posterior probability that prolonged infusions were associated with lower 90-day mortality. Prolonged infusion of β-lactam antibiotics was associated with a reduced risk of intensive care unit mortality (risk ratio, 0.84; 95% credible interval, 0.70-0.97; high certainty) and an increase in clinical cure (risk ratio, 1.16; 95% credible interval, 1.07-1.31; moderate certainty).

Conclusions and Relevance Among adults in the intensive care unit who had sepsis or septic shock, the use of prolonged β-lactam antibiotic infusions was associated with a reduced risk of 90-day mortality compared with intermittent infusions. The current evidence presents a high degree of certainty for clinicians to consider prolonged infusions as a standard of care in the management of sepsis and septic shock.

Trial Registration PROSPERO Identifier: CRD42023399434

Editorial Resolving the Dilemma on Continuous vs Intermittent β-Lactam Antibiotics in Sepsis
JAMA

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Abdul-Aziz MH, Hammond NE, Brett SJ, et al. Prolonged vs Intermittent Infusions of β-Lactam Antibiotics in Adults With Sepsis or Septic Shock: A Systematic Review and Meta-Analysis. JAMA. Published online June 12, 2024. doi:10.1001/jama.2024.9803

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Prolonged vs Intermittent Infusions of β-Lactam Antibiotics in Adults With Sepsis or Septic Shock (2024)

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