Prolonged vs Intermittent Infusions of β-Lactam Antibiotics in Adults With Sepsis or Septic Shock: A Systematic Review and Meta-Analysis

Mohd H Abdul-Aziz; Naomi E Hammond; Stephen J Brett; Menino O Cotta; Jan J De Waele; Anthony Devaux; Gian Luca Di Tanna; Joel M Dulhunty; Hatem Elkady; Lars Eriksson; M Shahnaz Hasan; Ayesha Bibi Khan; Jeffrey Lipman; Xiaoqiu Liu; Giacomo Monti; John Myburgh; Emmanuel Novy; Shahed Omar; Dorrilyn Rajbhandari; Claire Roger; Fredrik Sjövall; Irene Zaghi; Alberto Zangrillo; Anthony Delaney; Jason A Roberts

doi:10.1001/jama.2024.9803

. 2024 Jun 12;332(8):638–648. doi: 10.1001/jama.2024.9803

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

A Systematic Review and Meta-Analysis

Mohd H Abdul-Aziz ¹, Naomi E Hammond ^2,³, Stephen J Brett ⁴, Menino O Cotta ¹, Jan J De Waele ⁵, Anthony Devaux ⁶, Gian Luca Di Tanna ^6,^7,⁸, Joel M Dulhunty ^2,^9,^10,¹¹, Hatem Elkady ¹², Lars Eriksson ¹³, M Shahnaz Hasan ¹⁴, Ayesha Bibi Khan ¹⁵, Jeffrey Lipman ^1,^9,^16,¹⁷, Xiaoqiu Liu ^6,¹⁸, Giacomo Monti ^19,²⁰, John Myburgh ^2,²¹, Emmanuel Novy ^22,²³, Shahed Omar ¹⁵, Dorrilyn Rajbhandari ², Claire Roger ^24,²⁵, Fredrik Sjövall ^26,²⁷, Irene Zaghi ²⁸, Alberto Zangrillo ^19,²⁰, Anthony Delaney ^2,³, Jason A Roberts ^1,^9,^17,^29,^✉

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

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

Accepted for Publication: May 7, 2024.

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

^✉

Corresponding Author: Jason A. Roberts, BPharm, PhD, UQ Centre for Clinical Research, Bldg 71/918 RBWH Herston, Brisbane QLD 4029, Australia (j.roberts@uq.edu.au).

Author Contributions: Drs Abdul-Aziz and Devaux had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Drs Abdul-Aziz, Hammond, Delaney, and Roberts contributed equally.

Concept and design: Abdul-Aziz, Hammond, Cotta, De Waele, Di Tanna, Dulhunty, Lipman, Myburgh, Delaney, Roberts.

Acquisition, analysis, or interpretation of data: Abdul-Aziz, Hammond, Brett, De Waele, Devaux, Di Tanna, Dulhunty, Elkady, Eriksson, Hasan, Khan, Liu, Monti, Novy, Omar, Rajbhandari, Roger, Sjövall, Zaghi, Zangrillo, Delaney, Roberts.

Drafting of the manuscript: Abdul-Aziz, Hammond, Di Tanna, Dulhunty, Eriksson, Delaney, Roberts.

Critical review of the manuscript for important intellectual content: Abdul-Aziz, Hammond, Brett, Cotta, De Waele, Devaux, Di Tanna, Dulhunty, Elkady, Hasan, Khan, Lipman, Liu, Monti, Myburgh, Novy, Omar, Rajbhandari, Roger, Sjövall, Zaghi, Zangrillo, Delaney, Roberts.

Statistical analysis: Devaux, Di Tanna, Liu.

Administrative, technical, or material support: Abdul-Aziz, Hammond, Brett, Cotta, Dulhunty, Hasan, Lipman, Monti, Myburgh, Rajbhandari, Roger, Sjövall, Zangrillo, Delaney, Roberts.

Supervision: Abdul-Aziz, Hammond, De Waele, Di Tanna, Delaney, Roberts.

Creation of search terms: Abdul-Aziz.

Risk of bias assessment: Abdul-Aziz, Elkady, Zaghi.

Study selection and data collection: Abdul-Aziz, Elkady.

Conflict of Interest Disclosures: Dr Abdul-Aziz reported being a writing committee member of the BLISS trial, which is included in this meta-analysis. Dr Hammond reported being a writing committee member of the BLING III trial, which is included in this meta-analysis. Dr Brett reported a consultancy payment to his university from GSK for work on an analysis of sotrovimab in COVID-19 infection outside the submitted work; and reported being a writing committee member of the BLING III trial. Dr De Waele reported receiving honoraria from Pfizer, Menarini, and MSD paid to his institution; and consultancy fees from Viatris paid to his institution outside the submitted work. Dr Dulhunty reported being a writing committee member of the BLING I, BLING II, and BLING III trials, which are included in this meta-analysis. Dr Khan reported receiving grants from the Critical Care Society of Southern Africa outside the submitted work. Dr Liu reported being a writing committee member of the BLING III trial. Dr Monti reported receiving honoraria and consultancy fees from AOP Health, InfectoFos, and Pfizer outside the submitted work; and being a writing committee member of the MERCY trial, which is included in this meta-analysis. Dr Myburgh reported being a writing committee member of the BLING I, BLING II, and BLING III trials. Dr Omar reported receiving honoraria from Jafron Biomedical Co for lectures given on the removal of toxins using hemoadsorption therapy in poisoned patients outside the submitted work. Ms Rajbhandari reported being a writing committee member of the BLING III trial. Dr Roger reported receiving honoraria and consultancy fees from Shionogi, bioMérieux, Advanz Pharma, MSD, AOP Orphan, Viatris, Pfizer, and Fresenius outside the submitted work. Dr Zangrillo reported being a writing committee member of the MERCY trial. Dr Roberts reported receiving consulting fees from Qpex Biopharma, Gilead, Advanz Pharma, Pfizer, Sandoz, MSD, Cipla, and bioMérieux; receiving grants from Qpex Biopharma, the British Society for Antimicrobial Chemotherapy, Pfizer, and bioMérieux outside the submitted work; and being a writing committee member of the BLING I, BLING II, and BLING III trials. Dr Roberts reported being a writing committee member of the BLING I, BLING II, and BLING III trials and of the BLISS trial. No other disclosures were reported.

Funding/Support: The George Institute for Global Health and the Centre of Research Excellence–Personalising Antimicrobial Dosing to Reduce Resistance (CRE RESPOND; Australian National Health and Medical Research Council Centres of Research Excellence, APP2007007), The University of Queensland, provided in-kind support for this work. Dr Hammond was supported by an Emerging Leadership grant (APP1196320) from the National Health and Medical Research Council of Australia. Dr De Waele was supported by a Senior Clinical Investigator Fellowship from the Research Foundation–Flanders (FWO 7881020N). Dr Sjövall was supported by a grant from the Swedish Research Council (2019-05908). Drs Myburgh and Roberts were supported by leadership Investigator Grant fellowships (APP1173079 [Dr Myburgh]; APP2009736 and APP2007007 [Dr Roberts]) from the National Health and Medical Research Council of Australia. Dr Roberts was supported by an Advancing Queensland clinical research fellowship and a Centre of Research Excellence fellowship.

Role of the Funder/Sponsor: Other than the specified roles of the coauthors, The George Institute for Global Health and The University of Queensland had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Meeting Presentation: Presented at the Critical Care Reviews (CCR) meeting; June 12, 2024; Belfast, UK.

Data Sharing Statement: See Supplement 2.

^✉

Corresponding author.

PMCID: PMC11170459 PMID: 38864162

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.

This systematic review and bayesian meta-analysis investigated whether administration of β-lactam antibiotics by prolonged infusion reduces 90-day mortality compared with intermittent infusion in adult patients with sepsis or septic shock.

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

Introduction

Critically ill adults who develop sepsis and septic shock face high morbidity and mortality. Early and appropriate antibiotic administration is central to the treatment of such patients. There is uncertainty about effective antibiotic dosing, specifically the duration of infusion in this patient population, due to physiologic perturbations and supportive treatments that may alter antibiotic pharmacokinetics.^1,2,3 Pathogens causing an infection during an intensive care unit (ICU) admission may have reduced antibiotic susceptibility.

β-Lactam antibiotics are widely used as first-line antibiotics for the treatment of sepsis and septic shock. These agents display time-dependent bactericidal activity that is optimal when the free drug concentration remains above the minimum inhibitory concentration of the infecting pathogen for at least 40% to 70% of the dosing interval.⁴ There is a biological rationale that prolonged infusions of β-lactam antibiotics may be more effective compared with conventional intermittent dosing.^5,6 This rationale is supported by pharmacokinetic-pharmacodynamic studies, which demonstrate that prolonged infusions achieve β-lactam antibiotic exposures associated with maximal bacterial-killing more consistently than intermittent infusions.⁷ Whether the effects of prolonged β-lactam antibiotic infusion compared with intermittent infusion result in improved patient-centered outcomes remains uncertain.^{8,9,10,11,12,13}

Two recently published multinational randomized clinical trials, the Continuous Infusion vs Intermittent Administration of Meropenem in Critically Ill Patients (MERCY)¹⁴ and the Beta-Lactam Infusion Group (BLING) III¹⁵ trials, have added substantially to the body of evidence. To provide an updated summary of current evidence, this systematic review and bayesian meta-analysis was conducted to assess whether administration of β-lactam antibiotics by prolonged infusion was associated with reduced 90-day all-cause mortality and other relevant outcomes compared with intermittent infusion.

Methods

A systematic review of randomized clinical trials was performed according to a prespecified published protocol (eAppendix 1 in Supplement 1).¹⁶ The review was reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) statement¹⁷ and was registered at the International Prospective Register of Systematic Reviews (CRD42023399434).

Eligibility Criteria

Randomized clinical trials that recruited critically ill adult participants with sepsis or septic shock and compared the administration of prolonged infusions with intermittent infusions of 1 or more β-lactam antibiotics were included. Conventional and current definitions of sepsis and septic shock at participant recruitment were accepted.^18,19,20,21 Prolonged infusion was defined as either an extended infusion (intravenous β-lactam antibiotic administration for 2 hours or longer during a dosing interval) or a continuous infusion (constant intravenous β-lactam antibiotic administration that could be administered as a sequential 6-, 8-, 12-, or 24-hour infusion). Intermittent infusion was defined as intravenous β-lactam antibiotic administration for fewer than 2 hours during a dosing interval.

Search Strategy

A systematic search of MEDLINE (via PubMed), CINAHL, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), and ClinicalTrials.gov from inception to May 2, 2024, was conducted. The search was performed with no restrictions on language, publication date, or publication status. The search terms were created by a research librarian (L.E.) in collaboration with content area experts in antibiotic pharmacokinetics-pharmacodynamics, critical care, and infectious diseases. The search strategy included a combination of key words and Medical Subject Headings terms to identify randomized clinical trials that included “critically ill patients” or “intensive care unit,” “sepsis” or “septic shock,” “beta-lactam” or “carbapenem” or “cephalosporin” or “monobactam” or “penicillin,” and “continuous infusion” or “extended infusion” or “prolonged infusion” or “intermittent infusion.”

Manual searches of reference lists of included studies and other systematic reviews were undertaken to identify additional studies. eAppendix 2 in Supplement 1 provides additional details of the electronic search strategy.

Study Selection

Using the Covidence systematic review software (Veritas Health Innovation), a minimum of 2 reviewers (H.E., E.N., or I.Z.) independently screened all identified references for inclusion based on the study title and abstract. A minimum of 2 reviewers (H.E., E.N., or I.Z.) independently assessed the full text for inclusion of potentially eligible studies, with disagreements resolved by consensus or, if necessary, consultation with a third reviewer (M.H.A.-A., N.E.H., A.D., or J.A.R.).

Data Collection

Two reviewers (H.E. and I.Z.) independently extracted data from each included study by using a standardized data collection form. Discrepancies were resolved by consensus or, if necessary, by consultation with a third reviewer (M.H.A.-A.). Available data were extracted as outlined in the protocol (eAppendix 1 in Supplement 1),¹⁶ including characteristics of the included studies, study design, demographic and clinical details of the study population, details of the intervention and comparison group (study antibiotic, study antibiotic dosing regimen, and concomitant antibiotics), and study outcomes. Attempts were made to contact corresponding authors of included studies to obtain essential aggregate-level data. There was no imputation for missing data. Access to aggregate-level data of 2 trials^15,22 before their publication was obtained from the respective corresponding authors.

Risk of Bias Assessment

Using the Cochrane Risk of Bias Tool for randomized trials version 2, 2 reviewers (H.E. and I.Z.) with no affiliation with the included trials independently assessed the risk of bias for each trial. The risk of bias was assessed for all outcomes of interest. Any discrepancies were resolved by consensus or, if necessary, consultation with a third reviewer (M.H.A.-A., N.E.H., or A.D.).

Outcomes

The primary outcome was all-cause 90-day mortality. For studies in which 90-day mortality was not reported, the closest time to day 90 (before or after) was used.

Data were also collected for the following secondary outcomes: ICU mortality, ICU length of stay (as reported in the original study), clinical cure (as defined in the original study), microbiologic cure (as defined in the original study), and adverse events (as defined in the original study).

Subgroup Analyses

There were 7 prespecified subgroups for the primary outcome: (1) administration of meropenem vs piperacillin-tazobactam; (2) culture-positive infection vs culture-negative infection; (3) gram-negative infection vs gram-positive infection; (4) receipt of kidney replacement therapy vs no kidney replacement therapy; (5) lung infection vs other infections; (6) sepsis vs septic shock; and (7) male vs female participants. The prespecified hypotheses for these comparisons are detailed in the protocol (eAppendix 1 in Supplement 1).¹⁶ When results suggested possible subgroup effects, the Instrument to Assess the Credibility of Effect Modification Analyses (ICEMAN)²³ guidelines were used to assess their credibility.

Data Synthesis

A bayesian framework was used as the primary statistical approach, and a frequentist framework was used as the secondary approach. A random-effects model was used in the analyses and pooled estimates of effect sizes as risk ratios (RRs) for binary outcomes, and mean differences for continuous outcomes were presented. Continuous variables presented in formats not readily amenable to pooling were converted to mean and SD with the method described by Wan et al.²⁴ Along with the pooled estimates of effect sizes, 95% credible intervals (CrIs) for the bayesian meta-analysis and 95% CIs for the frequentist model were presented.

For the bayesian approach, primary analysis using vague priors (log of the RR assumed to have a normal distribution with a mean of 0 and an SD of 2) and sensitivity analyses examining treatment effects using weakly informative priors of effect and heterogeneity parameters were conducted.²⁵ The full description of priors is presented in the protocol (eAppendix 1 and eAppendix 3 in Supplement 1).¹⁶ For the frequentist approach, a random-effects model using Hartung-Knapp-Sidik-Jonkman²⁶ and DerSimonian-Laird estimates of the between-study variance was used. A random-effects model was chosen a priori for all analyses because of anticipated between-study variation in trial design and implementation of the interventions.

Quantitative heterogeneity was assessed with the posterior estimates of the heterogeneity parameter (τ) with its 95% CrI. The proportion of variation across studies owing to heterogeneity rather than chance was assessed with the I² statistic. Subgroup heterogeneity was assessed by including an interaction term in the bayesian analysis to obtain an estimate and 95% CrI for the ratio of RRs (RRRs) from the posterior distribution of the interaction estimate. The presence of small-study effects was assessed by visual assessment of the contour-enhanced funnel plots and formal Egger regression test.^27,28

All statistical analyses were performed with R version 4.3.1 (R Foundation for Statistical Computing). The bayesian analysis was performed with the bayesmeta package for bayesian analysis,²⁹ and the metafor package was used for the frequentist analysis.³⁰

Confidence in the Cumulative Evidence

The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach was used to evaluate the overall certainty of evidence that prolonged infusions of β-lactam antibiotics compared with intermittent infusions improve each outcome measure to any degree.^31,32

Results

The results of the search and reasons for study exclusion are detailed in eFigure 1 and eTable 1 in Supplement 1. From 2494 records, 18 eligible randomized clinical trials including 9108 critically ill adult participants with sepsis or septic shock were included (5961 men [65%] and 3147 women [35%]).^{14,15,22,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47} Table 1 presents the characteristics of included trials. Details on microbiologic characteristics, β-lactam antibiotic dosing regimens, and outcome definitions of included trials are summarized in eTables 2 and 3 in Supplement 1. Apart from 1 trial that is not yet published,²² all other trials were published in peer-reviewed journals. Aggregate-level data from the unpublished trial,²² as well as additional unpublished aggregate-level data from 10 trials,^{14,15,35,36,37,39,40,41,42,43} were obtained directly from study authors (eTable 4 in Supplement 1).

Table 1. Characteristics of Included Randomized Clinical Trials^a.

Source	Country	Population^b	Participants		Age, y		Male sex		APACHE II score^c		SOFA score^d		Mortality time closest to 90 d
Source	Country	Population^b	Prolonged infusion	Intermittent infusion	Prolonged infusion	Intermittent infusion	Prolonged infusion	Intermittent infusion	Prolonged infusion	Intermittent infusion	Prolonged infusion	Intermittent infusion	Mortality time closest to 90 d
Georges et al,³³ 2005	France	Sepsis^e	26	24	50 (17)	46 (24)	21 (80.8)	20 (83.3)	45 (26-72)^f	44 (22-72)^f	NR	NR	Not defined
Rafati et al,³⁴ 2006	Iran	Sepsis^g	20	20	50.1 (22.2)	48 (20.7)	12 (60)	15 (75)	16.4 (6.3)	14.2 (6.1)	NR	NR	ICU mortality
Roberts et al,³⁵ 2007	Australia	Sepsis^e	29	28	43 (19)	52 (16)	16 (55)	17 (61)	18.8 (5.9)	16.4 (4.4)	4 (1.9)	3.9 (2.0)	ICU mortality
Roberts et al,³⁶ 2009	Australia	Sepsis^e	5	5	57 (54-63)	55 (48-61)	4 (80)	3 (60)	NR	NR	5 (2-8)	3 (3-4)	ICU mortality
Roberts et al,³⁷ 2010	Australia	Sepsis^e	8	8	30 (23-40)	41 (22-65)	6 (75)	5 (62.5)	20 (16-22)	24 (18-26)	4 (3-6)	3 (3-3)	ICU mortality
Chytra et al,³⁸ 2012	Czech Republic	Sepsis^g	120	120	44.9 (17.8)	47.2 (16.3)	78 (65.0)	83 (69.2)	21.4 (7.9)	22.1 (8.79)	10.4 (2.9)	10.6 (3.5)	In-hospital mortality
Dulhunty et al,³⁹ 2013	Australia, Hong Kong	Severe sepsis^e	30	30	54 (19)	60 (19)	23 (76.7)	19 (63.3)	21 (8.6)	23 (7.6)	NR	NR	In-hospital mortality (28 d)
Dulhunty et al,⁴⁰ 2015	Australia, Hong Kong, New Zealand	Severe sepsis^g^,^h	212	220	64 (54-72)	65 (53-72)	130 (61.3)	135 (61.4)	21 (17-26)	20 (16-25)	NR	NR	90-d Mortality
Jamal et al,⁴¹ 2015	Malaysia	Sepsis^g^,^h	8	8	44 (33.8-70)	62.5 (46-70.5)	8 (100)	4 (50)	33 (29.8-34.8)	33.5 (28.3-40.5)	15.5 (14-17.5)	14 (13-17.8)	ICU mortality
Jamal et al,⁴² 2015	Malaysia	Sepsis^g^,^h	8	8	47.5 (32-63.3)	44.5 (29-60.8)	7 (87.5)	4 (50)	30 (26.5-32.5)	32.5 (29.8-37.8)	15.5 (13.3-18.5)	14.5 (14-17.8)	ICU mortality
Abdul-Aziz et al,⁴³ 2016	Malaysia	Severe sepsisⁱ	70	70	54 (42-63)	56 (41-68)	46 (66)	50 (71)	21 (17-26)	21 (15-26)	8 (6-10)	7 (5-9)	In-hospital mortality (30 d)
Zhao et al,⁴⁴ 2017	China	Severe sepsis or septic shockⁱ	25	25	68 (15.4)	67 (12.2)	10 (40)	11 (44)	19.4 (5.0)	19.7 (5.9)	8.0 (2.8)	8.5 (2.4)	ICU mortality
Khan and Omar,²² 2023	South Africa	Sepsis^j	64	58	31 (26-39)	36 (25-50)	41 (64)	34 (59)	8 (5-13)	10 (6-13)	NR	NR	90-d Mortality
Mirjalili et al,⁴⁵ 2023	Iran	Sepsis or septic shock^j	68	68	53.8 (15.8)	53.1 (16.2)	37 (54.5)	38 (55.9)	19.14 (6.37)	19.19 (5.82)	NR	NR	In-hospital mortality
Monti et al,¹⁴ 2023	Croatia, Italy, Kazakhstan, Russia	Sepsis or septic shock^e^,^g^,^h^,^j	303	304	65.5 (14)	63.4 (15)	195 (64)	209 (69)	44 (35-55)^f	43 (34-53)^f	9 (6-11)	9 (6-11)	90-d Mortality
Saad et al,⁴⁶ 2024	Egypt	Sepsis^e	30	30	54.4 (10.6)	53.8 (10.7)	NR	NR	21.49 (6.05)	22.75 (5.62)	10.82 (2.73)	10.84 (3.43)	ICU mortality
Álvarez-Moreno et al,⁴⁷ 2024	Colombia	Sepsis, severe sepsis or septic shock^g	12	13	60.2 (16.9)	54.2 (1.4)	8 (67)	4 (31)	12.7 (6.3)	15.2 (8.01)	8 (3.5)	6 (3.3)	Mortality at discharge^k
Dulhunty et al,¹⁵ 2024	Australia, Belgium, France, Malaysia, New Zealand, Sweden, UK	Sepsis^g	3498	3533	59.3 (16.4)	59.6 (16.1)	2308 (66.0)	2300 (65.1)	19.6 (7.6)	19.5 (7.4)	NR	NR	90-d Mortality

Open in a new tab

Abbreviations: APACHE II, Acute Physiology and Chronic Health Evaluation II; ICU, intensive care unit; NR, not reported; SOFA, Sequential [Sepsis-related] Organ Failure Assessment.

^{^a}

Age, APACHE II score, and SOFA score are presented as mean (SD) or median (IQR). Male sex is presented as counts (percentage).

^{^b}

All trials recruited participants with sepsis or septic shock according to conventional and contemporary definitions in place at recruitment. The population presented in the table refers to the patient population as reported in the trial protocol, original article, or both.

^{^c}

APACHE II is a disease severity classification system that uses 12 routine physiologic measurements, age, and previous health status to provide a general measure of disease severity. A higher score (range, 0-71) indicates higher severity of disease and higher risk of mortality for ICU patients.

^{^d}

The SOFA score is assessment of organ dysfunction for 6 organs/systems (respiratory, coagulation, hepatic, cardiovascular, renal, and central nervous systems). The score ranges between 0 and 24, and a higher score indicates higher severity of disease and higher risk of mortality for ICU patients.

^{^e}

As defined by ACCP/SCCM Consensus Conference Committee 1992 definitions for sepsis and organ failure.

^{^f}

Simplified Acute Physiology Score II.

^{^g}

As defined by the 2001 SCCM/ESICM/ACCP/ATS/SIS International Sepsis Definitions Conference.

^{^h}

Included patients receiving kidney replacement therapy before randomization.

^ⁱ

As defined by Surviving Sepsis Campaign 2008.

^{^j}

As defined by the Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3).

^{^k}

Whether mortality was mortality at ICU discharge or hospital discharge was not specified.

The 18 included trials had a median of 59 trial participants (IQR, 28-139 participants). The median age of participants in the included trials was 54 years (IQR, 48-57 years). The median Acute Physiology and Chronic Health Evaluation II score was 20 (IQR, 18-22), and the median Sequential [Sepsis-related] Organ Failure Assessment score was 8 (IQR, 6-11). Of the included randomized clinical trials, 17 trials compared continuous infusions of β-lactam antibiotics with intermittent infusions,^{14,15,22,33,34,35,36,37,38,39,40,41,42,43,44,46,47} and 1 trial compared extended infusion with intermittent infusion.⁴⁵ Meropenem was studied in 11 trials,^{14,15,22,36,38,39,40,41,43,44,46} piperacillin-tazobactam in 8 trials,^{15,22,34,37,39,40,42,43} cefepime in 3 trials,^33,43,47 ticarcillin-clavulanate in 2 trials,^39,40 and amoxicillin-clavulanate,²² ampicillin-sulbactam,⁴⁵ ceftriaxone,³⁵ and imipenem-cilastatin²² in 1 trial each. In 13 trials, an equivalent total daily dose of β-lactam antibiotics was used in both the prolonged and intermittent infusion groups.^{14,15,33,35,36,39,40,41,42,44,45,46,47} The median duration of randomly assigned β-lactam antibiotic treatment was 7 days (IQR, 6-10 days) and 9 days (IQR, 6-11 days) in the prolonged and intermittent infusion groups, respectively.

Risk of Bias

Risks of bias assessments are presented in eFigure 2 in Supplement 1. Four trials were adjudicated as having low risk of bias in all domains for all outcomes of interest.^14,15,39,40 The overall risk of bias was adjudicated as low for 10 of 17 trials contributing all-cause 90-day mortality data.^{14,15,35,36,38,39,40,41,42,43}

Primary Outcome

There were 17 randomized clinical trials (9014 participants) that contributed data to the primary outcome. The times of follow-up differed across the included trials: 7 trials (n = 249) reported mortality at ICU discharge,^{34,35,36,41,42,44,46} 3 trials (n = 436) reported mortality at hospital discharge,^38,39,45 4 trials (n = 8117) reported mortality at day 90,^14,15,22,40 1 trial (n = 140) reported mortality at day 30,⁴³ and 2 trials (n = 72) did not provide the definition of the mortality end point,^33,47 as shown in eTable 3 in Supplement 1.

Using a bayesian random-effects model with vague priors, the pooled estimated RR for all-cause 90-day mortality for prolonged infusions of β-lactam antibiotics compared with intermittent infusions was 0.86 (95% CrI, 0.72-0.98; τ = 0.11; I² = 21.5%), with a 99.1% posterior probability that prolonged infusions were associated with lower 90-day mortality (Figure 1, Figure 2, and Figure 3; eTable 5 in Supplement 1). The certainty in the evidence was adjudicated as high, as presented in Table 2. The primary outcome results were similar in the sensitivity analyses using semi-informative priors and the specified frequentist methods (Figures 1 and 2; eTable 5 in Supplement 1). There was no evidence of small-study effects by visual assessment of the contour-enhanced funnel plots or by Egger regression test (eFigure 3A in Supplement 1).

Figure 1. — The black boxes represent point estimates, and the areas of the boxes are proportional to the weight of the studies. The weights displayed are based on bayesian analysis with vague priors. The whiskers represent CIs. Width of the diamonds represents the trials’ pooled estimate CI, and the middle point represents the point estimates.

ªCredible intervals are presented for bayesian analysis.

Figure 2. — The black boxes represent point estimates, and the whiskers represent the pooled estimate CrIs from bayesian analysis. CrI indicates credible interval; ICU, intensive care unit.

ªCIs are presented for frequentist analysis.

Figure 3. — A, The cumulative posterior distribution of the estimated RR, with the y-axis corresponding to the probability the RR is less than or equal to the value on the x-axis. The blue-gray area indicates a beneficial intervention (ie, RR lower than 1). The dashed vertical line indicates the median. B, The full posterior distribution of the estimated RR, with the dashed vertical line indicating the median value and the area highlighted in tan indicating the percentile-based 95% credible interval. The orange area is related to an RR greater than 1 (ie, the intervention is associated with higher mortality vs standard care). The dotted line at an RR of 1 indicates no treatment effect. The figure demonstrates that the probability that prolonged infusions of β-lactam antibiotics is associated with a reduced risk of all-cause 90-day mortality (to any extent) compared with intermittent infusions is more than 99%.

Table 2. Grading of Recommendations Assessment, Development and Evaluation (GRADE) Summary of Findings.

Outcome	No. of trials/No. of participants	Certainty of evidence (quality of the evidence)^a	Infusion, No./No. (%)		(95% CrI)
Outcome	No. of trials/No. of participants	Certainty of evidence (quality of the evidence)^a	Prolonged	Intermittent	Absolute difference	Risk ratio
All-cause 90-d mortality	17/9014	High, ++++	1152/4488 (25.7)	1275/4526 (28.2)	−0.03 (−0.08 to 0.00)	0.86 (0.72 to 0.98)
ICU mortality	15/8967	High, ++++	806/4466 (18.0)	911/4501 (20.2)	−0.03 (−0.08 to 0.0)	0.84 (0.70 to 0.97)
Clinical cure	12/8301	Moderate,^b +++–	2367/4137 (57.2)	2106/4164 (50.6)	0.11 (0.05 to 0.18)	1.16 (1.07 to 1.31)
Microbiologic cure	4/352	Very low,^c +−−−	145/174 (83.3)	126/178 (70.8)	0.13 (−0.02 to 0.28)	1.18 (0.96 to 1.48)
Adverse events	4/7761	Very low,^d +−−−	42/3868 (1.1)	49/3893 (1.3)	−0.00 (−0.06 to 0.04)	0.89 (0.51 to 1.57)
ICU length of stay, d	12/8935	Low,^e ++−	12.6	13.1	−0.42 (−1.09 to 0.26)	NA

Open in a new tab

Abbreviations: CrI, credible interval; ICU, intensive care unit; NA, not applicable.

^{^a}

The GRADE approach specifies 4 levels of certainty, as follows: high certainty (++++), very confident that the true effect lies close to that of the estimate of effect; moderate certainty (+++−), moderately confident in the effect estimate (the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different); low certainty (++−−), limited confidence in the effect estimate (the true effect may be substantially different from the estimate of effect); and very low certainty (+−−−), very little confidence in the effect estimate (the true effect is likely to be substantially different from the estimate of effect).

^{^b}

Downgraded due to inconsistency because most studies used subjective and variable definitions of clinical cure.

^{^c}

Downgraded due to risk of bias of this outcome in the included trials (eFigure 2E in Supplement 1), inconsistency because studies used variable definitions of microbiologic cure, indirectness because microbiologic cure is not directly an important patient outcome, and imprecision due to small sample size with wide CrI.

^{^d}

Downgraded due to inconsistency because most studies used variable definitions of adverse events, indirectness because adverse events may not directly be an important patient outcome, and imprecision because the CrIs for the effect on adverse events (0.51-1.58) are consistent with both an appreciable benefit and appreciable harm.

^{^e}

Downgraded due to risk of bias of this outcome in the included trials (eFigure 2C in Supplement 1) and indirectness because duration of ICU stay is not directly an important patient outcome.

Subgroup Analyses

The primary outcome of all-cause 90-day mortality was evaluated in 7 prespecified subgroups (Figure 2). As presented in eTable 5 and eFigures 4 through 10 in Supplement 1, there was no evidence that the pooled estimate for prolonged infusions of β-lactam antibiotics compared with intermittent infusions for all-cause 90-day mortality was different by meropenem vs piperacillin-tazobactam (RRR, 1.00; 95% CrI, 0.75-1.29); culture-positive vs culture-negative infection (RRR, 1.13; 95% CrI, 0.91-1.72); gram-negative vs gram-positive infection (RRR, 1.13; 95% CrI, 0.85-1.79); kidney replacement therapy vs no kidney replacement therapy (RRR, 1.08; 95% CrI, 0.82-1.53); lung infection vs other infections (RRR, 0.90; 95% CrI, 0.64-1.15); sepsis vs septic shock (RRR, 0.97; 95% CrI, 0.75-1.23); and male vs female participants (RRR, 0.91; 95% CrI, 0.71-1.12).

Secondary Outcomes

The secondary outcomes are presented in Table 2 and Figure 2 (eTable 5 and eFigures 11-15 in Supplement 1). Assessment of small-study effects is presented in eFigure 3B-F in Supplement 1. Compared with the use of intermittent infusions, use of prolonged infusions of β-lactam antibiotics was associated with a reduced risk of ICU mortality (RR, 0.84; 95% CrI, 0.70-0.97; high certainty) (eFigure 11 in Supplement 1) and an increase in clinical cure (RR, 1.16; 95% CrI, 1.07-1.31; moderate certainty) (eFigure 12 in Supplement 1). There were no detectable differences in microbiologic cure (RR, 1.18; 95% CrI, 0.96-1.48; very low certainty) (eFigure 13 in Supplement 1), adverse events (RR, 0.89; 95% CrI, 0.51-1.57; very low certainty) (eFigure 14 in Supplement 1), and duration of ICU length of stay (mean difference, −0.42; 95% CrI, −1.09 to 0.26; low certainty) (eFigure 15 in Supplement 1).

Discussion

In this systematic review and meta-analysis, β-lactam antibiotic administration by prolonged infusion was associated with a reduced risk of mortality at 90 days for critically ill adult participants with sepsis or septic shock compared with intermittent infusion. The bayesian analysis found a 14-percentage-point relative reduction in the risk of mortality at 90 days with prolonged β-lactam antibiotic infusions compared with intermittent infusions. The number needed to treat for prolonged β-lactam antibiotic infusions to prevent 1 death was 26 patients. The use of prolonged infusions of β-lactam antibiotics was associated with a reduced risk of mortality at ICU discharge. In addition, the use of prolonged infusions was associated with an increased probability of clinical cure. Compared with that of intermittent infusions, the effect of prolonged infusions on microbiologic cure, adverse events, and the duration of ICU length of stay was uncertain.

The observation of reduced risk of mortality in the present analysis is consistent with findings from previous meta-analyses.^{9,10,11,12,13} In combination, the current evidence presents a higher degree of certainty for clinicians to consider prolonged β-lactam antibiotic infusions as a standard of care in the management of sepsis and septic shock.

Strengths and Limitations

The present review has several strengths. Authors of previous meta-analyses^{9,10,11,12,13} have acknowledged limitations in the quality of the included trials. By incorporating data from 6 recently published trials,^{14,15,22,45,46,47} this review provides the most up-to-date evidence, to our knowledge, on the treatment effect of prolonged infusions of β-lactam antibiotics compared with intermittent infusions for critically ill adult patients with sepsis or septic shock. This review included trials that recruited critically ill adult participants with sepsis or septic shock to mitigate population heterogeneity reported in previous meta-analyses.⁴⁸ The addition of these trials has increased the sample size of the present analysis, providing greater confidence and precision in estimating the effects of prolonged infusions of β-lactam antibiotics on clinically important outcomes. Ten trials assessed as having a low risk of bias contributed 95% of the data to this analysis. The inclusion of trials that have recruited patients from geographically diverse regions (18 countries across 5 continents) enhances the generalizability of findings to a broader range of treatment settings. The use of both bayesian and frequentist analyses ensures a comprehensive assessment and robust interpretation of the treatment effect under study.

Potential challenges associated with prolonged infusion administration, including drug instability and incompatibility with other intravenous medications, the need for a dedicated intravenous portal, and the potential effect on clinical workload, require some considerations before broad implementation. Future studies should determine the optimal duration of infusion when β-lactam antibiotics are administered as prolonged infusions. Because no credible subgroup was identified in this analysis, studies to further identify specific subsets of patients with sepsis or septic shock who are most likely to benefit from prolonged β-lactam antibiotic infusions are warranted. Including specific health economic analyses in future trials may provide additional insights for routine use of prolonged β-lactam antibiotic infusions, and this recommendation can then be considered for inclusion in future sepsis treatment guidelines and treatment bundles.

This study has several limitations. First, the trials included used various definitions for sepsis and septic shock. To allow for this variation, we accepted all conventional and contemporary definitions for sepsis and septic shock used at the original trials. Second, although the present analysis combined both extended and continuous infusions as prolonged infusions, only 1 trial compared extended infusions with intermittent infusions. Third, variable definitions of clinical cure were used across studies and the determination of cure can be subjective. Fourth, the association between prolonged infusions of β-lactam antibiotics and microbiologic cure, adverse events, and the duration of ICU length of stay remains very uncertain because the quality of evidence concerning these outcomes was very low.

Conclusions

Among adults in the ICU with 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.

Section Editor: Christopher Seymour, MD, Associate Editor, JAMA (christopher.seymour@jamanetwork.org).

Supplement 1.

eAppendix 1. Study Protocol

eAppendix 2. Electronic Search Strategy

eAppendix 3. Semi-Informative Priors for Heterogeneity Parameter Details

eFigure 1. Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Flowchart of Search Strategy and Included Studies

eTable 1. Excluded Reports and Reasons for Exclusion

eTable 2. Microbiological Characteristics and Beta-Lactam Antibiotic Dosing Regimen Details of Included Randomized Controlled Trials

eTable 3. Definition of Primary and Secondary Outcomes in Studies

eTable 4. Unpublished Outcome Data Obtained From Study Authors

eFigure 2. Risk of Bias Assessments

eTable 5. Additional Outcome Statistics for the Primary Bayesian Model, Sensitivity Analyses, and Secondary Outcomes

eFigure 3. Funnel Plots

eFigure 4. All-Cause 90-Day Mortality by Study Beta-Lactam Antibiotic i.e. Piperacillin/Tazobactam Versus Meropenem

eFigure 5. All-Cause 90-Day Mortality by Culture-Positive Infection Versus Culture-Negative Infection

eFigure 6. All-Cause 90-Day Mortality by Gram-Negative Infection Versus Gram-Positive Infection

eFigure 7. All-Cause 90-Day Mortality by Receipt of Kidney Replacement Therapy Versus No Kidney Replacement Therapy

eFigure 8. All-Cause 90-Day Mortality by Lung Infection Versus Other Infections

eFigure 9. All-Cause 90-Day Mortality by Sepsis Versus Septic Shock

eFigure 10. All-Cause 90-Day Mortality by Sex i.e. Male Versus Female Participants

eFigure 11. Forest Plot for ICU Mortality for the Comparison Between Prolonged Infusions of Beta-Lactam Antibiotics Versus Standard Intermittent Infusions

eFigure 12. Forest Plot for Clinical Cure for the Comparison Between Prolonged Infusions of Beta-Lactam Antibiotics Versus Standard Intermittent Infusions

eFigure 13. Forest Plot for Microbiological Cure for the Comparison Between Prolonged Infusions of Beta-Lactam Antibiotics Versus Standard Intermittent Infusions

eFigure 14. Forest Plot for Adverse Events for the Comparison Between Prolonged Infusions of Beta-Lactam Antibiotics Versus Standard Intermittent Infusions

eFigure 15. Forest Plot for ICU Length of Stay for the Comparison Between Prolonged Infusions of Beta-Lactam Antibiotics Versus Standard Intermittent Infusions

jama-e249803-s001.pdf^{(10.7MB, pdf)}

Supplement 2.

Data Sharing Statement

jama-e249803-s002.pdf^{(10.4KB, pdf)}

References

1.Roberts JA, Paul SK, Akova M, et al. ; DALI Study . DALI: defining antibiotic levels in intensive care unit patients: are current β-lactam antibiotic doses sufficient for critically ill patients? Clin Infect Dis. 2014;58(8):1072-1083. doi: 10.1093/cid/ciu027 [DOI] [PubMed] [Google Scholar]
2.Roberts JA, Joynt GM, Lee A, et al. ; SMARRT Study Collaborators and the ANZICS Clinical Trials Group . The effect of renal replacement therapy and antibiotic dose on antibiotic concentrations in critically ill patients: data from the Multinational Sampling Antibiotics in Renal Replacement Therapy study. Clin Infect Dis. 2021;72(8):1369-1378. doi: 10.1093/cid/ciaa224 [DOI] [PubMed] [Google Scholar]
3.Shekar K, Abdul-Aziz MH, Cheng V, et al. Antimicrobial exposures in critically ill patients receiving extracorporeal membrane oxygenation. Am J Respir Crit Care Med. 2023;207(6):704-720. doi: 10.1164/rccm.202207-1393OC [DOI] [PubMed] [Google Scholar]
4.Craig WA. Pharmacokinetic/pharmacodynamic parameters: rationale for antibacterial dosing of mice and men. Clin Infect Dis. 1998;26(1):1-10. doi: 10.1086/516284 [DOI] [PubMed] [Google Scholar]
5.Mouton JW, Vinks AA. Is continuous infusion of beta-lactam antibiotics worthwhile? efficacy and pharmacokinetic considerations. J Antimicrob Chemother. 1996;38(1):5-15. doi: 10.1093/jac/38.1.5 [DOI] [PubMed] [Google Scholar]
6.Abdul-Aziz MH, Portunato F, Roberts JA. Prolonged infusion of beta-lactam antibiotics for gram-negative infections: rationale and evidence base. Curr Opin Infect Dis. 2020;33(6):501-510. doi: 10.1097/QCO.0000000000000681 [DOI] [PubMed] [Google Scholar]
7.Dhaese S, Heffernan A, Liu D, et al. Prolonged versus intermittent infusion of β-lactam antibiotics: a systematic review and meta-regression of bacterial killing in preclinical infection models. Clin Pharmacokinet. 2020;59(10):1237-1250. doi: 10.1007/s40262-020-00919-6 [DOI] [PubMed] [Google Scholar]
8.Roberts JA, Webb S, Paterson D, Ho KM, Lipman J. A systematic review on clinical benefits of continuous administration of beta-lactam antibiotics. Crit Care Med. 2009;37(6):2071-2078. doi: 10.1097/CCM.0b013e3181a0054d [DOI] [PubMed] [Google Scholar]
9.Roberts JA, Abdul-Aziz MH, Davis JS, et al. Continuous versus intermittent β-lactam infusion in severe sepsis: a meta-analysis of individual patient data from randomized trials. Am J Respir Crit Care Med. 2016;194(6):681-691. doi: 10.1164/rccm.201601-0024OC [DOI] [PubMed] [Google Scholar]
10.Vardakas KZ, Voulgaris GL, Maliaros A, Samonis G, Falagas ME. Prolonged versus short-term intravenous infusion of antipseudomonal β-lactams for patients with sepsis: a systematic review and meta-analysis of randomised trials. Lancet Infect Dis. 2018;18(1):108-120. doi: 10.1016/S1473-3099(17)30615-1 [DOI] [PubMed] [Google Scholar]
11.Kondo Y, Ota K, Imura H, Hara N, Shime N. Prolonged versus intermittent β-lactam antibiotics intravenous infusion strategy in sepsis or septic shock patients: a systematic review with meta-analysis and trial sequential analysis of randomized trials. J Intensive Care. 2020;8:77. doi: 10.1186/s40560-020-00490-z [DOI] [PMC free article] [PubMed] [Google Scholar]
12.Li X, Long Y, Wu G, et al. Prolonged vs intermittent intravenous infusion of β-lactam antibiotics for patients with sepsis: a systematic review of randomized clinical trials with meta-analysis and trial sequential analysis. Ann Intensive Care. 2023;13(1):121. doi: 10.1186/s13613-023-01222-w [DOI] [PMC free article] [PubMed] [Google Scholar]
13.Lokhandwala A, Patel P, Isaak AK, et al. Comparison of the effectiveness of prolonged infusion and intermittent infusion of meropenem in patients with sepsis: a meta-analysis. Cureus. 2023;15(10):e46990. doi: 10.7759/cureus.46990 [DOI] [PMC free article] [PubMed] [Google Scholar]
14.Monti G, Bradic N, Marzaroli M, et al. ; MERCY Investigators . Continuous vs intermittent meropenem administration in critically ill patients with sepsis: the MERCY randomized clinical trial. JAMA. 2023;330(2):141-151. doi: 10.1001/jama.2023.10598 [DOI] [PMC free article] [PubMed] [Google Scholar]
15.Dulhunty JM, Brett SJ, De Waele J, et al. Continuous vs intermittent β-lactam antibiotic infusions in critically ill patients with sepsis: the BLING III randomized clinical trial. JAMA. Published online June 12, 2024. doi: 10.1001/jama.2024.9779 [DOI] [PMC free article] [PubMed] [Google Scholar]
16.Abdul-Aziz MH, Hammond NE, Brett SJ, et al. Prolonged infusion versus intermittent infusion dosing of beta-lactam antibiotics in critically ill patients with sepsis: a protocol for a systematic review and meta-analysis of randomised controlled trials. Preprint posted online May 16, 2023. medRxiv 2023.05.15.23289889. doi: 10.1101/2023.05.15.23289889 [DOI]
17.Page MJ, McKenzie JE, Bossuyt PM, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ. 2021;372(71):n71. doi: 10.1136/bmj.n71 [DOI] [PMC free article] [PubMed] [Google Scholar]
18.Singer M, Deutschman CS, Seymour CW, et al. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA. 2016;315(8):801-810. doi: 10.1001/jama.2016.0287 [DOI] [PMC free article] [PubMed] [Google Scholar]
19.Dellinger RP, Levy MM, Carlet JM, et al. Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock: 2008. Intensive Care Med. 2008;34(1):17-60. doi: 10.1007/s00134-007-0934-2 [DOI] [PMC free article] [PubMed] [Google Scholar]
20.Levy MM, Fink MP, Marshall JC, et al. ; International Sepsis Definitions Conference . 2001 SCCM/ESICM/ACCP/ATS/SIS International Sepsis Definitions Conference. Intensive Care Med. 2003;29(4):530-538. doi: 10.1007/s00134-003-1662-x [DOI] [PubMed] [Google Scholar]
21.Bone RC, Balk RA, Cerra FB, et al. ; The ACCP/SCCM Consensus Conference Committee; American College of Chest Physicians/Society of Critical Care Medicine . Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. Chest. 1992;101(6):1644-1655. doi: 10.1378/chest.101.6.1644 [DOI] [PubMed] [Google Scholar]
22.Khan AB, Omar S. Continuous vs intermittent beta-lactam dosing in critically ill patients with sepsis: a randomized controlled trial. World Health Organization. Accessed May 2, 2024. https://trialsearch.who.int/Trial2.aspx?TrialID=PACTR202009811610400
23.Schandelmaier S, Briel M, Varadhan R, et al. Development of the Instrument to Assess the Credibility of Effect Modification Analyses (ICEMAN) in randomized controlled trials and meta-analyses. CMAJ. 2020;192(32):E901-E906. doi: 10.1503/cmaj.200077 [DOI] [PMC free article] [PubMed] [Google Scholar]
24.Wan X, Wang W, Liu J, Tong T. Estimating the sample mean and standard deviation from the sample size, median, range and/or interquartile range. BMC Med Res Methodol. 2014;14:135. doi: 10.1186/1471-2288-14-135 [DOI] [PMC free article] [PubMed] [Google Scholar]
25.Turner RM, Jackson D, Wei Y, Thompson SG, Higgins JP. Predictive distributions for between-study heterogeneity and simple methods for their application in bayesian meta-analysis. Stat Med. 2015;34(6):984-998. doi: 10.1002/sim.6381 [DOI] [PMC free article] [PubMed] [Google Scholar]
26.IntHout J, Ioannidis JPA, Borm GF. The Hartung-Knapp-Sidik-Jonkman method for random effects meta-analysis is straightforward and considerably outperforms the standard DerSimonian-Laird method. BMC Med Res Methodol. 2014;14:25. doi: 10.1186/1471-2288-14-25 [DOI] [PMC free article] [PubMed] [Google Scholar]
27.Doleman B, Freeman SC, Lund JN, Williams JP, Sutton AJ. Funnel plots may show asymmetry in the absence of publication bias with continuous outcomes dependent on baseline risk: presentation of a new publication bias test. Res Synth Methods. 2020;11(4):522-534. doi: 10.1002/jrsm.1414 [DOI] [PubMed] [Google Scholar]
28.Doleman B, Mathiesen O, Jakobsen JC, et al. Methodologies for systematic reviews with meta-analysis of randomised clinical trials in pain, anaesthesia, and perioperative medicine. Br J Anaesth. 2021;126(4):903-911. doi: 10.1016/j.bja.2021.01.004 [DOI] [PubMed] [Google Scholar]
29.Röver C. Bayesian random-effects meta-analysis using the bayesmeta R package. J Stat Softw. 2020;93(6):1-51. doi: 10.18637/jss.v093.i06 [DOI] [Google Scholar]
30.Viechtbauer W. Conducting meta-analyses in R with the metafor package. J Stat Softw. 2010;36(3):1-48. doi: 10.18637/jss.v036.i03 [DOI] [Google Scholar]
31.Guyatt GH, Oxman AD, Vist GE, et al. ; GRADE Working Group . GRADE: an emerging consensus on rating quality of evidence and strength of recommendations. BMJ. 2008;336(7650):924-926. doi: 10.1136/bmj.39489.470347.AD [DOI] [PMC free article] [PubMed] [Google Scholar]
32.Guyatt G, Oxman AD, Akl EA, et al. GRADE guidelines, 1: introduction—GRADE evidence profiles and summary of findings tables. J Clin Epidemiol. 2011;64(4):383-394. doi: 10.1016/j.jclinepi.2010.04.026 [DOI] [PubMed] [Google Scholar]
33.Georges B, Conil JM, Cougot P, et al. Cefepime in critically ill patients: continuous infusion vs an intermittent dosing regimen. Int J Clin Pharmacol Ther. 2005;43(8):360-369. doi: 10.5414/CPP43360 [DOI] [PubMed] [Google Scholar]
34.Rafati MR, Rouini MR, Mojtahedzadeh M, et al. Clinical efficacy of continuous infusion of piperacillin compared with intermittent dosing in septic critically ill patients. Int J Antimicrob Agents. 2006;28(2):122-127. doi: 10.1016/j.ijantimicag.2006.02.020 [DOI] [PubMed] [Google Scholar]
35.Roberts JA, Boots R, Rickard CM, et al. Is continuous infusion ceftriaxone better than once-a-day dosing in intensive care? a randomized controlled pilot study. J Antimicrob Chemother. 2007;59(2):285-291. doi: 10.1093/jac/dkl478 [DOI] [PubMed] [Google Scholar]
36.Roberts JA, Kirkpatrick CM, Roberts MS, Robertson TA, Dalley AJ, Lipman J. Meropenem dosing in critically ill patients with sepsis and without renal dysfunction: intermittent bolus versus continuous administration? Monte Carlo dosing simulations and subcutaneous tissue distribution. J Antimicrob Chemother. 2009;64(1):142-150. doi: 10.1093/jac/dkp139 [DOI] [PubMed] [Google Scholar]
37.Roberts JA, Kirkpatrick CM, Roberts MS, Dalley AJ, Lipman J. First-dose and steady-state population pharmacokinetics and pharmacodynamics of piperacillin by continuous or intermittent dosing in critically ill patients with sepsis. Int J Antimicrob Agents. 2010;35(2):156-163. doi: 10.1016/j.ijantimicag.2009.10.008 [DOI] [PubMed] [Google Scholar]
38.Chytra I, Stepan M, Benes J, et al. Clinical and microbiological efficacy of continuous versus intermittent application of meropenem in critically ill patients: a randomized open-label controlled trial. Crit Care. 2012;16(3):R113. doi: 10.1186/cc11405 [DOI] [PMC free article] [PubMed] [Google Scholar]
39.Dulhunty JM, Roberts JA, Davis JS, et al. Continuous infusion of beta-lactam antibiotics in severe sepsis: a multicenter double-blind, randomized controlled trial. Clin Infect Dis. 2013;56(2):236-244. doi: 10.1093/cid/cis856 [DOI] [PubMed] [Google Scholar]
40.Dulhunty JM, Roberts JA, Davis JS, et al. ; BLING II Investigators for the ANZICS Clinical Trials Group . A multicenter randomized trial of continuous versus intermittent β-lactam infusion in severe sepsis. Am J Respir Crit Care Med. 2015;192(11):1298-1305. doi: 10.1164/rccm.201505-0857OC [DOI] [PubMed] [Google Scholar]
41.Jamal JA, Mat-Nor MB, Mohamad-Nor FS, et al. Pharmacokinetics of meropenem in critically ill patients receiving continuous venovenous haemofiltration: a randomised controlled trial of continuous infusion versus intermittent bolus administration. Int J Antimicrob Agents. 2015;45(1):41-45. doi: 10.1016/j.ijantimicag.2014.09.009 [DOI] [PubMed] [Google Scholar]
42.Jamal JA, Roberts DM, Udy AA, et al. Pharmacokinetics of piperacillin in critically ill patients receiving continuous venovenous haemofiltration: a randomised controlled trial of continuous infusion versus intermittent bolus administration. Int J Antimicrob Agents. 2015;46(1):39-44. doi: 10.1016/j.ijantimicag.2015.02.014 [DOI] [PubMed] [Google Scholar]
43.Abdul-Aziz MH, Sulaiman H, Mat-Nor MB, et al. Beta-Lactam Infusion in Severe Sepsis (BLISS): a prospective, two-centre, open-labelled randomised controlled trial of continuous versus intermittent beta-lactam infusion in critically ill patients with severe sepsis. Intensive Care Med. 2016;42(10):1535-1545. doi: 10.1007/s00134-015-4188-0 [DOI] [PubMed] [Google Scholar]
44.Zhao HY, Gu J, Lyu J, et al. Pharmacokinetic and pharmacodynamic efficacies of continuous versus intermittent administration of meropenem in patients with severe sepsis and septic shock: a prospective randomized pilot study. Chin Med J (Engl). 2017;130(10):1139-1145. doi: 10.4103/0366-6999.205859 [DOI] [PMC free article] [PubMed] [Google Scholar]
45.Mirjalili M, Zand F, Karimzadeh I, et al. The clinical and paraclinical effectiveness of four-hour infusion vs half-hour infusion of high-dose ampicillin-sulbactam in treatment of critically ill patients with sepsis or septic shock: an assessor-blinded randomized clinical trial. J Crit Care. 2023;73:154170. doi: 10.1016/j.jcrc.2022.154170 [DOI] [PubMed] [Google Scholar]
46.Saad SI, Aglan BM, Shaboob EA, Abdelghany HH. Continuous versus intermittent use of meropenem in septic critically ill patients: a randomized controlled trail. Benha Med J. 2024;41(2):38-48. doi: 10.21608/bmfj.2023.247556.1949 [DOI] [Google Scholar]
47.Álvarez-Moreno CA, Nocua-Báez LC, Ortiz G, et al. Efficacy of continuous vs intermittent administration of cefepime in adult ICU patients with gram-negative bacilli bacteremia: a randomized double-blind clinical study. Antibiotics (Basel). 2024;13(3):229. doi: 10.3390/antibiotics13030229 [DOI] [PMC free article] [PubMed] [Google Scholar]
48.Abdul-Aziz MH, Dulhunty JM, Bellomo R, Lipman J, Roberts JA. Continuous beta-lactam infusion in critically ill patients: the clinical evidence. Ann Intensive Care. 2012;2(1):37. doi: 10.1186/2110-5820-2-37 [DOI] [PMC free article] [PubMed] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials