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

doi:10.1001/jama.2024.9803

Meta-Analysis

. 2024 Aug 27;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-Aziz¹, Naomi E Hammond^{2

3}, Stephen J Brett⁴, Menino O Cotta¹, Jan J De Waele⁵, Anthony Devaux⁶, Gian Luca Di Tanna^{6

7

8}, Joel M Dulhunty^{2

9

10

11}, Hatem Elkady¹², Lars Eriksson¹³, M Shahnaz Hasan¹⁴, Ayesha Bibi Khan¹⁵, Jeffrey Lipman^{1

9

16

17}, Xiaoqiu Liu^{6

18}, Giacomo Monti^{19

20}, John Myburgh^{2

21}, Emmanuel Novy^{22

23}, Shahed Omar¹⁵, Dorrilyn Rajbhandari², Claire Roger^{24

25}, Fredrik Sjövall^{26

27}, Irene Zaghi²⁸, Alberto Zangrillo^{19

20}, Anthony Delaney^{2

3}, Jason A Roberts^{1

9

17

29}

Affiliations

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

PMID: 38864162
PMCID: PMC11170459 (available on 2024-12-12)
DOI: 10.1001/jama.2024.9803

Meta-Analysis

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 et al. JAMA. 2024.

. 2024 Aug 27;332(8):638-648.

doi: 10.1001/jama.2024.9803.

Authors

Affiliations

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

PMID: 38864162
PMCID: PMC11170459 (available on 2024-12-12)
DOI: 10.1001/jama.2024.9803

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.

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Conflict of interest statement

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.

Comment in

Resolving the Dilemma on Continuous vs Intermittent β-Lactam Antibiotics in Sepsis.
Wiersinga WJ, van Agtmael MA. Wiersinga WJ, et al. JAMA. 2024 Aug 27;332(8):623-625. doi: 10.1001/jama.2024.10168. JAMA. 2024. PMID: 38864160 No abstract available.

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Do prolonged infusions of β-lactam antibiotics improve outcomes in critically ill patients with sepsis? It is time to say yes.
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A Retrospective Analysis of Intravenous Push versus Extended Infusion Meropenem in Critically Ill Patients.
Johnson EG, Maki Ortiz K, Adams DT, Kaur S, Faust AC, Yang H, Alvarez CA, Hall RG 2nd. Johnson EG, et al. Antibiotics (Basel). 2024 Sep 2;13(9):835. doi: 10.3390/antibiotics13090835. Antibiotics (Basel). 2024. PMID: 39335009 Free PMC article.
Continuous infusion of beta-lactam antibiotics in critically ill patients with sepsis: implementation considerations.
Barton G, Rickard CM, Roberts JA. Barton G, et al. Intensive Care Med. 2024 Dec;50(12):2150-2153. doi: 10.1007/s00134-024-07650-x. Epub 2024 Sep 23. Intensive Care Med. 2024. PMID: 39311902 No abstract available.
Identifying optimal dosing strategies for meropenem in the paediatric intensive care unit through modelling and simulation.
Morales Junior R, Mizuno T, Paice KM, Pavia KE, Hambrick HR, Tang P, Jones R, Gibson A, Stoneman E, Curry C, Kaplan J, Tang Girdwood S. Morales Junior R, et al. J Antimicrob Chemother. 2024 Oct 1;79(10):2668-2677. doi: 10.1093/jac/dkae274. J Antimicrob Chemother. 2024. PMID: 39092928

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
1. 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
1. 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
1. 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
1. 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

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[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

[2] 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

[3] 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

[4] 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

[5] 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

[6] 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

[7] 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

[8] 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

[9] 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

[10] 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

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

Affiliations

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

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