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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-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
Affiliations
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. .

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.

Figures

Figure 1.
Figure 1.. All-Cause 90-Day Mortality for the Comparison Between Prolonged Infusions of β-Lactam Antibiotics vs Intermittent Infusions
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.
Figure 2.. Primary Outcome, Secondary Outcomes, and Subgroup Analyses for the Comparison Between Prolonged Infusions of β-Lactam Antibiotics vs Intermittent Infusions
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.
Figure 3.. Posterior Probability of the Risk Ratio (RR) for All-Cause 90-Day Mortality for Prolonged Infusions of β-Lactam Antibiotics Compared With Intermittent Infusions
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%.
See this image and copyright information in PMC

Comment in

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