IMPORTANCE: There is uncertainty about whether prolonged infusions of ß-lactam antibiotics improve clinically important outcomes in critically ill adults with sepsis or septic shock.
OBJECTIVE: To determine whether prolonged ß-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 ß-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 ß-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 ß-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 ß-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.
| Discipline Area | Score |
|---|---|
| Infectious Disease |  |
| Intensivist/Critical Care |  |
| Hospital Doctor/Hospitalists | |
| Internal Medicine | |
Data has been increasingly supportive of this practice, but this meta-analysis presents a clear case for transitioning this to standard of care.
This meta-analysis concluded that "prolonged" (2 hr or more) infusions of beta-lactams in sepsis resulted in mortality reduction (estimated at 86% of that with conventional dosing) at 90 days. The extent and rigor of this study augments the biologic rationale for prolonged infusions, a practice which has become common in some settings and which may, as a result, become even more common.
Practice-changing.