Randomized trial, meta-analysis shed new light on optimal antibiotic strategy for sepsis

Hospital patient with IV drip

Jacob Wackerhausen / iStock

Two studies published yesterday in JAMA indicate that continuous infusions of beta-lactam antibiotics reduce the risk of mortality in critically ill sepsis patients.

The authors of the studies say the findings should provide enough evidence for clinicians to make continuous infusions of beta-lactam antibiotics the standard of care for management of sepsis, which is a major cause of mortality worldwide.

Trial finds 2% reduction in 90-day mortality

The first study reports results from the Beta-Lactam Infusion Group (BLING) III trial, an international randomized clinical trial that included critically ill adults treated for sepsis in 104 intensive care units (ICUs) in Australia, Belgium, France, Malaysia, New Zealand, Sweden, and the United Kingdom. The aim of the trial was to determine whether continuous infusion of piperacillin-tazobactam or meropenem reduced 90-day mortality in sepsis compared with short, intermittent infusions, which has been the conventional treatment strategy.

From January 11 to April 12, 2023, 7,031 patients (mean age, 59 years; 65% men) were randomized to receive an equivalent 24-hour dose of beta-lactam antibiotic by either continuous (3,498 patients) or intermittent (3,533) infusion for a clinician-determined duration or until ICU discharge. The primary outcome was all-cause mortality within 90 days of randomization. Secondary outcomes included clinical cure at 14 days after randomization, ICU mortality, and new acquisition, colonization, or infection with a multidrug-resistant organism.

Within 90 days, 24.9% of patients in the continuous-infusion group and 26.8% in the intermittent-infusion group had died, for an absolute difference (AD) of –1.9% (95% confidence interval [CI], –4.9% to 1.1%; odds ratio [OR], 0.91; 95% CI, 0.81 to 1.01]. Clinical cure at 14 days post randomization also favored continuous (55.7%) over intermittent (50.0%) infusion (AD, 5.7%; 95% CI, 2.4% to 9.1%; OR, 1.26; 95% 1.15 to 1.38).

No statistically significant differences were observed for other outcomes.

The trial investigators note that while the reduction in 90-day mortality wasn't statistically significant, the confidence interval includes a clinically important benefit, and the absolute reduction in mortality of nearly 2% means that 50 patients would need to be treated to prevent 1 death. 

"This led us to conclude that there is possibly no difference between the two methods of administration, or there is a possible clinically important benefit with using continuous infusions for patients receiving beta-lactam antibiotics for the treatment of sepsis," lead investigator Joel Dulhunty, MD, PhD, of the University of Queensland and Royal Brisbane and Women's Hospital, told JAMA Deputy Editor Preeti Malani, MD, in an interview about the two studies.

Dulhunty and his colleagues added that the clinical significance of this finding is supported by the consistent effect on 90-day mortality seen in patient subgroups, and by increased rates of clinical cure observed in the continuous-infusion group.

Meta-analysis bolsters case for continuous infusion

The second study was a systematic review and meta-analysis of 18 randomized clinical trials comparing 90-day mortality in critically ill adults with sepsis or septic shock who received either prolonged (continuous or extended) or intermittent infusions of beta-lactam antibiotics. BLING III was among the studies reviewed by the international team of researchers, which included many of the investigators from the trial.

Among the 17 trials that contributed to the primary outcome, there were 9,104 participants (median age, 54 years; 65% men). The pooled estimated risk ratio (RR) for all-cause 90-day mortality for prolonged infusions of beta-lactam antibiotics compared with intermittent infusions was 0.86 (95% credible interval, 0.72 to 0.98), with a 99.1% posterior probability that prolonged infusions were associated with lower 90-mortality. The number needed to treat for prolonged beta-lactam infusions to prevent 1 death was 26 patients.

The meta-analysis also found that continuous infusion of beta-lactam antibiotics was associated with a reduced risk of ICU mortality (RR, 0.84; 95% credible interval [CrI], 0.70 to 0.97) and an increase in clinical cure (RR, 1.16; 95% CrI, 1.07 to 1.31). 

"The observation of reduced risk of mortality in the present analysis is consistent with findings from previous meta-analyses," the study authors wrote. "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."

Changing clinical practice

Corresponding author Jason Roberts, BPharm, PhD, also of the University of Queensland and Royal Brisbane and Women's Hospital, told Malani he believes the findings, combined with the results of the BLING III trial, should prompt a change in clinical practice. He noted that a recent survey of ICU practice and antibiotic use—conducted prior to the two studies—found that 60% of ICUs were already using continuous infusion of beta-lactams for critically ill sepsis patients.

"I think it supports the other 40% changing to prolonged infusions of beta-lactams, and certainly that is an approach that our intensive care unit in Brisbane will be moving towards," he said.

A similar assessment comes from Joost Wiersinga, MD, PhD, and Michiel van Agtmael, MD, PhD, of the University of Amsterdam Medical Center, who wrote an accompanying editorial on the results of the BLING II trial and the meta-analysis.

"Despite the statistical nonsignificance of its primary end point, clinical guidelines are likely to use this new landmark study and accompanying meta-analysis to strengthen their recommendation to use continuous β-lactam antibiotics over intermittent dosing in adult patients with sepsis in the ICU," they wrote.

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.

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