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Prolonged infusion of beta-lactam antibiotics for sepsis or septic shock tended to improve mortality compared with conventional intermittent infusion in the BLING III trial, and a meta-analysis including those findings affirmed a significant survival advantage.

The trial narrowly missed its primary endpoint, reducing 90-day all-cause mortality by a relative 9% (24.9% vs 26.8%; OR 0.91, P=0.08), researchers led by Joel M. Dulhunty, MD, PhD, of Royal Brisbane and Women's Hospital in Australia, reported in and at the in Belfast, Ireland.

The absolute mortality reduction of 1.9%, had a 95% confidence interval ranging from a reduction of 4.9% to an increase of 1.1%, which "includes the possibility of both no important effect and a clinically important benefit in the use of continuous infusions in this group of patients," the group wrote.

The number needed to treat to save one life with prolonged infusion was 50.

Meta-analysis of BLING III together with 17 other randomized trials tipped the scale in favor of a clinically important benefit. Pooled results showed that prolonged infusions reduced 90-day all-cause mortality by a relative 14% (RR 0.86, 95% credible interval [CrI] 0.72-0.98), with a 99.1% posterior probability of superiority.

It also showed high certainty of reduced ICU mortality (RR 0.84, 95% CrI 0.70-0.97) and moderate certainty of an increase in clinical cure (RR 1.16, 95% CrI 1.07-1.31).

"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," concluded Jason A. Roberts, BPharm, PhD, of the UQ Centre for Clinical Research in Brisbane, and colleagues, .

These "major new contributions strengthen the evidence" in support of the Surviving Sepsis Campaign guidelines recommending prolonged infusion of beta-lactams for adults with sepsis or septic shock, which up until now had been only a weak recommendation based on a moderate quality of evidence, according to W. Joost Wiersinga, MD, PhD, MBA, and Michiel van Agtmael, MD, PhD, both of Amsterdam University Medical Center, in an .

They noted the mechanistic reason for potential advantage: "Most beta-lactams have a half-life of 1 to 2 hours and continuous infusion will improve their pharmacokinetic target. The longer the half-life, the less benefit from continuous infusion."

However, there may be cases where prolonged infusion isn't preferable, they noted. For example, they wrote, "Incompatibility of intravenous comedications with the antibiotic [ceftriaxone] makes administration over a second intravenous entry necessary."

Feasibility and cost-effectiveness are likely in favor of prolonged dosing, since the total daily antibiotic dose is similar and probably less nursing time is needed, the editorialists wrote. "One should be aware that some beta-lactams have a limited pharmaceutical stability. For meropenem, the stability is about 8 hours at room temperature, so it is not suitable for 24-hour infusion, thus affecting bedside logistics."

Importantly, none of the studies included in the meta-analyses showed an increase in toxicity or increase in development of resistance with prolonged dosing, and it might actually be better since low beta-lactam levels at the end of intermittent dosing intervals might increase resistance rates (and failure), Wiersinga and van Agtmael suggested.

BLING (Beta-Lactam Infusion Group) III was conducted in 104 ICUs in Australia, Malaysia, New Zealand, and Europe. It randomized 7,202 critically ill adults age 18 and older (median age 59, 65% male) to open-label treatment with piperacillin-tazobactam or meropenem for sepsis on an equivalent 24-hour dose by either continuous or intermittent (over 30 minutes) infusion for a clinician-determined duration of treatment or until ICU discharge.

The meta-analysis included a total of 18 randomized clinical trials comparing continuous or extended beta-lactam infusion against intermittent infusions in a total of 9,108 critically ill adults with sepsis or septic shock (median age 54, 65% male).

Prespecified subgroup analysis didn't show a difference in all-cause 90-day mortality between treatment groups by antibiotic used (meropenem vs piperacillin-tazobactam), whether the infection was culture positive, kidney replacement therapy status, location of infection (lung vs other), sepsis versus septic shock, or gender. Unlike in some prior reports, the meta-analysis also showed no difference by gram-negative versus gram-positive infection.

"A main challenge for follow-up studies will be to identify subgroups of patients that will benefit most from this treatment option," the editorialists wrote, noting that for "patients with a high renal clearance and infected with a pathogen with a high [minimum inhibitory concentration], increased exposure by continuous infusion could be convincingly superior."