Extended infusion of beta-lactam therapy was associated with reduced mortality in patients with severe gram-negative bloodstream infections, according to a retrospective cohort study.

At 90 days, 22% of patients receiving extended-infusion beta-lactam therapy had died compared with 28% of patients who received intermittent infusions (adjusted OR 0.71, 95% CI 0.52-0.97), reported Pranita Tamma, MD, MHS, of Johns Hopkins University School of Medicine in Baltimore, and colleagues.

However, this survival benefit was limited to patients with severe illness or those with bacterial isolates with elevated minimum inhibitory concentrations, they noted in JAMA Network Open.

For patients with a Pitt bacteremia score of at least 4 points, 38.7% who received extended-infusion therapy had died at 90 days versus 55.6% of those who received intermittent infusions (aOR 0.47, 95% CI 0.28-0.81, P=0.006). Meanwhile, 7.1% of patients with elevated beta-lactam minimum inhibitory concentrations in the extended-infusion group died compared with 23.8% of those in the intermittent-infusion group (aOR 0.06, 95% CI 0.01-0.66, P=0.02).

When researchers excluded these two subgroups in a stratified analysis, extended infusions did not offer any survival benefit.

"Taken together with the increase in adverse events we observed, this study helps define populations [in whom] this strategy has 'the most bang for its buck,'" co-author Sara Karaba, MD, PhD, MHS, also of Johns Hopkins, told MedPage Today in an email.

As Karaba noted, there were increased odds of catheter complications in the extended-infusion group (aOR 3.14, 95% CI 1.66-5.96), as well as increased odds of antibiotic discontinuation because of adverse events, such as acute kidney injury, cytopenias, and seizures (aOR 3.66, 95% CI 1.68-7.95).

"The potential benefits of extended-infusion beta-lactam therapy need to be balanced against the increased risk of complications that may be associated with this infusion strategy," the study authors cautioned.

They also observed that emergence of resistance was similar in the extended-infusion therapy group (2.9%) versus the intermittent-infusion therapy group (7.2%), but the difference was not statistically significant (P=0.35).

"Whether infusion strategy -- i.e., extended infusion -- may reduce the development of subsequent resistance warrants additional investigation," Karaba noted.

Clinical trials assessing outcomes with prolonged intravenous administration of beta-lactams have shown conflicting results. For example, a randomized trial showed that prolonged administration of the beta-lactam meropenem in sepsis or septic shock conferred no survival benefit compared with intermittent infusions. Another recent study and a meta-analysis showed that prolonged infusion for sepsis or septic shock tended to improve mortality compared with conventional intermittent infusion.

In an accompanying editorial, Miranda So, PharmD, MPH, of the University of Toronto, noted that "this study supports prior knowledge about extended infusion of beta-lactam, which has been taught in clinical education and implemented in many centers in recent years. By improving how beta-lactams are administered, extended infusion can overcome isolates with a higher MIC."

"The study also supports that extended infusion may have an advantage over intermittent infusion in patients with more severe infections," she wrote. "In turn, reliance on non-beta-lactam antibiotics, which are often second- or third-line therapy, may be reduced."

Of note, the study population included patients with severe immune compromise, such as those with bone marrow or solid organ transplant and those with neutropenia, "all of whom are in great need of effective antimicrobials," So pointed out.

This retrospective cohort study included 4,861 adults (median age 67, 52.4% men) with gram-negative bloodstream infections who were hospitalized in the U.S. from January through December 2019. Of these patients, 1,408 were included in a 1:3 nearest-neighbor propensity score matching without replacement: 352 were in the extended-infusion group and 1,056 were in the intermittent-infusion group.

Patients in the extended-infusion group received intravenous antibiotics for at least 72 hours, while the intermittent-infusion group received intravenous antibiotics over 1 hour or less. Antibiotics included piperacillin-tazobactam, aztreonam, ceftazidime, cefepime, and meropenem, among others.

One limitation to the study was that it used data from 2019 and the use of extended-infusion beta-lactam therapy may not reflect current practices, Tamma and colleagues said.