Sepsis Outcomes No Different With Prolonged Beta-Lactam Antibiotic

Critically ill sepsis patients did not fare better with prolonged infusions of meropenem compared with intermittent infusions of the beta-lactam antibiotic, a randomized trial showed.

Among over 600 patients with sepsis or septic shock prescribed meropenem, the incidence of the primary outcome -- a composite of all-cause mortality or pan-drug resistant or extensively drug-resistant bacteria at day 28 -- was not statistically different between groups, at 47% with continuous infusions and 49% with intermittent infusions (RR 0.96, 95% CI 0.81-1.13, P=0.60).

No significant differences were seen between groups for deaths (30% vs 33%, respectively) or drug-resistance (24% vs 25%) at 28 days, or for any of the secondary outcomes, reported Giovanni Landoni, MD, of the IRCCS San Raffaele Scientific Institute in Milan, and colleagues in JAMA.

"The results of the current study suggest that continuous administration of meropenem does not improve clinically relevant outcomes," they concluded from their double-blind MERCY trial, the largest of its kind to date.

Notably, MERCY included patients with largely hospital-onset sepsis, which carries a poor prognosis compared with community-onset sepsis and may explain the relatively high mortality in this cohort.

"Notwithstanding the negative results of this trial, guidelines and clinical practice may continue to favor prolonged dosing of β-lactam antibiotics when circumstances allow given the ongoing possibility of benefit and absence of harm," according to Chanu Rhee, MD, MPH, and colleagues from Harvard Medical School and Brigham and Women's Hospital in Boston.

But they stressed in an accompanying editorial that "there remains an urgent need to identify new interventions to realize the shared aspiration to reduce sepsis mortality and antimicrobial resistance."

Beta-lactam antibiotics are time-dependent, meaning they are most effective when their serum concentration is above the target pathogen's minimum inhibitory concentration, explained Rhee and coauthors. Decreases in serum concentrations below this threshold are associated with less bacterial killing and the development of antibiotic resistance.

Pooled analyses of prior observational studies and clinical trials suggested prolonged infusions could improve mortality, clinical cure rates, or both. As such, many hospitals have already implemented prolonged infusion of beta-lactam antibiotics as a default hospital-wide dosing strategy, Rhee's group said.

In 2021, the Surviving Sepsis Campaign updated its management guidelines to include a "weak" recommendation for prolonged infusion of beta-lactam antibiotics over standard intermittent infusion based on "moderate-quality" evidence, to avoid delays in achieving effective drug concentrations.

"However, questions remain about the true clinical benefit of prolonged infusions because most prior [randomized clinical trials] have been limited by small sample sizes, poor study quality (including open-label designs), and heterogeneous patient populations," Rhee's group wrote.

More definitive answers, they noted, are expected from the ongoing BLING III trial comparing continuous piperacillin-tazobactam or meropenem versus intermittent infusion on 90-day all-cause mortality in 7,000 critically ill patients with sepsis.

The previously largest randomized trial to date, counting 432 people, had shown continuous infusion of beta-lactam antibiotics to make no difference for 90-day mortality in severe sepsis (26% vs 28%, P=0.67).

Landoni's group reported the same 42% rate of 90-day mortality in MERCY's two study groups. Among the other secondary outcomes in the current study, no differences were seen between the continuous and intermittent infusion groups for: median antibiotic-free days at 28 days (3 vs 2, P=0.57); median days alive and free from the ICU at 28 days (0 in each arm, P=0.40).

MERCY was conducted at 31 participating intensive care units (ICUs) across four countries -- Croatia, Italy, Kazakhstan, and Russia -- with a total of 607 sepsis patients enrolled from 2018 to 2022.

Participants averaged age 65 years and two-thirds were men. The majority (61%) had septic shock while 39% had sepsis.

White race was reported for 95% of the cohort. Comorbidities included diabetes in about 25%, chronic kidney disease in less than 20%, and active cancer in approximately 10%.

Participants were randomized to treatment with continuous (3 g over 24 hours) or intermittent meropenem (1 g over 30-60 minutes three times daily). The continuous administration group received a median overall dose of 24 g of meropenem and the intermittent group got 21 g.

The most common site of infection was the respiratory tract (33%). With a causative pathogen identified for 70-72% of cases, the most frequently identified bacterial species were gram-positive coagulase-negative Staphylococci and gram-negative Klebsiella and Pseudomonas species.

The MERCY investigators acknowledged that the dose of meropenem could be reduced or doubled based on kidney function, or based on clinical judgement. Moreover, routine drug monitoring was not carried out, and concurrent therapy with other antimicrobials was given (to about 75% of patients in each arm), possibly offering protection during low meropenem concentration periods.

Furthermore, the results cannot be extrapolated to other antibiotics. Lastly, detailed data about microbiological cure of the baseline infection was not collected after randomization and the study may have been underpowered.

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