A randomized controlled trial found that continuous administration of the antibiotic meropenem does not improve clinical outcomes in critically ill sepsis patients compared with intermittent administration, researchers reported today in JAMA.

Meropenem is typically administered intermittently to treat several types of infections in critically ill patients, but several systematic reviews and meta-analyses show that continuous administration may decrease mortality in sepsis patients and reduce the emergence of antibiotic resistance. To test this hypothesis, investigators enrolled critically ill patients with sepsis or septic shock at 26 hospitals in four countries (Croatia, Italy, Kazakhstan, and Russia) and randomly assigned them 1:1 to receive an equal dose of meropenem by either continuous administration or intermittent administration.

The primary outcome was a composite of all-cause mortality, and emergence of pandrug-resistant or extensively drug-resistant bacteria at day 28. There were four secondary outcomes, including all-cause mortality at day 90.

A total of 607 patients (mean age, 64 years; 33% female) were included in both the measurement of the 28-day primary outcome and completed the 90-day mortality follow-up. The majority (369 patients, 61%) had septic shock. The median time from hospital admission to randomization was 9 days and the median duration of meropenem therapy was 11 days.

The primary outcome occurred in 142 patients (47%) in the continuous administration group and in 149 patients (49%) in the intermittent administration group (relative risk, 0.96; 95% confidence interval [CI], 0.81 to 1.13). No adverse events were reported. At day 90, mortality was 42% in both groups. No statistically significant differences were found for the other secondary outcomes.

In an accompanying editorial, experts from Harvard Medical School say that because there was no evidence of harm from continuous administration of meropenem, it's unclear whether the trial results will influence clinical guidelines.

"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," they wrote. "Meanwhile, there remains an urgent need to identify new interventions to realize the shared aspiration to reduce sepsis mortality and antimicrobial resistance."

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