Continuous, Intermittent Administration of Meropenem for Sepsis Yield Similar Outcomes

Continuous administration of meropenem did not improve clinical outcomes compared with intermittent administration of the antibiotic in critically ill patients with sepsis, a recent study found.

The double-blind, randomized clinical trial, published in JAMA, included 607 critically ill patients with sepsis or septic shock at 26 hospitals in Croatia, Italy, Kazakhstan and Russia from June 5, 2018, to Aug. 9, 2022.

“A correct strategy for antimicrobial administration in order to reduce mortality and reduce antimicrobial resistance is a key point in fighting against sepsis,” lead author Giacomo Monti, MD, of the IRCCS San Raffaele Scientific Institute and Vita-Salute San Raffaele University in Milan, Italy, told Contagion. “Beta lactams are the most prescribed antibiotic in ICUs; meropenem is a broad-spectrum beta lactam that has been covering for years an important role in treatment of serious infections in ICUs. There has been a long debate on the advantages of continuous administration of beta lactams and meropenem itself.”

Patients were randomized into two groups, with 303 receiving continuous administration of meropenem and 304 receiving intermittent administration. Investigators compared the two groups based on a composite of mortality and emergence of drug resistance.

“Even though the pharmacologic rationale is evident, when tested on real patient population the results were variable,” Monti said. “Focusing on meropenem, one of the most prescribed antibiotics in ICUs, our study is the largest to date.”

Most of the study participants (61%) had septic shock. The average time from hospital admission to randomization was 9 days, and the average length of treatment was 11 days.

The primary outcome composite of all-cause mortality and emergence of pandrug-resistant or extensively drug-resistant bacteria at Day 28 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% CI, 0.81-1.13], P = .60). Mortality was 42% at Day 90 in both groups.

“That means that administration technique did not cause any difference in survival of the patient (even long term survival) and in the emergence of more dangerous antibiotic resistant pathogens,” Monti said. “We dived deeper and found the same ‘no difference’ also in selected populations of our patients such as most critically ill patients, patients with the worst resistance profile infections and patients with the most dangerous pathogens.”

No statistically significant differences were found in secondary outcomes, which included days alive and free from antibiotics at Day 28, days alive and free from the ICU at Day 28 and all-cause mortality at Day 90. No adverse events were reported.

“We think that the results of the study themselves can be seen as a surprise from many points of view,” Monti said. “Theoretically, the pharmacologic rationale was in favor of continuous infusion, especially in critically ill patients where modification of renal function and volume of distribution of the drug are present. However, this never translated clearly in a better outcome. and previous meta-analyses found advantage only on selected populations (ex. critically ill) or only for some outcomes (ex. Clinical cure of the infection). If an effect of the strategy of administration exists, that is not what our trial demonstrated.”

Monti noted that while the study showed no difference in patient outcomes based on administration technique, it is limited to a specific patient population.

“Our results are important and clear, but everybody should keep in mind that should be not immediately generalized to all patients and to all beta-lactams,” he said. “The point with meropenem is: what could we do instead? Is the dose that can impact on the mortality? Maybe efforts should be put in other measures, even simpler like hand hygiene? The second is, could we care better for the patient since we don’t need continuous infusion? Maybe we can mobilize the patient sooner and easier?”

Monti said the study is a starting point for further research into new strategies for treating sepsis.