• Giacomo Monti, Nikola Bradic, Matteo Marzaroli, Aidos Konkayev, Evgeny Fominskiy, Yuki Kotani, Valery V Likhvantsev, Elena Momesso, Pavel Nogtev, Rosetta Lobreglio, Ivan Redkin, Fabio Toffoletto, Andrea Bruni, Martina Baiardo Redaelli, Natascia D'Andrea, Gianluca Paternoster, Anna Mara Scandroglio, Francesca Gallicchio, Mariano Ballestra, Maria Grazia Calabrò, Antonella Cotoia, Romina Perone, Raffaele Cuffaro, Giorgia Montrucchio, Vincenzo Pota, Sofia Ananiadou, Rosalba Lembo, Mario Musu, Simon Rauch, Carola Galbiati, Fulvio Pinelli, Laura Pasin, Fabio Guarracino, Giuseppe Santarpino, Felice Eugenio Agrò, Tiziana Bove, Francesco Corradi, Francesco Forfori, Federico Longhini, Maurizio Cecconi, Giovanni Landoni, Rinaldo Bellomo, Alberto Zangrillo, and MERCY Investigators.
• Department of Anesthesia and Intensive Care, IRCCS San Raffaele Scientific Institute, Milan, Italy.
• JAMA. 2023 Jul 11; 330 (2): 141151141-151.

ImportanceMeropenem is a widely prescribed β-lactam antibiotic. Meropenem exhibits maximum pharmacodynamic efficacy when given by continuous infusion to deliver constant drug levels above the minimal inhibitory concentration. Compared with intermittent administration, continuous administration of meropenem may improve clinical outcomes.ObjectiveTo determine whether continuous administration of meropenem reduces a composite of mortality and emergence of pandrug-resistant or extensively drug-resistant bacteria compared with intermittent administration in critically ill patients with sepsis.Design, Setting, And ParticipantsA double-blind, randomized clinical trial enrolling critically ill patients with sepsis or septic shock who had been prescribed meropenem by their treating clinicians at 31 intensive care units of 26 hospitals in 4 countries (Croatia, Italy, Kazakhstan, and Russia). Patients were enrolled between June 5, 2018, and August 9, 2022, and the final 90-day follow-up was completed in November 2022.InterventionsPatients were randomized to receive an equal dose of the antibiotic meropenem by either continuous administration (n = 303) or intermittent administration (n = 304).Main Outcomes And MeasuresThe primary outcome was a composite of all-cause mortality and emergence of pandrug-resistant or extensively drug-resistant bacteria at day 28. There were 4 secondary outcomes, including days alive and free from antibiotics at day 28, days alive and free from the intensive care unit at day 28, and all-cause mortality at day 90. Seizures, allergic reactions, and mortality were recorded as adverse events.ResultsAll 607 patients (mean age, 64 [SD, 15] years; 203 were women [33%]) were included in 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 (IQR, 3-17 days) and the median duration of meropenem therapy was 11 days (IQR, 6-17 days). Only 1 crossover event was recorded. 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% CI, 0.81-1.13], P = .60). Of the 4 secondary outcomes, none was statistically significant. No adverse events of seizures or allergic reactions related to the study drug were reported. At 90 days, mortality was 42% both in the continuous administration group (127 of 303 patients) and in the intermittent administration group (127 of 304 patients).Conclusions And RelevanceIn critically ill patients with sepsis, compared with intermittent administration, the continuous administration of meropenem did not improve the composite outcome of mortality and emergence of pandrug-resistant or extensively drug-resistant bacteria at day 28.Trial RegistrationClinicalTrials.gov Identifier: NCT03452839.

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