Continuous vs Intermittent Meropenem Administration in Critically Ill Patients With Sepsis
Authors: Monti Giacomo , Bradić Nikola , Marzaroli Matteo , Konkayev Aidos , Fominskiy Evgeny , Kotani Yuki , Likhvantsev Valery V. , Momesso Elena , Nogtev Pavel , Lobreglio Rosetta , Redkin Ivan , Toffoletto Fabio , Bruni Andrea , Baiardo Redaelli Martina , D’Andrea Natascia , Paternoster Gianluca , Scandroglio Anna Mara , Gallicchio Francesca , Ballestra Mariano , Calabrò Maria Grazia , Cotoia Antonella , Perone Romina , Cuffaro Raffaele , Montrucchio Giorgia , Pota Vincenzo , Ananiadou Sofia , Lembo Rosalba , Musu Mario , Rauch Simon , Galbiati Carola , Pinelli Fulvio , Pasin Laura , Guarracino Fabio , Santarpino Giuseppe , Agrò Felice Eugenio , Bove Tiziana , Corradi Francesco , Forfori Francesco , Longhini Federico , Cecconi Maurizio , Landoni Giovanni , Bellomo Rinaldo , Zangrillo Alberto ,   MERCY Investigators, Ajello Silvia , Baldetti Luca , Belletti Alessandro , Borghi Giovanni , Crivellari Martina , Fazio Maria , Franco Annalisa , Giardina Giuseppe , Moizo Elena , Mucci Milena , Nakhnoukh Cristina , Nardelli Pasquale , Ortalda Alessandro , Pasculli Nicola , Pazzanese Vittorio , Pieri Marina , Plumari Valentina , Tomasi Enrico , Turi Stefano , Boffa Nicoletta , Parente Marcella , Petrova Marina , Ilina Anna , Kalov Amirkhan , Garofalo Eugenio , Caroleo Antonio , Saraco Giuseppe , Trompeo Anna , Brazzi Luca , Sales Gabriele , Balzani Eleonora , Vetrugno Luigi , Marcuzzi Gabriella , Millin Chiara , Pittella Giuseppe , Vitiello Michelangelo , Vignale Rosaria , Zingarelli Giulia , Zecchillo Elisa , Dazzi Federico , Taddei Erika , Bologna Maria Lidia , Kadralinova Assiya , Yeltayeva Aigerim , Pace Maria Caterina , Coppolino Francesco , Azzali Barbara , Mattei Alessia , Sardo Salvatore , Aru Giannicola , Congiu Lara , Aliev Vladimir , Khalikova Elen​​​​​​a , Yavorovskaya Daria , Greco Massimiliano , Leggieri Carlo , Seraglio Paolo ME , Della Selva Andrea , Pelagatti Filippo , Boraso Sabrina , Brizzi Giulia , Baldassarri Rubia , La Scala Stefano , Persec Jasminka , Torrente Sergio , Fiorito Roberta , Ti Lian Kah , Biondi-Zoccai Giuseppe , Benedetto Umberto , D’Ascenzo Fabrizio , Hajjar Ludhmila A 
Published: June 2023

Importance

Meropenem 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.

Objective

To 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 Participants

A 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.

Interventions

Patients 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 Measures

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 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.

Results

All 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 Relevance

In 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 Registration

ClinicalTrials.gov Identifier: NCT03452839