Continuous vs Intermittent Meropenem Administration in Critically Ill Patients with Sepsis: The MERCY Randomized Clinical Trial

Monti G. Bradić N. Marzaroli M. Konkayev A. Fominskiy E. Kotani Y. Likhvantsev V.V. Momesso E. Nogtev P. Lobreglio R. Redkin I. Toffoletto F. Bruni A. Baiardo Redaelli M. DAndrea N. Paternoster G. Scandroglio A.M. Gallicchio F. Ballestra M. Calabrò M.G. Cotoia A. Perone R. Cuffaro R. Montrucchio G. Pota V. Ananiadou S. Lembo R. Musu M. Rauch S. Galbiati C. Pinelli F. Pasin L. Guarracino F. Santarpino G. Agrò F.E. Bove T. Corradi F. Forfori F. Longhini F. Cecconi M. Landoni G. Bellomo R. Zangrillo A.
11 July 2023 American Medical Association

JAMA
2023 #330 Issue 2 141 - 151 pp.

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.

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Department of Anesthesia and Intensive Care, IRCCS, San Raffaele Scientific Institute, Milan, Italy
Vita-Salute San Raffaele University, Milan, Italy
Clinical Department of Anesthesiology Resuscitation and Intensive Medicine, University Hospital Dubrava, Zagreb, Croatia
University North, Varazdin, Croatia
National Scientific Center of Traumatology and Orthopedia Named Acad NBatpenov, Astana Medical University, Astana, Kazakhstan
Kameda Medical Center, Kamogawa, Japan
V. Negovsky Reanimatology Research Institute, Moscow, Russian Federation
UOC Anestesia Rianimazione Ospedale San Donà di Piave, San Donà di Piave, Italy
I. M. Sechenov First Moscow State Medical University, The Ministry of Health of the Russian Federation, Sechenov University, Moscow, Russian Federation
Department of Anesthesia Intensive Care and Emergency, Citta della Salute e della Scienza University Hospital, Turin, Italy
Federal Research and Clinical Center of Resuscitation and Rehabilitation, Moscow, Russian Federation
Anesthesia and Intensive Care, Department of Medical and Surgical Sciences, Magna Graecia University of Catanzaro, Catanzaro, Italy
Department of Anesthesia and Intensive Care Medicine, ASUFC, University Hospital of Udine, Udine, Italy
Azienda Ospedaliera Regionale San Carlo, Potenza, Italy
Rianimazione Ospedali Galliera, Genova, Italy
University Hospital Policlinico of Foggia, Foggia, Italy
Department of Cardio Thoracic and Vascular Surgery, Pineta Grande Hospital, Pineta Grande, Italy
Department of Surgical Sciences, University of Turin, Turin, Italy
Università della Campania L. Vanvitelli, Napoli, Italy
Anestesia e Rianimazione ASST Cremona, Cremona, Italy
Dipartimento di Scienze Mediche e Sanità Pubblica, Università Degli Studi di Cagliari, Cagliari, Italy
Azienda Ospedaliero Universitaria di Cagliari, Cagliari, Italy
Department of Anaesthesiology and Intensive Care Medicine, Hospital of Merano, Merano, Italy
Azienda Ospedaliera Universitaria Careggi, Florence, Italy
Azienda Ospedale Università Padova, Padua, Italy
Dipartimento Anestesia e Rianimazione, Azienda Ospedaliero Universitaria Pisana, Pisa, Italy
Department of Experimental and Clinical Medicine, Magna Graecia University of Catanzaro, Catanzaro, Italy
GVM Care and Research, Department of Cardiac Surgery, Città di Lecce Hospital, Lecce, Italy
Department of Cardiac Surgery, Paracelsus Medical University, Nuremberg, Germany
Research Unit of Anesthesia and Intensive Care, Department of Medicine and Surgery, Università Campus Bio-Medico, Rome, Italy
Operative Research Unit of Anesthesia and Intensive Care, Fondazione Policlinico, Universitario Campus Bio-Medico, Rome, Italy
Department of Medicine, University of Udine, Udine, Italy
Department of Surgical, Medical, Molecular Pathology, and Critical Care Medicine, University of Pisa, Pisa, Italy
Department of Biomedical Sciences, Humanitas University Pieve Emanuele, Milan, Italy
Department of Anaesthesia and Intensive Care, IRCCS, Humanitas Research Hospital, Milan, Rozzano, Italy
Department of Critical Care, University of Melbourne, Melbourne, Australia
Australian and New Zealand Intensive Care Research Centre, Monash University, Melbourne, Australia

Department of Anesthesia and Intensive Care
Vita-Salute San Raffaele University
Clinical Department of Anesthesiology Resuscitation and Intensive Medicine
University North
National Scientific Center of Traumatology and Orthopedia Named Acad NBatpenov
Kameda Medical Center
V. Negovsky Reanimatology Research Institute
UOC Anestesia Rianimazione Ospedale San Donà di Piave
I. M. Sechenov First Moscow State Medical University
Department of Anesthesia Intensive Care and Emergency
Federal Research and Clinical Center of Resuscitation and Rehabilitation
Anesthesia and Intensive Care
Department of Anesthesia and Intensive Care Medicine
Azienda Ospedaliera Regionale San Carlo
Rianimazione Ospedali Galliera
University Hospital Policlinico of Foggia
Department of Cardio Thoracic and Vascular Surgery
Department of Surgical Sciences
Università della Campania L. Vanvitelli
Anestesia e Rianimazione ASST Cremona
Dipartimento di Scienze Mediche e Sanità Pubblica
Azienda Ospedaliero Universitaria di Cagliari
Department of Anaesthesiology and Intensive Care Medicine
Azienda Ospedaliera Universitaria Careggi
Azienda Ospedale Università Padova
Dipartimento Anestesia e Rianimazione
Department of Experimental and Clinical Medicine
GVM Care and Research
Department of Cardiac Surgery
Research Unit of Anesthesia and Intensive Care
Operative Research Unit of Anesthesia and Intensive Care
Department of Medicine
Department of Surgical
Department of Biomedical Sciences
Department of Anaesthesia and Intensive Care
Department of Critical Care
Australian and New Zealand Intensive Care Research Centre

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